Case 3:12-cv-01141-SMY-DGW Document 176 *SEALED* Filed 12/01/14 Page 1 of 60 Case: 16-3334 Document:Page 55-1 ID #2101 Filed: 02/08/2017 Pages: 60 (1 of 1511) UNITED STATES DISTRICT COURT SOUTHERN DISTRICT OF ILLINOIS EAST ST. LOUIS DIVISION CHARLENE EIKE et al., Plaintiffs, v. ALLERGAN, INC., et al., Defendants. ) ) ) ) ) ) ) ) ) Cause No. 3:12-cv-01141-SMY-DGW BRIEF IN SUPPORT OF PLAINTIFFS’ MOTION FOR CLASS CERTIFICATION Case 3:12-cv-01141-SMY-DGW Document 176 *SEALED* Filed 12/01/14 Page 2 of 60 Case: 16-3334 Document:Page 55-1 ID #2102 Filed: 02/08/2017 Pages: 60 (2 of 1511) TABLE OF CONTENTS I. INTRODUCTION AND NATURE OF THE CASE .................................................... 1 II. PROCEDURAL HISTORY .......................................................................................... 7 III. PUTATIVE CLASSES ................................................................................................. 8 IV. THE PARTIES’ EXPERT WITNESSES...................................................................... 9 A. Plaintiffs’ Experts .................................................................................................. 9 B. Defendants’ Experts ............................................................................................. 15 V. LEGAL STANDARD ................................................................................................. 17 VI. PLAINTIFFS SATISFY THE REQUIRMENTS OF RULE 23(A) ........................... 19 A. Plaintiffs Satisfy the Numerosity Requirement Because Defendants Have Agreed Not To Contest It ..................................................................................... 19 B. There are Common Issues of Law and Fact......................................................... 19 C. The Claims of the Representative Plaintiffs Are Typical of Those of the Class . 21 D. The Representative Plaintiffs Will Fairly and Adequately Protect the Interests of the Class ........................................................................................................... 24 VII. 1. The class counsel will adequately represent the class. ................................. 24 2. The named plaintiffs will adequately represent the class. ............................ 25 PLAINTIFFS SATISFY THE REQUIREMENTS OF RULE 23(B)(3) .................... 27 A. Questions of Law and Fact Common to Class Members Predominate Over Any Questions Affecting Only Individual Members ........................................... 27 1. Common questions ....................................................................................... 30 2. Individual questions: proximate cause and damages .................................. 34 a. Proximate cause ...................................................................................... 34 b. Damages ................................................................................................. 35 B. A Class Action Is Superior to Other Available Methods for Fairly and Efficiently Adjudicating the Controversy ............................................................ 40 ii Case 3:12-cv-01141-SMY-DGW Document 176 *SEALED* Filed 12/01/14 Page 3 of 60 Case: 16-3334 Document:Page 55-1 ID #2103 Filed: 02/08/2017 Pages: 60 (3 of 1511) C. The Four Factors Used to Evaluate Superiority Weigh in Favor of Class Certification ......................................................................................................... 41 1. The class members’ interest in individually controlling the prosecution of separate actions ............................................................................................ 42 2. The extent and nature of litigation concerning the controversy already begun by class members ............................................................................... 42 3. The desirability or undesirability of concentrating the litigation of the claims in the particular forum ...................................................................... 43 4. Likely difficulties in managing a class action .............................................. 43 VIII. CONCLUSION ........................................................................................................... 45 APPENDIX ........................................................................................................................... A-1 iii Case 3:12-cv-01141-SMY-DGW Document 176 *SEALED* Filed 12/01/14 Page 4 of 60 Case: 16-3334 Document:Page 55-1 ID #2104 Filed: 02/08/2017 Pages: 60 (4 of 1511) TABLE OF AUTHORITIES Cases Amchem Prods, Inc. v. Windsor, 521 U.S. 591 (1997) ....................................................................................................... 25, 29 Amgen Inc. v. Connecticut Ret. Plans & Trust Funds, 133 S. Ct. 1184, (2013) .................................................................................................. 19, 33 Beringer v. Standard Parking Corp., 2008 WL 4390626 (N.D. Ill. Sept. 24, 2008) ....................................................................... 41 Boundas v. Abercrombie & Fitch Stores, Inc., 280 F.R.D. 408 (N.D. Ill. 2012) ........................................................................................... 41 Brewer v. Missouri Title Loans, 364 S.W.3d 486 (Mo. 2012) ................................................................................................. 24 Brunner v. City of Arnold, 427 S.W.3d 201 (Mo. App. E.D. 2013)................................................................................ 24 Butler v. Sears, Roebuck & Co., 727 F.3d 796 (7th Cir. 2013), ......................................................................................... passim Campbell v. PricewaterhouseCoopers, LLP, 253 F.R.D. 586 (E.D. Cal. 2008) .......................................................................................... 44 Carnegie v. Household Int'l., Inc., 376 F.3d 656 (7th Cir. 2004) ..................................................................................... 40, 41, 45 Comcast Corp. v. Behrend, 133 S. Ct. 1426 (2013) ......................................................................................................... 37 Damon v. City of Kansas City, 419 S.W.3d 162 (Mo. App. W.D. 2013) .............................................................................. 24 De La Fuente v. Stokely–Van Camp, Inc., 713 F.2d 225 (7th Cir. 1983) ................................................................................................. 22 East Tex. Motor Freight System, Inc. v. Rodriguez, 431 U.S. 395 (1977) ............................................................................................................. 25 Edwards v. City of Ellisville, 426 S.W.3d 644 (Mo. App. E.D. 2013)................................................................................ 24 Eike v. Allergan, Inc., 2014 WL 1040728 (S.D. Ill. Mar. 18, 2014) ................................................................. passim iv Case 3:12-cv-01141-SMY-DGW Document 176 *SEALED* Filed 12/01/14 Page 5 of 60 Case: 16-3334 Document:Page 55-1 ID #2105 Filed: 02/08/2017 Pages: 60 (5 of 1511) Elias v. Ungar's Food Products, Inc., 252 F.R.D. 233 (D.N.J. 2008) .............................................................................................. 23 Eubank v. Pella Corp., 753 F.3d 718 (7th Cir. 2014) ................................................................................................. 26 Fallick v. Nationwide Mut. Ins. Co., 162 F.3d 410 (6th Cir. 1998) ................................................................................................. 23 Franklin v. City of Chicago, 102 F.R.D. 944 ..................................................................................................................... 20 General Telephone Co. v. Falcon, 457 U.S. 147 (1982) ............................................................................................................. 25 Howland v. First Am. Title Ins. Co., 672 F.3d 525 (7th Cir. 2012) ................................................................................................. 27 Hoxworth v. Blinder, Robinson & Co., Inc., 980 F.2d 912 (3d Cir. 1992) ........................................................................................... 23, 24 Huch v. Charter Communications, Inc., 290 S.W.3d 721 (Mo. 2009) ................................................................................................. 24 In re Bridgestone/Firestone, Inc., 288 F.3d 1012 (7th Cir. 2002) ............................................................................................... 45 In re Emerson Electric Co. Wet/Dry Vac Marketing and Sales Practices Litig., 4:12-md-02382-HEA (E.D. Mo.) ......................................................................................... 24 In re Hydrogen Peroxide Antitrust Litig., 552 F.3d 305 (3d Cir. 2008) ................................................................................................. 28 In Re IKO Roofing Shingle Products Liability Litigation, 757 F.3d 599 (2014) ...................................................................................................... passim In re Pharm. Indus. Average Wholesale Price Litig., 233 F.R.D. 229 (D. Mass. 2006) .......................................................................................... 23 In re S. Cent. States Bakery Prods. Antitrust Litig., 86 F.R.D. 407 (M.D. La.1980) ............................................................................................. 43 In re Visa Check/MasterMoney Antitrust Litig., 280 F.3d 124 (2d Cir. 2001) ................................................................................................. 43 In re Whirlpool Corp. Front-Loading Washer Products Liab. Litig., 722 F.3d 838 (6th Cir. 2013), cert. denied sub nom. Whirlpool Corp. v. Glazer, 134 S. Ct. 1277 298 (2014) .................................................................................................................. 28 v Case 3:12-cv-01141-SMY-DGW Document 176 *SEALED* Filed 12/01/14 Page 6 of 60 Case: 16-3334 Document:Page 55-1 ID #2106 Filed: 02/08/2017 Pages: 60 (6 of 1511) In re Yasmin & Yaz (Drospirenone) Mktg., Sales Practices & Products Liab. Litig., 2012 WL 865041 (S.D. Ill. Mar. 13, 2012) .......................................................................... 26 Keele v. Wexler, 149 F.3d 589 (7th Cir. 1998) ................................................................................................. 20 Klay v. Humana, Inc., 382 F.3d 1241 (11th Cir. 2004) ............................................................................................. 44 Kohen v. Pacific Inv. Management Co., 571 F.3d 672 (7th Cir. 2009) ........................................................................................... 29, 32 Lewis Tree Serv., Inc. v. Lucent Technologies Inc., 211 F.R.D. 228 (S.D.N.Y. 2002) .......................................................................................... 24 Martin v. Heinold Commodities, Inc., 643 N.E.2d 734 (Ill. 1994) ................................................................................................... 44 Matter of Rhone-Poulenc Rorer, Inc., 51 F.3d 1293 (7th Cir. 1995) ................................................................................................. 42 Mejdrech v. Met–Coil Sys. Corp., 319 F.3d 910 (7th Cir.2003) .................................................................................................. 20 Messner v. Northshore Univ. HealthSystem, 669 F.3d 802 (7th Cir. 2012) ............................................................................... 18, 27, 28, 29 Mezyk v. U.S. Bank Pension Plan, 2011 WL 601653 (S.D. Ill. Feb. 11, 2011) .......................................................................... 21 Mississippi ex rel. Hood v. AU Optronics Corp., 134 S. Ct. 736 (2014) ........................................................................................................... 17 Mowry v. JP Morgan Chase Bank, N.A., 2007 WL 1772142 (N.D. Ill. Jun. 19, 2007) ........................................................................ 26 Muehlbauer v. Gen. Motors Corp., 431 F. Supp. 2d 847 (N.D. Ill. 2006).................................................................................... 45 Olson v. Brown, 594 F.3d 577 (7th Cir. 2010) ................................................................................................. 18 Ormond v. Anthem, Inc., 2009 WL 3163117 (S.D. Ind. Sept. 29, 2009)...................................................................... 36 Parko v. Shell Oil Co., 739 F.3d 1083 (7th Cir. 2014) ......................................................................................... 28, 38 vi Case 3:12-cv-01141-SMY-DGW Document 176 *SEALED* Filed 12/01/14 Page 7 of 60 Case: 16-3334 Document:Page 55-1 ID #2107 Filed: 02/08/2017 Pages: 60 (7 of 1511) Pella Corp. v. Saltzman, 606 F.3d 391 (7th Cir. 2010) .......................................................................................... passim Pettway v. American Cast Iron Pipe Co., 494 F.2d 211 ......................................................................................................................... 37 Phillips v. Asset Acceptance, LLC, 736 F.3d 1076 (7th Cir. 2013) ............................................................................................... 25 Retired Chicago Police Ass'n v. City of Chicago, 7 F.3d 584 (7th Cir. 1993) ..................................................................................................... 22 Rosario v. Livaditis, 963 F.2d 1013 (7th Cir.1992) .................................................................................... 20, 21, 25 Schleicher v. Wendt, 618 F.3d 679 (7th Cir. 2010) ............................................................................... 18, 27, 29, 33 Secretary of Labor v. Fitzsimmons, 805 F.2d 682 (7th Cir. 1986) ................................................................................................. 25 Smith v. Greystone Alliance LLC, 2011 WL 307457 (N.D. Ill. Jan. 25, 2011) .......................................................................... 41 Stewart v. General Motors Corp., 542 F.2d 445 ................................................................................................................... 36, 37 Suchanek v. Sturm Foods, Inc., 764 F.3d 750 (7th Cir. 2014) .......................................................................................... passim Susman v. Lincoln American Corp., 561 F.2d 86 (7th Cir. 1977) ............................................................................................. 24, 26 Szabo v. Bridgeport Machines, Inc., 249 F.3d 672 (7th Cir.2001) .................................................................................................. 18 Thorogood v. Sears, Roebuck & Co., 547 F.3d 742 (7th Cir. 2008) ..................................................................................... 27, 29, 36 Uhl v. Thoroughbred Tech. & Telecomms., Inc., 309 F.3d 978 (7th Cir. 2002) ................................................................................................. 25 United States v. City of Miami, 195 F.3d 1292 ....................................................................................................................... 37 Wal-Mart Stores, Inc. v. Dukes, 131 S. Ct. 2541 (2011) ................................................................................................... 20, 33 vii Case 3:12-cv-01141-SMY-DGW Document 176 *SEALED* Filed 12/01/14 Page 8 of 60 Case: 16-3334 Document:Page 55-1 ID #2108 Filed: 02/08/2017 Pages: 60 (8 of 1511) Wetzel v. Liberty Mut. Ins. Co., 508 F.2d 239 (3rd Cir. 1975) ................................................................................................. 24 Wiener v. Dannon Co., 255 F.R.D. 658 (C.D. Cal. 2009) ......................................................................................... 24 Wyeth v. Levine, 555 U.S. 555 (2009) ............................................................................................................. 32 Statutes 815 ILCS § 505/1 ....................................................................................................................... 7 815 ILCS. § 505/2 .................................................................................................................... 44 Class Action Fairness Act of 2005, Pub. L. No. 109–2, 119 Stat 4 (2005).............................. 17 FTC Act § 5(a), 15 U.S.C. § 45(a) ........................................................................................... 44 Mo. Rev. Stat. § 407.010 ............................................................................................................ 7 Rules Fed. R. Civ. P. 23 ......................................................................................................... 18, 27, 45 Fed. R. Civ. P. 23(a) ................................................................................................................. 19 Fed. R. Civ. P. 23(a)(2) ............................................................................................................ 19 Fed. R. Civ. P. 23(a)(4) ...................................................................................................... 24, 27 Fed. R. Civ. P. 23(b) ................................................................................................................. 18 Fed. R. Civ. P. 23(b)(3) ..................................................................................................... passim Fed. R. Civ. P. 30(b)(6) .............................................................................................................. 8 Rules Mo. Code Regs. tit. 15, § 60–8.020 .......................................................................................... 44 Other Authorities FOOD AND DRUG ADMINISTRATION, Guidance for Industry: Container Closure Systems for Packaging Human Drugs and Biologics, 1999 WL 33935258 (1999) ................................. 12 H. Newberg, Class Actions (1977) ........................................................................................... 22 Herbert B. Newberg & Alba Conte, Newberg on Class Actions (4th ed. 2002) ....................... 36 viii Case 3:12-cv-01141-SMY-DGW Document 176 *SEALED* Filed 12/01/14 Page 9 of 60 Case: 16-3334 Document:Page 55-1 ID #2109 Filed: 02/08/2017 Pages: 60 (9 of 1511) Manual on Complex Litigation .......................................................................................... 41, 42 W.B. Rubenstein, 4 Newberg on Class Actions (5th ed. 2014) .............................. 37, 40, 42, 43 ix Case 3:12-cv-01141-SMY-DGW Document 176 *SEALED* Filed 12/01/14 Page 10 of 60 Case: 16-3334 Document:Page 55-1 ID #2110 Filed: 02/08/2017 Pages: 60 (10 of 1511) TABLE OF EXHIBITS Exhibit A Richard Fiscella et al., Efficiency of Instillation Methods for Prostaglandin Medications ................................................................................................................... 1 B Expert Report of Alan Robin, M.D. ........................................................................... 1,4 C Pfizer Document, PFIZER_XALATAN_00024641 ..................................................... 1 D Deepta Ghate & Henry F. Edelhauser, Barriers to Glaucoma Drug Delivery ............. 1 E Supplemental Expert Report of Alan Robin, M.D. ....................................................... 3 F Expert Report of Brian Kriegler, Ph.D. ............................................................... 4,13,22 G Deposition Transcript of Alan Robin, M.D. (8/6/14) .................................................... 5 H Bausch & Lomb Document, BHLB_BRIM_0001076 ............................................. 6,13 I Deposition Transcript of Matthew Jonasse (3/11/14) ......................................... 6,13,14 J Alcon Document, AD_Dorzolamide_Eike_000603-000626 ...................................... 11 K Alcon Document, AD_VIGAMOX_EIKE016359 ..................................................... 11 L Alcon Document, AD_DORZ-TIM_EIKE001214 ..................................................... 11 M Alcon Document, AD_LATANOPROST_EIKE000121 ............................................ 11 N Alcon Document, AD_EIKE001281 ........................................................................... 11 O Allergan Document, ARGN_0002642 ........................................................................ 12 P Deposition Transcript of Lon Spada (3/26/14)............................................................ 12 Q Allergan Document, ARGN_LUM03_0005878 ......................................................... 12 R Allergan Document, ARGN_LUM03_0005995 .................................................... 12,13 S Allergan Document, ARGN_LUM03_0006106 ......................................................... 12 T Bausch & Lomb Document, BHLB_BRIM_0001052 ................................................ 12 U Bausch & Lomb Document, BHLB_BRIM_0000861 ................................................ 12 V Pfizer Document, PFIZER_XALATAN_00001531 ................................................... 12 x Case 3:12-cv-01141-SMY-DGW Document 176 *SEALED* Filed 12/01/14 Page 11 of 60 Case: 16-3334 Document:Page 55-1 ID #2111 Filed: 02/08/2017 Pages: 60 (11 of 1511) W Pfizer Document, PFIZER_XALATAN_00024279 ................................................... 12 X Deposition Transcript of David Walker (2/18/14) ................................................. 12,13 Y Prasco Document, Prasco 000092 ............................................................................... 12 Z Alcon Document, AD_DORZ-TIM_EIKE001234 ..................................................... 13 AA Alcon Document, AD_TRAVATAN_EIKE040560 ................................................... 13 BB Allergan Document, ARGN_00002865 ...................................................................... 13 CC Deposition Transcript of Daniel Arenson (3/14/14).................................................... 13 DD Merck Prasco Document, NDA_Merck_Prasco 00000328 ........................................ 13 EE Merck Prasco Document, NDA_Merck_Prasco 00009193 and 9227 ......................... 13 FF Deposition Transcript of Brian Kriegler, Ph.D. (8/20/14) .......................................... 14 GG Expert Report Janet B. Arrowsmith, M.D., F.A.C.P., F.A.C.E................................... 15 HH Expert Report of Jimmy D. Bartlett, O.D., D.O.S., D.Sc. ...................................... 15,44 II Expert Report of Michael W. Belin, M.D. ............................................................ 15,31 JJ Expert Report of Dr. David Lin................................................................................... 15 KK Expert Report of Steven N. Wiggins ...................................................................... 15,16 LL 1/30/14 Letter to James Muehlberger (SHB) re Allergan’s Objections to Plaintiffs’ 30(b)(6) Deposition Topics .................................................................................... 17,19 MM 1/30/14 Letter to Robyn Bladow (K&E) re Pfizer’s Objections to Plaintiffs’ Notices of Rule 30(b)(6) Deposition ...................................................................... 17,19 NN 1/30/14 Letter to James Muehlberger (SHB) re Bausch & Lomb’s Objections to Plaintiffs’ Notices of Rule 30(b)(6) Deposition ..................................................... 17,19 OO 1/30/14 Letter to Stephen Strauss (BC) re Merck Prasco Objections to Plaintiffs’ Notices of Rule 30(b)(6) Deposition ...................................................................... 17,19 PP 2/14/14 Letter From Stephen Strauss (BC) re Merck & Prasco’s Responses and Objections to Plaintiffs’ Amended Notices of Rule 30(b)(6) Deposition .............. 17,19 QQ 2/28/14 Letter From Douglas Maddock (SHB) re Plaintiff’s 1/30/14 Letter re Allergan’s Objections to Plaintiffs’ Notices of Rule 30(b)(6) Deposition ............. 17,19 xi Case 3:12-cv-01141-SMY-DGW Document 176 *SEALED* Filed 12/01/14 Page 12 of 60 Case: 16-3334 Document:Page 55-1 ID #2112 Filed: 02/08/2017 Pages: 60 (12 of 1511) RR 3/7/14 Letter From Douglas Maddock (SHB) re Plaintiff's 1/30/14 Letter re Bausch & Lomb’s Objections to Plaintiffs’ Notices of Rule 30(b)(6) Deposition ............. 17,19 SS 3/10/14 Letter From Robyn Bladow (K&E) re Plaintiff’s 1/30/14 Letter re Pfizer’s 9/6/13 Objections to Topics Contained in Plaintiff’s 8/2/13 Notices of Rule 30(b)(c) Deposition ................................................................................................ 17,19 TT Deposition Transcript of Charlene Eike (3/7/14) ........................................................ 22 UU Deposition Transcript of Shirley Fisher (2/24/14) ...................................................... 22 VV Deposition Transcript of Jordan Pitler (2/10/14) ........................................................ 22 WW Deposition Transcript of Alan Raymond (2/27/14) .................................................... 22 XX Charlene Eike Pharmacy Records ............................................................................... 22 YY Shirley Fisher Pharmacy Records ............................................................................... 22 ZZ Jordan Pitler Pharmacy Records.................................................................................. 22 AAA Alan Raymond Pharmacy Records.............................................................................. 22 BBB The Simon Law Firm, P.C. and Law Office of Richard S. Cornfeld Firm Resumes .. 24 xii Case 3:12-cv-01141-SMY-DGW Document 176 *SEALED* Filed 12/01/14 Page 13 of 60 Case: 16-3334 Document:Page 55-1 ID #2113 Filed: 02/08/2017 Pages: 60 (13 of 1511) I. INTRODUCTION AND NATURE OF THE CASE Studies have shown that the bioavailability and efficacy of [eye] drops as small as 15 µL are equivalent to those of larger drops. Therefore, smaller [eye] drops would be preferable to minimize systemic exposure and spilled or wasted medication. Obviously, a smaller drop size would mean that more doses could be dispensed from each bottle of medication, providing cost savings to patients and managed care providers. -- Scientists from Allergan and University of Chicago 1 The human eye can absorb approximately 7 µL of fluid. The remaining drop fluid beyond 7 µL is not absorbed by the eye. -- Pfizer 2 Reducing the drop size to 5-15 μL would reduce overflow, decrease systemic absorption, reduce cost of therapy while maintaining equivalent or even enhanced ocular bioavailability. -- Emory University scientists 3 The eye can absorb a drop of no more than 15 microliters (“µL”), or even less as Pfizer states above. Yet Defendants have sold their prescription glaucoma medications in dispensers that emit eye drops two and three times that size and no more effective than they would be with only 15 µL. The excess provides no therapeutic benefit, does not even enter the eye, and costs glaucoma and ocular-hypertension patients staggering amounts of money in the aggregate. Defendant Allergan not only knows all of that to be true, but as quoted above, it has admitted it. Remarkably, that admission, summarizing the basis of this lawsuit in three simple sentences, was not whispered in an office hallway or shared in intra-company email; it was published in the peer-reviewed Journal of Ocular Pharmacology and Therapeutics by company scientists, as well as colleagues from the University of Chicago. 1 Ex. A, Richard Fiscella et al., Efficiency of Instillation Methods for Prostaglandin Medications, 22 J. OCULAR PHARMACOLOGY AND THERAPEUTICS 477, 478 (2006). This statement is cited in First Amended Complaint (“Compl.” or “Complaint”), Doc. 44, ¶¶ 7, 62, 67, and endorsed by Plaintiffs’ Expert Alan Robin. Ex. B, Expert Report of Alan Robin, M.D. (“Robin Rept.”), ¶ 23. 2 Ex. C, PFIZER_XALATAN_00024641-24645 at 24643(emphasis added); see Robin Rept. ¶ 47. 3 Ex. D, Deepta Ghate & Henry F. Edelhauser, Barriers to Glaucoma Drug Delivery, 17 J. Glaucoma 147, 147 (2008); Compl. ¶¶ 49, 60. 1 Case 3:12-cv-01141-SMY-DGW Document 176 *SEALED* Filed 12/01/14 Page 14 of 60 Case: 16-3334 Document:Page 55-1 ID #2114 Filed: 02/08/2017 Pages: 60 (14 of 1511) Plaintiffs brought this putative class action to obtain redress from this unfair practice, which Defendants have engaged in for many years. The original sources of Plaintiffs’ allegations are 20-plus scientific publications by scientists from institutions as varied and distinguished as Yale University, Johns Hopkins University, the University of Wisconsin, Emory University, and the University of Chicago, including the Allergan study quoted above. (Compl. at A-1, Bibliography.) This vast and undisputed scientific literature – undisputed at least in the scientific community or for that matter anywhere outside of lawsuits brought against these defendants – establishes that, despite knowing that larger drop sizes are no more effective than those of 15 or 16 µL but lead to product wastage, systemic exposure with risk of adverse effects, and resultant economic losses, Defendants 4 have persisted in selling much larger drops. That literature establishes the scientific foundation of this case beyond reasonable dispute. First, the amount of medicine that the eye can absorb is limited by the eye’s capacity. (Compl. ¶¶ 5, 54-58.) Any amount larger than 15 µL drains through the patient’s tear duct or is blinked out and runs down his or her cheek and provides no benefit. (Id.) No more than 15 µL can enter the eye to treat the patient’s disease, no matter how large the drop. The Pfizer document quoted above – a set of meeting minutes regarding its glaucoma drug Xalatan – goes even further to state that the only 7 µL enters the eye. As Plaintiffs’ expert Alan Robin explained, the excess “either drains through the nasolacrimal or tear duct or is blinked onto the patient’s cheek.” (Robin Rept. ¶ 48.) He stated that the principle expressed by Pfizer is consistent with scientific papers published between 1973 and 2008 that advocated 5-15 µL drops. (Id., ¶ 49 and n. 11.) One of those papers is the Emory study quoted above, published in 4 The defendants can be placed into five groupings: “Allergan” (Allergan, Inc., Allergan USA, Inc., and Allergan Sales, LLC), “Alcon” (Alcon Laboratories, Inc., Alcon Research Ltd., Falcon Pharmaceuticals, Ltd., and Sandoz Inc.),”B&L” ( Bausch & Lomb Incorporated); “Pfizer” (Pfizer, Inc.); and “Merck/Prasco” (Merck & Co., Inc., Merck, Sharp & Dohme Corp. and Prasco, LLC.). Compl. at ¶¶ 19-33. The drugs at issue are set forth in the class definitions in the accompanying Motion. 2 Case 3:12-cv-01141-SMY-DGW Document 176 *SEALED* Filed 12/01/14 Page 15 of 60 Case: 16-3334 Document:Page 55-1 ID #2115 Filed: 02/08/2017 Pages: 60 (15 of 1511) the Journal of Glaucoma, which advocated a drop size of 5-15 μL to “reduce cost of therapy while maintaining equivalent or even enhanced ocular bioavailability.” (See Compl. ¶¶ 49, 60.) These numbers, 5-15 µL, were not drawn out of the air. As study after study found, including by these Defendants, larger drops are no more effective than smaller ones. (See id. ¶¶ 6-7.) One such study, published in the peer-reviewed American Journal of Ophthalmology, was written by three doctoral-degreed Alcon scientists, including its then-Vice President of Research (the company’s head of research), along with co-authors from Johns Hopkins, including the senior author, Dr. Robin, now one of Plaintiffs’ experts. (Robin Rept. ¶ 26.) Known as the “Vocci study,” it found that 16 µL drops of a glaucoma drug were as effective as 30 µL drops, while causing fewer side effects. (Id. ¶¶ 6, 63, 74.) A study by Allergan’s scientists, published with co-authors from Yale and other institutions, found 20 µL drops of a glaucoma drug to be as effective as drops of 35 and 50 µL. Unpublished studies by Defendants Allergan and Alcon, which saw the light of day only when produced in this case, found similar results. (Robin Rept. ¶¶ 38-44; Ex. E, Robin Supp. Rept.) But the scientific community did not need access to company files to know how large (or rather, small) eye drops should be. Based on published studies, for many years scientists have advocated reducing the sizes of eye drops to 15 µL or smaller. (Compl. ¶¶ 87-89.) In his expert report, Dr. Robin stated that, to be conservative, he would recommend an average size of 16 µL, the size used in his study. (Robin Rept. ¶ 52.) Defendants’ larger drops cost glaucoma patients, primarily elderly, huge amounts of money as they use up their bottles and need to replace them sooner than they would if drops were smaller and bottles lasted longer. (Compl. ¶¶ 103-04.) Most patients take these drugs every day for life to prevent total blindness, going through bottle after bottle and paying for large quantities that provide no benefit. (Id. ¶ 11.) Alcon measured drops of its Azopt to be 35.3 µL on average, 3 Case 3:12-cv-01141-SMY-DGW Document 176 *SEALED* Filed 12/01/14 Page 16 of 60 Case: 16-3334 Document:Page 55-1 ID #2116 Filed: 02/08/2017 Pages: 60 (16 of 1511) meaning that more than half of each drop goes to waste. 5 A patient therefore would need more than twice as many bottles than if drops had been only 16 µL. Some drops are worse. Merck measured drops of Timoptic-XE as 48.3 µL, meaning patients had to pay for three times as many bottles than if Merck had provided drops of only 16 µL. (Kriegler Rept., Ex. E-1.) The amount of money wasted as a result is stunning. (Compl. ¶¶ 75-77. ) A year’s worth of Allergan’s Alphagan P costs nearly $2,000 for 18.25 bottles with what the scientific literature reports to be 43 µL drops. (Id. ¶ 75.) (Allergan itself measured Alphagan P 0.15% as 43.7 µL on average. Kriegler Rept. at Ex. E-1.) That is 12 bottles more than the patient needs because nearly two-thirds of the drug goes to waste. (Compl. ¶ 75.) The wasted part costs a patient well over $1,000 a year. (Id.) Retail sales of Pfizer’s Xalatan exceeded $500 million in the U.S. in 2010 alone. (Id. ¶ 77.) But most of every drop went to waste, and the wasted portion cost U.S. patients hundreds of millions of dollars that year in the aggregate. (Id.) The medical and scientific communities, as well as these defendants, know the economic costs of oversized drops. A study in the American Journal of Ophthalmology reported that a bottle emitting 15 µL drops would yield more drops and result in substantial savings. (Id. ¶ 72.) Scientists from Emory University, writing in the Journal of Glaucoma, stated, as quoted above: “Reducing the drop size to 5-15 µL would … reduce cost of therapy ….” (Id. ¶¶. 60, 73.) And as quoted above, Allergan knew that the principle that larger drops impose excess costs for patients was, well, obvious: “Obviously,” it told the medical and scientific community, “a smaller drop size would mean that more doses could be dispensed from each bottle of medication, providing cost savings to patients and managed care providers.” (Ex. A at 478.) 6 5 Ex. F, Expert Report of Brian Kriegler, Ph.D (“Kriegler Rept.”) at Ex. E-1, showing 54.7% wasted based on mean and median drop size. 6 The purpose of this study was to determine whether drop sizes varied according to the angle of the dropper. The passage quoted here and at the outset of this brief was the authors’ explanation of why drop size is important. Dr. Robin stated in his report that he agreed with the statement. Ex. B hereto, ¶ 23. 4 Case 3:12-cv-01141-SMY-DGW Document 176 *SEALED* Filed 12/01/14 Page 17 of 60 Case: 16-3334 Document:Page 55-1 ID #2117 Filed: 02/08/2017 Pages: 60 (17 of 1511) Yet Defendants could have reduced their drop sizes simply by changing the tip dimensions of their dispensers. (Id. ¶¶ 86-92.) They have known how to do it for decades. A 1985 publication in the American Journal of Ophthalmology by authors from Johns Hopkins reported the dimensions of dropper tips that would emit drops of only 11 and 19 µL. (Id. ¶ 89.) They also published this picture comparing their 19 µL drop with a standard-sized drop (Id.): Dr. Robin’s expert report, includes the following photograph comparing the 16 µL dropper that Alcon created for the Vocci study with Alcon’s existing dropper. (Robin Rept. ¶ 29.) The existing dropper is on the left: Dr. Robin testified that Alcon told him that the new dropper was commercially usable. 7 7 Ex. G, Robin Dep., 110:6:13, 111:9-17, 112:2-112:12. Dr. York, to whom Dr. Robin refers in this testimony, was Alcon’s head of research. Robin Rept. 7, ¶ 26. 5 Case 3:12-cv-01141-SMY-DGW Document 176 *SEALED* Filed 12/01/14 Page 18 of 60 Case: 16-3334 Document:Page 55-1 ID #2118 Filed: 02/08/2017 Pages: 60 (18 of 1511) A catalogue in Defendant B&L’s files 8 shows an available dispenser emitting 55 drops per mL, an average of only 18 µL per drop, compared to 23 drops per mL, 43 µL per drop on average (or 58% smaller), for the dropper tips B&L used. However, none of the defendants have used the bottles emitting the smaller drops. In the face of this overwhelming proof that smaller drops are feasible and better for patients, both economically and pharmacologically, Defendants have kept their drops too large. Why? Alcon’s top marketing executives told Dr. Robin why after his study was published. They stated “that they were unwilling to reduce the drop size because it would mean that patients would be able to use the bottles longer and Alcon would therefore sell less product.” (Robin Rept. ¶ 34; emphasis added.) That statement is an admission as clear as Allergan’s quoted above about the economic benefits of smaller drops to those paying for the drops. Reducing drop sizes would mean bottles would last longer, but companies would sell less product and, therefore, make less money. Instead, they made more money at the expense of patients by keeping drops too large. Class treatment is an ideal method to adjudicate the claims of thousands of glaucoma patients in Illinois and Missouri because the primary issues apply to all members of the putative class identically – whether glaucoma eye drops should be 16 µL on average to avoid product wastage, whether those smaller drop sizes are as effective as existing drops, whether existing drops are larger than 16 µL, and whether it would it have been feasible for defendants to have supplied drops of 16 µL. Moreover, the damages of each class member are too small to justify separate lawsuits. Accordingly, Plaintiffs respectfully request that this action be certified as a class action pursuant to Fed. R. Civ. P. 23(b)(3). 8 Ex. H, BHLB_BRIM_0001076; Ex. I, Jonasse Dep. 108:24-119:10, 126:1-133:13 (Mar. 11, 2014). These comparisons are for distilled water. 6 Case 3:12-cv-01141-SMY-DGW Document 176 *SEALED* Filed 12/01/14 Page 19 of 60 Case: 16-3334 Document:Page 55-1 ID #2119 Filed: 02/08/2017 Pages: 60 (19 of 1511) II. PROCEDURAL HISTORY Plaintiffs filed this case on November 1, 2012, on behalf of users of prescription eye drops manufactured by Defendants in Missouri and Illinois, alleging violations of the Illinois Consumer Fraud & Deceptive Business Practices Act, 815 ILCS § 505/1, et seq. (“ICFA”), and Missouri Merchandising Practices Act, Mo. Rev. Stat. § 407.010 et seq. (“MMPA”). 9 Between them, the two Illinois plaintiffs, Charlene Eike and Shirley Fisher asserted claims against all Defendants except Pfizer. The two Missouri plaintiffs, Jordan Pitler and Alan Raymond, between them asserted claims against all Defendants but Merck and Prasco. After Defendants filed motions to dismiss, Docs. 19, 22, 24, 26, 28, Plaintiffs filed an amended complaint, principally to make clear that the gravamen of their allegations was violation of the statutes’ unfair-practices prohibitions, not deception. In response, Defendants filed new motions to dismiss, one termed “omnibus” on behalf of all defendants, Doc. 52, as well as defendant-specific motions by Alcon, Merck and Pfizer, Docs. 54, 55, 57. Defendants followed these with multiple motions for leave to file supplemental briefs and the supplemental briefs themselves. Docs. 86, 88, 91, 93, 94, 100, 102, 102-1, 106, 144. They argued that the Complaint did not adequately allege unfair conduct, causation and proximate cause (because of an alleged intervening cause) or damages; in addition, they asked the court to dismiss the Complaint pursuant to an affirmative defense of federal preemption by the United States Food & Drug Administration (“FDA”), as well as other grounds. On March 18, 2014, Judge Herndon denied the motions in their entirety. Doc. 147. The court ruled, inter alia, that Plaintiffs had sufficiently alleged an unfair practice under both state statutes, that defendants had not “met their 9 Class Action Compl. for Damages, Punitive Damages, and Injunctive Relief, Doc. 2. This is one of three pending cases making the same substantive allegations on behalf of residents of different states. The others are Cottrell et al., v. Alcon Laboratories, Inc., et al., No. 14-5859 (D.N.J.) (Florida, California, Illinois, New Jersey, North Carolina and Texas) and Gustavsen et al. v. Alcon Laboratories, Inc et al., No. 1:14-cv-11961 (D. Mass.). Cottrell was filed after the plaintiffs voluntarily dismissed Freburger v. Alcon Laboratories, Inc., et al., No. 1:13cv24446 (S.D. Fla.), which was based on the same states’ laws. 7 Case 3:12-cv-01141-SMY-DGW Document 176 *SEALED* Filed 12/01/14 Page 20 of 60 Case: 16-3334 Document:Page 55-1 ID #2120 Filed: 02/08/2017 Pages: 60 (20 of 1511) burden of proving that the physicians are an intervening cause,” that it would be reasonable “to infer, as the Court must, that patients would buy less medication absent defendants' conduct,” and “that there remain[ed] questions of fact to be determined and that the record needs to be further developed” to decide Defendants’ affirmative defenses based on federal preemption. Eike v. Allergan, Inc., 2014 WL 1040728 (S.D. Ill. Mar. 18, 2014). Meanwhile, the parties undertook discovery limited to issues of class certification. Defendants deposed each plaintiff, and Plaintiffs deposed corporate designees of Defendants pursuant to Fed. R. Civ. P. 30(b)(6). Defendants also produced thousands of documents. Of most significance for class certification, the documents included the results of drop-size tests done by the companies on their glaucoma drugs. Following the close of fact discovery on class certification, the parties designated expert witnesses on class certification. Defendants took depositions of Plaintiffs’ experts. Plaintiffs did not depose Defendants’ experts but rely on their reports to support this motion, as described below. III. PUTATIVE CLASSES Plaintiffs seek to represent separate Missouri and Illinois classes of consumers who purchased the glaucoma drugs 10 manufactured and sold by each Defendant within the applicable period of limitations (three years for Illinois; five years for Missouri) and continuing until the date of certification. 11 The Illinois classes are asserted against each Defendant except Pfizer. The Missouri classes are asserted against each Defendant but Merck/Prasco. For example, here is the putative Allergan Illinois class: All persons who, in the State of Illinois, purchased prescription eye drops manufactured and sold by Allergan in multi-dose dispensers for treatment of 10 In their Complaint, Plaintiffs made allegations regarding other classes of prescription eye drops used to treat other conditions. However, Dr. Robin’s opinion was limited to Defendants’ glaucoma drugs. Accordingly, Plaintiffs limit their putative classes to consumers of Defendants’ glaucoma drugs. 11 For convenience, the classes are sometimes referred to herein collectively with the singular “class.” 8 Case 3:12-cv-01141-SMY-DGW Document 176 *SEALED* Filed 12/01/14 Page 21 of 60 Case: 16-3334 Document:Page 55-1 ID #2121 Filed: 02/08/2017 Pages: 60 (21 of 1511) glaucoma and/or reduction of elevated intraocular pressure, including Alphagan P, Betagan, Combigan and Lumigan, within the period of the applicable statute of limitations of three years prior to the filing of this lawsuit and up to the date of certification. 12 See Plaintiffs’ Motion, filed contemporaneously herewith, for each proposed class definition. IV. THE PARTIES’ EXPERT WITNESSES A. Plaintiffs’ Experts To support their case for class certification, Plaintiffs designated two expert witnesses, Ophthalmologist Alan Robin and Statistician Brian Kriegler. Dr. Robin is a member of the faculties of Johns Hopkins University, the University of Maryland and the University of Michigan and one of the world’s leading experts on glaucoma. He is also a former consultant for most of the defendants, as well as the recipient of Alcon Laboratories’ Research Excellence Award. 13 In Dr. Robin’s expert report, he stated that he had reviewed ¶¶1-14 and 41-95 of the Complaint, the portions regarding defendants’ liability, agreed with the scientific propositions stated therein and agreed that they are supported by the scientific literature. (Robin Rept. ¶ 23.) Specifically, he opined “that any drop size larger than an average of 5-15 μL is larger than the capacity of the eye and provides more medication than necessary. Indeed, the literature indicates that larger drops are no more effective than drops of 15 μL or even smaller.” (Robin Rept. ¶ 16.) He also stated that “to prevent undue waste of medication, eye drops should probably be no larger than 15 μL,” but to be conservative, in light of his Vocci study, he set forth a standard under which drops should “be no larger than 16 μL on average.” (Id. ¶ 17; see also id. ¶ 52.) In 12 Excluded are officers, directors, and employees of Defendants and any entity affiliated with or controlled by Defendants, counsel, and members of the immediate families of counsel, for the parties herein, the judge presiding over this action and any member of the judge’s immediate family. 13 Robin Rept. ¶¶ 1-13. To call Dr. Robin one of the world’s leading experts on glaucoma is not unfounded hype. Among other honors, the Eye Care System of India called him “one of the reputed glaucoma specialists renowned the world over” and credited his work with saving the vision of “millions of people affected by glaucoma in India and possibly elsewhere ….” Id. ¶ 8 and Ex. A thereto. 9 Case 3:12-cv-01141-SMY-DGW Document 176 *SEALED* Filed 12/01/14 Page 22 of 60 Case: 16-3334 Document:Page 55-1 ID #2122 Filed: 02/08/2017 Pages: 60 (22 of 1511) his deposition, asked whether patients would receive adequate medication even if, as a result of drop-size variability, individual drops were as small as 11 µL, he said yes. (Robin Dep. 444:19445:3.) In his expert report, he agreed with Pfizer’s statement that the eye can only absorb 7 µL. (Robin Rept. ¶¶ 47-48.) Dr. Robin also discussed several studies he had conducted that show the difficulties some patients have using eye drops. He explained in detail why the studies do not contradict the principle that patients, including those with difficulty instilling drops, would benefit from smaller drop sizes. (Id., ¶¶ 53-78.) He also stated that whether patients would benefit from smaller drops is not “an individual issue that varies from person to person.” (Id., ¶ 78. ) For example, although some patients miss their eye and instill two or more drops to get one in, such a patient “would be better off if he or she missed the eye with smaller, rather than larger, drops because less medicine would be wasted in the drop(s) that missed.” (Id., ¶ 59.) In his deposition, he acknowledged that the method of eye-drop administration “varies tremendously from person to person.” (Robin Dep. 73:13-15.) But asked whether that “can result in variances in drop size,” his answer was succinct: “Minimal.” (Id. 72:23-25; see also id. 79:25 [“It’s minimal difference.”], 79:7-8 [“minimal variability”], 160:1-14 [“minimal, if any at all”]; 389:6-390:14.) By minimal he meant “Less than five percent.” (Id. 160-15:18.) A five percent range around an average drop size of 16 µL is 15.2-16.8 µL. Plaintiffs’ other expert, Dr. Brian Kriegler, a statistician in private practice with an economics consulting firm, reviewed the Defendants’ corporate designee depositions, the company measurements of drop size and other documents related to those studies, as well as Dr. Robin’s report and testimony, and reached the following conclusions 14: 14 See Kriegler Rept. ¶9. 10 Case 3:12-cv-01141-SMY-DGW Document 176 *SEALED* Filed 12/01/14 Page 23 of 60 Case: 16-3334 Document:Page 55-1 ID #2123 Filed: 02/08/2017 Pages: 60 (23 of 1511) • According to company documents, their drop-size measurements are representative of patients’ usage. • Despite differences in methods of administration, such as user technique, angle of administration and room temperature, drop sizes are, according to defendants’ documents, consistent and uniform. (This is consistent with Dr. Robin’s opinion that variations in drop sizes due to such factors are minimal.) • Based on his statistical analysis of Defendants’ drop-size tests and Dr. Robin’s opinion that drops should be no larger than 16 µL, class members dispensed drops that universally (or virtually so) went partially to waste. • A methodology can be used to calculate the cost to the class attributed to wasted medicine due to excessive eye-drop sizes with no need for individualized inquiry. At the heart of Dr. Kriegler’s analysis were Defendants’ drop size testing programs. Initially, Dr. Kriegler had to determine whether these measurements could be used to draw conclusions regarding the drop sizes when the products were used by the patients in the class. Although these were laboratory tests (since it would be impossible to measure the size of a drop once it was emitted by a patient onto his or her eye), Dr. Kriegler found that, according to the Defendants’ documents, they did these tests in order to know the drop sizes that their products would provide to patients during actual use and, at times, used them to tell consumers how long they could expect a bottle to last. 15 Specifically: • Alcon. In multiple documents submitted to the FDA, Alcon referred to “[a] drop size study to simulate patient use of the product ….” 16 Another Alcon document, describing a study comparing the drop sizes of Alcon’s Travatan with Pfizer’s Xalatan and two products whose identities were redacted from the document produced to Plaintiffs, states that the study “was intended to mimic actual patient use of these products with two drops being dispensed and measured daily to simulate a QD [i.e., four times a day] dosing regimen ….” 17 • Allergan states that its “hand” method of drop-size tests (as opposed to a robotic arm) “has a person delivering drops in the same way as someone using the 15 See Kriegler Rept. ¶¶ 12-19. E.g., Ex. J, AD_DORZOLAMIDE_EIKE,000603 at 624 (emphasis added). See also similar statements made for the products Vigamox (Ex. K, AD_VIGAMOX_EIKE16359 at 16364); Ex. L, Dorzolamide Timolol (AD_ DORZTIM_ EIKE001214 at 1217); and Ex. M, Latanoprost (AD LATANOPROST EIKE000121 at 125). 17 Ex. N, AD_EIKE001281-1282 at 1281 (emphasis added). 16 11 Case 3:12-cv-01141-SMY-DGW Document 176 *SEALED* Filed 12/01/14 Page 24 of 60 Case: 16-3334 Document:Page 55-1 ID #2124 Filed: 02/08/2017 Pages: 60 (24 of 1511) product.” 18 According to Technical Memoranda, the MP500 series of container closure systems, 19 in use since approximately 2003, 20 provides the correct drop size when the container is used by patients. Kriegler Rept. ¶ 15. One such document, after stating that the container closure system “was tested to assure that it is suitable for ophthalmic pharmaceutical products,” states that “[t]he system provides the correct drop weight and is easy to use.” 21 • Bausch & Lomb states in a study protocol, “The purpose of the study is to ‘demonstrate uniformity of drops delivered from the container under conditions of normal patient use and to determine minimum required fill volume to deliver product label claim....’ ” 22 Similarly, a report of a drop size study of its Brimonidine Tartrate and Allergan’s Alphagan states that “[d]ata was collected … under normal conditions of patient use.” 23 • Pfizer. A report of drop-size testing on Pfizer’s Xalatan by Pfizer’s predecessor Pharmacia states: “The purpose of this investigation was to simulate practical use and evaluate the total yield, number of drops and drop size from the oval 5 µl ALP bottles using Eye Drops Latanoprost 50 µg/ml [the generic name of Xalatan]." 24 An undated Pfizer document written on or later than November 15, 2010, uses this study to estimate the number of days of therapy that patients could expect per bottle. 25 • Merck/Prasco. Prasco, the distributor of Merck’s generic version of its branded Cosopt and Trusopt, used Merck’s drop size tests as the basis for telling customers how long a bottle would last. 26 Moreover, as Dr. Kriegler found, Defendants all state that their droppers provide consistent or uniform drop sizes in conditions of patient use. (Kriegler Rept. ¶¶ 20-32.) • Alcon. One of the attributes that Alcon considers “necessary to ensure product performance” is “drop-size studies to confirm consistency of the drug product 18 Ex. O, ARGN_0002642 at 2655. A container closure system is “the sum of packaging components that together contain and protect the dosage form.” FOOD AND DRUG ADMINISTRATION, Guidance for Industry: Container Closure Systems for Packaging Human Drugs and Biologics, 1999 WL 33935258 at *2 (1999) (“Container Guidance”), available at http://www.fda. gov/downloads/Drugs/Guidances/ucm070551.pdf. Thus, as applied to these products, except for the outer package it is what a layperson would consider to be the eye dropper or dispenser. 20 Ex. P, Spada Dep. 120:5-12 (March 26. 2014). 21 Ex. Q, ARGN_LUM03_0005878-5915 at 5879 (emphasis added). See identical statements regarding other configurations within the MP500 series, Ex. R, ARGN_LUM03_0005995-6026 at 5996, Ex. S, ARGN_LUM03_000 6106-6137 at 6107. 22 Ex. T, BHLB BRIM_0001052 at 1053 (emphasis added). 23 Ex. U, BHLB BRIM_0000861 at 862 (emphasis added). 24 Ex. V, PFIZER_ XALATAN_ 00001531 at 1538 (emphasis added). 25 Ex. W, PFIZER_XALATAN_00024279. 26 Ex. X, Walker Dep 38:22-39:2 (Feb. 18, 2014); Ex. Y, Prasco 000092-93 at 93 (emphasis added). 19 12 Case 3:12-cv-01141-SMY-DGW Document 176 *SEALED* Filed 12/01/14 Page 25 of 60 Case: 16-3334 Document:Page 55-1 ID #2125 Filed: 02/08/2017 Pages: 60 (25 of 1511) delivery.” 27 In testing a new dosing aid, Alcon found that its bottle “demonstrates consistency of drop size with and without dosing aid.” 28 • Allergan. In the early 2000s Allergan developed its MP500 series of container closure systems. One of its objectives was to “provide an advantage to the consumer in terms of ergonomics, consistent drops and no leakage.” 29 Allergan achieved that objective. In testing its new system, it found that it “provides a consistent drop weight ….” 30 • Bausch & Lomb. A Bausch & Lomb document on selection of dropper tips lists as one criterion whether it “’[d]elivers a consistent drop size.” 31 As an example, in selecting a container closure system for its product Brimonidine Tartrate, which is a generic version of Allergan’s Alphagan 0.2%, Bausch & Lomb demonstrated that it provided a “uniform” drop both by itself and in comparison to Alphagan. 32 • Pfizer. Pfizer introduced a dosing aid called “Xal-Ease” to make administration of eye drops easier and to provide a consistent drop size. 33 However, Pfizer’s tests found drop size results with and without use of the Xal-Ease to be marginally different at best. 34 Dr. Kriegler calculated the variation in drop sizes using the Xal-Ease to be comparable to the variation without it. 35 • Merck/Prasco. Merck describes its Ocumeter and its later Ocumeter Plus container closure systems as providing a “controlled drop size” or “controlled drop tip,” meaning, according to company witness David Walker, that “the drop size would be more reproducible by each use of the patient.” 36 Dr. Kriegler also analyzed the extent to which Defendants’ documents showed variability in drop size due to various factors and, where they did so, statistically analyzed them to determine the extent of such variability. He found that, despite testimony by company witnesses that drop size can vary due to factors such as squeezing technique, temperature and bottle angle, none of the documents produced by Defendants quantified any such differences and none of their witnesses were aware of studies quantifying such differences, except to a limited extent with 27 Ex. Z, AD DORZ -TIM EIKE001234-35 at 1235. Ex. AA, AD TRAVATAN EIKE040560 at 40577. 29 Ex. BB, ARGN_2865-2882 at 2867. 30 Ex. R, ARGN_LUM03_0005995-6026 at 6024 31 Ex. H, BHLB BRIM 0001076-1134 at 1076. 32 Ex. I, Jonasse Dep. 72:8 -12 (Mar. 11, 2014) (emphasis added). 33 Ex. CC, Arenson Dep. 83:20-84:11 (March 14, 2014),. 34 Ex. F, Kriegler Rept. ¶ 32. 35 Ex. F, Kriegler Rept. ¶ 32. 36 Ex. DD, NDA_Merck_Prasco 00000328-353 at 349; Ex. X, Walker Dep. (Feb. 18, 2014) 51:3-51:15, 56:18-57:19 Ex. EE, NDA_Merck_Prasco 00009193, 9227 (excerpts from labels showing “controlled drop tip”). 28 13 Case 3:12-cv-01141-SMY-DGW Document 176 *SEALED* Filed 12/01/14 Page 26 of 60 Case: 16-3334 Document:Page 55-1 ID #2126 Filed: 02/08/2017 Pages: 60 (26 of 1511) bottle angle. (Kriegler Rept. ¶¶ 33-45.) With respect to angle, a few tests compared drop sizes when the bottle was held at 45° (considered by two companies to be the “normal” angle) and at 90° and found the angle made little difference. In fact, as Dr. Kriegler stated: “One Allergan study was expressly designed to show that the angle had no impact, and Allergan's 30(b)(6) witness agreed that it showed that the drop sizes at two angles were not statistically different.” Id. ¶ 44 (footnotes omitted). In answering Defendants’ questions regarding drop-size variability during his deposition, Dr. Kriegler relied on Dr. Robin’s testimony that variability due to interpersonal factors was minimal, and he stated that “in fact, looking at the data that I’ve reviewed, it conforms with that.” 37 With all that as background, Dr. Kriegler performed statistical analyses of Defendants’ drop-size data. As a B&L company witness testified, “[u]niformity doesn’t mean that every drop has to be exactly the same number of microliters.” 38 Thus, company drop size results are often reported with an average and a standard deviation. Id., ¶ 47. Dr. Kriegler found that those studies “show a small amount of variability in drop size relative to the average drop size.” Id., ¶ 46. He also found that drop sizes were uniformly so large “that it is virtually impossible for a consumer to use a bottle that dispensed an average drop size of 16 µL or less, for any individual bottle.” In fact, the chance that an average drop out of any bottle was smaller than 16 µL was well below one in a trillion. Id., ¶ 48.d. Accordingly, “all or virtually all class members paid for a portion of the eye drops that was wasted in every bottle that they purchased.” Id., ¶ 46. Then, he used his analysis of the drop-size studies to determine the feasibility of calculating class-wide and individual damages. Id. ¶¶ 49-55. He specifically looked to plaintiffs’ claim in the Complaint, ¶¶ 141, 151, to recover the “allocated purchase price for the 37 38 Ex. FF, Kriegler Dep. 181:2-17 (Aug. 20, 2014). Ex. I, Jonasse Dep. 77:2-6 (Mar. 11, 2014). 14 Case 3:12-cv-01141-SMY-DGW Document 176 *SEALED* Filed 12/01/14 Page 27 of 60 Case: 16-3334 Document:Page 55-1 ID #2127 Filed: 02/08/2017 Pages: 60 (27 of 1511) portion of their eye drops in excess of 15 µL,” which he modified to include a “floor” of 16 µL instead of 15 µL in light of Dr. Robin’s opinion. He stated that, to determine classwide damages, one would calculate, from Defendants’ drop-size studies, the cost incurred by the class for wasted medication using either the mean (numerical average) drop size, median drop size or, to be extra conservative since it would provide the smallest amount of loss, minimum average drop size. One would then calculate the percentage of the mean, median, or minimum average drop in excess of 16 µL and multiply that times the amount paid at retail by the class. For example, using Allergan’s five studies on Lumigan 0.01%, which found an average drop size of 23.6, 23.7, 23.9, 24.1 and 25.4 µL, one would calculate the arithmetic mean (24.1 µL), median (23.9 µL) and smallest average (23.6 µL). Depending on which of those numbers the fact finder decided to use, the amount wasted for the class would be 33.6%, 33.1% or 32.2%. Kriegler Rept. ¶ 52. To determine class-wide damages, one would then multiply that percentage times the total retail sales of the drug in the state during the class period. Sales data is available from various services. Id. ¶ 55. B. Defendants’ Experts In response, Defendants named five experts. Of these, four (Janet Arrowsmith, Jimmy Bartlett, Michael Belin and David Lin) addressed Dr. Robin’s opinion, and one (Steven Wiggins) opposed Dr. Kriegler. 39 Two experts, Drs. Bartlett and Belin, disagreed that drops should or could be reduced to 15 or 16 µL. 40 They offered various purported reasons for their opinions, while not even acknowledging, much less attempting to explain away, the statement by Allergan quoted at the 39 The reports are attached hereto as Ex. GG (Arrowsmith), HH (Bartlett), II (Belin), JJ (Lin), and KK (Wiggins). Drs. Bartlett and Belin also offer opinions regarding differences between glaucoma drugs and other classes of ocular medications, such as steroids and allergy drugs, that might affect whether small drops would be effective or feasible. Bartlett Rept. ¶¶ 30-32, Belin Rept. ¶¶ 13, 54. These opinions are irrelevant since, as noted above, Drs. Robin and Kriegler limited their opinions to Defendants’ glaucoma drugs, and non-glaucoma drugs are not part of Plaintiffs’ proposed class definitions. 40 15 Case 3:12-cv-01141-SMY-DGW Document 176 *SEALED* Filed 12/01/14 Page 28 of 60 Case: 16-3334 Document:Page 55-1 ID #2128 Filed: 02/08/2017 Pages: 60 (28 of 1511) outset of this brief, the Pfizer “7 µL” document quoted above, the statement by Alcon’s marketers as to the real reason why it kept drops so large (which had nothing to do with feasibility or benefit to patients), or any of the statements in the literature advocating small drops. For purposes of this motion, however, none of those reasons matter. As Plaintiffs demonstrate below, Defendants’ own expert opinions support class certification in that they present pure common questions of law or fact applicable to the entire class, not individual questions. Specifically, they did not opine that drops should be 16 µL for some but not all class members, but instead stated that drops should not or could not be 16 µL for anybody. 41 Drs. Arrowsmith, Lin and, to a lesser extent, Belin opined that Defendants could not change drop sizes without first obtaining the prior approval of the FDA. These opinions relate to Defendants’ affirmative defenses of FDA preemption. As with the opinions of Drs. Bartlett and Belin claiming that a 16 µL drop size is inadvisable or infeasible, they present a common question of law or fact, as we show below. 42 Dr. Wiggins, an economist, reviewed Plaintiffs’ damage claim and attempted to refute Dr. Kriegler’s methodology. 43 He criticized Dr. Kriegler for ignoring patient variability and patient errors in instilling eye drops, as well as the economics of drug pricing. (Ex. KK, Wiggins Rept. ¶ 8.) He also opined – presumably as an economist, his expertise – that drop size variability could lead some patients to instill drops “that were inadequate for effective dosing.” 41 The only one of these two experts who addressed patient variability was Dr. Belin, but he did not mention the company documents showing that drop-size measurements simulate patient use and that their dispensers provide consistent and uniform drops. Because of this failure to consider relevant evidence, his opinion would be inadmissible at trial, but Plaintiffs accept it for purposes of this motion because at this point the court is merely deciding class certification, including whether there are common questions, but not resolving those questions. 42 Although it is premature to resolve the issue at this point, the opinions are particularly unpersuasive. Dr. Lin, for example stated that he has reviewed “numerous” FDA submissions by Defendants and “[a]ll contained information on the container closure systems,” but only “some” contained drop volume data. Lin Rept. ¶ 24. This case` would not be preempted if the FDA did not mandate specific drop sizes for prescription eye drops across the board. But how the FDA could have mandated specific drop volumes without being provided the data, he does not explain. 43 Ex. KK, Wiggins Rept. ¶ 6. 16 Case 3:12-cv-01141-SMY-DGW Document 176 *SEALED* Filed 12/01/14 Page 29 of 60 Case: 16-3334 Document:Page 55-1 ID #2129 Filed: 02/08/2017 Pages: 60 (29 of 1511) Id., ¶ 15. Once again, as we show below, his opinions, even if they were accepted, 44 present only common questions. For example, his opinion on drug pricing was that, if the companies made their drops smaller, they would adjust their prices. That obviously applies to the price paid by everyone, not merely a few class members, and therefore presents a common question. The same is true for his opinion that drops should not be 16 µL on average because they would inadequately treat those who obtain drops smaller than average (even assuming he is qualified to offer that opinion). 45 Id. V. LEGAL STANDARD “Class action lawsuits are an important and valuable part of the legal system when they permit the fair and efficient resolution of legitimate claims of numerous parties by allowing the claims to be aggregated into a single action against a defendant that has allegedly caused harm.” Class Action Fairness Act of 2005, Pub. L. No. 109–2, 119 Stat 4 (2005); see Mississippi ex rel. Hood v. AU Optronics Corp., 134 S. Ct. 736, 739 (2014) (“Congress recognized that ‘[c]lass action lawsuits are an important and valuable part of the legal system.’ ” (quoting the above statute). “[E]nforcement against tortious ‘harms of enormous aggregate magnitude but so widely distributed as not to be remediable in individual suits’” is “Rule 23(b)(3)’s purpose.” Suchanek 44 At trial, Dr. Wiggins’ opinions would be inadmissible on several grounds. His opinion on the amount of medication needed for adequate treatment is outside his expertise (economics). Moreover, unlike Dr. Kriegler, who relied on Dr. Robin’s opinions on the necessary amount of medication, Dr. Wiggins did not even include the reports of Defendants’ medical experts (Dr. Belin, an ophthalmologist, and Dr. Bartlett, an optometrist) in his materials reviewed, much less rely on their medical opinions. His criticism of Dr. Kriegler’s conclusions regarding patient variability was improperly reached without consideration of the evidence on which Dr. Kriegler relied – or if he did consider it, without explaining why he discounted it. In addition, although this might not be an issue at trial, where evidence will relate to merits, not class certification, his opinion on pricing is contrary to Judge Wilkerson’s decision overruling Plaintiffs’ request for documents related to pricing as irrelevant at this stage of the case, Order, Aug. 21, 2013, ¶ 3, Doc. 118, as well as a blatant violation of Defendants’ agreement not to offer evidence on pricing in exchange for Plaintiffs’ withdrawal of discovery pertaining to pricing. See Ex. LL-OO (offering to withdraw deposition topics if Defendants agree not to introduce evidence on pricing; see last paragraph), and Ex. PP-SS responses from Defendants acknowledging that the paragraphs are accordingly withdrawn. 45 Two months following the deadline for naming experts and three weeks before this motion was due, Alcon purported to designate an additional expert, its employee Lisa Blackwell, to testify on the commercial feasibility of the dropper used in the Vocci study. Because of the late designation, which Alcon made without seeking leave or an amendment to the scheduling order, Plaintiffs contemporaneously move to strike her designation. In any event, like Drs. Bartlett and Belin, if allowed she would present only a common question on feasibility. 17 Case 3:12-cv-01141-SMY-DGW Document 176 *SEALED* Filed 12/01/14 Page 30 of 60 Case: 16-3334 Document:Page 55-1 ID #2130 Filed: 02/08/2017 Pages: 60 (30 of 1511) v. Sturm Foods, Inc., 764 F.3d 750, 760 (7th Cir. 2014) (quoting Butler v. Sears, Roebuck & Co., 727 F.3d 796, 801 (7th Cir. 2013), cert. denied, 134 S. Ct. 1277 (2014)). Thus, Fed. R. Civ. P. 23 provides that plaintiffs may sue as representative of a class if they meet all four elements of Rule 23(a) (numerosity, commonality, typicality and adequacy of representation) and the requirements of one part of Rule 23(b). Here, Plaintiffs seek certification under Rule 23(b)(3), which requires “that the questions of law or fact common to class members predominate over any questions affecting only individual members, and that a class action is superior to other available methods for fairly and efficiently adjudicating the controversy.” The rule further provides that in determining whether superiority is met, the court is to consider four factors, (A) class members’ interests in individually controlling prosecution of the action, (B) the extent and nature of any litigation concerning the controversy already begun by class members, (C) the desirability or undesirability of concentrating the claims in the forum, and (D) likely difficulties in managing the class action. Id. “A district court has broad discretion to determine whether certification of a class action lawsuit is appropriate.” Olson v. Brown, 594 F.3d 577, 584 (7th Cir. 2010); see also Suchanek 764 F.3d at 755. But the issues are limited to whether Rule 23’s requirements are met. Although “a court may take a peek at the merits before certifying a class, … this peek [is] limited to those aspects of the merits that affect the decisions essential under Rule 23.” Schleicher v. Wendt, 618 F.3d 679, 685 (7th Cir. 2010) (citing Szabo v. Bridgeport Machines, Inc., 249 F.3d 672 (7th Cir.2001)). “In conducting this analysis, the court should not turn the class certification proceedings into a dress rehearsal for the trial on the merits.” Messner v. Northshore Univ. HealthSystem, 669 F.3d 802, 811 (7th Cir. 2012). “The chance, even the certainty, that a class will lose on the merits does not prevent its certification.” Schleicher 618 F.3d at 687. Thus, the court is not to weigh the opinions of Plaintiffs’ experts against Defendants’ experts on the merits 18 Case 3:12-cv-01141-SMY-DGW Document 176 *SEALED* Filed 12/01/14 Page 31 of 60 Case: 16-3334 Document:Page 55-1 ID #2131 Filed: 02/08/2017 Pages: 60 (31 of 1511) of the case, but merely to determine whether they do or do not indicate that the elements of Rule 23 are met. As the Supreme Court recently stated, “the office of a Rule 23(b)(3) certification ruling is not to adjudicate the case; rather, it is to select the “‘metho[d]’ best suited to adjudication of the controversy ‘fairly and efficiently.’” Amgen Inc. v. Connecticut Ret. Plans & Trust Funds, 133 S. Ct. 1184, 1191, (2013) (citations omitted). VI. PLAINTIFFS SATISFY THE REQUIRMENTS OF RULE 23(A) A. Plaintiffs Satisfy the Numerosity Requirement Because Defendants Have Agreed Not To Contest It Rule 23(a) requires that a class be “so numerous that joinder of all members is impracticable.” In light of the prevalence of glaucoma, (Compl. ¶ 11), the class is undoubtedly numerous. Thus, defendants have agreed not to contest numerosity (as well as superiority and issues related to pricing). After Defendants objected to topics in Plaintiffs’ Rule 30(b)(6) deposition notices as unrelated to class certification, Plaintiffs offered to withdraw those topics “unless Defendants intend to contest numerosity or superiority or intend to argue against class certification on some basis related to pricing. In that event, these topics would be permissible.” 46 In response, Defendants agreed to Plaintiffs’ proposal. For example, counsel for Merck and Prasco responded: “Merck and Prasco acknowledge that Plaintiffs have withdrawn Paragraphs … 48-53 as outlined in your letter.” 47 Accordingly, numerosity is not an issue. B. There are Common Issues of Law and Fact Rule 23(a)(2) requires that there be “questions of law or fact common to the class.” “The critical point is “‘the need for conduct common to members of the class.’” Suchanek, 764 F.3d at 756 (quoting In Re IKO Roofing Shingle Products Liability Litigation, 757 F.3d 599, 602 (2014) (emphasis added by Suchanek). “‘What matters to class certification ... [is] the capacity 46 47 Ex. LL, MM, NN and OO (see last paragraph of each letter). Ex. PP, QQ, RR and SS. See also Ex. LL, MM, NN and OO. 19 Case 3:12-cv-01141-SMY-DGW Document 176 *SEALED* Filed 12/01/14 Page 32 of 60 Case: 16-3334 Document:Page 55-1 ID #2132 Filed: 02/08/2017 Pages: 60 (32 of 1511) of a classwide proceeding to generate common answers apt to drive the resolution of the litigation.’” Id. (quoting Wal-Mart Stores, Inc. v. Dukes, 131 S. Ct. 2541, 2551 (2011)). “A common nucleus of operative fact is usually enough to satisfy the commonality requirement of Rule 23(a)(2).” Rosario v. Livaditis, 963 F.2d 1013, 1018 (7th Cir.1992) (citing Franklin v. City of Chicago, 102 F.R.D. 944, 949–50 (N.D.Ill.1984)); accord, Keele v. Wexler, 149 F.3d 589, 594 (7th Cir. 1998) (“Common nuclei of fact are typically manifest where …the defendants have engaged in standardized conduct towards members of the proposed class.”) Nor need every issue be common. The Supreme Court has held that “for purposes of Rule 23(a)(2) even a single common question will do.” Wal-Mart 131 S. Ct. at 2556. And, the Seventh Circuit observed, “[i]t is routine in class actions to have a final phase in which individualized proof must be submitted.” Suchanek, 764 F.3d at 756. In Suchanek, the court distinguished the Supreme Court’s decision in Wal-Mart from Seventh Circuit decisions finding commonality. The court stated, “Where the defendant’s allegedly injurious conduct differ[ed] from plaintiff to plaintiff, as it did among Wal-Mart’s 2,000 stores, no common answers are likely to be found. That is why the Court there held that plaintiffs could not proceed with a class action without a showing that Wal–Mart had adopted a company-wide discriminatory policy.” Id. at 756. On the other hand, the court cited the following Seventh Circuit cases where “the same conduct or practice by the same defendant gives rise to the same kind of claims from all class members ...” (764 F.3d at 756): Pella Corp. v. Saltzman, 606 F.3d 391, 394 (7th Cir. 2010) (common questions whether product sold to all class members was inherently defective, whether defendant knew of this defect, and whether the product warranty covered the defect); Mejdrech v. Met–Coil Sys. Corp., 319 F.3d 910, 911 (7th Cir. 2003) (common questions whether defendant unlawfully leaked dangerous chemicals and whether the chemicals contaminated the contiguous area underlying class members' homes); IKO Roofing (common question whether roofing shingles sold to all class members complied with national industry standard as represented on packaging); Butler v. Sears, Roebuck & Co., 727 F.3d 796, 20 Case 3:12-cv-01141-SMY-DGW Document 176 *SEALED* Filed 12/01/14 Page 33 of 60 Case: 16-3334 Document:Page 55-1 ID #2133 Filed: 02/08/2017 Pages: 60 (33 of 1511) 798 (7th Cir. 2013) (common question whether products sold to class members contained certain defects, “although damages [were] likely to vary across class members”). Suchanek, 764 F.3d at 756. Similarly, in Suchanek the plaintiffs made one claim of liability: misleading consumers into believing that its single-serving “GSC” coffee pods contained ground rather than instant coffee. Id. at 753. The court found that “the question whether the GSC packaging was likely to deceive a reasonable consumer is common. The claims of every class member will rise or fall on the resolution of that question.” Id. at 757. That is true in the present case as well. Plaintiffs make one claim of liability, that dispensers that emit drops larger than 16 µL lead to wastage of medicine that has no therapeutic effect. The entire litigation will rise or fall on whether that claim is accurate. Although there are many questions subsumed within it (see Compl. ¶ 116, listing various questions of law or fact common to the classes), that is the claim in the same kind of nutshell that the Seventh Circuit listed in the parentheticals quoted above. In fact, in this sense the claim is similar to the one in IKO Roofing, where the court found that common issues existed because it was “a suit alleging a defect common to all instances of a consumer product ….” In re IKO Roofing, 757 F.3d at 602. There it was a defect leading to wood rot. Here the design leads to wastage of product. For these reasons, the element of commonality is present. C. The Claims of the Representative Plaintiffs Are Typical of Those of the Class The third 23(a) requirement is typicality, which is “closely related to the … question of commonality,” Rosario, 963 F.2d at 1018, with the “focus on whether the named representatives' claims have the same essential characteristics as the claims of the class at large.” Mezyk v. U.S. Bank Pension Plan, 2011 WL 601653, at *6 (S.D. Ill. Feb. 11, 2011) (Gilbert, J.). The Seventh Circuit has held that “[a] plaintiff's claim is typical if it arises from the same event or practice or course of conduct that gives rise to the claims of other class members and his or her claims are 21 Case 3:12-cv-01141-SMY-DGW Document 176 *SEALED* Filed 12/01/14 Page 34 of 60 Case: 16-3334 Document:Page 55-1 ID #2134 Filed: 02/08/2017 Pages: 60 (34 of 1511) based on the same legal theory.” De La Fuente v. Stokely–Van Camp, Inc., 713 F.2d 225, 232 (7th Cir. 1983) (quoting H. Newberg, Class Actions § 1115(b) at 185 (1977)). Factual distinctions will not preclude this element from being met so long as the class representatives’ claims “have the same essential characteristics as the claims of the class at large.” Id.; accord, Retired Chicago Police Ass'n v. City of Chicago, 7 F.3d 584, 597 (7th Cir. 1993). Here that is unquestionably the case. As listed below, each plaintiff used prescription eye-drop products manufactured by Defendants that dispensed drops larger than 16 µL and therefore caused them to purchase product that went to waste:” 48 Plaintiff Charlene Eike (Illinois) Shirley Fisher (Illinois Jordan Pitler (Missouri) Alan Raymond (Missouri) Defendant (Product) Allergan (Lumigan, Combigan, Alphagan P); Alcon (Azopt) Alcon (Timolol GFS [Gel]), Dorzolamide/Timolol); B&L (Brimonidine Tartrate; Merck/Prasco (Dorzololamide Timolol) Allergan (Alphagan P); Alcon (Azopt, Travatan, Dorzolamide, Latanoprost), B&L (Latanoprost) Allergan (Lumigan); Alcon (Latanoprost, Timolol Maleate); Pfizer (Xalatan) Their claims are therefore typical of other putative class members who used Defendants’ glaucoma drugs. True, some class members would certainly have used glaucoma drugs that the named Plaintiffs did not. For example, some class members would have used Alcon’s Travatan Z, not its Travatan as Mr. Pitler did. But the essential characteristics of the claims are the same, the excess average size of the two drugs (25.5 µL for Travatan and 28.8 µL for Travatan Z according to Alcon’s testing 49) and the inherent wastage of significant portions, as well as Alcon’s intent to keep the drop sizes too large in order to sell more product. Indeed, none of the literature cited in the Complaint, nor Drs. Robin’s or Kriegler’s expert reports, suggest either that 48 Ex. TT, Eike Dep. 19:20-22 ,99:22-25; Ex. UU, Fisher Dep., 37:20-38:9, 125:19;130:17; Ex. VV, Pitler Dep. 19:25-20:3, 23:7-25:3, 26:21-27:12, 25:2-3, 63:3-8, 67:15-24, Ex. WW, Raymond Dep. 18:10-19:4, 30:25-33:11, 32:6-33:3, 34:3-34:17. Plaintiffs’ pharmacy records showing these drugs are attached as Ex. XX, YY, ZZ and AAA. See also Kriegler Rept. for evidence that the drops were larger than 16 µL on average. 49 Ex. F, Kriegler Rept. at Ex. D-1. 22 Case 3:12-cv-01141-SMY-DGW Document 176 *SEALED* Filed 12/01/14 Page 35 of 60 Case: 16-3334 Document:Page 55-1 ID #2135 Filed: 02/08/2017 Pages: 60 (35 of 1511) the average drop sizes of some glaucoma drugs are not significantly larger than 16 µL or that some portion of those drops does not go to waste. This is not the first time that the court will be called upon to decide whether similar products that the named plaintiffs did not use are properly in this case. Defendants argued in support of their motions to dismiss that Plaintiffs lacked standing to make claims about products they did not use. Judge Herndon rejected that argument (Eike, 2014 WL 1040728 at *4): Furthermore, plaintiffs' claims are premised on their seeking to represent classes of consumers who bought and used similar products from these companies. They need not have used every prescription eye drop manufactured by every defendant. The issue of substantial similarity is one for class certification review, not an issue that the Court will take up on a motion to dismiss. The issue is now ripe, and there is sufficient similarity in claims involving all of the Defendants’ glaucoma eye drops to include users of them all in the Classes. In other cases where the essential characteristics of the claim were the same, courts have likewise found that typicality is present among different products. Elias v. Ungar's Food Products, Inc., 252 F.R.D. 233, 243 (D.N.J. 2008) (“the fact that the named plaintiffs did not purchase some of the products at issue does not render plaintiffs' claims atypical from the potential class members nor does it defeat commonality”); In re Pharm. Indus. Average Wholesale Price Litig., 233 F.R.D. 229, 230 (D. Mass. 2006) (“The representative of a Subclass need only have paid for one of the Subject Drugs manufactured or marketed by a defendant group.”). See also Fallick v. Nationwide Mut. Ins. Co., 162 F.3d 410, 422 (6th Cir. 1998) (“[A]n individual in one ERISA benefit plan can represent a class of participants in numerous plans other than his own, if the gravamen of the plaintiff's challenge is to the general practices which affect all of the plans.”); Hoxworth v. Blinder, 23 Case 3:12-cv-01141-SMY-DGW Document 176 *SEALED* Filed 12/01/14 Page 36 of 60 Case: 16-3334 Document:Page 55-1 ID #2136 Filed: 02/08/2017 Pages: 60 (36 of 1511) Robinson & Co., Inc., 980 F.2d 912, 923 (3d Cir. 1992) (class certified with representatives for 15 of 21 class securities). 50 D. The Representative Plaintiffs Will Fairly and Adequately Protect the Interests of the Class Under Fed. R. Civ. P. 23(a)(4), the “adequacy of representation” requirement has two factors: “(a) the plaintiff's attorney must be qualified, experienced, and generally able to conduct the proposed litigation, and (b) the plaintiff must not have interests antagonistic to those of the class.” Susman v. Lincoln American Corp., 561 F.2d 86, 90 (7th Cir. 1977) (quoting Wetzel v. Liberty Mut. Ins. Co., 508 F.2d 239, 247 (3rd Cir. 1975)). Both are present here. 1. The class counsel will adequately represent the class. Plaintiffs do not anticipate a dispute regarding whether their attorneys are sufficiently qualified. See Ex. BBB , firm resumes for The Simon Law Firm, P.C. (“Simon”), and The Law Offices of Richard Cornfeld. U.S. News has repeatedly ranked Simon as one of the “Best Law Firms” in multiple areas. The firm was appointed co-lead counsel in an MDL class action, In Re: Emerson Electric Co. Wet/Dry Vac Marketing and Sales Practices Litigation, 4:12-md-02382HEA (E.D. Mo.), has argued several class actions before the Missouri Supreme Court, including Huch v. Charter Communications, Inc., 290 S.W.3d 721 (Mo. 2009), deemed “Best Appellate Win of the Year” in Missouri, and has won notable appeals of class-action cases as lead counsel: Brunner v. City of Arnold, 427 S.W.3d 201 (Mo. App. E.D. 2013) (red light camera ordinance declared unconstitutional); Damon v. City of Kansas City, 419 S.W.3d 162 (Mo. App. W.D. 2013) (red light camera ordinance declared void); Edwards v. City of Ellisville, 426 S.W.3d 644 (Mo. App. E.D. 2013) (same); Brewer v. Missouri Title Loans, 364 S.W.3d 486 (Mo. 2012) 50 Typicality is absent where the facts regarding other products are distinct from those bought by the plaintiffs. See Wiener v. Dannon Co., 255 F.R.D. 658, 666 (C.D. Cal. 2009) (“different health benefit claims”); Lewis Tree Serv., Inc. v. Lucent Technologies Inc., 211 F.R.D. 228, 234 (S.D.N.Y. 2002) (among other differences, “representations and negotiations made by the defendants were highly individualized and differed from case to case”). 24 Case 3:12-cv-01141-SMY-DGW Document 176 *SEALED* Filed 12/01/14 Page 37 of 60 Case: 16-3334 Document:Page 55-1 ID #2137 Filed: 02/08/2017 Pages: 60 (37 of 1511) (arbitration clause held unconscionable). Mr. Cornfeld started his firm two years ago after a 30year career in mass-tort litigation at Thompson Coburn LLP and is one of only three plaintiffs’ lawyers in St. Louis named by Best Lawyers in Mass Tort Litigation/Class Actions. 2. The named plaintiffs will adequately represent the class. In reversing the denial of class certification on adequacy-of-representation grounds, the Seventh Circuit advised district courts not to be “unrealistic about the role of the class representative in a class action suit. The role is nominal.” Phillips v. Asset Acceptance, LLC, 736 F.3d 1076, 1080 (7th Cir. 2013). Class representatives receive “modest compensation … for what usually are minimal services in the class action suit, …which is in fact entirely managed by class counsel. Id. Still, there are factors a court should look at. “A class is not fairly and adequately represented if class members have antagonistic or conflicting claims.” Rosario v. Livaditis, 963 F.2d 1013, 1018 (7th Cir. 1992) (citing Secretary of Labor v. Fitzsimmons, 805 F.2d 682, 697 (7th Cir. 1986)). The representatives must “possess the same interest and suffer the same injury as the class members.” Uhl v. Thoroughbred Tech. & Telecomms., Inc., 309 F.3d 978, 985 (7th Cir. 2002) (quoting East Tex. Motor Freight System, Inc. v. Rodriguez, 431 U.S. 395, 403 (1977)). This requirement “tend[s] to merge” with the commonality and typicality criteria of Rule 23(a).” Amchem Prods, Inc. v. Windsor, 521 U.S. 591, 626 n. 20 (1997) (quoting General Telephone Co. v. Falcon, 457 U.S. 147, 157, n. 13 (1982)). Here, Plaintiffs meet this requirement for the same reason they satisfy the commonality and typicality requirements. See Secs. VI.A and B, above. Each one purchased the challenged eye drop bottles from two or more of the defendants and suffered the same injury and now seek the same remedy as the putative class members. 25 Case 3:12-cv-01141-SMY-DGW Document 176 *SEALED* Filed 12/01/14 Page 38 of 60 Case: 16-3334 Document:Page 55-1 ID #2138 Filed: 02/08/2017 Pages: 60 (38 of 1511) Nor does any Plaintiff possess close personal, business, or familial relationships with class counsel, a factor that sometimes disqualifies a putative class representative. Eubank v. Pella Corp., 753 F.3d 718, 728 (7th Cir. 2014) (father-in-law of financially troubled counsel); Susman v. Lincoln Am. Corp., 561 F.2d 86, 95 (7th Cir. 1977) (law partner or brother of counsel); In re Yasmin & Yaz (Drospirenone) Mktg., Sales Practices & Products Liab. Litig., 2012 WL 865041, at *5 (S.D. Ill. Mar. 13, 2012) (“good friend” and becoming better friends with attorney’s wife); Mowry v. JP Morgan Chase Bank, N.A., 2007 WL 1772142, at *3-4 (N.D. Ill. Jun. 19, 2007) (“long-time friend” and former roommate of counsel). None of the Plaintiffs has such a relationship with these attorneys. Neither Charlene Eike nor Shirley Fisher knew the attorneys beforehand, and the extent of their interaction with them has been solely in relation to the case. (Eike Dep. 52:24-53:2; 77:11-15, Mar. 7, 2014; Fisher Dep. 95:17-97:21, 201:11-16.) Since they have no personal relationship with class counsel, these Plaintiffs have no incentive to benefit anyone other than themselves and the class, lack any antagonistic or conflicting interests to those of the class, and make adequate representatives. Plaintiffs Pitler and Raymond knew Mr. Cornfeld prior to this litigation, but neither possesses a close relationship with him that would render him an inadequate representative. All three attend the same 1200-family synagogue in St. Louis (Pitler Dep. 76:15-20, Feb. 10, 2014; Raymond Dep. 48:6-11, Feb. 27, 2014), but both testified that they are not “social friends.” (Pitler Dep. 76:21-22; Raymond Dep. 50:25-51:9, 52:2-3.) Messrs. Pitler and Cornfeld have seen each other outside of the synagogue only three times: twice for synagogue-related events and a third when Mr. Pitler paid a condolence visit to Mr. Cornfeld. (Pitler Dep. 77:6-11.) Mr. Raymond has interacted socially with Mr. Cornfeld outside the synagogue only while attending a convention in Washington, D.C., in 2009. (Raymond Dep. 47:22-51:15.) These are not the 26 Case 3:12-cv-01141-SMY-DGW Document 176 *SEALED* Filed 12/01/14 Page 39 of 60 Case: 16-3334 Document:Page 55-1 ID #2139 Filed: 02/08/2017 Pages: 60 (39 of 1511) kinds of relationships that have led courts to disqualify class representatives. They thus satisfy the F.R.C.P. 23(a)(4) requirement that the class representatives adequately represent the class. VII. PLAINTIFFS SATISFY THE REQUIREMENTS OF RULE 23(B)(3) The two requirements for a 23(b)(3) class, predominance and superiority, are clearly present here, whether considered with or without the four factors set forth in the rule. A. Questions of Law and Fact Common to Class Members Predominate Over Any Questions Affecting Only Individual Members The requirements to establish predominance in this Circuit are well-established. In fact, in recent years, the Seventh Circuit has had a number of occasions to consider this element of class certification. In chronological order: • Thorogood v. Sears, Roebuck & Co., 547 F.3d 742, 746-48 (7th Cir. 2008) (predominance lacking because of “absence of any reason to believe that there is a single understanding of the significance of labeling or advertising clothes dryers as containing a ‘stainless steel drum’” when portion was made of porcelain; court found “no common issues of law or fact ….”) (emphasis in original). • Pella, 606 F.3d at 393 (affirmed class certification where plaintiff claimed defendant’s windows “suffer from a single, inherent design defect leading to wood rot”; individual issue of proximate causation and damages “does not necessarily preclude class certification”; rejected argument “that consumer fraud cases as a general matter are not amenable to class treatment, due to problems with causation, reliance, and calculating damages”) . • Schleicher, 618 F.3d at 683, 685, 686 (class certification affirmed over argument that individual issues such as loss and damages predominated; court rejected argument that “before a class can be certified plaintiffs must prove everything (except falsity) required to win on the merits”; “Rule 23 allows certification of classes that are fated to lose as well as classes that are sure to win.”). • Howland v. First Am. Title Ins. Co., 672 F.3d 525 (7th Cir. 2012) (attorneys allegedly received kickbacks, rather than fees for legitimate legal services; court affirmed denial of class certification because of need to perform case-by-case determination of fees and services to determine liability; district court had made no Rule 23(a) findings, including on existence of common issues). • Messner, 669 F.3d at 818-19 (reversed denial of class certification of claim by hospital patients that a merger between two hospitals had increased prices; nominal price increases, the alleged antitrust impact of merger, did not need to be 27 Case 3:12-cv-01141-SMY-DGW Document 176 *SEALED* Filed 12/01/14 Page 40 of 60 Case: 16-3334 Document:Page 55-1 ID #2140 Filed: 02/08/2017 Pages: 60 (40 of 1511) uniform for predominance; impact merely needed to be “capable of proof at trial through evidence that is common to the class rather than individual to its members.” 51 Nor did it matter if some class members were unharmed because that was “a fact generally irrelevant to the district court's decision on class certification.” Id. at 823.). • Butler, 727 F.3d at 796, 801-802 (plaintiffs alleged defects in washing machines causing mold and shut-down; predominance met despite defendant’s argument that various design modifications had diminished the problems to different degrees on different machines, creating individual issues regarding damages; court also endorsed “class action[s] limited to determining liability on a classwide basis,” with separate hearings to determine individual damages). 52 • Parko v. Shell Oil Co., 739 F.3d 1083, 1087 (7th Cir. 2014) (finding of predominance reversed for reconsideration in suit alleging groundwater contamination from leaks occurring for 95 years from plant with multiple successive owners in light of individual issues, such as source of benzene and identity of polluter; “if the defendants are right there is no common issue, only individual issues that will vary from homeowner to homeowner.”). • IKO Roofing¸ 757 F.3d at 602, 603 (denial of certification reversed where plaintiffs alleged misrepresentation that roofing shingles met industry standards; “[c]ommonality of damages” not “legally indispensible”; “confining any class certification to questions of liability” might be appropriate on remand). • Suchanek, 764 F.3d at 394 (denial of class certification reversed where plaintiffs alleged defendant misrepresented coffee pod as containing ground coffee rather than instant; individual issue of proximate cause did not prevent certification because “need for individual proof alone does not necessarily preclude class certification” (quoting Pella, 606 F.3d at 394)). Thus, nine times in the last six years the Seventh Circuit visited predominance. Six times it either found certification proper or reversed the denial of certification, while three times the court found predominance not established (or perhaps not yet in Parko, which was remanded for reconsideration), but in none of those three cases was it even clear that there was a common issue, only numerous individual ones. In Thorogood, for example, the court found that “there are 51 Quoting In re Hydrogen Peroxide Antitrust Litig., 552 F.3d 305, 311-12 (3d Cir. 2008) (emphasis in original). The Sixth Circuit reached the same result in In re Whirlpool Corp. Front-Loading Washer Products Liab. Litig., 722 F.3d 838 (6th Cir. 2013), cert. denied sub nom. Whirlpool Corp. v. Glazer, 134 S. Ct. 1277 (2014). 52 28 Case 3:12-cv-01141-SMY-DGW Document 176 *SEALED* Filed 12/01/14 Page 41 of 60 Case: 16-3334 Document:Page 55-1 ID #2141 Filed: 02/08/2017 Pages: 60 (41 of 1511) no common issues of law or fact, so there would be no economies from class action treatment.” 547 F.3d at 747 (emphasis in original). But where there are common issues regarding liability, class certification is appropriate despite individual issues of causation and damages. Pella, 606 F.3d at 393. As the court stated in Butler, “[i]t would drive a stake through the heart of the class action device … to require that every member of the class have identical damages.” 727 F.3d at 801. “The critical point is ‘the need for conduct common to members of the class.” Suchanek, 764 F.3d at 756 (citing IKO Roofing, at 602). Thus, “[i]f the issues of liability are genuinely common issues, and the damages of individual class members can be readily determined in individual hearings, in settlement negotiations, or by creation of subclasses, the fact that damages are not identical across all class members should not preclude class certification.” Butler, 727 F.3d at 801. Nor does it matter, at this point, who is likely, or even certain, to prevail on the common issues. Suchanek, 764 F.3d at 758; Schleicher, 618 F.3d at 686. Similarly, it does not matter at this point if the class includes individuals who were not injured. “Such a possibility or indeed inevitability does not preclude class certification.” Messner, 669 F.3d at 823 (quoting Kohen v. Pacific Inv. Management Co., 571 F.3d 672, 677 (7th Cir. 2009)). As noted above, “[i]n conducting this analysis, the court should not turn the class certification proceedings into a dress rehearsal for the trial on the merits.” Messner, 669 F.3d at 811. In the next two subsections we show that the issues regarding liability are common and that the possible individual issues are the sort that in the Seventh Circuit do not preclude certification. Indeed, they fit the Seventh Circuit’s observation in Suchanek: “The importance of the class action device in vindicating the rights of consumers is one reason why the Supreme Court held that “[p]redominance is a test readily met in certain cases alleging consumer ... fraud,” among others. 764 F.3d at 760 (quoting Amchem, 521 U.S. at 615). 29 Case 3:12-cv-01141-SMY-DGW Document 176 *SEALED* Filed 12/01/14 Page 42 of 60 Case: 16-3334 Document:Page 55-1 ID #2142 Filed: 02/08/2017 Pages: 60 (42 of 1511) 1. Common questions Plaintiffs’ claims can be summarized as encompassing the following questions: 1. Appropriate eye drop size: Should eye drops be 16 µL on average to avoid product wastage? In other words, are drop sizes of 16 µL as effective and as safe as existing drop sizes? 2. Actual drop size: Are existing average drop sizes larger than 16 µL? 3. Wastage of medicine: Do existing eye drops lead to wastage as a result? 4. Feasability of small drops: Would it have been feasible for defendants to have supplied drops of 16 µL? Plaintiffs allege that the answer to each of these questions is yes. As shown above, these allegations are supported by scientific literature, defendants’ documents and the expert opinions of Drs. Robin and Kriegler. Defendants dispute Plaintiffs’ answers to the above questions and have offered expert testimony to support their positions. Far from creating individual issues, those disputes apply to class members across the board: 1. Appropriate eye drop size. Plaintiffs contend that the average drop size should be no larger than 16 µL for all class members. As described above, according to Dr. Robin and the scientific literature on which he relies, including the paper by Allergan’s scientists, larger drops are no more effective than smaller ones and equally safe. Defendants offered expert testimony to the contrary, but this is inherently a common issue for the entire class. If it applied only to some class members – in other words, if drops should be larger than 16 µL for some, but not all, users – the entire case would fall apart. That would mean that drops would have to be larger than 16 µL for all because Plaintiffs are not contending that Defendants should have sold their products in two versions with different drop sizes, and neither are Defendants. Indeed, when Defendants’ experts opined that small drops are ill-advised for a subset of patients, they gave that as a reason why sizes should not be reduced across the board. For example, Dr. Belin 30 Case 3:12-cv-01141-SMY-DGW Document 176 *SEALED* Filed 12/01/14 Page 43 of 60 Case: 16-3334 Document:Page 55-1 ID #2143 Filed: 02/08/2017 Pages: 60 (43 of 1511) opined that patients instill eye drops differently, many with great difficulty, including missing their eyes, resulting in differing drop sizes and differing amounts that make it to the eye. (Ex. II, Belin Rept. ¶ 17.) But he did not go from that premise to the conclusion that there are individual issues – something that would contradict Dr. Robin’s opinion that, notwithstanding these difficulties and differences (which result in minimally different drop sizes), all patients would benefit from smaller drops. To the contrary, Dr. Belin concluded that this was why all drops should stay large. In the concluding sentence of this paragraph, he stated: “Companies must design a product that is safe and efficacious for all patients, notwithstanding the complicating variations in the patient population and their usage abilities.” Id. Similarly, Dr. Bartlett stated that many patients use more than one eye-drop medication, leading to the possibility that the second drop can “wash out” the first and, “[i]f an eyedrop were only 15 or 16 µL, this would be of a significant concern from an efficacy standpoint.” (Bartlett Rept. ¶53.) But again this was a reason why he opined that no drops should be 16 µL. He was not saying that companies should offer a large drop for users of multiple medications and a smaller one for “solo” users, which might allow for recovery of damages by “solo” users, but not others. 2. Actual drop size. The size of eye drops is inherently a common issue. As described above, Dr. Kriegler calculated average drop sizes from Defendants’ testing, supported by Defendants’ documents stating that the tests are designed to simulate or mimic patient use and that their dispensers emit consistent and uniform sizes. In opposition, Defendants’ experts opined that the sizes shown in those tests do not reflect drop sizes when the products are used by consumers (while ignoring those documents). This is not an individual issue because it is impossible to measure the precise size of a drop once it has landed on an individual patient’s eye, much less measure all the drops a class member instilled during the class period. Defendants’ laboratory tests, designed to determine the size of drops in use, are as good as it gets. In fact, in 31 Case 3:12-cv-01141-SMY-DGW Document 176 *SEALED* Filed 12/01/14 Page 44 of 60 Case: 16-3334 Document:Page 55-1 ID #2144 Filed: 02/08/2017 Pages: 60 (44 of 1511) any individual lawsuit making the claims herein, the plaintiff would use these same test results to show the average drop size. 3. Wastage of medicine. Dr. Kriegler did statistical calculations that showed that it is exceedingly unlikely (less than one-in-a-trillion) that any single bottle of eye drops would emit average drops of 16 µL or less and therefore would not result in wastage. The possibility that some class members may not have been injured – even if the chance is more than one in a trillion – does not preclude certification so long as the class does not “contain[] a great many persons who have suffered no injury at the hands of the defendant ….” Kohen, 571 F.3d at 677. One in a trillion is not a “great many” by any estimation. 4. Feasibility of small drops. Plaintiffs’ evidence that drops of 16 µL were feasible comes from the scientific literature, from what Dr. Robin states that Alcon told him, and from a product catalog that shows a dropper tip capable of emitting drops 58% smaller than the tip that one defendant used. Again, Defendants’ experts disagree and opine that it would not be feasible to reduce drop sizes to 16 µL. And again this is a merits issue for the class as a whole that Plaintiffs will have to prove to prevail at trial. Whether small drops are feasible does not vary from class member to class member. Defendants’ Preemption Defense. Defendants offer no fewer than three experts, Drs. Arrowsmith, Belin and Lin, to support their affirmative defense of federal preemption. They all state that Defendants could not have reduced drop sizes without prior approval of the FDA. Like the issues discussed above, that presents only a common question: Could Defendants have complied with their alleged state-law obligations by reducing drop size without violating their obligations to the FDA? If Defendants sustain their “demanding” burden on this issue, 53 they win. But they win across the board against all class members, not just some, because if federal 53 Wyeth v. Levine, 555 U.S. 555, 573 (2009) (“Impossibility pre-emption is a demanding defense.”) 32 Case 3:12-cv-01141-SMY-DGW Document 176 *SEALED* Filed 12/01/14 Page 45 of 60 Case: 16-3334 Document:Page 55-1 ID #2145 Filed: 02/08/2017 Pages: 60 (45 of 1511) law bars them from reducing drop size, it does not do so with respect to some class members and not others – and Defendants do not claim otherwise. Each of these is a common question, an issue on which Plaintiffs have to prevail to win the case, “central to the validity of each one of the claims,” Butler, 727 F.3d at 801 (quoting WalMart, 131 S. Ct. at 2551), and “apt to drive the resolution of the litigation.” Suchanek, 764 F.3d at 756 (quoting Wal-Mart, 131 S. Ct. at 2551). As in Suchanek, “[t]he claims of every class member will rise or fall on [their] resolution ….” Suchanek, 764 F.3d at 757. Thus, for the same reasons that the Seventh Circuit found in that case, class certification is proper here. In short, if these defense experts are correct (and Defendants’ legal position on preemption is correct), all class members lose on the merits. Defendants’ presentation of these merits opinions is such a clear indication of predominance of common issues over individual ones that the court may wonder whether Defendants even intend to contest predominance and, if so, why they offered these expert opinions on common issues at this time? Moreover, the Supreme Court and the Seventh Circuit are clear that now is not the time to decide these factual issues. At this point, it matters not who will finally prevail (though we cannot resist pointing out that much of what the experts said in the privacy of this lawsuit contradicts what Allergan said publicly to the scientific community, as quoted at the outset of this brief). “Rule 23(b)(3) requires a showing that questions common to the class predominate, not that those questions will be answered, on the merits, in favor of the class.” Amgen, 133 S. Ct. at 1191(emphasis in original); see also Schleicher, 618 F.3d at 686. (“even the certainty[] that a class will lose on the merits does not prevent its certification.”) Id. at 687. Thus, Defendants should, as the court stated in Butler, welcome certification. In Butler, the defendant argued that most class members had not experienced a mold problem. If so, the court stated, “that was an argument not for refusing to certify the class but for certifying it and then entering a 33 Case 3:12-cv-01141-SMY-DGW Document 176 *SEALED* Filed 12/01/14 Page 46 of 60 Case: 16-3334 Document:Page 55-1 ID #2146 Filed: 02/08/2017 Pages: 60 (46 of 1511) judgment that would largely exonerate Sears—a course it should welcome, as all class members who did not opt out of the class action would be bound by the judgment.” 727 F.3d at 799. 2. Individual questions: proximate cause and damages Defendants’ experts who counter Dr. Robin have offered one opinion that presents an individual issue. That is Dr. Bartlett’s opinion purporting to support a proximate-cause defense. In addition, Dr. Wiggins takes issue with Dr. Kriegler’s proposed damages model. Neither of these opinions precludes certification, regardless of the individual issues they may present. a. Proximate cause In support of their motion to dismiss, Defendants argued that the decisions by doctors to prescribe prescription eye drops rather than alternative therapies is an intervening cause that breaks the causal chain and defeats the case on proximate-cause grounds. Defendants have framed this as an individual issue; Dr. Bartlett stated that it “would require knowledge of the patient’s medical condition and history” to determine whether alternative treatments were available. However, as noted above, individual issues of causation or proximate cause do not preclude certification. Suchanek, 764 F.3d at 759; Pella, 606 F.3d at 394. In the latter case, in which the plaintiffs alleged that a product defect caused window frames to rot and the defendants countered that there were many other causes of window rot, the court stated in affirming certification of the class: “[P]roximate cause is an individual issue and will not be addressed by the class jury …. Issues of causation and damages issues, such as whether that defect caused the damage to a particular window and how much the design contributed to the rot, will be handled individually.” Id. Similarly, here, any proximate-cause defense will be in individual proceedings after a finding in the class trial on the common issues in Plaintiffs’ favor. But whether Defendants have a viable proximate-cause defense is questionable at best. Judge Herndon rejected Defendants’ proximate-cause argument in denying their motion to 34 Case 3:12-cv-01141-SMY-DGW Document 176 *SEALED* Filed 12/01/14 Page 47 of 60 Case: 16-3334 Document:Page 55-1 ID #2147 Filed: 02/08/2017 Pages: 60 (47 of 1511) dismiss because, to break the causal chain, an intervening cause, such as a doctor’s decision to prescribe a defendant’s drug, must be unforeseeable. Judge Herndon stated: “It is not unforeseeable that a physician would be responsible for prescribing the prescription eye drops to plaintiffs.” Eike, 2014 WL 1040728, at *3. Nothing in what Defendants have presented thus far shows that they could not foresee that physicians would prescribe their medications. Until they offer such evidence – which seems unlikely; why else did they sell these drugs? – there will not even be an individual issue to try after the class trial. b. Damages The other issue that will vary among class members is the amount of damages. However, this does not preclude class certification for two reasons. First, damages are typically individualized in consumer cases, but individual damage questions do not outweigh common issues. In finding a class appropriate in “a case involving a defect that may have imposed costs on tens of thousands of consumers, yet not a cost to any one of them large enough to justify the expense of an individual suit,” the court stated in Butler: “A determination of liability could be followed by individual hearings to determine the damages sustained by each class member.” 727 F.3d at 798. That is the case here. Put simply, “common proof of damages … is not required.” Id. at 801. “If the issues of liability are genuinely common issues, and the damages of individual class members can be readily determined in individual hearings, in settlement negotiations, or by creation of subclasses, the fact that damages are not identical across all class members should not preclude class certification.” Id. Second, Dr. Kriegler presented a method to determine damages for the class as a whole. His method is based on a simple formula that can also be applied to any class member. First, one estimates the actual drop size (mean, median or minimum average) from the company drop size tests for a particular drug and subtracts 16 µL, the appropriate average size according to Dr. 35 Case 3:12-cv-01141-SMY-DGW Document 176 *SEALED* Filed 12/01/14 Page 48 of 60 Case: 16-3334 Document:Page 55-1 ID #2148 Filed: 02/08/2017 Pages: 60 (48 of 1511) Robin. The difference is the amount wasted, and that amount as a percentage of the actual size is the percentage wasted. Multiplying the percentage times the retail sales in the state during the class period for that drug gives the aggregate damages. For each class member, multiplying that percentage times the retail amount paid for that class member’s medication gives the individual’s damages. The formula is simple and easy to apply. The only issue at this point is whether to use the mean, median or minimum average drop size from company tests in the calculations. That would be for the factfinder to decide. Similarly, in Suchanek the plaintiffs’ damages expert presented two potential models. 764 F.3d at 760 (court refers to plaintiffs’ experts “two potential damages models”). Nor does it matter that Dr. Kriegler’s method takes an average, when the actual drop sizes encompass a range around that average and individual drop sizes may have fallen outside the average but within the range. In Thorogood, the Seventh Circuit observed that any difficulty in “determining the relief to which the individual class members are entitled” is not a “deal breaker.” 547 F.3d at 748. To the contrary, “a settlement that provided each [class member] with an amount equal to an estimate of the average damages they had sustained would be a sensible and legally permissible alternative to remitting all the buyers to individual suits each of which would cost orders of magnitude more to litigate than the claims would be worth to the plaintiffs.” Id. (emphasis added); accord, Ormond v. Anthem, Inc., 2009 WL 3163117, at *7 (S.D. Ind. Sept. 29, 2009). As support, Thorogood cites 3 Herbert B. Newberg & Alba Conte, Newberg on Class Actions § 10.3, p. 480 (4th ed. 2002) (“Aggregate class proof of monetary relief may ... be based on sampling techniques or other reasonable estimates, under accepted rules of evidence”), as well as appellate decisions that upheld damage awards that could only be estimated because precise measurements were unavailable. Stewart v. General Motors Corp., 36 Case 3:12-cv-01141-SMY-DGW Document 176 *SEALED* Filed 12/01/14 Page 49 of 60 Case: 16-3334 Document:Page 55-1 ID #2149 Filed: 02/08/2017 Pages: 60 (49 of 1511) 542 F.2d 445, 452–53 (7th Cir. 1976); United States v. City of Miami, 195 F.3d 1292, 1299–1300 (11th Cir. 1999); Pettway v. American Cast Iron Pipe Co., 494 F.2d 211, 259–63 (5th Cir. 1974). The current edition of Newberg on Class Actions likewise indicates that an approximating method of determining damages is acceptable. Its section on “Methods of proving individual damages” states: Plaintiffs may proffer an expert who offers a formula that she derived from the facts of the case that can be applied generally to all class members in order to approximate the aggregate amount of damages the defendant must pay. This approach is well-established and tends to be workable except, perhaps, in cases involving more intangible harms, such as discrimination injuries. W.B. Rubenstein, 4 Newberg on Class Actions, § 12.5 (5th ed. database updated September 2014) (emphasis added; footnote omitted) (“Newberg”). That is what Dr. Kriegler has done. Nevertheless, Dr. Wiggins takes exception to Dr. Kriegler’s model on the purported grounds that Dr. Kriegler ignored patient variability and errors in instilling eye drops, as well as the economics of drug pricing, and that the average drop size Dr. Kriegler used could lead some patients to obtain an inadequate dose. But as with the four experts named to counter Dr. Robin, his criticisms all raise common questions. What is required at the class-certification stage is that Dr. Kriegler’s model be “consistent with [Plaintiffs’] liability case,” under the standard set by the Supreme Court in Comcast Corp. v. Behrend, 133 S. Ct. 1426, 1433 (2013). See Butler, 727 F.3d at 799 (“Comcast holds that a damages suit cannot be certified to proceed as a class action unless the damages sought are the result of the class-wide injury that the suit alleges.”). Dr. Kriegler’s model does that. He calculates the average amount of medication that was inherently wasted because the eye drop was larger than needed to treat the disease and applies that to the money spent on the drug. But – despite Dr. Robin’s opinion, on which Dr. Kriegler relied, that an average drop of 16 µL would provide an adequate amount of medication for glaucoma patients, and despite the 37 Case 3:12-cv-01141-SMY-DGW Document 176 *SEALED* Filed 12/01/14 Page 50 of 60 Case: 16-3334 Document:Page 55-1 ID #2150 Filed: 02/08/2017 Pages: 60 (50 of 1511) Pfizer document, which Dr. Wiggins does not mention, that the human eye can absorb only 7 µL – Economist Wiggins believes that a 16 µL average size would mean that patients who obtained drops on the lower-than-average side would be “commonly receiving inadequate doses.” (Wiggins Rept. ¶ 15; see also id., ¶¶21-29.) Even assuming that the court would allow an economist to express an opinion about the amount of medication needed to treat eye disease (unless the economist relied on medical testimony, which Dr. Wiggins did not do), this opinion relates only to a common question. If Dr. Wiggins is correct (and Dr. Robin and Pfizer, who really do know about treatment of eye disease, are wrong), the plaintiffs will all lose the case because of the inability to prove their basic claim that drops should be an average of 16 µL. Nor does Dr. Wiggins present an individual issue with his opinion that Dr. Kriegler failed to account for price increases that would occur if drop sizes were reduced because of the companies’ need to recover existing and increased costs. If Dr. Kriegler’s model is flawed for the failure to account for possible price adjustments, that affects the claim of every class member equally because Dr. Kriegler did not include pricing in his model for anyone. 54 At this point that hardly matters. As the Seventh Circuit stated in Suchanek in reversing the district court, “If the court thought that no class can be certified until proof exists that every member has been harmed, it was wrong.” 764 F.3d at 757. The court quoted Parko’s statement, “How many (if any) of the class members have a valid claim is the issue to be determined after the class is certified.” Id. at 757 (quoting Parko, 739 F.3d at 1085 (first emphasis added, second emphasis in original). Indeed, Dr. Wiggins’ opinion on pricing stands in stark contrast to Defendants’ objection, as irrelevant to class certification, to Plaintiffs’ requests for discovery on costs and pricing, as well 54 Moreover, Dr. Wiggins’ criticism misses the point. Plaintiffs seek a refund of what they were unfairly compelled to pay for wasted medicine in the real world, not hypothetical damages based on a “would-be” world where Defendants might have changed their prices. In any event, even if Dr. Wiggins’ argument would be proper at the merits stage, it simply relates to the amount of damages since, as the Allergan article states, “a smaller drop size would … provid[e] cost savings to patients and managed care providers.” Robin Rept. ¶ 23. It is the amount that might be impacted by a price adjustment. 38 Case 3:12-cv-01141-SMY-DGW Document 176 *SEALED* Filed 12/01/14 Page 51 of 60 Case: 16-3334 Document:Page 55-1 ID #2151 Filed: 02/08/2017 Pages: 60 (51 of 1511) as Judge Wilkerson’s statement in sustaining that objection, that, “[a]t this stage of the litigation,” pricing is “irrelevant.” (Order, 8/21/13, Doc. 118, ¶ 3. It was irrelevant then, and it is irrelevant now, but it may become relevant in the merits stage. Similarly, Dr. Wiggins’ arguments that Dr. Kriegler failed to adequately account for patient variability are either common points or related to damages. Presumably, Dr. Wiggins would offer the same opinion if any eye-drop user brought an individual lawsuit and sought damages based on company tests. In the merits phase of this case, he can explain why, again as an economist, he believes that Dr. Robin is wrong that the variation in drop size caused by patient variability is “minimal.” He can also explain why Plaintiffs should not use these tests in their damages calculations even though the companies state that they are conducted to simulate patient use and even though defendants use the test results to tell patients how long they can expect their eye drop bottles to last. At this point, his opinion does not create an individual issue. Nor does Dr. Wiggins’ complaint that Dr. Kriegler overlooked other causes of waste, such as missed drops or even “spills” and “tip occlusion” (Wiggins’ Rept. ¶¶ 31-32), matter for class certification. Whether any class member’s damages should be reduced because they lost a bottle of medicine to a spill or occluded tip is the same type of issue that the defendant unsuccessfully argued should preclude certification in Pella (“Pella argues that too many individual variances between class members exist, because wood … is affected by specific conditions such as improper installation.”). 606 F.3d at 394. Certification was proper there – deferring individual damages determination to a later phase, where the defendant could present its defense of “improper window installation” – as it is here if Defendants wish to present a defense of “improper eye-drop instillation.” As for patients who miss their eyes with the dropper and need to instill a second or even third drop, Dr. Wiggins overlooks the simple fact that, as Dr. Robins stated, patients would be better off missing their eyes with smaller drops. 39 Case 3:12-cv-01141-SMY-DGW Document 176 *SEALED* Filed 12/01/14 Page 52 of 60 Case: 16-3334 Document:Page 55-1 ID #2152 Filed: 02/08/2017 Pages: 60 (52 of 1511) Finally, if Defendants’ argument is that the uncertainty of drop sizes when patients use eye drops precludes any award of damages because damages cannot be calculated – it is not clear at this point if that will be their argument – that again applies to the class as a whole and is a common, not individual issue. In short, common questions predominate over individual ones. B. A Class Action Is Superior to Other Available Methods for Fairly and Efficiently Adjudicating the Controversy Rule 23(b)(3)’s other requirement is “superiority” – that a class action be “superior to other available methods for fairly and efficiently adjudicating the controversy.” As noted above, Defendants agreed not to contest superiority in exchange for Plaintiffs’ withdrawal of topics from their notices of depositions of Defendants’ corporate designees pursuant to Rule 30(b)(6). See Sec. VI.B, above, and exhibits cited therein. Even if they had not done so, there would be no problem finding this element present. With regard to this requirement, Newburg states: “A primary purpose of class action lawsuits, particularly money damages claims aggregated under Rule 23(b)(3), is to enable the litigation of claims that are worth too little money to be pursued individually.” Newberg § 4:65 at 252-253. This is an observation the Seventh Circuit has commonly made in discussing the certification requirements of Rule 23(b)(3). In Carnegie v. Household Int'l., Inc., 376 F.3d 656, 661 (7th Cir. 2004), the court stated, “[T]he more claimants there are, the more likely a class action is to yield substantial economies in litigation. It would hardly be an improvement to have in lieu of this single class 17 million suits each seeking damages of $15 to $30.” The court went on to state, in language that has been widely quoted: “The realistic alternative to a class action is not 17 million individual suits, but zero individual suits, as only a lunatic or a fanatic sues for $30.” Id. 40 Case 3:12-cv-01141-SMY-DGW Document 176 *SEALED* Filed 12/01/14 Page 53 of 60 Case: 16-3334 Document:Page 55-1 ID #2153 Filed: 02/08/2017 Pages: 60 (53 of 1511) (emphasis in original). 55 And why don’t courts jump at the chance to end up with “zero … suits,” individual or common? “[A] class action has to be unwieldy indeed before it can be pronounced an inferior alternative – no matter how massive the fraud or other wrongdoing that will go unpunished if class treatment is denied – to no litigation at all.” Id.; see also Suchanek, 764 F.3d at 760 (“The district court might conclude on remand that the class device is superior, because no rational individual plaintiff would be willing to bear the costs of this lawsuit.”). In ruling that the class should be certified in Butler, the court applied this principle to a case with larger individual claims than the $15-$30 involved in Carnegie: “The present case is less extreme: tens of thousands of class members, each seeking damages of a few hundred dollars. But few members of such a class, considering the costs and distraction of litigation, would think so meager a prospect made suing worthwhile.” Butler, 727 F.3d at 801. In the present case, some class members may have claims amounting to a few thousand dollars. The claims of others, especially those who take inexpensive generic drugs, will be small. But each claim would be dwarfed by the time and expense of bringing an individual case involving these scientific issues. In this case alone, Defendants have named five experts to address merits issues. Taking the deposition of even one of them for one seven-hour day, considering their hourly rates (Dr. Wiggins: $800), would likely exceed a plaintiff’s damages. C. The Four Factors Used to Evaluate Superiority Weigh in Favor of Class Certification Rule 23(b)(3) lists four factors, enumerated above, to consider in deciding certification. The rule itself is unclear on whether the factors relate both to predominance and superiority, but the Manual on Complex Litigation states that they “are factors that might affect superiority.” 55 This statement has been quoted, in whole or in part, in the following class-certification decisions within this Circuit: Suchanek, 764 F.3d at 760; Butler, 727 F. 3d at 801; Smith v. Greystone Alliance LLC, 2011 WL 307457, at *2 (N.D. Ill. Jan. 25, 2011); Beringer v. Standard Parking Corp., 2008 WL 4390626, at *6 (N.D. Ill. Sept. 24, 2008); Boundas v. Abercrombie & Fitch Stores, Inc., 280 F.R.D. 408, 417 (N.D. Ill. 2012). 41 Case 3:12-cv-01141-SMY-DGW Document 176 *SEALED* Filed 12/01/14 Page 54 of 60 Case: 16-3334 Document:Page 55-1 ID #2154 Filed: 02/08/2017 Pages: 60 (54 of 1511) Manual for Complex Litig., Fourth, § 22.921 at 587 n.1478 (2014). Thus, Newberg notes that “most courts analyze the Rule 23(b)(3)(A) to (D) factors solely in determining whether a class suit will be a superior method of litigation.” Newberg § 4:68. Since, as stated above, Defendants agreed not to contest superiority in exchange for Plaintiffs’ withdrawal of deposition topics, none of the factors requires much discussion, but in any event each supports certification. 1. The class members’ interest in individually controlling the prosecution of separate actions If class members are interested in individually controlling their own case, that weighs against certification. Newberg cites “two reasons why individuals may have little interest in pursuing litigation themselves: first, their claims may be so closely related to the claims of others that litigation by others will achieve their ends without the need for their involvement; second, their claims may be so small that it would be a waste of their time and/or resources to litigate individually.” Newberg § 4:69 (emphasis in original). Both aspects are present here. On this point, Newberg quotes Matter of Rhone-Poulenc Rorer, Inc., 51 F.3d 1293, 1300 (7th Cir. 1995), which recognized that submitting an issue to multiple juries “would not be a feasible option if the stakes to each class member were too slight to repay the cost of suit, even though the aggregate stakes were very large and would repay the costs of a consolidated proceeding.” 2. The extent and nature of litigation concerning the controversy already begun by class members The second factor points toward certification because there is no other suit by class members raising this controversy, except for one partially overlapping class suing one defendant in a case filed nearly two years after this one. 56 As Newberg states, “[t]he presence of a few 56 As noted above, two lawsuits are pending in other districts involving similar claims on behalf of other classes. Cottrell (Florida, California, Illinois, New Jersey, North Carolina and Texas) and Gustavsen (all other states). Except for one Illinois plaintiff in Gustavsen, those plaintiffs all seek to represent eye-drop users in other states. The Illinois plaintiff seeks to represent Illinois Pfizer users, not involved in this case, and Alcon users, who are involved in this case. Cottrell, Doc. 1. This case was on file for nearly two years, when Cottrell was filed. 42 Case 3:12-cv-01141-SMY-DGW Document 176 *SEALED* Filed 12/01/14 Page 55 of 60 Case: 16-3334 Document:Page 55-1 ID #2155 Filed: 02/08/2017 Pages: 60 (55 of 1511) other suits does not undercut that conclusion as the filing of but a few cases indicates that a minute percentage of the class has an interest in individual litigation.” Newberg § 4:70. 3. The desirability or undesirability of concentrating the litigation of the claims in the particular forum According to Newberg, the third factor asks “whether consolidation makes sense in that district.” Newberg § 4:71 (emphasis in original). Newberg states that “[c]ourts have found that class actions in a particular forum are particularly appropriate when that court has already made several preliminary rulings[] [and] when a particular forum is more geographically convenient for the parties ….” Both factors are present here. Half the classes consist of Illinois residents and the other are Missouri classes (with plaintiffs residing in the St. Louis area). This court has also already denied Plaintiffs’ motions to dismiss. Thus, this district “makes sense” and, in any event, is not “undesirab[le].” 4. Likely difficulties in managing a class action As a Circuit Judge, Justice Sotomayor wrote, “failure to certify an action under Rule 23(b)(3) on the sole ground that it would be unmanageable is disfavored and ‘should be the exception rather than the rule.’” In re Visa Check/MasterMoney Antitrust Litig., 280 F.3d 124, 140 (2d Cir. 2001) (quoting In re S. Cent. States Bakery Prods. Antitrust Litig., 86 F.R.D. 407, 423 (M.D. La.1980)). Thus, “courts deny class certification on manageability grounds relatively infrequently ….” Newberg, § 4:72. One of the reasons for that is that this factor is “part of the superiority inquiry.” Id. As noted above, Defendants here have agreed not to contest superiority. But even if they had not done so, this element would weigh toward certification. “[T]he question that courts consider when they analyze manageability is not whether a class action is manageable in the abstract but how the problems might occur in managing litigation without a class suit.” Id. “Manageability concerns must be weighed against the alternatives and 43 Case 3:12-cv-01141-SMY-DGW Document 176 *SEALED* Filed 12/01/14 Page 56 of 60 Case: 16-3334 Document:Page 55-1 ID #2156 Filed: 02/08/2017 Pages: 60 (56 of 1511) ‘will rarely, if ever, be in itself sufficient to prevent certification of a class.’” Campbell v. PricewaterhouseCoopers, LLP, 253 F.R.D. 586, 605 (E.D. Cal. 2008) (quoting Klay v. Humana, Inc., 382 F.3d 1241, 1272 (11th Cir. 2004)). Here, the alternative would be trying thousands of individual eye-drop claims. But even if a class trial were simply likened to one trial of these Plaintiffs’ individual claims, a class action would not have manageability problems by comparison. In both alternatives, two state statutes would be involved, but they are similar in that both incorporate Section 5(a) of the FTC Act, 15 U.S.C. § 45(a) (prohibiting “unfair … acts or practices in or affecting commerce”) and interpretive decisions of the Federal Trade Commission. 815 ILCS § 505/2; Mo. Code Regs. tit. 15, § 60–8.020. Plaintiffs in both states allege that Defendants’ practices violated the FTC’s Policy Statement on Unfairness. See Eike, 2014 WL 1040728 at *3. Moreover, the Missouri claims would be decided by a jury, while the court is the factfinder of the Illinois claims, Martin v. Heinold Commodities, Inc., 643 N.E.2d 734, 755 (Ill. 1994), limiting the potential for jury confusion. And again that would be true in either a class or individual trial. Defendants attempt to complicate things by presenting Dr. Bartlett’s opinions regarding differences among five classes of eye-drop medication ( Ex. HH, Bartlett Rept. ¶¶ 30-32, 37), but only one of them, glaucoma drugs, is encompassed by the classes. The others are used for other diseases and are irrelevant. Dr. Bartlett also describes differences among five classes of glaucoma (IOP) drugs (Id. at 10-12, ¶¶ 33-36), but they would hardly present management difficulties in a class action compared to individual cases since his entire discussion of these differences takes up only two pages and four paragraphs in his 30-page, 77-paragraph report. Moreover, based on what is in his report, drugs in four of these classes were taken by the named Plaintiffs and would therefore be at issue in a trial of only their claims, as well as in a class trial. (See Appendix, showing the drugs taken by Plaintiffs that fall within these classes.) He does not 44 Case 3:12-cv-01141-SMY-DGW Document 176 *SEALED* Filed 12/01/14 Page 57 of 60 Case: 16-3334 Document:Page 55-1 ID #2157 Filed: 02/08/2017 Pages: 60 (57 of 1511) identify any specific drugs in the fifth class, cholinergic agonists, and it is unclear that any of them are even mentioned in the Complaint, much less used by any of the Plaintiffs. (Id.) Nor does the need for separate damages determinations present unsolvable management problems. “Rule 23 allows district courts to devise imaginative solutions to problems created by the presence in a class action litigation of individual damages issues.” Carnegie, 376 F.3d at 661. Among these are bifurcating liability and damages, appointing a special master or magistrate judge to oversee individual damages proceedings, and decertifying the class after the liability trial and providing notice to class members on how to proceed to prove damages. Id. Thus, this case is hardly the exception that would preclude certification for lack of manageability. Compare In re Bridgestone/Firestone, Inc., 288 F.3d 1012, 1018-19 (7th Cir. 2002) (unmanageable in light of consumers’ uses of tires at issue on different vehicles, different instructions, and 67 tire specifications with different safety features, as well as other features that determine if a given safety feature is needed for safe operation of a particular tire), with Muehlbauer v. Gen. Motors Corp., 431 F. Supp. 2d 847, 870-72 (N.D. Ill. 2006) (distinguishing Bridgestone/Firestone and finding class case manageable). Moreover, as the Seventh Circuit has repeatedly observed, the alternative to a class trial is not thousands of trials, but zero trials. “[A] class action has to be unwieldy indeed before it can be pronounced an inferior alternative—no matter how massive the fraud or other wrongdoing that will go unpunished if class treatment is denied—to no litigation at all.” Suchanek, 764 F.3d at 760 (quoting Butler, 727 F.3d at 798). VIII. CONCLUSION For the foregoing reasons, Plaintiffs respectfully ask that their Motion for Class Certification be granted. 45 Case 3:12-cv-01141-SMY-DGW Document 176 *SEALED* Filed 12/01/14 Page 58 of 60 Case: 16-3334 Document:Page 55-1 ID #2158 Filed: 02/08/2017 Pages: 60 (58 of 1511) Dated: December 1, 2014 Respectfully submitted, LAW OFFICE OF RICHARD S. CORNFELD By: /s/ Richard S. Cornfeld Richard S. Cornfeld 1010 Market Street, Suite 1720 St. Louis, MO 63101 (314) 241-5799 (314) 241-5788 (fax) rcornfeld@cornfeldlegal.com and THE SIMON LAW FIRM, P.C. By: /s/ John G. Simon (with consent) John G. Simon Ryan A. Keane 800 Market Street, Suite 1700 St. Louis, MO 63101 (314) 241-2929 (314) 241-2029 (fax) jsimon@simonlawpc.com rkeane@simonlawpc.com Attorneys for Plaintiffs 46 Case 3:12-cv-01141-SMY-DGW Document 176 *SEALED* Filed 12/01/14 Page 59 of 60 Case: 16-3334 Document:Page 55-1 ID #2159 Filed: 02/08/2017 Pages: 60 (59 of 1511) CERTIFICATE OF SERVICE The undersigned hereby certifies that a copy of the foregoing was electronically filed with the Court with service upon all counsel of record via the Court’s CM/ECF system on this 1st day of December, 2014. /s/ Richard S. Cornfeld 47 Case 3:12-cv-01141-SMY-DGW Document 176 *SEALED* Filed 12/01/14 Page 60 of 60 Case: 16-3334 Document:Page 55-1 ID #2160 Filed: 02/08/2017 Pages: 60 (60 of 1511) APPENDIX Drugs Within Glaucoma Classes Identified By Dr. Bartlett and Plaintiffs Who Used Them Glaucoma Drug Class 1 Drug Identified by Dr. Bartlett 2 Beta Blockers Timolol 3 Alpha-Adrenergic Agonists Brimonidine (Alphagan P) 4 Dorzolamide 5 Carbonic Anhydrase Inhibitors Brinzolomide (Azopt) 6 Latanoprost (Xalatan) 7 Prostaglandin Analogs Lumigan 8 Travoprost 9 Cholinergic Agonists Unidentified in Report 10 1 Plaintiff Shirley Fisher, Alan Raymond Charlene Eike, Jordan Pitler Jordan Pitler Charlene Eike, Jordan Pitler Alan Raymond Charlene Eike, Alan Raymond Jordan Pitler --- Dr. Bartlett identifies these as classes of IOP (intra-ocular pressure) or glaucoma drugs. Bartlett Report, ¶ 33. Brand Name in Parentheses 3 Bartlett Report, ¶ 36. 4 Bartlett Report, ¶¶ 71, 72 fn.5. 5 Bartlett Report, ¶ 35. 6 Bartlett Report, ¶¶ 35, 37. 7 Bartlett Report, ¶ 33. 8 Bartlett Report, ¶ 73. 9 Bartlett Report, ¶ 75. 10 It is unclear that any cholinergic agonists are still on the market or, if so, are sold in significant numbers. According to the American Academy of Ophthalmologists, “[t]he use of cholinergic agents has declined in recent years with the availability of newer medications that have comparable efficacy and fewer side effects.” http://eyewiki.aao.org/Medical_Management_for_Primary_Open_Angle_Glaucoma. 2 A-1 Case 3:12-cv-01141-SMY-DGW Document 176-1 *SEALED* Filed 12/01/14 Page 1 of 7 Page ID #2161 Case: 16-3334 Document: 55-2 Filed: 02/08/2017 Pages: 7 (61 of 1511) JOURNAL OF OCULAR PHARMACOLOGY AND THERAPEUTICS Volume 22, Number 6, 2006 © Mary Ann Liebert, Inc. Efficiency of Instillation Methods for Prostaglandin Medications RICHARD FISCELLA,1,2 JACOB T. WILENSKY,l TINA H CHIANG,3 and JOHN G. WALT3 ABSTRACT Purpose: The aim of this study was to determine the most efficient methods for instillation of prostaglandin analogs. Methods: Drops were dispensed at room temperature from 2.5-mL bottles of bimatoprost, travoprost, and latanoprost. Two determinations of drop count were each made from bottles held vertically, at a 45-degree angle, and horizontally. The total volumes of medication dispensed from each bottle were measured. Results: The mean number of drops dispensed was 111.0, 105.1, and 76.1 drops for bimatoprost bottles; 81.4, 101.1, and 85.3 drops for travoprost bottles; and 94.3, 88.4, and 67.1 drops for latanoprost bottles, held vertically, at 45 degrees, and horizontally, respectively. The mean volume of medication dispensed per 2.5-mL bottle was 3.17 mL for bimatoprost, 2.54 mL for travoprost, and 3.02 mL for latanoprost. The most efficient instillation methods provided 56 days of bilateral therapy per 2.5-mL bottle for bimatoprost, 51 days for travoprost, and 47 days for latanoprost, with corresponding yearly medication costs of $408 for bimatoprost, $449 for travoprost, and $475 for latanoprost. Yearly savings of $109 to $192 could be achieved by using the most efficient instillation methods, representing 5.6 months of medication saved for patients using bimatoprost, 3.0 months for patients using travoprost, and 4.9 months for patients using latanoprost. Conclusions: Health care providers are urged to instruct glaucoma patients in the most efficient method of instillation. For bimatoprost and latanoprost, vertical instillation is recommended, with 45 degrees nearly as efficient, and for travoprost, instillation at 45 degrees is recommended. INTRODUCTION irreversible ocuG lar disease that affects the optic nerve, causing loss of visual field and contrast sensitivity. LAUCOMA IS A PROGRESSIVE, Therapeutic intervention with intraocular pressure (IOP)-lowering medication slows the progression of the disease and helps glaucoma pa- tients to retain visual function. l -4 Topically administered prostaglandin analogs, comprising bimatoprost, travoprost, and latanoprost, are the most effective and widely prescribed treatments for glaucoma and ocular hypertension.5--7 They have the added advantage of once-daily administration, which helps to improve patients' adherence to their therapeutic regimen.8-10 lDepartments of Ophthalmology and 2Pharmacy Practice, University of Chicago, Chicago, IL. Inc., Irvine, CA. Research for this work was funded by Allergan, Inc. (Irvine, CA). 3 Allergan 477 PL-000385 Case 3:12-cv-01141-SMY-DGW Document 176-1 *SEALED* Filed 12/01/14 Page 2 of 7 Page ID #2162 Case: 16-3334 Document: 55-2 Filed: 02/08/2017 Pages: 7 (62 of 1511) 478 FlSCELLA ET AL. The cost-consciousness of managed care METHODS providers and of individuals who pay for most or all of their own prescriptions has prompted Procedures mimicking normal instillation were studies analyzing costs and cost-effectiveness of employed to determine the number of drops disthe prostaglandin analog class of lOP-lowering pensed from 2.5-mL bottles of the once-daily medications.1 1- 13 One area that has not yet been lOP-lowering glaucoma medications, bimatoinvestigated is whether patients instill once-daily prost (Lumigan®; Allergan Inc., Irvine, CA), lOP-lowering drugs in the most efficient manner travoprost (Travatan®; Alcon Laboratories, Inc., possible. Instillation of a smaller-size drop would Ft. Worth, TX), and latanoprost (Xalatan®; Pfizer be desirable because the volume of individual Inc., New York, NY). Drops were dispensed drops dispensed by most bottles of ophthalmic slowly and evenly at room temperature into a medications exceeds the maximum volume that graduated cylinder. Drops were counted from the palpebral fissure can accommodate, which is eight 2.5-mL bottles of each medication at each approximately 30 p,L.14 Normal tear volume is es- instillation angle (vertical, 45 degrees, and horitimated to be 7-10 p,L,15,16 giving a net volume zontal), and the total volume of medication disavailable for instillation of 20-23 p,L. Any med- pensed from each bottle was recorded. Mean ication in excess of 20-23 p,L probably overflows drop volume was calculated by dividing the immediately after administration. Because nor- mean measured volume of medication per bottle mal tear volume is restored within 2-3 min by re- by the mean number of drops per bottle. In an flex blinking, tearing, and drainage through the additional analysis, drops were counted from the nasal-lacrimal duct, additional medication is bottles held at 45 degrees, only 2 drops at a time, probably lost as well.14 By waiting 5 min in be- with the bottles placed back on the table between tween administration of eye drop solutions, the administration of 2 drops, to simulate daily doseffect of diluting the first medication is mini- ing to both eyes. The yearly cost of lOP-lowering medication mized. Studies have shown that the bioavailability and was calculated for each instillation method. Onceefficacy of drops as small as 15 p,L are equivalent daily bilateral treatment requires 730 drops per to those of larger drops14 Therefore, smaller year. The number of bottles that would be redrops would be preferable to minimize systemic quired per year for once-daily bilateral treatment exposure and spilled or wasted medication. Ob- was first calculated by dividing 730 drops by the viously, a smaller drop size would mean that mean number of drops found per 2.5-mL bottle. more doses could be dispensed from each bottle Then, the calculated number of bottles per year of medication, providing cost savings to patients (which was not rounded to an integer value) was multiplied by the published average wholesale and managed care providers. Drop sizes of ophthalmic solutions depend on price (AWP; Price Alert 2005, Medi-Span, Indiproperties of the solution itself, such as viscosity anapolis, IN). The A WPs for 2.5-mL bottles were and surface tension, which probably vary little $62.10 for bima toprost, $62.19 for travoprost, and among medications with similar formulations. $61.29 for latanoprost. The dimensions and design of the dropper tip Statistical analyses employed unpaired Stugreatly influence drop size, as does the angle at dent t tests. which the bottle is held when the drops are dispensed. 14 The one variable affecting drop size that patients are able to control is the angle at which the bottle is held when the drops are inRESULTS stilled. In this study, we measured the number of drops dispensed from 2.5-mL bottles of the onceThe mean number of drops dispensed from daily lOP-lowering drugs, bimatoprost, travo- 2.5-mL bottles of prostaglandin analogs is preprost, and latanoprost, when the bottles were sented in Figure 1. For bimatoprost, the greatest held vertically, at 45 degrees, and horizontally. mean number of drops (111.0) was dispensed The results show that patients can achieve sig- from bottles held vertically, with nearly as many nificant savings in the cost of their lOP-lowering drops (105.1) from bottles held at 45 degrees, medication by choosing the most efficient angle and the least (76.1) from bottles held horizonfor instillation. tally. A similar pattern was seen for latanoprost, PL-000386 Case 3:12-cv-01141-SMY-DGW Document 176-1 *SEALED* Filed 12/01/14 Page 3 of 7 Page ID #2163 Case: 16-3334 Document: 55-2 Filed: 02/08/2017 Pages: 7 (63 of 1511) 479 INSTILLATION METHODS FOR PROSTAGLANDIN MEDS Angle 01 instillation • Horizontal 045 degrees II Vertical P< .0001 140 Ql E I 120 P = .0006 I 0 II P = .018 .0 ...J E 1.0 N 100 80 (j; 0. UJ 0. 0 -0 c 60 40 Cll Ql :2 20 0 Travoprost Bimatoprost Latanoprost FIG. 1. Numbers of drops dispensed at room temperature from 2.5-mL bottles of prostaglandin analogs held at three different angles. Each bar represents the mean of 8 determinations, with standard deviations shown as error bars. P-values for comparisons between angles of instillation that yielded the greatest numbers of drops are shown in the figure. Other statistically significant comparisons were: bimatoprost, vertical versus 45 degrees (P = 0.022), vertical versus horizontal, and 45 degrees versus horizontal (P < 0.0001); travoprost, 45 degrees versus vertical (P < 0.0001), 45 degrees versus horizontal (P = 0.0033); latanoprost, vertical versus horizontal and 45 degrees versus horizontal (P < 0.0001). with 94.3, 88.4, and 67.1 drops dispensed from bottles held vertically, at 45 degrees, and horizontally, respectively. For travoprost, the greatest number of drops was dispensed from bottles held at 45 degrees (101.1), with fewer drops dispensed from bottles held at horizontally (85.3) and vertically (81.4). The number of drops dispensed at the most efficient instillation angle would provide 56 days of once-daily bilateral therapy from a 2.5-mL bottle of bimatoprost, 51 TABLE Bimatoprost Travoprost Latanoprost days for travoprost, and 47 days for latanoprost (Table 1) . In the method where only 2 drops were dispensed from the bottles with table placement between administrations, the number of drops and recorded volume dispensed from the bimatoprost and travoprost bottles were similar to the previous results. However, for latanoprost bottles, fewer drops (83 vs. 88 drops) and less volume was captured into the graduated cylinder (2.6 vs. 3.0 mL). Visual observation of the tip of the latanoprost bottle during the procedure demonstrated liquid running down the outside the length of the tip after replacement of the bottle on the table. Measurement of the total volume of medication that could be dispensed from 2.5-mL bottles showed that, on average, bottles of bimatoprost contained 3.17 mL, bottles of travoprost contained 2.54 mL, and bottles of latanoprost contained 3.02 mL (Fig. 2). The angle of instillation had no effect on the total volume of medication per bottle that could be dispensed. When drops were dispensed at the angles yielding the greatest number of drops, the calculated average drop volume was 28.7 ILL for bimatoprost, 25.4 ILL for travoprost, and 32.9 ILL for latanoprost (Table 1). The yearly costs of treatment with prostaglandin analogs are presented in Figure 3. For bimatoprost, the yearly costs were $408, $431, and $596 for medication instilled vertically, at 45 degrees, and horizontally, respectively. For latanoprost, yearly costs were $475, $506, and $667 for vertical, 45-degree, and horizontal instillation, respectively. For travoprost, yearly costs were $449, $532, and $558 for 45degree, horizontal, and vertical instillation, respectively. Vertical instead of horizontal instillation would save $187 per year for patients using bimatoprost, and $192 for patients using latanoprost (Table 1). Patients using travoprost would save $108 per year by instilling at 45 degrees instead of vertically. 1. DAYS OF THERAPY PER BOTILE, DROP VOLUME, AND YEARLY COST WHEN THE MOST EFFICIENT INSTILLATION METHOD WAS USED Maximum days of therapy per bottle Drop volume Lowest yearly cost Most efficient instillation angle Yearly savings· 56 51 47 28.7 ILL 25.4 ILL 32.9 ILL $408 $449 $475 vertical 45 degrees vertical $187 $109 $192 "Savings that would be achieved by using the most efficient instillation angle, as compared with the least efficient angle. PL-000387 Case 3:12-cv-01141-SMY-DGW Document 176-1 *SEALED* Page ID #2164 Case: 16-3334 Document: 55-2 o ""§ u '6 _~ ~ 0 0.0 ~....J -gE 3.5 3.0 2.5 2.0 ~11)1 ~ ~ .5 ~ ~ 1.0 > c: ~ :i! Filed: 02/08/2017 Pages: 7 (64 of 1511) FISCELLA ET AL. 480 c: Filed 12/01/14 Page 4 of 7 0.5 0.0 Sima!opros! Travoprost la!anopros! FIG. 2. Mean total volumes dispensed from 2.S-mL bottles of prostaglandin analogs. Each bar represents the mean of 24 determinations at all three instillation angles, with standard deviations shown as error bars. DISCUSSION methods. Trying to account for any variations noted in actual patient administration, latanoprost may not last as long as bimatoprost or travoprost. This discrepancy may reflect the loss of latanoprost down the side of the dropper tip after each administration. This does not appear to be a problem with the bottle design of bimatoprost or travoprost. Many aspects of eye drop formation and delivery may affect the size of the drop that falls from the bottle. 14 These include, changing from a vertical position to a horizontal position when administering the drop, the design of the outer surface of the dropper tip and the surface tension of the solution. As an example, a bottle with an annular recess at the tip may dispense a decreased drop size when tilted from 90 to 45 degrees.1 4 However, tilting may also result in partially formed drop resulting in a variable drop size, depending upon the surface tension of the solution. A dropper tip with no annular recess and a lower surface tension may actually demonstrate an increase in drop size when the bottle is tilted from 90 to 45 degrees. Each bottle of the prostaglandin analogs studied was a different design. The bimatoprost bottle appeared to have a small rounded tip with no annular recess. The latanoprost bottle appears to have the largest inner and outer diameter tapered tip of all the prostaglandin analogs. Although modification of the latanoprost bottle years before allowed for Data presented in this study show that the angle at which prostaglandin analogs are dispensed greatly affects the numbers of drops that can be obtained from a 2.5-mL bottle. Vertical instillation was most efficient and instillation at 45 degrees was nearly as efficient for bimatoprost and latanoprost, yielding significantly more drops per bottle (31%-46%) than horizontal instillation of these 2 medications (P < 0.0001). By contrast, instillation at 45 degrees was most efficient for travoprost, yielding significantly more drops per bottle (19%-24%) than horizontal or vertical instillation (P :s 0.0033). The mean number of drops Angle of instillation dispensed by the most efficient instillation angle • Horizontal was significantly greater for bimatoprost than 045 degrees travoprost and latanoprost (P = 0.0006 and III Vertical P < 0.0001, respectively), and was significantly $700 greater for travoprost than latanoprost (P = $600 0.018). The mean numbers of drops dispensed at 45 degrees from 2.5-mL bottles of bimatoprost, CQl E $500 travoprost, and latanoprost in this study, 105.1, ~ 101.1, and 88.4 drops, respectively, correlated ~ $400 0 well with previously published findings, 103, 98, U5 0 $300 and 92 drops,ll and 111.3, 102.9, and 97.6 drops, u £ respectively.12.17 The calculated volumes of drops Qlco $200 dispensed at the most efficient angles of instilla- >$100 tion, 28.7 ~L for bimatoprost and 32.9 ~L for latanoprost instilled vertically, and 25.4 ~L for $0 Simatoprost Travoprost travoprost instilled at 45 degrees, exceed the vollatanopros! ume of the palpebral fissure available for instilFIG. 3. Yearly costs for bilateral administration of lation, suggesting that fully efficacious volumes prostaglandin analogs instilled at various angles. See of medication are delivered by these instillation Methods for calculations. PL-000388 Case 3:12-cv-01141-SMY-DGW Document 176-1 *SEALED* Filed 12/01/14 Page 5 of 7 Page ID #2165 Case: 16-3334 Document: 55-2 Filed: 02/08/2017 Pages: 7 (65 of 1511) 481 INSTILLATION METHODS FOR PROSTAGLANDIN MEDS better control of drop administration, the drop itself appears to be larger with the newer bottle design. 12 Both bimatoprost and latanoprost produced more drops in the vertical, 45-degree, and horizontal positions, respectively, possibly reflecting the bottle tip design. The travoprost bottle has a conical design that appears to have a slight increase in internal diameter as it approaches the end of the tip. Travoprost produced the most drops in the 4S-degree position. Although the tip does not appear to have an annular recess, perhaps the slight increase in the inner diameter at the end of the tip may affect the drop size as the bottle tilting proceeds from vertical to 45-degree positions. Other considerations previously mentioned, such as surface tension, may also be variables that may affect the drop size in various positions. 14 The total volume of once-daily lOP-lowering medication dispensed from 2.5-mL bottles averaged 3.17 mL for bimatoprost (a 0.67-mL overfill), a volume significantly greater than that dispensed from bottles of travoprost, 2.54 mL (negligible overfill; P < 0.0001), and latanoprost, 3.02 mL (a 0.62-mL overfill; P = 0.0001). Previous studies reported medication volumes of 3.06, 2.92, and 2.98 mLY and 3.3, 3.0, and 3.05 mLY for 2.5-mL bottles of bimatoprost, travoprost, and latanoprost, respectively. Of the 3 prostaglandin analogs, bimatoprost provided the greatest number of days of bilateral therapy per 2.5-mL bottle, 56 days, and the lowest cost per year, $408, when dispensed vertically. Vertical instillation of bimatoprost and latanoprost would save $187 and $192 per year, compared with horizontal instillation. Instillation of travoprost at a 45-degree angle would save $108 per year relative to instillation from a vertical angle. These savings are substantial: They represent the cost of 3.0 bottles and 5.6 months of bilateral therapy with bimatoprost, 1.8 bottles and 3.0 months of therapy with travoprost, and 3.1 bottles and 4.9 months of therapy with latanoprost. CONCLUSIONS Health care providers are urged to instruct glaucoma patients in the most efficient method of instillation for their prostaglandin analogs. For bimatoprost and latanoprost, the most efficient method is instillation with the bottle held verti- cally, with 45 degrees nearly as efficient. For travoprost, the most efficient method is instillation at 45 degrees. ACKNOWLEDGMENT The authors gratefully acknowledge John Keener, PhD., for assistance with the development of the manuscript. REFERENCES 1. The Advanced Glaucoma Intervention Study (AGIS). 7. The relationship between control of intraocular pressure and visual field deterioration. Am. f. Ophthalmol. 130:429-440, 2000. 2. Fiscella, RG. Pharmacological considerations in the treatment of glaucoma. Manag. Care ll(Supp1. 1): 16-20, 2002. 3. Fiscella, RG. Glaucoma medications: A drug-therapy review. Manag. Care ll(Suppl. 11):25-31,2002. 4. Kass, M.A., Heuer, O.K., Higginbotham, E.J., et a!. The Ocular Hypertension Treatment Study: A randomized trial determines that topical ocular hypotensive medication delays or prevents the onset of primary open-angle glaucoma. Arch. Ophthalmol. 120:701-713, 2002. 5. Hedman, K., and Aim, A. A pooled-data analysis of three randomized, double-masked, 6-month clinical studies comparing the intraocular pressure reducing effect of latanoprost and timolol. fur. J. Ophthalmol. 10:95-104, 2000. 6. Fellman, RL., Sullivan, E.K., Ratliff, M., et a!., and the Travoprost Study Group. Comparison of travoprost 0.0015% and 0.004% with timolol 0.5% in patients with elevated intraocular pressure: A 6-month, masked, multicenter trial. Ophthalmology 109:9981008,2002. 7. Cohen, J.S., Gross, RL., Cheetham, J.K., et a1. Twoyear, double-masked comparison of bimatoprost with timolol in patients with glaucoma or ocular hypertension. Surv. Ophthalmol. 49(Suppl. 1):545-S52, 2004. 8. Tsai, J.C, McClure, CA., Ramos, S.E., et a!. Compliance barriers in glaucoma: A systematic classification. J. Glaucoma 12:393-398, 2003. 9. Jampel, H.D., Parekh, P., Johnson, E., et a!. Preferences for eye drop characteristics among glaucoma specialists: A willingness-to-pay analysis. f. Glaucoma 14:151-156,2005. 10. Olthoff, CM., Schouten, J.S., van de Borne, B.W., et al. Noncompliance with ocular hypotensive treatment in patients with glaucoma or ocular hypertension an evidence-based review. Ophthalmology 112:953-961, 2005. PL-000389 Case 3:12-cv-01141-SMY-DGW Document 176-1 *SEALED* Page ID #2166 Case: 16-3334 Document: 55-2 Filed 12/01/14 Page 6 of 7 Filed: 02/08/2017 (66 of 1511) FISCELLA ET AL. 482 11. Mick, A.B., Gonzalez,S., Dunbar, M.T., et a1. A cost analysis of the prostaglandin analogs. Optometry 73:614-619, 2002. 12. Fiscella, RG., Green, A., Patuszynski, D.H., et aJ. Medical therapy cost considerations for glaucoma. Am. J. Ophthnlmol. 136:18-25, 2003. 13. Walt, J.G., and Lee, J.T. A cost-effectiveness comparison of bimatoprost versus latanoprost in patients with glaucoma or ocular hypertension. Surv. Ophthalmol. (49 Suppl. 1):536--544, 2004. 14. Van Santvliet, L., and Ludwig, A. Determinants of eye drop size. Surv. Ophtha/mol. 49:197-213,2004. 15. Eter, N., and Gobbels, M. A new technique for tear film fluorophotometry. Br. J. Ophthalmol. 86:616-619, 2002. 16. Yokoi, N., Bron, A.J., Tiffany, J.M., et al. Relationship between tear volume and tear meniscus curvature. Arch. Ophthalmol. 122:1265-1269,2004. Pages: 7 17. Fiscella, RG., Geller, J.L., Gryz, L.L., et a1. Cost considerations of medical therapy for glaucoma. Am. J. Ophthalmol. 128:426-433, 1999. Received: July 10, 2006 Accepted: August 22, 2006 Reprint Requests: Richard Fiscella University of C11icago 833 s. Wood Street Room 164 Chicago, IL 60612 E-mail: fisc@uic.edu PL-000390 Case 3:12-cv-01141-SMY-DGW Document 176-1 *SEALED* Page ID #2167 Case: 16-3334 Document: 55-2 Filed 12/01/14 Page 7 of 7 Filed: 02/08/2017 Pages: 7 (67 of 1511) Copyright of Journal of Ocular Pharmacology & Therapeutics is the property of Mary Ann Liebert, Inc. and its content may not be copied or emailed to multiple sites or posted to a listserv without the copyright holder's express written permission. However, users may print, download, or email articles for individual use. PL-000391 Case 3:12-cv-01141-SMY-DGW Document 176-26 *SEALED* Filed 12/01/14 Page 1 of 22 Case: 16-3334 Document:Page 55-3 ID #2795 Filed: 02/08/2017 Pages: 22 (68 of 1511) CONFIDENTIAL PURSUANT TO THE PROTECTIVE ORDER Case 3:12-cv-01141-SMY-DGW Document 176-26 *SEALED* Filed 12/01/14 Page 2 of 22 Case: 16-3334 Document:Page 55-3 ID #2796 Filed: 02/08/2017 Pages: 22 (69 of 1511) Page 2 RISK ASSESSMENT REPORT APPROVAL ALCM RESSJAP1231 LISTED 6310i SC4ITS FREEWAY FOS 7 WORTH. TEXAS 76134 Project (Project Name); TRAVATANT4 Dosing Aid Project Number: 22-5742 FID No. (Optional): NA Risk Assessment Report No.: 001:065742:0405 Revision No.: 1 Document Revision; Document Change Table 1, Summary of Revisions During Development Risk Analysis Worksheet, Page 1 Item Al Risk Analysis Worksheet, Page 2 Item k1 Risk Analysis Worksheet, Page 2 Item A.4 Risk Analysis Worksheet, Page 3 Item B.1 Risk Analysis Worksheet, Page 4 Item C.2 Risk Analysis Worksheet, Page 4 Item D2 Risk Analysis Worksheet, Page 5 Item E.6 and 7 Change description and reason tot change Changed the heading on the third column from Risk Mitigation to Design Change to more accurately reflect the development process Added reference to testing of the handle to demonstrate robustness during use. Added reference to testing of the handle to demonstrate robustness during use. Added clarification related to functional testing and additional patient and physician booklet changes. Added the ship testing results Added Toxicology test results for the drop guider. Added industry standard reference for MD controls. Added the IEC safety testing infomiation Risk Assessment Introduction/Product Description: Introduction The TRAVATANTm Dosing Aid (TDA) has been designed to remind TRAVATAN patients to dose their medication within an established window. A record of these events Is maintained in the unit until it is downloaded in their physician's office for appropriate compliance counseling. TVIAVATAtie DosIno Aid Product Description TDA is comprised of three elements, the individual dosing aid, communication cradle and software. A presentation of the two hardware elements can be seen in Figure 1. Rev. 03,02 RD 231 SOP PR000000159 CONFIDENTIAL PURSUANT TO THE PROTECTIVE ORDER Page 1 af 10 AD TRAVATAN_EIKE040561 Case 3:12-cv-01141-SMY-DGW Document 176-26 *SEALED* Filed 12/01/14 Page 3 of 22 Case: 16-3334 Document:Page 55-3 ID #2797 Filed: 02/08/2017 Pages: 22 (70 of 1511) Page 3 ALOONFIESEMCM LAVED 6201 SOvTi4 pEpwAy t-ORT*OPIT11.71NAt moo RISK ASSESSMENT REPORT APPROVAL RAMS 1 Dosing Aid and Communication Cradle Con monent DescrIotIonti ThEigagm. The dosing aid is given to the patient by the physician. Each dosing aid is shipped with two baskets, each of which slide into the oval shaped opening on the top side of the dosing aid. The baskets are designed to hold different size bottles, i.e. one basket is designed to hold the 2.5mL bottle and the other is designed for the Smi bottle. Each dosing aid has an LCD display on the front panel and a delivery lever on the back panel. The LCD will display a tear drop icon for the patient as a reminder to take the medication. The dosing aid also emits a beep at the medication time as an additional reminder. The lever on the back provides a larger gripping surface to squeeze in comparison with the sidewall of the bottle when dispensing a drop. Each time the handle is fully depressed it contacts a switch and records the date and time. The unit records all depressions of the handle within a 15 minute window with a single time and date stamp. The bottom of each unit has a IR window that serves as a communication port between the dosing aid and the cradle. This unit is powered by a 3 volt lithium battery which is accessible and replaceable by the user. Communication Cradle The cradle has a matching IR window. There are two lights on the front of the cradle, one to indicate the unit has power from the computer and the second Muminates when a dosing aid is placed in the cradle and It is ready to read. The cradle connects to the computer with a serial interface. See Figure 2 for a presentation of the back panel of the cradle and dosing aid. Rev. 0302 RO 231 SOP PROC-0003/59 CONFIDENTIAL PURSUANT TO THE PROTECTIVE ORDER Pap 2 of 10 AD_TRAVATAN_EIKE040562 Case 3:12-cv-01141-SMY-DGW Document 176-26 *SEALED* Filed 12/01/14 Page 4 of 22 Case: 16-3334 Document:Page 55-3 ID #2798 Filed: 02/08/2017 Pages: 22 (71 of 1511) Page 4 RISK ASSESSMENT REPORT APPROVAL 0400111.1121EARCH UNITED 620 SOUTH FREEWAY FORT WORTH. TEl 7E1 VI Figure 2 Beck panels of Dosing Aid and Communication Cradle Software The software is designed to run on a windows based PC computer. ft is compatible with Windows XP and Windows 2000 operating system. The software has been designed to be as simple as possible for the user and for the presentation of the information for the physician. The first step in establishing a patient as a TDA user is to select a dosing aid, remove it from the carton, insert the battery and set it in the cradle. Open the software, log in, and select the patient information screen. On this screen the physician or their designee must enter the first and last name the patient. M other patient parameters are automatically defaulted to the following: Bilateral dosing (both eyes) Reminder time is 9:00pm The visual reminder window (tear drop icon) is displayed for a total of 6 hours, 6:00pm-t2:00arn. The audio reminder will beep 3 times at each of the default times, 8:30pm, 9:00pm, and 9:30pm Rev. 0302 RD 231 SOP FR00030010 CONFIDENTIAL PURSUANT TO THE PROTECTIVE ORDER Page 30110 AD TRAVATAN El/CB:1440563 Case 3:12-cv-01141-SMY-DGW Document 176-26 *SEALED* Filed 12/01/14 Page 5 of 22 Case: 16-3334 Document:Page 55-3 ID #2799 Filed: 02/08/2017 Pages: 22 (72 of 1511) Page 5 ALCON RESENICA LOWED RISK ASSESSMENT REPORT APPROVAL 8201 SOWN FREEWAY FORT wC0tft Toms 76134 Figure 3 shows the TRAVATAN dosing aid in reminder mode with the tear drop icon displayed. Figure 3 Tear Drop Icon Display Changes to the default parameters, if desired, must be manually entered in either the patient data screen or the TRAVATAN dosing aid parameters screen at the physician's office. Once the unit is programmed, the patient takes the dosing aid home and uses It for dosing TRAVATAN. When the patient returns to their physician for a follow-up visit and brings their dosing aid with them, and the unit Wii be placed back in the cradle. The data is downloaded and may be presented in two potential formats, a calendar or drop log. The calendar dspiays the number of times the handle is depressed each calendar day. The drop log is a simple list of dates, times and number of handle depressions. Depressing the handle squeezes the bottle and delivers the drop. The drop dispensing characteristics of the dosing aid have been designed to not interfere with the typical mechanism of action, i.e. inverting the bottle and squeezing the side of the bottle to express a drop. The dropper tip has not changed by the addition of the dosing aid. The consistency of the drop size has been confirmed in laboratory testing as was done for the initial approval of the primary package for TRAVATAN®. The average drop size for TRAVATAN with and without the dosing aid are essentially identical with the slight reduction in variation when the dosing aid is used. The reduction in variation is most likely attributed to the consistent squeezing of the bottle. An individual's ability to squeeze a bottle and produce a drop depends on a number of human factors. Drop size is a highly subjective measurement and individual human factors plays a key role in the variability between people and within a person. The information from the eldier the calendar or drop log report will be used as a toot for the doctor Rel. 00102 RO 231 SOP PROC-00001S9 CONFIDENTIAL PURSUANT TO THE PROTECTIVE ORDER Pagel d 10 AD TRAVATAN EIKE040564 Case 3:12-cv-01141-SMY-DGW Document 176-26 *SEALED* Filed 12/01/14 Page 6 of 22 Case: 16-3334 Document:Page 55-3 ID #2800 Filed: 02/08/2017 Pages: 22 (73 of 1511) Page 6 RISK ASSESSMENT REPORT APPROVAL PLCONIIESENICH UNITED facti SOUTH FREEWAY PORT WORTH. TEXAS 70134 to evaluate patient dosing compliance after they have reviewed all the primary intraocular pressure (10P) diagnostic evaluation test results. if the 10P i at contro for a specifio patient then the information provided by the dosing aid may provide e insight Into potential explanations. Design change hl,story: Table 1 Summary of Revisions dud _ Risk Design Feature Design Change Dosing aid shape The smooth finish could be harder Added texture Mold Tech MTand texture to hold, especially If damp or use 11010 and changed the shape with wet hands from an hour glass to A line. .The handle was texturized with bumps to improve the gripping Oval opening on top During usage, a bottle could Added basket to more for product slowly (seep out of the unit, consistently hold the bottle in potentially resulting in difficulty in position optimizing thepotential dispensing a drop for the user. for consistent drop delivery. Also provided a larger panel to press against the side of the bottle for dosing giving a more positive point of contact. Visual reminder Frequent battery change required By replacing the LED with the LCD the battery life was extended by at least 9 months. LCD reminder image Interpreting the numerical dosing AN numbers have been reminder may not be easily eliminated. The reminder is now understood by all users. a tear drop Icon. Removing the minters simplifies the programming of the firmware and the ease of use for the patient. Basket assembly The basket would come apart Solvent weld the front and back increasing potential to loose 1/2 of parts of the basket together the part and also led to increase making one piece. Solvent weld in user damage to the basket. the base to the body to ensure the The bottom was designed as units may not be opened. friction fit but could still be pulled out with effort. Dispensing handle Handle breakage that would Optimized the performance and cause the unit to not function. strength of the handle through material testing and configuration evaluations. Communication Malfunctioning unit confusing and Decreased potential for mechanism problematic for the physician or malfunction by replacing the designee resulting In potential connector with the IR screen customer dissatisfaction. allowing the connection to occur if the dosing aid is positioned above the cradle. It will still function without being firmly seated. ' Cradle power Separate coni required to power The power (*Id for the cradle was the cradle creating additional removed and the cradle is now need for receptacle and making it powered by the computer it is more bulks, and less user friendly. linked to. Pegs5ot 10 Rev. 03102 RD 231 SOP PROD-0000159 CONFIDENTIAL PURSUANT TO THE PROTECTIVE ORDER 471,11.41.04ZUTAIN.I.P.el.relatAIMOMIIIIMIAM064050...0.11W AD TRAVATAN_EIKE040585 f/1.1....MI/11...M9.0144,91.0VIRIMMOMIONIONOVN....V464.914!KOKININIWNWAMI Case 3:12-cv-01141-SMY-DGW Document 176-26 *SEALED* Filed 12/01/14 Page 7 of 22 Case: 16-3334 Document:Page 55-3 ID #2801 Filed: 02/08/2017 Pages: 22 (74 of 1511) Page 7 PLOOT.1 TIEWJX:14 UN/TED scuTH I-TWEWAV FORT WORTH. TEXAS MIN RISK ASSESSMENT REPORT APPROVAL Design Feature Battery access Software default RISK Removing and replacing screws to change the battery could result in minor injuries or inability to maintain unit The original software did not have default settings. This required the person doing) the set up to input many fields of information potentially resulting In data entry Design Change Changed the battery access to user friendly removable panel that does not require tools. Added defaults for dosing and medication, which reduced the number of fields for data entry from 7 to 2 and reduced the potential for entry error. errors. Software install program Software Installer resulted in many error messages frequently resulting in failure to install, Dosing Aid closure The risk of loosing a closure and having the unit remain active would run down the battery and lead to customer dissatisfaction. Changed installer to be compatbie with most windows based software thereby Increasing the probability of successful installs With existing solhvare systems. Removed the closure to eliminate this potential problem. Conclusion: The risks identified with the TRAVATANtle dosing aid have considered human factors, as well as design and manufacturing criteria. Risks identified have resulted in various design changes to improved usability of the accessory and minimize risks. No new risks were generated from the risk controls that were put in place. The benefits to the patient and physician outweigh the risks associated with using the dosing aid. The information gekted from the dosing aid is intended as useful information to assist the physician in understanding the patients dosing compliance. In case of malfunction, dosing may continue for the patient by simply removing the bottle from the dosing aid and resuming use. For this reason a normal course of therapy can be accomplished with or without the use of the dosing aid by the patient. There are no other known electronic dosing aids devices on the market. Therefore literature information related to this type of dosing aid system is not available. There are, however, extensive references related to the correlation of patient compliance and drug therapy effectiveness. These literature references are summarized in Appendix A. Rev. 05V2 RD z31 SOP PROC-00001S9 CONFIDENTIAL PURSUANT TO THE PROTECTIVE ORDER Page Bell° AD TRAVATAN ElKE040566 Case 3:12-cv-01141-SMY-DGW Document 176-26 *SEALED* Filed 12/01/14 Page 8 of 22 Case: 16-3334 Document:Page 55-3 ID #2802 Filed: 02/08/2017 Pages: 22 (75 of 1511) Page 8 RISK ASSESSMENT REPORT APPROVAL ALCOI RESEVICN LASTED $ISOUTH FREEWAY FORT WORN. TEXAS mod Team Members: Marls Sanne Function: Sup /9-7-05 ate Function: R&D QAD Date Quality Assurance ZRierre-Mril Function: Marinating Date 04nti -Michael Bergamini, Ph.D. Date Steve M. Goode,M.D. Function- Medical Monitor Date Date , Ph.D. Function: Pharmaceutical Technology Date Function: Fiedical Specie Scott Krueger, D. Function; Medical Specialty Director Dev. 0a402 RD 231 SOP PROC-0000159 CONFIDENTIAL PURSUANT TO THE PROTECTIVE ORDER Page 7of AD TRAVATAN E1KE040567 wowsweammaxauftemacasei Case 3:12-cv-01141-SMY-DGW Document 176-26 *SEALED* Filed 12/01/14 Page 9 of 22 Case: 16-3334 Document:Page 55-3 ID #2803 Filed: 02/08/2017 Pages: 22 (76 of 1511) Page 9 RISK ASSESSMENT REPORT APPROVAL AVX.CALSINVC. kW 65 8.X.111., CAMAVA. rilal VW. rkIlki. 7513.1 APPROVAL (5): IVAAilE/TITI.E/SIGNATUREfaATE Team Captain: Julie A. Clifford Data Team Membilm: Jk1118 Clifford Data Function: R&D Package Development Sari3rt j Mark Senna Function: Supplier Quality Assurance Glen Riddle Function: Ft&D QAU Date Pierre Morival Function: Marketing Michael Bergamini, Ph.D. Function: Medical Specialty Date Steve M. Goode,M.D. Function: Medical Monitor Date Scott Krueger, Ph.D. Function: Medical. Specialty Director DOW Larry Colson, Ph.D. Function: Phannaosulical Technotorg Date CONFIDENTIAL PURSUANT TO THE PROTECTIVE ORDER AD TRAVATAN EIKEN0668 Case 3:12-cv-01141-SMY-DGW Document 176-26 *SEALED* Filed 12/01/14 Page 10 of 22 Case: 16-3334 Document:Page 55-3 ID #2804 Filed: 02/08/2017 Pages: 22 (77 of 1511) Page 10 20/07/1005 MU PAZ 811 331 1070 limo* woos "V CLAPSakw. RISK A.SSESSMENT REPORT APPROVAL pinam loVnin Motet* Woo uountviewpar FINITVIORIN cocsa I•004 Development 44/fr Date Date Mork Samna Function: Suppler Quay AMMO Glen FacliSe Function: R&D QAU — Micheal lika;garnini Rime= Modloal. PhD. Date Date Pierre Marian! ,..j mu a 411.5r Scott Krueger, Ph.D. FUltalork Medical Speciaky Director Play. m112,10251 atiePPOOM001611 CONMENTIAL PURSUANT TO THE PROTECTIVE ORDER Ph.D. Function: Pharmaceutical Technology i4p.70 AD TRAVATAN ErKE040569 Case 3:12-cv-01141-SMY-DGW Document 176-26 *SEALED* Filed 12/01/14 Page 11 of 22 Case: 16-3334 Document:Page 55-3 ID #2805 Filed: 02/08/2017 Pages: 22 (78 of 1511) Page 11 RISK ASSESSMENT REPORT APPROVAL sums nEsEss011 UMITED WM SOWN FAY r loCS-114. MOS MU Appendix A The following are the relevant literature references relating to compliance and its perceived value in the treatment of patients with open angle intraocular pressure. References 1. DiMatteo MR. Variations in patients' adherence to medical recommendations: a quantitative review of 50 years of research. Med Care 2004;42:200-209. 2. Roter DL, Hall JA, Merisca R, Nordstrom 8, Cretin D. Svarstad B. Effectiveness of interventions to improve patient compliance: a meta-analysis. Med Care 1998;36:1138-1161. 3. Kass MA, Gordon M. Meltzer OW. Can ophthalmologists correctly Identify patients defaulting from pilocarpine therapy? Am J Ophthalmol 1986;101:524-530. 4. Kass MA, Meltzer OW, Gordon M, Cooper D, Goldberg J. Compliance with topical pilocarpine treatment. Am J Oplithalmol 1986;101:515-523. 5. Padgett D. Mumford E, Hynes M, Carter R. Meta-analysis of the effects of educational and psychosocial interventions on management of diabetes mellitus. J Clin Epidemic)! 1988;41:1007-1030. 6. Busch. S. Gramer E. [Improved eyedrop administration and compliance in glaucoma patients. A clinical study]. Kiln Monatsbl Augenheilkd 1997;211257-262. 7. Gurwitz JH, Glynn R..1, Monett(' M, Everitt DE, Gliden D, Smith N, Avom J. Treatment for glaucoma: adherence by the elderly. Am J Public Health 1993;83:711-716. 8. Gurwitz JH, Yoemans S. Glynn R, Lewis BE, Levin R, Avom J. Patient noncompliance in the managed care setting: the case of medical therapy for glaucoma. Medical Care 1998;36:357-369. 9. Spooner JJ, Bullano MF, Ikeda U. Cockerham TR, Waugh WJ, Johnson T, Mazatlan E. Rates of discontinuation and change of glaucoma therapy in a managed care setting. Am J Manag Care 2002;8:S262-S270. 10. Lee MD, Fechtner FR, Fiscella FIG, Singh K, Stewart WC. Emerging perspectives on glaucoma: highlights of a roundtable discussion. Am J Ophthalmol 2000;130:61-11. 11. Konstas AG, kAaskaleris G, Gratsonidis S. Sardelli C. Compliance and viewpoint of glaucoma patients in Greece. Eye 2000;14 Pt 5:752-756. 12. Patel SC, Spaeth GL. Compliance in patients prescribed eyedrops for glaucoma. Ophthalmic Surg 1995;26:233-236. 13. Rotchford AP, Murphy KM. Compliance with *motel treatment in glaucoma. Eye 1998;12 Pt 2):234-236. 14. Claxton AJ, Cramer J, Pierce C. A systematic review of the associations between dose regimens and medication compliance. Clin Thai 2001;231296-1310. Rev. 03102 RD 231 SOP PROC-0000150 CONFIDENTIAL PURSUANT TO THE PROTECTIVE ORDER Pager ol 10 AD TRAVATAN EIKE-040570 3.1. • V, • Case 3:12-cv-01141-SMY-DGW Document 176-26 *SEALED* Filed 12/01/14 Page 12 of 22 Case: 16-3334 Document:Page 55-3 ID #2806 Filed: 02/08/2017 Pages: 22 (79 of 1511) Page 12 ALCON RE:100CH UNIFTOS RISK ASSESSMENT REPORT APPROVAL cool south FliftwAr FONT WORM. TEX% 76134 15. Garber M, Nau DP, Erickson SR. Alkens JE. Lawrence Ja The concordance of self-report with other measures of medication adherence: a summary of the literature. Medical Care 2004;42:649-052. 1a. winfiekl AJ. Jessiman D, Williams A, Evans JM. A study of the causes of non-oornplianoe by patients prescribed eyedrops. Br J Ophthalmia! 1990;74f:477-480. 17. DiMatteo MR, Giordani PJ, topper HS, Croghan "1"W. Patient adherence and medical treatment outcomes: a meta-analysis. Med Care 2002;40:794-811. 18. Granstrom PA. Progression of visual field defects in glaucoma. Relation to compliance with pilocarpine therapy. Arch Ophthalmol 1985;103:529-531. 19. Taylor SA, Galbraith SM, Mills RP. Causes of non-cornpLance with drug regimens in glaucoma patients: a qualitative study. J Ocul Pharrnacol Ther 2002113:401-409. 20. Mad(ean JM, Elldngton AR. Compliance with treatment of patients with chronic open-angle glaucoma. Br J Ophthalmol 1983;67:48-49. 21. Ikeda H, Salo M, Tsukemoto H, Sato E, Line' H, Kimura Y. Mkshirna H, Kihira K. Evakaation and multivariate statistical analysis of factors influencing patient adherence to ophthalmic solutions (article in Japanese). Yakugaku Zasshi 2001;121:799-806. 22. Kosoko 0, Quigley HA, Vitale S, Enger C. Kerrigan 1., Tielsch JM. Risk factors for noncompliance with glaucoma follow-up visits in a residents' eye clinic. Ophthalmology 1998;105:2105-2111. 23. Hall JA, Rater DL, Katz NR. Meta-analysis of correlates of provider behavior in medical encounters. Med Care 1988;261357-675. 24. Adarrnes, CJ, Sunahara JF. Hypertensive urgencies and emergencies in ambulatory care clinics. 1997:ASHP Midyear Clinical Meeting 32:93E. 25. Schweizer, RT, nova M, Palmed D., Vossler E., Hull, D. Bartus S. Noncompliance in organ transplant recipients. Transplantation, 1990;49:374-7. 26. Stewart WC, Chorak, RP, Hunt JJ, Sethuraman G. Factors associated with visual loss in patients with advanced glaucomatous changes in the optic nerve head Am I Ophth 1993;116:176-181. 27. Konstas AG, Maskaieris G, Gratsonidis S, Sardelli C. Compliance and viewpoint of glaucoma patients in Greece. Eye 2000;14152-756. 28. Granstrom P-A. Progression of visual field defects in glaucoma. Arch Ophthalmol 1985;103:529-531 29. Kau, MA. Compliance and Prognosis in Glaucoma. Arch Ophthalmol 1985;103:504. 30. Tielsch 3M. The epidemiology and control of open angle glaucoma: a population-based perspective. Ann Rev Public Health 1996;17:121-136. 31. 1Vfitchell P, Smith W, Auebo K, et al. Prevalence of open-angle glaucoma in Australia: the Reef. 03812 RD 231 SOP PROC.-000015B CONFIDENTIAL PURSUANT TO THE PROTECTIVE ORDER Page 9 of 10 AD TRAVATAN EIKE(101571 Case 3:12-cv-01141-SMY-DGW Document 176-26 *SEALED* Filed 12/01/14 Page 13 of 22 Case: 16-3334 Document:Page 55-3 ID #2807 Filed: 02/08/2017 Pages: 22 (80 of 1511) keotasiEssmot LIMED 6201 SOUTH MEMO, FONT WORM TEIOS 761$4 RISK ASSESSMENT REPORT APPROVAL Blue Mountain Eye Study. Ophthalmology 1996;103:1271-75. 32. Collaborative Normal-Tension Glaucoma Study Group. The effectiveness of intraocular pressure reduction in the treatment of normal-tension glaucoma. Amt Ophthalmol 1998;126:498-505. 33. Lichter PR, Muach DC, Gillespie BW, et al, and the Collaborative Initial Glaucoma Treatment Study comparing initial treatment randomized to medications or surgery. Ophthalmology 2001;108:1943-1953. 34. The AGIS Investigators. The Advanced Glaucoma Intervention Study (AGIS): 7. The relationship between control of intraocular pressure and visual field deterioration. Am I Ophthalmot 2000;130:429-440. S•v. 03/02 RD 231 SOP PROD-4000169 CONFIDENTIAL PURSUANT TO THE PROTECTIVE ORDER Page 10 of 10 AD TRAVATAN EIKE040572 Case 3:12-cv-01141-SMY-DGW Document 176-26 *SEALED* Filed 12/01/14 Page 14 of 22 Case: 16-3334 Document:Page 55-3 ID #2808 Filed: 02/08/2017 Pages: 22 (81 of 1511) Page 14 Risk Analysis V icsheet (ISO 14971) Product Description TRAVATAN Dosing Aid , .. ., Litt of risk categories Identify species poetised harmsodedatedlitebile ask cateterresetioast awe pletelleetWerOOdeteogeto billitlk*VialliOr Mutt speefettioteethe Mates tffeatteedeftltane Wove tor elbsimeleliatir felesseprodoet ices - follelelletefbarednigkeild vt* eek,fo'llInithill Isipeeks 1 . I • — A. DILSIGN 1. The TRAVATAN Dosing Aid is inoperable Patient will not dose as directed. Intraocular pressure is not controlled. The product can not be dispensed. Imrsocular presssure is not controlled, The unit stops reminding patient to dose. No data will to recorded. lntraocular pressure is not controlled. The product can not be dispensed. Intraocular manure is not controlled. 3 3 3 3 Reminder function both audible and visual fail to remind patient to dose. 1 The handle breaks off 1 The bottom falls out removing all the electronics I Posts which are part of the handle ere missing or broken 1 3 3 The units will be 1009b Inspected for functionality and compliance with existing specifications Pear to Packet* and aniPPillf, TDOC-0002284 validated the consistent functionality of the reminders. The nylon material chosen for the handle is strong and resilient TDOC.0002234 handle performed acceptably through validation. In addition, in a separate test the handle was depressed 4000 times without failure. 3 The bottom is a friction fit but will also be solvent welded to ensure a strong bond. 3 The nylon material chosen for the handle is strong and resilient. The tooling has bean approved based on ooesistent Quality evaluations. The units i 3 1 3 1 3 1 3 R0231A Ras 0102 SOP PROC4100009 CONFIDENTIAL PURSUANT TO THE PROTECTIVE ORDER arsaasar nn nor! .riB013.47.7741.14.ria.W.541907~...1..51040,P( AD TRAVATAN EIKE040573 Case 3:12-cv-01141-SMY-DGW Document 176-26 *SEALED* Filed 12/01/14 Page 15 of 22 Case: 16-3334 Document:Page 55-3 ID #2809 Filed: 02/08/2017 Pages: 22 (82 of 1511) Page 15 Risk Analysis V itsheet (ISO 14971) .... , . Willkeaftwon . Product Description — TRAVATAN Dosing Aid • 141SZbittig will be 100% inspected for functionality and compliance with specifications, to addition, in a separate test the handle was depressed 4000 times without failure. Patient will not dose as directed. Intraocular presasnre is not controlled. 3 The battery hose power 6 18 3 The battery is installed upside down. 4 12 The dose reminder malfunctions and alerts the patient in eta S of desired dosing regimen. 13 salon is damaged or missing pieces. 1 2 2 6 3 6 2. Dose minder malfunctions The patient doses more frequently than directed. 2 3. Basket failure Patient can not dose successfully or with great difficulty, bursocular measure is not controlled. 3 4. Improper working Delivery Aid Loss of accurate dosing record 2 Incorrect corrediance data The battery cons was 4 redesigned to stake it accessible without tools. A 2 Patient Booklet will provide guidance on how to install a new battery. iTDOC-0002284 demonstrates 1 the reminder functions performed consistently through the validation. The basket is now solvent 1 welded to ensure both pieces remain together. The tooling has been inspected and approved based on component evaluation against specification. TC0C-0002284 and TDOC0002285 demonstrate the consistency of the data recording and communicating. Testing indicates that there were 13 drops (0.7%) unrecorded out of 1800 drops dispensed. 11(04%) of these drops were the second of a pair and 2 (0.1%) was first of A pair of drops. The dosing aid design requite' the handle to fully depress and make 2 12 6 2 3 4 RD 231A Rtv 03/02 SOP PROC4000199 CONFIDENTIAL PURSUANT TO THE PROTECTIVE ORDER AD TRAVATAN_EIKE04057e • Case 3:12-cv-01141-SMY-DGW Document 176-26 *SEALED* Filed 12/01/14 Page 16 of 22 Case: 16-3334 Document:Page 55-3 ID #2810 Filed: 02/08/2017 Pages: 22 (83 of 1511) Page 16 Risk Analysis V *sheet (ISO 14971) Product Description — TRAVATAN Dosing Aid ~dt . PeterfentSongteurtentee Ithgregant positive contest with the switch and then be fully released to reset for the neat sequence. If a drop does not record it is likely that the manual motion required to complete this sequence was not accomplished. When a bouts is hill it is easier to get a drop out of the package without significant pressure. on the bottle sidewalls. Therefore, when the bottle is full a user is more likely to get a drop out prior to completing Cull handle motion. Patient instrucdons will be specific in the detail related to fully &gams and release the handle. This dispensing tool is not intended to COMM the dosing regimen of the patient, rather to simply assist the physician in evaluating dosing compliance should the routine diagnostic measurements indicate indent compliance should be reviewed. Therefore, there is huts or no potential effect on patient safety. B. PRIMARY AND SECONDARY PACKAGING I. Protective secondary I There are no units available for petioles due to domain Packaging 3 Units will not activate, or properly program at the physician office. 2 6 Shipping study was soccesehdly completed using Asrm 1)4169 Don 1 3 RD 231A Res 0342 S07 enoc-saams. CONFIDENTIAL PURSUANT TO THE PROTECTIVE ORDER AD TRAVATAN_EIKE040575 Case 3:12-cv-01141-SMY-DGW Document 176-26 *SEALED* Filed 12/01/14 Page 17 of 22 Case: 16-3334 Document:Page 55-3 ID #2811 Filed: 02/08/2017 Pages: 22 (84 of 1511) Page 17 Risk Analysis V *sheet (ISO 14971) Product Description — TRAVATAN Dosing Aid 2 Dosing aid, carton or shipper mislabeled Incorrect expiry/lot I Inadequate tnanufacturing controls for labeling operation 2 2 C. MATERIAL RIOCOMPATIBILTTY . ebititanhaal Labeling controls Master Each Record and incoming LIMS inspection criteria FWMDOC-01483 I I 1. Extractables from Dosing Aid Product efficacy or safety 3 Additional Extractable* or Impurities 2 6 Extractable Sealing TDOC0002464 1 3 2. Extractables from Drop Guider Skin irritation at contact site 3 Additional Extractables or Impurities 2 6 Toxicology Testing ISO 10993-12, 10993-5, 10993-10 TDOC-0003435, TDOC0003436, TDOC-0003437, TDOC-0003435. TDOC0003434. TARN Japan tearing results Two, 0003439,TD0C-0003440, TDOC-0003441 1 3 - — D. MANUFACTURING 1. Improper manufacturing Dosing unit or cradle does not initiate I 2. Environmental controls Dosing unit or cradle does not initiate 1 3. Shipping damage Dosing unit or cradle does not initiate 1 Improper board assembly Improper assembly of units Faulty connection or C011tleCtOf IR mechanism fails to operate Units have not been handled properly during production process resulting in SSD damage. Units are damaged in shipping between Variosystem facilities 1 1 Each lot will be impeded and released by Moon according to JAMS inspection criteria PWMDOC-02392 1 1 2 2 1 I 2 2 Procedures defining proper handling. Ragging. thinning and use of moisture/R.1'10w according to IPC/JEDEC JSID-033A will be observed. Each lot will be inspected and released by Alcoa according to LIMS inspection criteria. FWMDOC-02392 1 I RD ZIA Rey 03/02 SOP PROC.0000129 CONFIDENTIAL PURSUANT TO THE PROTECTIVE ORDER AD TRAVATAN EIKE040578 Case 3:12-cv-01141-SMY-DGW Document 176-26 *SEALED* Filed 12/01/14 Page 18 of 22 Case: 16-3334 Document:Page 55-3 ID #2812 Filed: 02/08/2017 Pages: 22 (85 of 1511) Page 18 Risk Analysis V *sheet (ISO 14971) Product Description — TRAVATAN Dosing Aid BilWalMeer 160110111ii . E. USE ENVIRONMENT 1.Patient pokes their eye with dosing aid Eye injury 2 Dropper tip of bottle could 4 contact eye. Patient could hold upside down 2 or sideways and contaci the eye with another surface of the dosing aid Drop guider or dropper tip 2 through improper usage becomes contaminated and could cause infection Failure to follow single use 1 physician restrictMas 8 4 Labeling instructions for use °ordains a precaution against mucking tiroPPcr tiP or anY pan of dosing aid to eye. 2 4 1 4 Labeling instructions for use (matins a precaution against touching dropper tip or any part of dosing aid to eye. Sales force to counsel physicians to not assign unit to multiple patients. Provide a contact number for patient to receive replacement components. TDOC-00022114 demonstrates consistency of drop size with and without the dosing aid Device designed and tested to comply with the IEC 60601-1 and 60601-1-1. Device designed and tested to comply with IEC 60601-1 1 3 1 3 2 2 I 1 1 2 I 2 2. Improper use Eye Infection 3 3. Use on multiple patients Cross-infection 3 4. Loss of basket Inconvenience to patient 1 Loss of one or both baskets that hold bottles in place for dosing 3 3 5. Drop size Results in significantly more or less drug being delivered to the eye Electric Shock 1 The dosing aid changes the delivery of the drop size 1 1 2 Trawler of unsafe voltage or current from computer system. 3 6 Burn (Excessive Temperature 2 3 6 Interference to other equipment 2 Overheating due to transfer of unsafe voltage or current to the body of the unit. Excess Radio Frequency Noise from TRAVATAN Dosing Aid 3 6 Device designed and tested to comply wit 15C 60601-1-2 1 2 Interference to TRAVATAN Dosing Aid or cradle from other equipment 2 The patient over or under doses because the reminder does not go off at correct time. Or the record is not transferred to the doctor's computer for proper evaluation 3 6 Device designed and tested to comply with 1EC 60601.1-2 1 2 6. Electrical Safety 7. Electromagnetic Compatibility 6 3 RD 731A Rev 03/02 SOP PROCA000159 CONFIDENTIAL PURSUANT TO THE PROTECTIVE ORDER SIM 1 IA Nil tt St aft 1111030.5.taMt.firl (VW G. AD TRAVATAN EIKE040577, • e ne....tracernaretnr..ae....Aerovaterereienwstontrearournasear,ramonwirtraurremorarremernenv.rereverearrou.wererarnammr Case 3:12-cv-01141-SMY-DGW Document 176-26 *SEALED* Filed 12/01/14 Page 19 of 22 Case: 16-3334 Document:Page 55-3 ID #2813 Filed: 02/08/2017 Pages: 22 (86 of 1511) Page 19 RELEASE FOR SUBMISSION GSF Coordinator: Angela C. Kothe, OD. PhD Regulatory Dossier/Type of Submission: NDA Jurisdiction: USA GSF No: 5- 1402_ (Assigned by OAU) Product/Project: TRAVATAN dosing aid We have reviewed the relevant documentation described below and affirm that all described information has been reviewed and appropriately authorized for inclusion within the described regulatory dossier. We endorse the inclusion of this information into the regulatory dossier. Description: Responses to FDA facsimile of July 27, 2005 regarding the TRAVATAN dosing aid. Endorsements: AU Multi-Function GSFs Require QAU Endorsement Audited 130AU: 6 rim /e2-1Z-05 NamerTitle Signature Date Signature Date Medical Specialty Director and Function VP: AV,VX1,3„ „ 4 0e,--al NamelTitle D. Scott Krueger, PhD NarnarTitle el‘fiz -orSignature Date NAME TITLE VP of Preclinical Science: Dr. Joe Hiddemen .A.820-4-41- dEd Signature Date VP Product Safety: Dr. Ralph Stone Signature UPON COMPLETION, COMPLETION, PLEASE RETURN DOCUMENTS TO: Angela C. Kothe / Reg Affairs Name a( Individual PRoC-0000151 CONFIDENTIAL PURSUANT TO THE PROTECTIVE ORDER Rev 09/15$05 RD225 AD TRAVATAN EIKE040578 OtVil'aatilM1,54,33. Case 3:12-cv-01141-SMY-DGW Document 176-26 *SEALED* Filed 12/01/14 Page 20 of 22 Case: 16-3334 Document:Page 55-3 ID #2814 Filed: 02/08/2017 Pages: 22 (87 of 1511) Page 20 GSF No: by 0Au) Mork KAN Muttl•Fuactlon GSF REGULATORY TRANSFER ENDORSEMENT GSF Coordinator: Angela C. Kothe / Reg Affairs Regulatory Dossier! Type of Submission: IND #51,000 Jurisdiction: USA Product/Project: TRAVATAN dosing aid Single Function GSF ❑ Multi-Function GSF (cheek en.) Function Name: Packaging I have reviewed the relevant documentation described below and find this documentation acceptable. 1 endorse the inclusion of this information Into the regulatory dossier. Description: Responses to FDA facsimile of July 27, 2006 regarding the TRAVATAN dosing aid. ENDORSEMENTS; Function Representative/Team Member: Name/Title Signature Date QAU Audit Not Single Function GSFs, except Product Safety Reports Wor 'Addition of Clinical investigator(s)', require QAU audit of R&D dataklocuments and endorsement via Applicable: RD224. Multi•Funclion GSFs are endorsed by QAU using RD225. If QAU endorsement is not required, or is accomplished to RD 225, mark N/A QAU Audit Completed: not applicable Name/Title Signature UPON COMPLETION, PLEASE RETURN DOCUMENTS TO: Date Angela Katie I Reg Affairs Name M individual Rev 06102 RD224 PROD-0000151 CONFIDENTIAL PURSUANT TO THE PROTECTIVE ORDER AD TRAVATAN EIKE0405T9 Am. Case 3:12-cv-01141-SMY-DGW Document 176-26 *SEALED* Filed 12/01/14 Page 21 of 22 Case: 16-3334 Document:Page 55-3 ID #2815 Filed: 02/08/2017 Pages: 22 (88 of 1511) Page 21 • ru N U.S CERTIFIED f•JlAIL •L--.70aost,c Orn'y No R 1 0.5;,,,,.4,:.cE ided, U) rrl CI Poe StalmIt Nem Mimi NI**Moo (Sydemproganwilwifl , lbeiteddlotry .4 Cardamon'%win* .411 1b Purs. a Paso a N Pr/PIA? 4:lei ec' AD_TRAVATAN_EIKE040580 CONFIDENTIAL PURSUANT TO THE PROTECTIVE ORDER .16414M1AVeso,...., Case 3:12-cv-01141-SMY-DGW Document 176-26 *SEALED* Filed 12/01/14 Page 22 of 22 Case: 16-3334 Document:Page 55-3 ID #2816 Filed: 02/08/2017 Pages: 22 (89 of 1511) Page 22 3 US Airbill FedEx. Etyma 8527 3393 6911 Surder's Copy Psailspfla hatpin= 725-7-19'fif•N. 1674-0792-7 kt... 11ftrine‘ ef) EleaV: ZieZzo". aZa• P.I.NMIlia././.1•••••••••• Blimati•10101060 .."ALCON RESEARCH LTD 0 tt44- m. 6201 SOUTH FWY Ad . FORT WORTH awl T X at .trwisrm. Soilosildolwo I N. —„L—. Nbelattr,701930037 U. fiJ 71 76134-2001 551010I sism musalladbi mrxm. I 15 WcracMt i g s• 9/P1-13 I3 rni rn not_s RD, H `.520 AMfw .Yhri Qt/7125 elttAsiA AdV: " - *1 ;27;j2 lax 7:3 4.851ans? VI* orriftio itisionoem wed tienchote mai= ❑ atlas_ COPMVWX1/ 04110.WhambeRbesimoireamoi•WOM4 ❑0 Thtl 'WV 0 "1,00 pwakethallaelbollimar•Mogh i; 0 Pa°100 Ara 11101.04116 1 262, IMI1=11 .0 05. ..m...2 2.16 0 0 rak,. 0 P•at • 0 ft...ftw. 0 Wm** 1601$0 11.408.1110$$%1•0 1%**/*parnsimosimpirMooltiliralialmistlinfoll x $.0, 11•010 a5.1Watitateaditway1968wa5ipmg 0310030395 464.1 AD TRAVATAN_EIKE040581 ..-MiKifWAITIA I Pi IRS IANT Tn THE PROTECTIVE ORDER Case 3:12-cv-01141-SMY-DGW Document 176-52 *SEALED* Filed 12/01/14 Page 1 of 10 Case: 16-3334 Document:Page 55-4 ID #3474 Filed: 02/08/2017 Pages: 10 (90 of 1511) Redacted Redacted Redacted Redacted Redacted AR-000021 Case 3:12-cv-01141-SMY-DGW Document 176-52 *SEALED* Filed 12/01/14 Page 2 of 10 Case: 16-3334 Document:Page 55-4 ID #3475 Filed: 02/08/2017 Pages: 10 (91 of 1511) Redacted Redacted Redacted Redacted AR-000022 Redacted Case 3:12-cv-01141-SMY-DGW Document 176-52 *SEALED* Filed 12/01/14 Page 3 of 10 Case: 16-3334 Document:Page 55-4 ID #3476 Filed: 02/08/2017 Pages: 10 (92 of 1511) Redacted Redacted Redacted Redacted Redacted AR-000023 Case 3:12-cv-01141-SMY-DGW Document 176-52 *SEALED* Filed 12/01/14 Page 4 of 10 Case: 16-3334 Document:Page 55-4 ID #3477 Filed: 02/08/2017 Pages: 10 (93 of 1511) Redacted Redacted Redacted Redacted AR-000024 Case 3:12-cv-01141-SMY-DGW Document 176-52 *SEALED* Filed 12/01/14 Page 5 of 10 Case: 16-3334 Document:Page 55-4 ID #3478 Filed: 02/08/2017 Pages: 10 (94 of 1511) Redacted Redacted Redacted Redacted AR-000025 Case 3:12-cv-01141-SMY-DGW Document 176-52 *SEALED* Filed 12/01/14 Page 6 of 10 Case: 16-3334 Document:Page 55-4 ID #3479 Filed: 02/08/2017 Pages: 10 (95 of 1511) Redacted Redacted Redacted AR-000026 Case 3:12-cv-01141-SMY-DGW Document 176-52 *SEALED* Filed 12/01/14 Page 7 of 10 Case: 16-3334 Document:Page 55-4 ID #3480 Filed: 02/08/2017 Pages: 10 (96 of 1511) Redacted Redacted Redacted AR-000027 Case 3:12-cv-01141-SMY-DGW Document 176-52 *SEALED* Filed 12/01/14 Page 8 of 10 Case: 16-3334 Document:Page 55-4 ID #3481 Filed: 02/08/2017 Pages: 10 (97 of 1511) Redacted Redacted Redacted Redacted Redacted AR-000028 Case 3:12-cv-01141-SMY-DGW Document 176-52 *SEALED* Filed 12/01/14 Page 9 of 10 Case: 16-3334 Document:Page 55-4 ID #3482 Filed: 02/08/2017 Pages: 10 (98 of 1511) Redacted Redacted Redacted Redacted Redacted Redacted AR-000029 Case 3:12-cv-01141-SMY-DGW Document 176-52 *SEALED* Filed 12/01/14 Page 10 of 10 Case: 16-3334 Document:Page 55-4 ID #3483 Filed: 02/08/2017 Pages: 10 (99 of 1511) Redacted Redacted Redacted Redacted AR-000030 Case 3:12-cv-01141-SMY-DGW Document 176-2 *SEALED* Filed 12/01/14 Page 1 of 80 Case: 16-3334 Document:Page 55-5 ID #2168 Filed: 02/08/2017 Pages: 80 (100 of 1511) Case 3:12-cv-01141-SMY-DGW Document 176-2 *SEALED* Filed 12/01/14 Page 2 of 80 Case: 16-3334 Document:Page 55-5 ID #2169 Filed: 02/08/2017 Pages: 80 (101 of 1511) Case 3:12-cv-01141-SMY-DGW Document 176-2 *SEALED* Filed 12/01/14 Page 3 of 80 Case: 16-3334 Document:Page 55-5 ID #2170 Filed: 02/08/2017 Pages: 80 (102 of 1511) Case 3:12-cv-01141-SMY-DGW Document 176-2 *SEALED* Filed 12/01/14 Page 4 of 80 Case: 16-3334 Document:Page 55-5 ID #2171 Filed: 02/08/2017 Pages: 80 (103 of 1511) Case 3:12-cv-01141-SMY-DGW Document 176-2 *SEALED* Filed 12/01/14 Page 5 of 80 Case: 16-3334 Document:Page 55-5 ID #2172 Filed: 02/08/2017 Pages: 80 (104 of 1511) Case 3:12-cv-01141-SMY-DGW Document 176-2 *SEALED* Filed 12/01/14 Page 6 of 80 Case: 16-3334 Document:Page 55-5 ID #2173 Filed: 02/08/2017 Pages: 80 (105 of 1511) Case 3:12-cv-01141-SMY-DGW Document 176-2 *SEALED* Filed 12/01/14 Page 7 of 80 Case: 16-3334 Document:Page 55-5 ID #2174 Filed: 02/08/2017 Pages: 80 (106 of 1511) Case 3:12-cv-01141-SMY-DGW Document 176-2 *SEALED* Filed 12/01/14 Page 8 of 80 Case: 16-3334 Document:Page 55-5 ID #2175 Filed: 02/08/2017 Pages: 80 (107 of 1511) Case 3:12-cv-01141-SMY-DGW Document 176-2 *SEALED* Filed 12/01/14 Page 9 of 80 Case: 16-3334 Document:Page 55-5 ID #2176 Filed: 02/08/2017 Pages: 80 (108 of 1511) Case 3:12-cv-01141-SMY-DGW Document 176-2 *SEALED* Filed 12/01/14 Page 10 of 80 Case: 16-3334 Document:Page 55-5 ID #2177 Filed: 02/08/2017 Pages: 80 (109 of 1511) Case 3:12-cv-01141-SMY-DGW Document 176-2 *SEALED* Filed 12/01/14 Page 11 of 80 Case: 16-3334 Document:Page 55-5 ID #2178 Filed: 02/08/2017 Pages: 80 (110 of 1511) Case 3:12-cv-01141-SMY-DGW Document 176-2 *SEALED* Filed 12/01/14 Page 12 of 80 Case: 16-3334 Document:Page 55-5 ID #2179 Filed: 02/08/2017 Pages: 80 (111 of 1511) Case 3:12-cv-01141-SMY-DGW Document 176-2 *SEALED* Filed 12/01/14 Page 13 of 80 Case: 16-3334 Document:Page 55-5 ID #2180 Filed: 02/08/2017 Pages: 80 (112 of 1511) Case 3:12-cv-01141-SMY-DGW Document 176-2 *SEALED* Filed 12/01/14 Page 14 of 80 Case: 16-3334 Document:Page 55-5 ID #2181 Filed: 02/08/2017 Pages: 80 (113 of 1511) Case 3:12-cv-01141-SMY-DGW Document 176-2 *SEALED* Filed 12/01/14 Page 15 of 80 Case: 16-3334 Document:Page 55-5 ID #2182 Filed: 02/08/2017 Pages: 80 (114 of 1511) Case 3:12-cv-01141-SMY-DGW Document 176-2 *SEALED* Filed 12/01/14 Page 16 of 80 Case: 16-3334 Document:Page 55-5 ID #2183 Filed: 02/08/2017 Pages: 80 (115 of 1511) Case 3:12-cv-01141-SMY-DGW Document 176-2 *SEALED* Filed 12/01/14 Page 17 of 80 Case: 16-3334 Document:Page 55-5 ID #2184 Filed: 02/08/2017 Pages: 80 (116 of 1511) Case 3:12-cv-01141-SMY-DGW Document 176-2 *SEALED* Filed 12/01/14 Page 18 of 80 Case: 16-3334 Document:Page 55-5 ID #2185 Filed: 02/08/2017 Pages: 80 (117 of 1511) Case 3:12-cv-01141-SMY-DGW Document 176-2 *SEALED* Filed 12/01/14 Page 19 of 80 Case: 16-3334 Document:Page 55-5 ID #2186 Filed: 02/08/2017 Pages: 80 (118 of 1511) Case 3:12-cv-01141-SMY-DGW Document 176-2 *SEALED* Filed 12/01/14 Page 20 of 80 Case: 16-3334 Document:Page 55-5 ID #2187 Filed: 02/08/2017 Pages: 80 (119 of 1511) Case 3:12-cv-01141-SMY-DGW Document 176-2 *SEALED* Filed 12/01/14 Page 21 of 80 Case: 16-3334 Document:Page 55-5 ID #2188 Filed: 02/08/2017 Pages: 80 (120 of 1511) Case 3:12-cv-01141-SMY-DGW Document 176-2 *SEALED* Filed 12/01/14 Page 22 of 80 Case: 16-3334 Document:Page 55-5 ID #2189 Filed: 02/08/2017 Pages: 80 (121 of 1511) Case 3:12-cv-01141-SMY-DGW Document 176-2 *SEALED* Filed 12/01/14 Page 23 of 80 Case: 16-3334 Document:Page 55-5 ID #2190 Filed: 02/08/2017 Pages: 80 (122 of 1511) Case 3:12-cv-01141-SMY-DGW Document 176-2 *SEALED* Filed 12/01/14 Page 24 of 80 Case: 16-3334 Document:Page 55-5 ID #2191 Filed: 02/08/2017 Pages: 80 (123 of 1511) Case 3:12-cv-01141-SMY-DGW Document 176-2 *SEALED* Filed 12/01/14 Page 25 of 80 Case: 16-3334 Document:Page 55-5 ID #2192 Filed: 02/08/2017 Pages: 80 (124 of 1511) Case 3:12-cv-01141-SMY-DGW Document 176-2 *SEALED* Filed 12/01/14 Page 26 of 80 Case: 16-3334 Document:Page 55-5 ID #2193 Filed: 02/08/2017 Pages: 80 (125 of 1511) Case 3:12-cv-01141-SMY-DGW Document 176-2 *SEALED* Filed 12/01/14 Page 27 of 80 Case: 16-3334 Document:Page 55-5 ID #2194 Filed: 02/08/2017 Pages: 80 (126 of 1511) Case 3:12-cv-01141-SMY-DGW Document 176-2 *SEALED* Filed 12/01/14 Page 28 of 80 Case: 16-3334 Document:Page 55-5 ID #2195 Filed: 02/08/2017 Pages: 80 (127 of 1511) Case 3:12-cv-01141-SMY-DGW Document 176-2 *SEALED* Filed 12/01/14 Page 29 of 80 Case: 16-3334 Document:Page 55-5 ID #2196 Filed: 02/08/2017 Pages: 80 (128 of 1511) Case 3:12-cv-01141-SMY-DGW Document 176-2 *SEALED* Filed 12/01/14 Page 30 of 80 Case: 16-3334 Document:Page 55-5 ID #2197 Filed: 02/08/2017 Pages: 80 (129 of 1511) Case 3:12-cv-01141-SMY-DGW Document 176-2 *SEALED* Filed 12/01/14 Page 31 of 80 Case: 16-3334 Document:Page 55-5 ID #2198 Filed: 02/08/2017 Pages: 80 (130 of 1511) Case 3:12-cv-01141-SMY-DGW Document 176-2 *SEALED* Filed 12/01/14 Page 32 of 80 Case: 16-3334 Document:Page 55-5 ID #2199 Filed: 02/08/2017 Pages: 80 (131 of 1511) Case 3:12-cv-01141-SMY-DGW Document 176-2 *SEALED* Filed 12/01/14 Page 33 of 80 Case: 16-3334 Document:Page 55-5 ID #2200 Filed: 02/08/2017 Pages: 80 (132 of 1511) Case 3:12-cv-01141-SMY-DGW Document 176-2 *SEALED* Filed 12/01/14 Page 34 of 80 Case: 16-3334 Document:Page 55-5 ID #2201 Filed: 02/08/2017 Pages: 80 (133 of 1511) Case 3:12-cv-01141-SMY-DGW Document 176-2 *SEALED* Filed 12/01/14 Page 35 of 80 Case: 16-3334 Document:Page 55-5 ID #2202 Filed: 02/08/2017 Pages: 80 (134 of 1511) Case 3:12-cv-01141-SMY-DGW Document 176-2 *SEALED* Filed 12/01/14 Page 36 of 80 Case: 16-3334 Document:Page 55-5 ID #2203 Filed: 02/08/2017 Pages: 80 (135 of 1511) Case 3:12-cv-01141-SMY-DGW Document 176-2 *SEALED* Filed 12/01/14 Page 37 of 80 Case: 16-3334 Document:Page 55-5 ID #2204 Filed: 02/08/2017 Pages: 80 (136 of 1511) Case 3:12-cv-01141-SMY-DGW Document 176-2 *SEALED* Filed 12/01/14 Page 38 of 80 Case: 16-3334 Document:Page 55-5 ID #2205 Filed: 02/08/2017 Pages: 80 (137 of 1511) Case 3:12-cv-01141-SMY-DGW Document 176-2 *SEALED* Filed 12/01/14 Page 39 of 80 Case: 16-3334 Document:Page 55-5 ID #2206 Filed: 02/08/2017 Pages: 80 (138 of 1511) Case 3:12-cv-01141-SMY-DGW Document 176-2 *SEALED* Filed 12/01/14 Page 40 of 80 Case: 16-3334 Document:Page 55-5 ID #2207 Filed: 02/08/2017 Pages: 80 (139 of 1511) Case 3:12-cv-01141-SMY-DGW Document 176-2 *SEALED* Filed 12/01/14 Page 41 of 80 Case: 16-3334 Document:Page 55-5 ID #2208 Filed: 02/08/2017 Pages: 80 (140 of 1511) Case 3:12-cv-01141-SMY-DGW Document 176-2 *SEALED* Filed 12/01/14 Page 42 of 80 Case: 16-3334 Document:Page 55-5 ID #2209 Filed: 02/08/2017 Pages: 80 (141 of 1511) Case 3:12-cv-01141-SMY-DGW Document 176-2 *SEALED* Filed 12/01/14 Page 43 of 80 Case: 16-3334 Document:Page 55-5 ID #2210 Filed: 02/08/2017 Pages: 80 (142 of 1511) Case 3:12-cv-01141-SMY-DGW Document 176-2 *SEALED* Filed 12/01/14 Page 44 of 80 Case: 16-3334 Document:Page 55-5 ID #2211 Filed: 02/08/2017 Pages: 80 (143 of 1511) Case 3:12-cv-01141-SMY-DGW Document 176-2 *SEALED* Filed 12/01/14 Page 45 of 80 Case: 16-3334 Document:Page 55-5 ID #2212 Filed: 02/08/2017 Pages: 80 (144 of 1511) Case 3:12-cv-01141-SMY-DGW Document 176-2 *SEALED* Filed 12/01/14 Page 46 of 80 Case: 16-3334 Document:Page 55-5 ID #2213 Filed: 02/08/2017 Pages: 80 (145 of 1511) Case 3:12-cv-01141-SMY-DGW Document 176-2 *SEALED* Filed 12/01/14 Page 47 of 80 Case: 16-3334 Document:Page 55-5 ID #2214 Filed: 02/08/2017 Pages: 80 (146 of 1511) Case 3:12-cv-01141-SMY-DGW Document 176-2 *SEALED* Filed 12/01/14 Page 48 of 80 Case: 16-3334 Document:Page 55-5 ID #2215 Filed: 02/08/2017 Pages: 80 (147 of 1511) Case 3:12-cv-01141-SMY-DGW Document 176-2 *SEALED* Filed 12/01/14 Page 49 of 80 Case: 16-3334 Document:Page 55-5 ID #2216 Filed: 02/08/2017 Pages: 80 (148 of 1511) Case 3:12-cv-01141-SMY-DGW Document 176-2 *SEALED* Filed 12/01/14 Page 50 of 80 Case: 16-3334 Document:Page 55-5 ID #2217 Filed: 02/08/2017 Pages: 80 (149 of 1511) Case 3:12-cv-01141-SMY-DGW Document 176-2 *SEALED* Filed 12/01/14 Page 51 of 80 Case: 16-3334 Document:Page 55-5 ID #2218 Filed: 02/08/2017 Pages: 80 (150 of 1511) Case 3:12-cv-01141-SMY-DGW Document 176-2 *SEALED* Filed 12/01/14 Page 52 of 80 Case: 16-3334 Document:Page 55-5 ID #2219 Filed: 02/08/2017 Pages: 80 (151 of 1511) Case 3:12-cv-01141-SMY-DGW Document 176-2 *SEALED* Filed 12/01/14 Page 53 of 80 Case: 16-3334 Document:Page 55-5 ID #2220 Filed: 02/08/2017 Pages: 80 (152 of 1511) Case 3:12-cv-01141-SMY-DGW Document 176-2 *SEALED* Filed 12/01/14 Page 54 of 80 Case: 16-3334 Document:Page 55-5 ID #2221 Filed: 02/08/2017 Pages: 80 (153 of 1511) Case 3:12-cv-01141-SMY-DGW Document 176-2 *SEALED* Filed 12/01/14 Page 55 of 80 Case: 16-3334 Document:Page 55-5 ID #2222 Filed: 02/08/2017 Pages: 80 (154 of 1511) Case 3:12-cv-01141-SMY-DGW Document 176-2 *SEALED* Filed 12/01/14 Page 56 of 80 Case: 16-3334 Document:Page 55-5 ID #2223 Filed: 02/08/2017 Pages: 80 (155 of 1511) Case 3:12-cv-01141-SMY-DGW Document 176-2 *SEALED* Filed 12/01/14 Page 57 of 80 Case: 16-3334 Document:Page 55-5 ID #2224 Filed: 02/08/2017 Pages: 80 (156 of 1511) Case 3:12-cv-01141-SMY-DGW Document 176-2 *SEALED* Filed 12/01/14 Page 58 of 80 Case: 16-3334 Document:Page 55-5 ID #2225 Filed: 02/08/2017 Pages: 80 (157 of 1511) Case 3:12-cv-01141-SMY-DGW Document 176-2 *SEALED* Filed 12/01/14 Page 59 of 80 Case: 16-3334 Document:Page 55-5 ID #2226 Filed: 02/08/2017 Pages: 80 (158 of 1511) Case 3:12-cv-01141-SMY-DGW Document 176-2 *SEALED* Filed 12/01/14 Page 60 of 80 Case: 16-3334 Document:Page 55-5 ID #2227 Filed: 02/08/2017 Pages: 80 (159 of 1511) Case 3:12-cv-01141-SMY-DGW Document 176-2 *SEALED* Filed 12/01/14 Page 61 of 80 Case: 16-3334 Document:Page 55-5 ID #2228 Filed: 02/08/2017 Pages: 80 (160 of 1511) Case 3:12-cv-01141-SMY-DGW Document 176-2 *SEALED* Filed 12/01/14 Page 62 of 80 Case: 16-3334 Document:Page 55-5 ID #2229 Filed: 02/08/2017 Pages: 80 (161 of 1511) Case 3:12-cv-01141-SMY-DGW Document 176-2 *SEALED* Filed 12/01/14 Page 63 of 80 Case: 16-3334 Document:Page 55-5 ID #2230 Filed: 02/08/2017 Pages: 80 (162 of 1511) Case 3:12-cv-01141-SMY-DGW Document 176-2 *SEALED* Filed 12/01/14 Page 64 of 80 Case: 16-3334 Document:Page 55-5 ID #2231 Filed: 02/08/2017 Pages: 80 (163 of 1511) Case 3:12-cv-01141-SMY-DGW Document 176-2 *SEALED* Filed 12/01/14 Page 65 of 80 Case: 16-3334 Document:Page 55-5 ID #2232 Filed: 02/08/2017 Pages: 80 (164 of 1511) Case 3:12-cv-01141-SMY-DGW Document 176-2 *SEALED* Filed 12/01/14 Page 66 of 80 Case: 16-3334 Document:Page 55-5 ID #2233 Filed: 02/08/2017 Pages: 80 (165 of 1511) Case 3:12-cv-01141-SMY-DGW Document 176-2 *SEALED* Filed 12/01/14 Page 67 of 80 Case: 16-3334 Document:Page 55-5 ID #2234 Filed: 02/08/2017 Pages: 80 (166 of 1511) Case 3:12-cv-01141-SMY-DGW Document 176-2 *SEALED* Filed 12/01/14 Page 68 of 80 Case: 16-3334 Document:Page 55-5 ID #2235 Filed: 02/08/2017 Pages: 80 (167 of 1511) Case 3:12-cv-01141-SMY-DGW Document 176-2 *SEALED* Filed 12/01/14 Page 69 of 80 Case: 16-3334 Document:Page 55-5 ID #2236 Filed: 02/08/2017 Pages: 80 (168 of 1511) Case 3:12-cv-01141-SMY-DGW Document 176-2 *SEALED* Filed 12/01/14 Page 70 of 80 Case: 16-3334 Document:Page 55-5 ID #2237 Filed: 02/08/2017 Pages: 80 (169 of 1511) Case 3:12-cv-01141-SMY-DGW Document 176-2 *SEALED* Filed 12/01/14 Page 71 of 80 Case: 16-3334 Document:Page 55-5 ID #2238 Filed: 02/08/2017 Pages: 80 (170 of 1511) Case 3:12-cv-01141-SMY-DGW Document 176-2 *SEALED* Filed 12/01/14 Page 72 of 80 Case: 16-3334 Document:Page 55-5 ID #2239 Filed: 02/08/2017 Pages: 80 (171 of 1511) Case 3:12-cv-01141-SMY-DGW Document 176-2 *SEALED* Filed 12/01/14 Page 73 of 80 Case: 16-3334 Document:Page 55-5 ID #2240 Filed: 02/08/2017 Pages: 80 (172 of 1511) Case 3:12-cv-01141-SMY-DGW Document 176-2 *SEALED* Filed 12/01/14 Page 74 of 80 Case: 16-3334 Document:Page 55-5 ID #2241 Filed: 02/08/2017 Pages: 80 (173 of 1511) Case 3:12-cv-01141-SMY-DGW Document 176-2 *SEALED* Filed 12/01/14 Page 75 of 80 Case: 16-3334 Document:Page 55-5 ID #2242 Filed: 02/08/2017 Pages: 80 (174 of 1511) Case 3:12-cv-01141-SMY-DGW Document 176-2 *SEALED* Filed 12/01/14 Page 76 of 80 Case: 16-3334 Document:Page 55-5 ID #2243 Filed: 02/08/2017 Pages: 80 (175 of 1511) Case 3:12-cv-01141-SMY-DGW Document 176-2 *SEALED* Filed 12/01/14 Page 77 of 80 Case: 16-3334 Document:Page 55-5 ID #2244 Filed: 02/08/2017 Pages: 80 (176 of 1511) Case 3:12-cv-01141-SMY-DGW Document 176-2 *SEALED* Filed 12/01/14 Page 78 of 80 Case: 16-3334 Document:Page 55-5 ID #2245 Filed: 02/08/2017 Pages: 80 (177 of 1511) Case 3:12-cv-01141-SMY-DGW Document 176-2 *SEALED* Filed 12/01/14 Page 79 of 80 Case: 16-3334 Document:Page 55-5 ID #2246 Filed: 02/08/2017 Pages: 80 (178 of 1511) Case 3:12-cv-01141-SMY-DGW Document 176-2 *SEALED* Filed 12/01/14 Page 80 of 80 Case: 16-3334 Document:Page 55-5 ID #2247 Filed: 02/08/2017 Pages: 80 (179 of 1511) Case 3:12-cv-01141-SMY-DGW Document 176-27 *SEALED* Filed 12/01/14 Page 1 of 17 Case: 16-3334 Document:Page 55-6 ID #2817 Filed: 02/08/2017 Pages: 17 Omm• ALLERCAN GLOBAL R&D PROJECT MANAGEMENT NEW GENERATION CONTAINER CLOSURE SYSTEMS Worldwide Integrated Development Plan Project# 200301201368 Original Approval: March 30,1999 Last Development Committee Approval: June 2000 Updated: March 20,2001 Significant Updates from previously approved WIDP: None WARNING The following document contains confidential, non-public information about Allergan and its plans. The presentation is intended solely for Allergan's personnel. All personnel at every level are prohibited by law as well as Company policy from -using non-public information about Allergan and its business plans in connection with the purchase or sale of Allergan stock. -disclosing such confidential information to persons outside the Company Any unauthorized use or disclosure of Allergan confidential information may subject the employee to civil and criminal penalties as well as dismissal. (180 of 1511) co co Case 3:12-cv-01141-SMY-DGW Document 176-27 *SEALED* Filed 12/01/14 Page 2 of 17 Case: 16-3334 Document:Page 55-6 ID #2818 Filed: 02/08/2017 Pages: 17 DON cialAkOZIIVINT0 LI 91 91 91 VI ET ET ET ZI ZI ZI ()I 66E" cICITAk :XICUslacklY sNouvormo TVILLDVIIINOD SfILVIS IlsIaLVd afrIVA INasaud lam UNITTMAILL INIa1AlcIOTJATI • (SDLLSRIalOVIIVHD iaouvn ssappas J.Darom do Ainnivaoua apriAl ag[um suopspqns aiatim saumnop z-9 • nalvils 1.9 A110,1,11111Dal1 acamamiom. 2uHaqt-Ou!2elaud rt. S'aLLIALIOV INIMAIcICTIaAala MAW-MOM TIVNIOLLVII(INV UN11011031DVEE Dlansimas sopsualounto 8uHaqui lonpoid Z.Z 2umomsoci lanpoid rz ustainisS'aSSV Ä1WS gAIlf1DaXa sjualuoD jo appj, 89£TOZIO£00Z #Parom uum watudolanau papaapq appippom aansoo numuojuo3enua9 AN ,LIslahla9VNYPi JZfoud a201 INT11019 • (181 of 1511) A. irpuaptTutuvdulop NI9031111 • 'ZI 'II '01 *6 '8 *L *9 '17 •£ 'Z '1 co cv Case 3:12-cv-01141-SMY-DGW Document 176-27 *SEALED* Filed 12/01/14 Page 3 of 17 Case: 16-3334 Document:Page 55-6 ID #2819 Filed: 02/08/2017 Pages: 17 CD, ALLAN (182 of 1511) GLOBAL R&D PROJECT MANAGEMENT 1. EXECUTIVE SUMMARY A. MARKETING RATIONALE AND SCIENTIFIC BASIS FOR DEVELOPMENT Allergan needs to develop container closure systems that meet the needs of the consumer as well as potential regulatory requirements on a worldwide basis. Allergan's current container closure systems available for ophthalmic products, including 6 (pencil bottle), 10 and 15 ml fill sizes, do not adequately meet these needs. Improving the container closure system will also put the corporation into a leadership position in the ophthalmic packaging area. Amongst the desired objectives is to manufacture bottles that can be terminally sterilized (potential future regulatory requirement), as well as provide an advantage to the consumer in terms of ergonomics, consistent drops and no leakage. The new container closure system is be incorporated into five, ten and 15-ml bottles. The bottle will not prohibit achieving a minimum 24 month shelf life due to water loss or extractables. The containers will be designed to eliminate ti clo 'ng, nsufficient dose and be less I -lineable. leakage, i-----A new container closure system may alleviate most of the deficiencies seen at present, which are as follows: • The permeability of containers made from low-density polyethylene(LDPE)causes high water loss that reduces shelf life. • The potential for ingress of extractables from resins and label inks and adhesive • The current container closure systems do not have the flexibility to match the product with the desired drop size. The tips are not interchangeable. Other • Leakage from the Neck/tip, Tip/cap (examples are • Insufficient drops for dosing time period. • Inelegant design of the "pencil bottle- present 6 ml size Company Confidential Page 3 of 17 01MAR2OWIDP NCC Case 3:12-cv-01141-SMY-DGW Document 176-27 *SEALED* Filed 12/01/14 Page 4 of 17 Case: 16-3334 Document:Page 55-6 ID #2820 Filed: 02/08/2017 Pages: 17 ALLEOLAN GLOBAL R&D PROJECT MANAGEMENT B. INDICATION AND DOSAGE FORMS Five, 10 and 15 mL bottles with the appropriate tips and caps for a dispensed dose of 20 to 30 or 30 to 40 microliters. Compan ( 01MAR2OWIDP NCC (183 of 1511) Case 3:12-cv-01141-SMY-DGW Document 176-27 *SEALED* Filed 12/01/14 Page 5 of 17 Case: 16-3334 Document:Page 55-6 ID #2821 Filed: 02/08/2017 Pages: 17 ALLERGAN GLOBAL R&D PROJECT MANAGEMENT C TARGET PRODUCT LABELING CHARACTERISTICS Not Applicable Company Confidential Page 5 of 17 01MAR2OWIDP NCC (184 of 1511) Case 3:12-cv-01141-SMY-DGW Document 176-27 *SEALED* Filed 12/01/14 Page 6 of 17 Case: 16-3334 Document:Page 55-6 ID #2822 Filed: 02/08/2017 Pages: 17 O (185 of 1511) • ALLEOLAN GLOBAL R&D PROJECT MANAGEMENT D. PROJECT MILESTONES/TIMELINE/BUDGET 2001 MILESTONES Milestone Finalize Regulatory Strategy Complete New Tip Design Complete Testing of 10 & 15 int. Prototype Bottles Research Release 5 mL Bottle Projected Completion Date Jan-01 Jun-01 Jul-01 Actual Completion Date Status - _ Sep-01 CURRENT YEAR GLOBAL DEVELOPMENT OUTSIDE COST 01 Budget($000,000) 0.03 0.03 PROJECT TIMELINE Activities 2001 2002 2003 2004 2005 2006 14 20 30 40 1C1 20 30 14Q 1Q 20 3Q 40 la 20 30 40 10 20 30 4Q 10 20 3Q 40 Project Elevation: Jan-99 ----7. NDA Submission tou.i Development Cost Development Outside Cost Marketing Outside Cost Labor Cost Total 2001 MINH MAA Submission 0.1 2002 0.0 2003 0.0 0.3 0.3 0.0 0.1 0.0 0.1 MJapan Submission 2 MO flegulato-y Approval 2006 2000 ---0.465 • Assumptions: At Cornpan ntidential Page 6 of" 01mAR2OwiDP NCC Case 3:12-cv-01141-SMY-DGW Document 176-27 *SEALED* Filed 12/01/14 Page 7 of 17 Case: 16-3334 Document:Page 55-6 ID #2823 Filed: 02/08/2017 Pages: 17 GLOBAL R&D PROJECT MANAGEMENT E. CRITICAL DECISION POINTS IN CURRENT PHASE OF DEVELOPMENT Timing: Success Criteria: November 2000 1. Probe Stability Study F. SUMMARY OF PRODUCT APPROVAL DATES/SALES/PATENT EXPIRATION Patent/Exclusivity/ Expiration-Best Case Patent/Exclusivity/ Expiration-Worst Case Company Confidential o o o TBD Page 7 of 17 TBD TBD 01MAR2OWIDP NCC (186 of 1511) Case 3:12-cv-01141-SMY-DGW Document 176-27 *SEALED* Filed 12/01/14 Page 8 of 17 Case: 16-3334 Document:Page 55-6 ID #2824 Filed: 02/08/2017 Pages: 17 ALIERGAN • GLOBAL R&D PROJECT MANAGEMENT G. SUMMARY OF NPV AND PROBABILITY OF SUCCESS Minimum Cliarnatistits NPV Worldwide $1MM Target phis NA Probability of Success(POS) NA Probability Adjusted NPV = POS x NA NPV Company Confidential Page 8 of 17 (187 of 1511) 00FEB15 W1DP NCC Case 3:12-cv-01141-SMY-DGW Document 176-27 *SEALED* Filed 12/01/14 Page 9 of 17 Case: 16-3334 Document:Page 55-6 ID #2825 Filed: 02/08/2017 Pages: 17 (188 of 1511) 11•••• ALEERGAN GLOBAL R&D PROJECT MANAGEMENT 2. MARKETING ASSESSMENT 2.1 Product Positioning Market and Customer Need A shelf life below 24 months due to water loss or extractables is not acceptable in today's market environment. Allergan is at a competitive disadvantage with some older products, but also with some high potential new products for this reason. Allergan is also receiving a significant number of complaints on leakage. Furthermore, the drop size of Allergan's products has been bigger than most competitive products, which not only can lead to more side effects but also is a disadvantage from a phamacoeconomic perspective. Competitive Environment • Aesthetically pleasing • Ergonomically acceptable • Eliminate tip clogging • Leakage • Meets duration of use claim • Increased product shelf-life • Less product complaints Opportunities • Interchangeable parts Time to Market Requirements Pricing Assumptions • Cost will be close to current bottles Company Confidential Page 9 of 17 00FEB15 WIDP NCC • Case 3:12-cv-01141-SMY-DGW Document 176-27 *SEALED* Filed 12/01/14 Page 10 of 17 Case: 16-3334 Document:Page 55-6 ID #2826 Filed: 02/08/2017 Pages: 17 ALIERGAN • GLOBAL R&D PROJECT MANAGEMENT 2.2 Product Labeling Characteristics New cc)litaiiter closure system capable of providing: e 1,ess dropt waste and mess • Tarnper evident Nc)lealcage Ergonomic • Squeezable * Vertical stability Deliver a 20 - 30j_iL or 39.-40 pl., drop upon instillatiori (riot less than 20) GC1M ......_, Emoi• TO stetilization , * Oile drop at a time --- -o•7 „ Meets duration of use requirement Not Applicable Extraetables equal to current 1)ottle Reduced vapor ts-atismission tbat does not hinder 24 month shelf life Company Confidential Page 10 of 17 (189 of 1511) 00FEB 15 WIDP NCC • Case 3:12-cv-01141-SMY-DGW Document 176-27 *SEALED* Filed 12/01/14 Page 11 of 17 Case: 16-3334 Document:Page 55-6 ID #2827 Filed: 02/08/2017 Pages: 17 ALTERGAN GLOBAL R&D PROJECT MANAGEMENT _ tam • wo--= teALAL,17:4: I': •-. 4171' ;.;;. 1 ,11, ft#: /It) Equivalent to current safety Profile for present container systems 6 smooth flash injury to the eyefree in rounded tip to Prevent case if conctact • Compatible with simple ophthalmic solutions. Size: * Bottles — 5 111",fill(R&D), 10 and 15 111!-- till (Operations) 41# Supply — 2 week (marketing sample) 1 2 and 3 month * Fill volume — <21r1L, 2.5, 5 7.5, 10 d an 15 mL a• c; ''tft-44 , 0,44 4 442-kJ: - Not Applicable Packaging: All Pharmaceutical grade materials meet compelidiai requirements * Lower medication expenses due to: decrease in product loss • Appearance, size, method of use and operation must be as acceptable as current eyedrop bottles to doctors and patients Company Confidential Page 11 of 17 00FEB15 WIDE'NCC (190 of 1511) 8 (13 0 W tzi ftl H 0 0 tzi tzi • 0 Case 3:12-cv-01141-SMY-DGW Document 176-27 *SEALED* Filed 12/01/14 Page 12 of 17 Case: 16-3334 Document:Page 55-6 ID #2828 Filed: 02/08/2017 Pages: 17 (191 of 1511) w W H ALSRGAN " I GLOBAL R&D PROJECT MANAGEMENT (13 oø W : 1 1 d, 1 a I-A H ■-3 I Z 0 ■-3 W 0 W i W 0 W 0 0 ,-3 Vi 3. SCIENTIFIC BACKGROUND AND RATIONALE Please refer to the Executive Summary. 4. WORLDWIDE DEVELOPMENT ACTIVITIES 4.1 Packaging/Labeling The primary packaging container is a container closure system consisting of the bottle, tip and cap, each manufactured as a single component. The resins and all product-contacting components of the formed, molded primary packaging container will be tested for suitability for ophthalmic pharmaceutical use. All components will be tested for potential of gamma,ETO sterilization by validated processes. z o Company Confidential ,,- Page 12 of 17 00FEB15 WIDP NCC Case 3:12-cv-01141-SMY-DGW Document 176-27 *SEALED* Filed 12/01/14 Page 13 of 17 Case: 16-3334 Document:Page 55-6 ID #2829 Filed: 02/08/2017 Pages: 17 ALCERGAN GLOBAL R&D PROJECT MANAGEMENT 6. WORLDWIDE REGULATORY 6.1 Strategy Global container closure systems that will be used in registration for future and current products. 6.2 List of Countries Where Submissions Will Be Made North America Europe Asia-pacific Latin America Japan Company Confidential Page 13 of 17 00FEB15 WIDP NCC (192 of 1511) 8 CO 0 W tzi H 0 O tzi tzi • IZ) ■-3 W W H • • ■-4 " • I o d, ALSRGAN GLOBAL R&D PROJECT MANAGEMENT 7. PROBABILITY OF PROJECT SUCCESS H W Case 3:12-cv-01141-SMY-DGW Document 176-27 *SEALED* Filed 12/01/14 Page 14 of 17 Case: 16-3334 Document:Page 55-6 ID #2830 Filed: 02/08/2017 Pages: 17 ■-3 0 xl 0 0 t.1 (No Template for Consumer Eye Care projects or Packaging Projects) From Year 2000 Portfolio Review: 63% Company Confidential Page 14 of 17 00FEB15 WIDP NCC (193 of 1511) Case 3:12-cv-01141-SMY-DGW Document 176-27 *SEALED* Filed 12/01/14 Page 15 of 17 Case: 16-3334 Document:Page 55-6 ID #2831 Filed: 02/08/2017 Pages: 17 (194 of 1511) GLOBAL R&D PROJECT MANAGEMENT 8. ID 0 47 49 50 51 52 53 54 55 Development Timeline MCC 1360 Finalize regulatory strategy Release FITI--JaPan,5 ml- bottle Stability study ErrL4apan,5 mL bottle mL bottle Research Release 5 10 & 15 mL prototype bottle mold manufacture 10& 15 mL prototype bottle manufacture 10 & 15 mL prototype bottle testing Tip design 2X2=4 configurations Company Confidential 673 days 1 day 4 wks 26 wks 4 vvIcs 3 wks 12 wks 12 wks 24 wks Actual Start Mon 1/4/99 I Mon 1/4/99 Wed 1/24/01 1 NA mori 12/18/007 NA Thu 1/18/01 Tue 7/24/01 NA Tut) 1/2/01 NA TUE11/23/01 NA NA Wed 4/18/01 Tue 1/2/01 N,, Page 15 of 17 Plod Finish Mon 8/20/01 Wed 1/24/01 Actual Finish Department 04 Q1 Q21 Q3104 Q1 NA REGAFF PHMANL NA 1 NA P T E HC MHPK ANIMon (1/20/01 TECIIPK K Mon 4/ NA TECHPK 1/1.22 7i/ „th.°1---Iii-- a Tue 4in' TEcCHlipPKK Tt;t1 TE " -Wed 6120/01 TEcliPK 00FEB15 WIDP NCC • Q'dQ CI) 0 tzi ftl H 0 tzi tzi • 0 ■-3 W W H Case 3:12-cv-01141-SMY-DGW Document 176-27 *SEALED* Filed 12/01/14 Page 16 of 17 Case: 16-3334 Document:Page 55-6 ID #2832 Filed: 02/08/2017 Pages: 17 (195 of 1511) OLLERGAN GLOBAL R&D PROJECT MANAGEMENT (13 0 d, 9. NET PRESENT VALUE H ■-3 W ■-3 0 O W 0 ■-3 $11V1M(From Portfolio Planning) 10. PATENT STATUS To be determined. 11. CONTRACTUAL OBLIGATIONS TBD Company Confidential Page 16 of 17 00FEB15 WIDP NCC 0 rj tzi Case 3:12-cv-01141-SMY-DGW Document 176-27 *SEALED* Filed 12/01/14 Page 17 of 17 Case: 16-3334 Document:Page 55-6 ID #2833 Filed: 02/08/2017 Pages: 17 ■-3 (196 of 1511) aLERGAN GLOBAL R&D PROJECT MANAGEMENT tzi ■-3 ■-3 0 12. APPENDIX: WIDP TEAM APPROVAL LISTS Approved on this date: March 2001 0 ■-3 tzi Departmen. Name Difrtment ■-3 Project Leader S. Gerondale Project Manager J. Ratzliff European Subteam Leader New Products Marketing D.Power Medical Affairs US Process Chemistry(API) Medical Affairs Europe Technical Packaging L.Spada PSO L. Gran Team Members: Clinical US J. Cheetham Clinical Europe Toxicology Biostatistics/Data Mgmnt. Pharmacokinetics Regulatory US E.Bancroft/J. Cheng Regulatory Europe Research Operations R.Kurjan VVWQA L.Hacche SIMCOM D.Yotter Operations(Med.Plastics) J. Vanden Dries Pharm. Analysis S. Ruckmick Company Confidential Page 17 of 17 00FEB15 WIDP NCC Case 3:12-cv-01141-SMY-DGW Document 176-53 *SEALED* Filed 12/01/14 Page 1 of 12 Case: 16-3334 Document:Page 55-7 ID #3484 Filed: 02/08/2017 Pages: 12 (197 of 1511) 4111111 law The Simon Law Firm, P.C. Attorneys and Counselors at Law FIRM PROFILE The attorneys at The Simon Law Firm have extensive courtroom experience representing individuals and businesses in a wide range of cases. Since its inception, The Simon Law Firm has twice obtained the largest jury verdict in the State of Missouri. The Simon Law Firm has been dubbed one of the "winningest firms" in the nation, and U.S. News ranked The Simon Law Firm as one of the "Best Law Firms" in multiple areas of litigation. For business clients, The Simon Law Firm prosecutes complex cases ranging from intellectual property to contract disputes. For individuals, The Simon Law Firm represents those who have been injured by dangerous products, consumer fraud, environmental waste, predatory lending, unfair labor practices, discrimination, prescription drugs, medical malpractice, and automobile and trucking accidents. CLASS ACTION AND COMPLEX LITIGATION The Simon Law Firm has a distinguished record of success in class action litigation. The Simon Law Firm has obtained tens of millions of dollars in relief for millions of consumers, homeowners, and employees. The Simon Law Firm has argued class action issues before the Missouri Supreme Court five times since 2009. The Simon Law Firm regularly appears before the Missouri Court of Appeals on complicated class action issues and has successfully argued class action issues before the Eighth Circuit Court of Appeals. In 2011, John Simon was voted one of the "Most Influential Appellate Attorneys" in Missouri because of The Simon Law Firm's class action success on behalf of consumers. The Simon Law Firm has been lead counsel in dozens of class actions involving a wide range of legal matters including the FLSA, ERISA, FDCPA, constitutional challenges, and the UDAP statutes of various states. The Simon Law Firm has handled hundreds of complex class action suits. They have published articles and given presentations around the country on a wide-range of class action topics. Currently, The Simon Law Firm serves as interim class counsel in a consumer protection class action MDL in the Eastern District of Missouri. In Re: Emerson Electric Co. Wet/Dry Vac Marketing and Sales Practices Litigation, MDL 2382. COMMUNITY INVOLVEMENT The Simon Law Firm is proud to be a vibrant participant in the St. Louis community. Annually, our firm sponsors seminars and contributes to many local causes: • Simon Law Firm Trial Practice Seminar to Benefit Legal Services of Eastern Missouri Beginning in 2005 the Simon Law Firm founded a trial practice seminar designed to do two things: 1) provide ongoing education for attorneys and 2) raise money for Legal Services of Eastern Missouri. Since 2005, the seminar has grown dramatically, regularly attracting over 100 attendees. Lectures are given by attorneys and judges on a diverse range of topics by people recognized as experts in their fields, and attorneys pay to attend. Every dollar is donated to Legal Services. • Project XOXO In 2009, The Simon Law Firm recognized that local charities were experiencing a perfect storm that jeopardized their work. Due to a bad economy, their services were needed more than ever, but their funding was as low as it had ever been. As a result, people suffered. In response to this, the Simon Law Firm reached out to other firms and organizations in St. Louis in an effort to start 800 Market Street, Suite 1700 St. Louis, Missouri 63101 Telephone 314.241.2929 www.simonlawpc.com Toll Free 877.767.3108 Facsimile 314.241.2029 Case 3:12-cv-01141-SMY-DGW Document 176-53 *SEALED* Filed 12/01/14 Page 2 of 12 Case: 16-3334 Document:Page 55-7 ID #3485 Filed: 02/08/2017 Pages: 12 (198 of 1511) ow 41111ft The Simon Law Firm, P.C. Attorneys and Counselors at Law a massive legal charity project. The result is Project XOXO. Sponsored by the Bar Association of Metropolitan St. Louis (BAMSL) and the Missouri Association of Trial Attorneys (MATA), the project is designed to reach out to firms, big and small, for donations for local charities. The event culminates with a reception at the Old Courthouse were donors are recognized, and those who run the charities who are receiving support can share with donors the good their money will do. Project XOXO hopes to raise $100,000 in 2014. Visit www.projectxoxo.com for updates on donations and a chance to give. • Kids' Chance Inc. of Missouri Provides educational scholarships for children whose parents have been killed or seriously injured in a Missouri compensable Workers' Compensation accident. • Habitat for Humanity Charity Golf Tournament HFHI seeks to eliminate poverty housing and homelessness from the world, and to make decent shelter a matter of conscience and action. Habitat invites people of all backgrounds, races and religions to build houses together in partnership with families in need. • Black History Month/The Lawyers Association Each February, the Lawyers Association of St. Louis teams up with the Mound City Bar Association to present its annual Black History Month dinner program. • Dan Devereaux Memorial Trust for the Danny Boy Golf Classic Awards scholarships to local grade school, middle school and high school students. • Legal Services Justice for All Ball Proceeds help provide civil legal services for low-income people. Only one in five people who contact Legal Services will be assisted due to limited funding. The funds raised from this Ball narrow the gap. • Daughters of St. Paul Fund-raising for needs ranging from the educational expenses of the St. Paul sisters to roof repairs and new equipment. • Project Angel Tree Provides Christmas gifts for children whose parents are incarcerated. HONORS AND AWARDS As litigation has become more complicated and competitive, the highly skilled lawyers of The Simon Law Firm have repeatedly excelled to achieve the following honors and awards: • PILG Award The Public Interest Law Group of Saint Louis University has awarded The Simon Law Firm their 2012 Excellence in Pro Bono and Public Service Award. 800 Market Street, Suite 1700 St. Louis, Missouri 63101 Telephone 314.241.2929 www.simonlawpc.com Toll Free 877.767.3108 043110— Facsimile 314.241.2029 Case 3:12-cv-01141-SMY-DGW Document 176-53 *SEALED* Filed 12/01/14 Page 3 of 12 Case: 16-3334 Document:Page 55-7 ID #3486 Filed: 02/08/2017 Pages: 12 (199 of 1511) 411M low The Simon Law Firm, P.C. Attorneys and Counselors at Law • Martindale-Hubbell The following The Simon Law Firm attorneys have earned an AV rating, the highest bestowed by the Martindale-Hubbell. This rating reflects the highest standard of professional excellence. • Best Lawyers in America Best Lawyers has come to be regarded — by both the legal community and the public — as the definitive guide to legal excellence in the US. Best Lawyers is a peer-review survey in which 15,000 leading attorneys throughout the country confidentially cast more than half a million "votes" on the legal abilities of other lawyers in their specialties. • Missouri & Kansas Super Lawyers Super Lawyers is an organization that supervises a "selection process is to create a credible, comprehensive and diverse listing of outstanding attorneys that can be used as a resource to assist attorneys and sophisticated consumers in the search for legal counsel." John Simon has been recognized as being among the Top 10 attorneys in the Missouri & Kansas Super Lawyers and among the Top 50 St. Louis attorneys. • John C. Shepherd Professionalism Award This is an annual award given to one young lawyer in the St. Louis area. This honor is awarded only to attorneys who most exemplify the tenets of professionalism of the Bar Association of Metropolitan St. Louis. • Million Dollar Advocates Million Dollar Advocates is a prestigious group of trial lawyers in the United States. Membership is limited to attorneys who have won million and multi-million dollar verdicts and settlements. Less than 1% of U.S. lawyers are members. • The International Network of Boutique Law Firms The International Network of Boutique Law Firms. The Simon Law Firm is a member of this organization in the areas of plaintiff personal injury, product liability and mass tort litigation. SELECTED CASES • Notable Class Action Settlements • • • • Woods v. QC Financial Services Inc., d/b/a/ Quik Cash, Case No. 12SL-CC00318 (St. Louis County Cir. Ct. Feb. 2012) ($25 million settlement obtained via class arbitration in predatory lending class action). Bauer v. DFM Investment Co., No. 07CC-003756 (St. Louis County Cir. Ct. June 2011) ($3.5 million settlement in consumer fraud class action). Richards v. Lou Fusz Automotive Network, No. 08SL-CC04594 (St. Louis County Cir. Ct. Aug 2011) ($2.5 million settlement in consumer fraud class action). Hooper v. Advance America, No. 2:08-cv-4045 (Mo. W.D. Nov 2010) (predatory lending class action settlement that yield a refund of $2 million in cash, $3.8 million in debt reduction, and nearly $11 million total in overall debt relief). 800 Market Street, Suite 1700 St. Louis, Missouri 63101 Telephone 314.241.2929 www.simonlawpc.com •'s— Toll Free 877.767.3108 facsimile 314.241.2029 Case 3:12-cv-01141-SMY-DGW Document 176-53 *SEALED* Filed 12/01/14 Page 4 of 12 Case: 16-3334 Document:Page 55-7 ID #3487 Filed: 02/08/2017 Pages: 12 (200 of 1511) 411111111 tow The Simon Law Firm, P.C. Attorneys and Counselors at Law Frazier v. Elco Chevrolet Inc., No. 07CC-03928 (St. Louis County Cir. Ct. June 2010) ($2.3 million settlement in consumer fraud class action). Titus v. Burns & McDonnell Inc., No. 4:09-cv-117 (Mo. W.D. Sept. 2011) ($1.15 million settlement in ERISA class action). Jost v. Commonwealth Land Title Insurance Co., No. 4:08-734-CDP. (multi-state FLSA collective action settlement obtained after conditional certification granted by Judge Perry in the ED of MO). • Recent Multidistrict Litigation • • Notable Class Action Appellate Victories • • • • • • • • • In Re: Emerson Electric Co. Wet/Dry Vac Marketing and Sales Practices Litigation, MDL 2382 (Appointed Interim Class Counsel in consumer protection case in EDMO). Brunner v. City of Arnold, 427 S.W.3d 201 (Mo. App. E.D. 2013) (red light camera ordinance declared unconstitutional and void); Damon v. City of Kansas City, 419 S.W.3d 162 (Mo. App. W.D. 2013) (red light camera ordinance declared void because it conflicted with state law); Edwards v. City of Ellisville, 426 S.W.3d 644 (Mo. App. E.D. 2013) (same); Unverferth v. City of Florissant, 419 S.W.3d 76 (Mo. App. E.D. 2013) (same). Brewer v. Missouri Title Loans, 364 S.W.3d 486 (Mo. 2012) (Missouri Supreme Court found that AT&T Mobility v. Concepcion was not controlling because the arbitration clause at issue was unconscionable under Missouri law). Huch v. Charter Comm 'ns, Inc., 290 S.W.3d 721 (Mo. 2009) ("Best Appellate Win of the Year" in Missouri). Hooper v. Advance America, Inc., 589 F.3d 917 (8th Cir. 2009) Woods v. QC Fin. Serv., Inc., 280 S.W.3d 90 (Mo. App. E.D. 2008) Other Notable Verdicts & Settlements • • • • Randy Dorman v. Bridgestone/Firestone, Inc. A jury awarded $105 million to a man who was seriously injured when a multi-piece wheel explosively separated while he was airing up a tire. This caused the rim to strike his face with such force that it could have lifted a 3000-pound car 15 feet off the ground. Maldonado v. Regal Riverfront Hotel A boxer was awarded $41 Million by a jury for brain damage due to a hotel's failure to have an ambulance at a boxing match. He was eventually diagnosed with severe brain damage. Walsh v. Mid-South Trucking $10 million settlement of a claim brought against a trucking company. An 80,000 pound tractor trailer crossed the center line, killing the occupants of an oncoming car. The lawyers of The Simon Law Firm determined that the truck driver had over 230 separate violations of the federal regulations in the ten months he had been employed by the trucking company. Creative Internet Advertising Corporation v. Yahoo! Inc., et al. 800 Market Street, Suite 1700 St. Louis, Missouri 63101 Telephone 314.241.2929 www.simonlawpc.com •' Toll Free 877.767.3108 facsimile 314.241.2029 Case 3:12-cv-01141-SMY-DGW Document 176-53 *SEALED* Filed 12/01/14 Page 5 of 12 Case: 16-3334 Document:Page 55-7 ID #3488 Filed: 02/08/2017 Pages: 12 (201 of 1511) 41111111 taw • • • • • The Simon Law Firm, P.C. Attorneys and Counselors at Law A federal jury awarded Acacia Research Corporation's (Nasdaq: ACTG) subsidiary, Creative Internet Advertising Corporation, $6.6 million in a patent infringement trial with Yahoo! Inc. Jane Doe v. Pharmaceutical Company Suit was filed in St. Louis Circuit Court alleging that the company failed to follow federal regulations pertaining to handling hazardous chemicals in the lab and that the company had failed to warn the mother of the dangers associated with exposure to phenylacetic acid. The petition alleged that the company negligently exposed a pregnant mother to phenylacetic acid vapors generated when the chemical, a known fetotoxin, was heated in an unventilated oven less than 10 feet away without the mother's knowledge. The mother was eleven weeks pregnant at the time; her daughter was later born with severe birth defects. The cost of care for the child was estimated to be $6 million. Settlement amount: $9.5 million. John Doe v. Switchgear Manufacturer A 48 year old man suffered third degree burn injuries to his upper body and had his arm amputated after he was electrocuted while at work in March of 2006. He was ordered by his supervisor to place a lead identification tag on an energized cable inside an energized 15,000 volt switchgear, a job which violated OSHA regulations and which other more highly-trained workers had refused to perform. To perform the task, he had to remove a protective removable barrier which should have shut off the electrical power automatically, however, the wires remained "live" and the worker was electrocuted. Suit was filed in St. Louis Circuit Court. Claims were brought against the supervisor under the "something more" theory of liability, thereby defeating worker's compensation immunity and claims were also brought against the manufacturer of the switchgear. The case was settled for $6 million against the switchgear manufacturer and $4 million against the supervisor. Total settlement: $10 million. Jone v. Coleman A claim was brought against Coleman by the mother of a young man named Cary Lam. Cary went camping with his uncle. They lit a lantern for warmth in the middle of a cool night, and Cary died of carbon monoxide poisoning. The Coleman propane cylinder that was used did not mention the risks of carbon monoxide and stated that the propane should be used in a ventilated area. Both 2' x 2' windows on the tent were wide open at the time of the accident. The case of Jone v. Coleman was settled in March of 2009 for a confidential amount. Coleman did not admit liability. Guidry, et al. v. UBS Realty Investors L.L.C., et al. The plaintiffs had alleged that they had been denied their continuing exclusive right to provide cable service to a large apartment complex. Simul-Vision had originally entered its contract with the Seven Trails West Apartment complex in 1984. That contract provided that Simul-Vision would be the exclusive provider of cable television service to residents of Seven Trails. The jury's May 19, 2006 verdict recognized that the breach defeated the original intentions of the parties that Simul-Vision would continue to have exclusive rights to provide cable service until a separate cable company would take over Simulvision's existing cable system at the complex, compensating Simul-Vision on a per subscriber basis. Brown v. Laclede Gas Co., Inc. A gas utility company paid $8 Million to settle this wrongful death case filed on behalf of the family of Louis Brown, who was killed in a natural gas explosion at his home. 800 Market Street, Suite 1700 St. Louis, Missouri 63101 Telephone 314.241.2929 www.simonlawpc.com •44111 Toll Free 877.767.3108 Facsimile 314.241.2029 Case 3:12-cv-01141-SMY-DGW Document 176-53 *SEALED* Filed 12/01/14 Page 6 of 12 Case: 16-3334 Document:Page 55-7 ID #3489 Filed: 02/08/2017 Pages: 12 (202 of 1511) 41111111 kamo • • • • The Simon Law Firm, P.C. Attorneys and Counselors at Law Storage Technology Company v. Custom Hardware Engineering & Consulting, Inc. After four years of protracted litigation, Fenton-based Custom Hardware Engineering & Consulting, originally sued for copyright infringement, received a cash settlement and promise not to sue from StorageTek, who had initiated the litigation, and its parent Sun Microsystems. Donald Edwards, et al. v. Air Products and Chemicals, Inc. $2.3 Million settlement for a worker in a products liability suit. A liquid oxygen cylinder fell over and exploded. Inverizon International, Inc. v. Verizon Communications, Inc. Confidential Settlement of trademark infringement case where the defendant was accused of "reverse confusion." The owner of a consulting company had sued Verizon Communications for trademark infringement, claiming that the use of that name confused his customers. Andrew Beavers v. Paradise Valley Residents Association $2.5 million settlement for a 16-year old boy who was paralyzed from the chest down after an automobile accident on an improperly maintained road (no guardrail at a sharp curve). There had been seven prior accidents at the site. Michael Lebrun v. Mine Safety Appliances Co. $6.5 million settlement of a product liability suit. The plaintiff was a fire fighter who suffered brain damage when the oxygen alarm on his oxygen tank malfunctioned while he fought a fire in a high-rise retirement center. This suit resulted in a national recall of the product. Jason Frede and Alicia Frede v. Ford Motor Company et al. Plaintiffs alleged serious injuries resulting from multiple design features of the Ford Explorer. In addition to the rollover issues often associated with the Explorer, this case involved a claim for Ford's defective design of the vehicle's door latch system. As the vehicle rolled over on the highway, both doors flew open, causing the occupants to be thrown about, held in the car only by their seat belts (both occupants were wearing seat belts). Both Plaintiffs sustained their injuries as a result of the doors coming open. The Plaintiffs received a settlement that was confidential in amount. 800 Market Street, Suite 1700 St. Louis, Missouri 63101 Telephone 314.241.2929 www.simonlawpc.com Toll Free 877.767.3108 Facsimile 314.241.2029 Case 3:12-cv-01141-SMY-DGW Document 176-53 *SEALED* Filed 12/01/14 Page 7 of 12 Case: 16-3334 Document:Page 55-7 ID #3490 Filed: 02/08/2017 Pages: 12 (203 of 1511) 4111111IN no The Simon Law Firm, P.C. Attorneys and Counselors at Law ATTORNEY BIOGRAPHIES John G. Simon John is the founder and managing attorney of The Simon Law Firm. He received his B.S. magna cum laude in 1983 and his J.D. in 1986 from Saint Louis University. John has been named BEST LAWYERS IN AMERICA (11) St. Louis Lawyer of the Year in the field of Product Liability, has been listed among the MISSOURI & KANSAS SUPER LAWYERS since 2005, MISSOURI & KANSAS SUPER LAWYERS Top 50 Attorneys in St. Louis since 2006, and was listed in the MISSOURI & KANSAS SUPER LAWYERS Top 10 Attorneys in 2009. He is a member of the Million Dollar Advocates Forum and the American College of Trial Lawyers, among many other professional associations. In the fourteen years since it was founded, The Simon Law Firm has been named one of the "winningest" law firms in the country by the National Law Journal. The firm had the highest recorded verdicts in the state of Missouri for two years in a row. Currently, the firm employs 12 attorneys and represents clients across the country. As a highly-respected member of the legal profession, John frequently leads legal seminars, sharing his expertise on advanced trial advocacy, products liability litigation and bad faith litigation. Anthony G. Simon Tony is a registered patent attorney. His practice focuses on intellectual property and other complex commercial litigation. Tony has served as lead trial counsel in over 200 patent, copyright, trademark, antitrust and other intellectual property cases in courts across the United States. Tony has tried cases to verdict in both state and federal courts, has argued in several federal courts of appeal across the country, and has handled numerous Markman and other pretrial and preliminary hearings. Tony has a Bachelor of Science degree in Electrical Engineering from the University of Notre Dame, and he earned his law degree at St. Louis University School of Law. In his 20 years of practice, Tony has represented both plaintiffs and defendants. He has been a partner at one of the largest firms in St. Louis and at a boutique patent firm before starting the IP Group at The Simon Law Firm. He has litigated cases against, and has been co-counsel with, a majority of the large intellectual property law firms across the country. His clients have included Fortune 500 companies, as well as small businesses and individuals. He was listed in SUPER LAWYERS in 2010-11, THE BEST LAWYERS IN AMERICA, and received an AV® rating from Martindale-Hubbell. Amy Collignon Gunn Amy graduated cum laude from Saint Louis University School of Law in 1996 where she served as Managing Editor of the Saint Louis University Law Journal. Amy has concentrates her practice on prosecuting lawsuits against individuals and companies responsible for defective products, medical malpractice and other negligent acts. She has tried cases in Missouri and Illinois and has obtained millions of dollars in compensation for her clients. Amy has been recognized for her commitment to her clients and the legal community through receipt of the John C. Shepherd Professionalism Award in 2006, named an "Up and Coming Lawyer" by the Missouri Lawyers Media in 2007. Amy was the recipient of the Lon 0. Hocker Trial Lawyer Award in 2007. She was also presented with the 40 Under 40 Award by the St. Louis Business Journal in 2008 and received the Women's Justice Rising Star Award in 2009. Amy has been listed by MISSOURI & KANSAS SUPER LAWYERS® since 2008 in the area of Products Liability and MISSOURI & KANSAS SUPER LAWYERS® Top 50 Women in 2010. BEST LAWYERS IN AMERICA® has listed Amy in the Personal Injury Litigation practice area since 2009. In 2011 Amy was named one of the Top 40 Under 40 Trial Lawyers by The National Lawyers Association. Amy has taught Pre-Trial Litigation at Washington University School of Law since 2001. Martindale-Hubbell has 800 Market Street, Suite 1700 St. Louis, Missouri 63101 Telephone 314.241.2929 www.simonlawpc.com 01411110.= Toll Free 877.767.3108 Facsimile 314.241.2029 Case 3:12-cv-01141-SMY-DGW Document 176-53 *SEALED* Filed 12/01/14 Page 8 of 12 Case: 16-3334 Document:Page 55-7 ID #3491 Filed: 02/08/2017 Pages: 12 (204 of 1511) immio The Simon Law Firm, P.C. Attorneys and Counselors at Law awarded Amy with an AV® rating and she has been nominated and accepted as a Fellow of the American Bar Foundation. Amy is licensed to practice law in Missouri and Illinois and is on the Board of the Women Lawyers' Association of Greater St. Louis and co-chair of the Women's Caucus of the Missouri Association of Trial Attorneys where she also sits on the Board of Governors. Ryan A. Keane Ryan has served as class counsel in dozens of class actions and has obtained millions of dollars in relief to thousands of class members. Ryan has tried cases in state and federal court. Recently, Ryan spearheaded several class actions challenging the constitutionality and validity of red light cameras throughout Missouri. As a result, Ryan obtained a number of significant appellate victories in 2013 that invalidated the majority of red light camera ordinances in Missouri. In doing so, Ryan successfully persuaded the Missouri Court of Appeals to also overrule the leading appellate decision that had previously endorsed red light cameras. He has argued before the U.S. Court of Appeals for the Eighth Circuit, and the Missouri Court of Appeals in the Western and Eastern Districts. Ryan Keane earned his J.D. degree from St. Louis University School of Law and his B.A. degree from Colgate University. At The Simon Law Firm, Ryan's areas of practice are primarily focused on class action litigation and product liability. After graduating from law school, Ryan worked as an attorney at Brown & James in the field of insurance litigation, before returning to The Simon Law Firm. In 2014, Ryan received the Up & Coming Award from Missouri Lawyers Weekly. Todd S. Hageman Todd received his law degree from the University of Oklahoma and has been licensed to practice law since 1994. He is licensed to practice in Missouri, Wisconsin and Illinois. Todd engages in a national practice representing people injured as a result of landfill, environmental, toxic and pharmaceutical exposures. He litigates cases against some of the largest pharmaceutical and drug supplement companies in the United States. He has also handled numerous cases on behalf of people injured by additional types of toxic exposures, including hundreds of children poisoned by lead paint. For example, Todd obtained a $1.25 million jury verdict on behalf of one lead poisoned child in the city of St. Louis. That verdict is a Missouri record for the largest lead paint poisoning jury verdict ever obtained in the state. Todd is a frequent lecturer and author in the areas of landfill, pharmaceutical, environmental and toxic tort litigation. He is a member of the American Trial Lawyers' Association, Missouri Association of Trial Attorneys, Wisconsin Academy of Trial Lawyers and Trial Lawyers for Public Justice. He is a member of the Million Dollar Advocacy Forum and named one of the Leading Plaintiff Lawyers in America by Lawdragon. His Martindale-Hubbell® rating is AV. Timothy M. Cronin Tim received his undergraduate degree from the University of Illinois at Urbana/Champaign with a major in Economics and graduated Magna Cum Laude from Saint Louis University School of Law, where he obtained a certificate in civil litigation. Tim was a recipient of the Dean's Honor Scholarship, received four Academic Excellence Awards during his studies, and also earned the top grade in his class in Trial Advocacy, Moot Court, and Civil Practice. While in law school, Tim clerked for Becker, Paulson, Hoerner & Thompson, P.C. and Lashly & Baer, P.C. gaining valuable litigation experience. Tim was selected for Moot Court, and also won an appeal in an unemployment benefits case while working for the Saint Louis University Civil Advocacy Clinic. Tim was made a member of the Order of the Woolsack after graduation. Tim concentrates his practice in personal injury including products liability, medical malpractice and business litigation. He is a member of the Illinois Bar, Bar Association of Metropolitan 800 Market Street, Suite 1700 St. Louis, Missouri 63101 Telephone 314141.2929 www.simonlawpc.com womb. Toll Fret 877.767.3108 Facsimile 314.241.2029 Case 3:12-cv-01141-SMY-DGW Document 176-53 *SEALED* Filed 12/01/14 Page 9 of 12 Case: 16-3334 Document:Page 55-7 ID #3492 Filed: 02/08/2017 Pages: 12 (205 of 1511) 41111 ftwo The Simon Law Firm, P.C. Attorneys and Counselors at Law St. Louis, St. Clair County Bar Association, East St. Louis Bar Association, and the Missouri Association of Trial Attorneys. Tim is licensed to practice law in Illinois and Missouri. Anne Brockland Anne received her Juris Doctor from Saint Louis University School of Law. During law school, Anne served as the Supervising Notes & Comments Editor of the Public Law Review and authored an article for the same publication. She was a recipient of the School of Law Academic Scholarship, the Irvin and Maggie Dagen Public Interest Fellowship and the Public Law Review Fellowship. Anne is licensed to practice law in Illinois and Missouri and concentrates her practice on personal injury cases including products and premises liability, automobile negligence and medical negligence cases. She was named an Up & Coming Lawyers by Missouri Lawyers Media in 2010. In 2011 Anne was named as one of the Top 100 Trial Lawyers in Missouri by The National Trial Lawyers and in 2012 The National Trial Lawyers named Anne one of the Top 40 Under 40 Trial Lawyers. Benjamin R. Askew Ben graduated from Truman State University in 2002 receiving his B.S. degree and received his J.D. in 2006 from The George Washington University School of Law. Ben is licensed to practice law in the State of Missouri and the State of Illinois. He is a Member of the Missouri State Bar Association, American Bar Association and the Bar Association of Metropolitan St. Louis. He was selected as a SUPER LAWYERS® Rising Star from 2009-2011. Ben focuses his practice on the areas of Patent, Trademark, Copyright and Trade Secrets litigation. Kevin M. Carnie, Jr. Kevin graduated summa cum laude and Phi Beta Kappa from Saint Louis University in 2005, with a double major in psychology and criminal justice. He earned his law degree at Saint Louis University School of Law in 2008, graduating cum laude. While in law school, Kevin was an editor of the Saint Louis University Public Law Review and received three academic excellence awards. After graduation, he was inducted into the Order of the Woolsack. He began his career litigating complex commercial cases at one of the largest law firms in St. Louis. As a result, his experience covers a wide range of litigation matters, including financial services, securities, antitrust, class action, insurance, patent infringement, and consumer fraud. At The Simon Law Firm, Kevin's practice focuses on product liability, personal injury, medical malpractice, business litigation, and intellectual property litigation. Kevin is licensed to practice in Missouri and Illinois. Timothy D. Krieger Tim has two Bachelor of Science degrees: Electrical Engineering and Computer Engineering from the University of Missouri-Columbia as well as a Bachelor of Arts degree in Applied Mathematics from Saint Louis University. He earned his law degree at Washington University School of Law. While in law school, he served as a judicial intern to the Honorable Judge Kathy Surratt-States in the United States Bankruptcy Court for the Eastern District of Missouri. He also worked for five years as an electrical engineer in automobile manufacturing plants and electrical power plants after receiving his undergraduate degrees. Tim focuses on complex intellectual property matters in both state and federal courts throughout the United States. He is also experienced in handling commercial and contract disputes. Tim prosecutes and defends claims of patent, copyright, and trademark infringement and trade secret misappropriation for individuals and private and public companies involving a wide array of products. Tim was named a "Rising Star" by Missouri/Kansas Super Lawyers® (2011-2012 and is a winner of the Burton Award for Legal Achievement in association with The Library of Congress (2007). 800 Market Street, Suite 1700 St. Louis, Missouri 63101 Telephone 314.241.2929 www.simonlawpc.com Toll free 877.767.3108 Facsimile 314.241.2029 Case 3:12-cv-01141-SMY-DGW Document 176-53 *SEALED* Filed 12/01/14 Page 10 of 12 Case: 16-3334 Document:Page 55-7 ID #3493 Filed: 02/08/2017 Pages: 12 (206 of 1511) 4111114 o The Simon Law Firm, P.C. ftw Attorneys and Counselors at Law Michael P. Kella Michael joined The Simon Law Firm as a Law Clerk in June, 2010. He graduated from Saint Louis University School of Law in 2011, receiving a J.D., Intellectual Property Law. Mike also received his B.S. degree in Computer Engineering in 2008 from the University of Missouri-Columbia, cum laude. Michael is licensed to practice law in the State of Missouri and is a member of the Missouri Bar Association of Metropolitan St. Louis. Mike focuses his practice on the areas of Patent, Trademark, Copyright and Trade Secrets litigation. Erica F. Blume Erica represents individuals who have been injured in complex product liability and medical negligence cases throughout Missouri and Illinois. After she obtained her undergraduate degrees in International Affairs and History from Marquette University in 2008, her interest in trial work led her to Saint Louis University School of Law. Ms. Blume graduated cum laude from SLU Law in 2011. That same year she received the Women's Justice Leader of Tomorrow Award from Missouri Lawyers Weekly, the Samuel I. Sievers Annual Writing Excellence Award, and the Student Legal Writers' Association Writing Excellence Award. During law school, Ms. Blume was elected Co-President of the Women Law Students' Association. Between 2011 and 2013, Ms. Blume volunteered as a Mock Trial Coach at her alma mater, Cor Jesu Academy. Ms. Blume is licensed to practice in Missouri and Illinois state courts as well as the Eastern District of Missouri, Western District of Missouri and the Southern District of Illinois Federal courts. Ms. Blume serves on the Board of Directors of the Woman Lawyer's Association of Greater St. Louis as a Member-At-Large. 800 Market Street, Suite 1700 St. Louis, Missouri 63101 Telephone 314141.2929 www.simonlawpc.com Toll Free 877.767.3108 Facsimile 314.241.2029 Case 3:12-cv-01141-SMY-DGW Document 176-53 *SEALED* Filed 12/01/14 Page 11 of 12 Case: 16-3334 Document:Page 55-7 ID #3494 Filed: 02/08/2017 12 (207 of 1511) 1010 Market Street, SuitePages: 1720 LAW OFFICE OF RICHARD S. CORNFELD St. Louis, Missouri 63101 Office: 314-241-5799 I Fax: 314-241-5788 rcornfeld@cornfeldlegal.com I www.cornfeldlegal.com Richard S. Cornfeld Richard S. Cornfeld spent 31 years with Thompson Coburn LLP and its predecessor Coburn Croft, defending some of the largest and most scientifically complex lawsuits ever brought, including the longest jury trial ever held, Kemner et al. v. Monsanto Co. (three years eight months), and the largest lawsuit in dollar terms ever tried, United States v. Philip Morris USA, Inc., et al. His work at that firm earned him selection in The Best Lawyers in America (Mass Tort Litigation/Class Actions - Defendants), Missouri Super Lawyers, and Who's Who in America, as well as a Martindale-Hubbell AV Preeminent® rating, signifying the highest level of professional excellence, according to his peers. He also served as Adjunct Professor at St. Louis University School of Law, teaching Toxic Tort Litigation in the Practical Skill Curriculum. In 2012 Mr. Cornfeld left Thompson Coburn to pursue a different kind of litigation. He now represents consumers whose rights have been infringed in ways that have unfortunately gone largely unnoticed by our legal system. Since starting his own practice, he has been selected in The Best Lawyers in America (Mass Tort Litigation/Class Actions - Plaintiffs), one of only three plaintiffs' side lawyers in the St. Louis area with that honor. Mr. Cornfeld graduated with a B.A. with distinction from the University of Michigan (where he was Associate Sports Editor for the Michigan Daily) and a J.D. from Northwestern University School of Law, where he was Notes and Comments Editor of the Law Review and was selected to the Order of the Coif for graduating in the top 10% of his class. While with Thompson Coburn, Mr. Cornfeld authored approximately 10 articles for professional publications, wrote two scholarly book chapters and gave more than a dozen lectures to professional and industry groups. Outside the practice of law, he is active in the Jewish community. He is past president of United Hebrew Congregation, one of the largest synagogues in the Midwest, and a member of the American Israel Public Affairs Committee (AIPAC), for which he serves on the National Council and co-chairs (with his wife Marcy) the St. Louis Council. See more at: http://www.cornfeldlegal.com. Case 3:12-cv-01141-SMY-DGW Document 176-53 *SEALED* Filed 12/01/14 Page 12 of 12 Case: 16-3334 Document:Page 55-7 ID #3495 Filed: 02/08/2017 12 (208 of 1511) 1010 Market Street, SuitePages: 1720 LAW OFFICE OF RICHARD S. CORNFELD St. Louis, Missouri 63101 Office: 314-241-5799 I Fax: 314-241-5788 rcornfeld@cornfeldlegal.com www.cornfeldlegal.com Notable Cases Green v. American Cleaners, Cause No.: 12SL CC03095 (Cir. Ct. St. L. County) (settled). Lead class counsel in case alleging unfair practice on behalf of St. Louis area consumers in connection with so-called "environmental surcharge" of 25 cents per item imposed by chain of dry cleaners. Class was certified. Settlement was valued at $1.7 million in relief for class, plus injunctive relief barring the surcharge. DeClue v. Higher One, Inc., Case No. 4:12-cv-2361 (E.D. Mo.). Represents putative class of students at St. Louis Community College alleging improper financial-aid fees. This case became part of MDL proceeding, In re: Higher One OneAccount Marketing and Sales Practices Litigation, No. 3:12-md-02407 (VLB) (D. Conn.). Plaintiffs have asked the court to approve a $15 million monetary settlement for nationwide classes, including the one represented by Ms. DeClue, along with injunctive relief. Eike et al. v. Allergan, Inc. et al., Cause No. 3:12-cv-01141-SMY-DGW (S.D. Ill.) (pending). Unfair practice claim on behalf of putative classes of Illinois and Missouri glaucoma patients who purchased prescription eye drops that were larger than the eye's capacity, leading to wastage of expensive medication. Court denied Defendants' motion to dismiss. 2014 WL 1040728 (Mar. 18, 2014). Gustaysen et al. v. Alcon Laboratories, Inc., et al., Civil Action No. 1:14-cv-11961 (D. Mass.) (pending). Claim with same factual basis as Eike on behalf of putative classes of consumers in Massachusetts, New York, 41 other states and the District of Columbia. Cottrell et al. v. Alcon Laboratories, Inc., et al., Civil Action No. 3:14-5859-FLW-LHG (D.N.J.) (pending). Claim with same factual basis as Eike on behalf of putative classes of consumers in New Jersey, California, Texas, Florida, North Carolina and Illinois. Graves v. Deluxe Corporation, 4:14-cv-01823-RLW (E.D. Mo.) (pending). Putative class action on behalf of Missouri consumers alleging improper delivery charges for personal checks. Case 3:12-cv-01141-SMY-DGW Document 176-3 *SEALED* Filed 12/01/14 Page 1 of 5 Case: 16-3334 Document:Page 55-8 ID #2248 Filed: 02/08/2017 Pages: 5 (209 of 1511) Pfizer Global Manufacturing Meeting Minutes Memo To: Distribution From: John Wydila Date:3-28-2011 Drug Product Technology Support & Transfer (DPTST) Subject: Resins for XalatanlXalcom Components Project Meeting Minutes Background There are supply and quality issues with the resins used to manufacture the Blow Fill Seal Container and the Preformed Bottle Container components. The manufacturer of the resin used in the Blow Fill Seal Container tip, Exxon Mobile, will no longer certify LLDPE 6202.19 for medical applications and will not guarantee supply beyond Dec. 12, 2008. LLDPE 6202.19 is the only resin registered for the XalatanlXalcom tip. The stock supply ofLLDPE 6202.19 will be exhausted by mid 2011. The production of the resin used the in the Blow Fill Seal Container bottle, Bormed LE6601PH, has been transferred from a Sweden Borealis production plant to a Norway Borealis production plant. The Norway Borealis production plant was sold to another resin manufacturer, Ineos. The Norway facility employs older manufacturing technology compared to the Sweden manufacturing plant. There have been a number quality issues with the resin produced in the Norway plant, and an alternate resin supplier may need to be identified. For the Preformed Bottle Container, only the Dupont resin is registered with the health authorities. The Dupont resin is more expensive compared to the resin used in producing the Blow Fill Seal Container. Moreover, the there are number of quality issues related to manufacturing of the Preformed Bottle Container bottle using the Dupont resin. Identification of an alternate resin supplier for Preformed Bottle Container may resolve the production quality issues and lead to a reduced cost of goods. There is only one resin registered with the health authorities for the Blow Fill Seal Container cap and the Preformed Bottle Container cap, Alathon, manufactured by Equistar. Although an alternate resin supplier should be identified to protect the resin supply and maintain competitive pricing, identification of alternate resin supplier is not an urgent need. The team will attempt to identify and qualify alternate resins and suppliers for Xalatan and Xalcom components, bottle, tip, and cap. Based on the supply issue with the Exxon resin, the team will give priority to identifying an alternative resin for the Blow Fill Seal Container tip. Candidate resins that provide good performance for the Blow Fill Seal Container tip will also be evaluated for the Preformed Bottle Container tip. 1 CONFIDENTIAL, SUBJECT TO PROTECTIVE ORDER, PRODUCED BY PFIZER IN CASE NO. 3:12-CV-01141-DRH-DGW (S.D. ILL.) PFIZER_XALATAN_00024641 Case 3:12-cv-01141-SMY-DGW Document 176-3 *SEALED* Filed 12/01/14 Page 2 of 5 Case: 16-3334 Document:Page 55-8 ID #2249 Filed: 02/08/2017 Pages: 5 (210 of 1511) Pfizer Global Manufacturing Meeting Minutes Participants Bob Grillo; Bernadette Mauser, Niek Hombrouckx, Katrien DePooter, Stan Danowski, Les Van Alstine, and John Wydila Summary No data points contained in the FDA inquiry histogram were greater than the upper specification limit. The drop size is not a medical dosing issue because the human eye can absorb only 7 III of fluid. The critical dosing parameter is the API concentration. Both the manual and Xal-Ease drop size qualification methods will be maintained. Puurs will develop a new manual testing method employing a constant pressure source on the container to form the drops. A revised response to the New Tip FDA inquiry will be reviewed at the next team meeting prior to regulatory submission. Development of a Xalatan and Xalacom regulatory submission timeline is in progress. The tip test water and drug product drop rates were proven to be statistically equivalent. Discussion • Drop size histogram data - response to FDA new tip inquiry Min (Ill) Max(lll) Purrs, 45° 25.7 3l.3 Purrs, 90° 24.1 30.8 Cardinal Health, 45° 24.7 31.4 Cardinal Health, 90° 26.9 3l.2 o Drop size normal distribution is not appropriate o Max data will round to 31 III - Question 4 response • No data points from the histogram data are outside the specification • Medical and regulatory implication of dispensing drops> 31 III o Summary of Bernadette's discussion with Mike Lynch, Pfizer internal documents, and ophthalmic literature. • Some of the new tip drop size data is > 31 ul 2 CONFIDENTIAL, SUBJECT TO PROTECTIVE ORDER, PRODUCED BY PFIZER IN CASE NO. 3:12-CV-01141-DRH-DGW (S.D. ILL.) PFIZER_XALATAN_00024642 Case 3:12-cv-01141-SMY-DGW Document 176-3 *SEALED* Filed 12/01/14 Page 3 of 5 Case: 16-3334 Document:Page 55-8 ID #2250 Filed: 02/08/2017 Pages: 5 (211 of 1511) Pfizer Global Manufacturing Meeting Minutes • Drop size is not a medical issue .:. The human eye can absorb approximately 7 III of fluid. The remaining drop fluid beyond 7 III is not absorbed by the eye . •:. Pharmacia reports - no medical reason for accurate measurement of drop size .:. API concentration is the dosing critical parameter. • Ophthalmic market drug product drop size range .:. 25 -56 Ill, average = 39 III • NDA review - drop size in not a tip specification. Drop size is found in the NDA development section • Drop size will affect the volume of drug product fluid in container available for dosing . •:. If drop size is too large, then there may be insufficient drug product in the container to provide required 30 doses .:. Calculations demonstrate that a drop size of 32 III will result in approximately 1 ml of drug product fluid remaining in the container at the end of the dosing period. o Broaden US specification? • Drop size is a tip qualification test • Do not set a tip specification for drop size o Employ Xal -Ease device for drop size testing? • Current manual method, operator dependent, some drops> 31 III • Team decision: .:. Maintain current manual drop size method and Xal-Ease drop size method .:. Puurs will develop a new manual method using a controlled, constant force device instead of human technicians to conduct the manual test. • Response to the New Tip FDA inquiry o Bernadette will compose a revised response to the FDA document which will be sent to the team. 3 CONFIDENTIAL, SUBJECT TO PROTECTIVE ORDER, PRODUCED BY PFIZER IN CASE NO. 3:12-CV-01141-DRH-DGW (S.D. ILL.) PFIZER_XALATAN_00024643 Case 3:12-cv-01141-SMY-DGW Document 176-3 *SEALED* Filed 12/01/14 Page 4 of 5 Case: 16-3334 Document:Page 55-8 ID #2251 Filed: 02/08/2017 Pages: 5 (212 of 1511) Pfizer Global Manufacturing Meeting Minutes o Les will prepare a table containing the percentage of drop size measurements >31 Il that will be included in the response to the FDA inquiry. o • • The response to the FDA document will be reviewed during the next team meeting. After review, the final document will be sent to Regulatory for submission. Statistical analysis on drop rates, water versus drug product o Water and drug product drop rates are statistically equivalent. o Les will send report to the team. Close in time Xalacom New Resins and Xalacom New Process Regulatory submissions with Pfizer Regulatory colleagues during the next team meeting o Regulatory submission sequence 1. US Xalatn new resin 2. EU Xalatan new resin 3. Xalacom improved process 4. Xalacon new resin o Niek will create a timeline for the regulatory submission after discussions with Puurs colleagues o Les will complete the statistical analysis of the new resins tip data and send the report to the team .. o The team will discuss the regulatory submission timeline during the next team meeting. Action Items 1. Review the Xal-Ease device submission for drop size and drop size specifications by 4/8 (Katrien and Valja) 2. Send a table containing percentage of drop sizes> 31 III by 411 (Les) 3. Send a response to the FDA revised draft document to the team by 4111 (Bernadette) 4. Review the response to the FDA document at the next team meeting (Team). 5. Send water versus drug product statistical analysis report to the team by 411 (Les) 6. Create a timeline for the Xalatan and Xalacom regulatory submissions by 4111 (Niek) 4 CONFIDENTIAL, SUBJECT TO PROTECTIVE ORDER, PRODUCED BY PFIZER IN CASE NO. 3:12-CV-01141-DRH-DGW (S.D. ILL.) PFIZER_XALATAN_00024644 Case 3:12-cv-01141-SMY-DGW Document 176-3 *SEALED* Filed 12/01/14 Page 5 of 5 Case: 16-3334 Document:Page 55-8 ID #2252 Filed: 02/08/2017 Pages: 5 (213 of 1511) Pfizer Global Manufacturing Meeting Minutes 7. Send the News Resins Tip data analysis report to the team by 411 (Les) 8. Review the regulatory submission timeline during the next team meeting (Team)/ 5 CONFIDENTIAL, SUBJECT TO PROTECTIVE ORDER, PRODUCED BY PFIZER IN CASE NO. 3:12-CV-01141-DRH-DGW (S.D. ILL.) PFIZER_XALATAN_00024645 Case 3:12-cv-01141-SMY-DGW Document 176-28 *SEALED* Filed 12/01/14 Page 1 of 27 Case: 16-3334 Document:Page 55-9 ID #2834 Filed: 02/08/2017 Pages: 27 (214 of 1511) DANIEL ARENSON 3/14/2014 Page 3 Page 1 2 3 4 5 6 7 1 2 UNITED STATES DISTRICT COURT SOUTHERN DISTRICT OF ILLINOIS EAST ST. LOUIS DIVISION 1 3 4 CHARLENE EIKE, et al., on ) behalf of themselves and all) others similarly situated, ) )Cause No. Plaintiffs, )3:12-cv-01141-DRH-DGW v. 6 7 8 ) ALLERGAN, INC., et al., 10 ) 11 ) 10 Defendants. ) 13 12 14 18 19 **CONFIDENTIAL** 15 KIRKLAND & ELLIS, LLP Attorneys for Pfizer, Inc. 333 S. Hope Street Los Angeles, California 90071 BY: ROBYN BLADOW, ESQ. SHOOK, HARDY & BACON, LLP Attorneys for Allergan, Inc.; Allergan USA, Inc.; Allergan Sales, LLC; and Bausch & Lomb, Inc. 2555 Grand Boulevard Kansas City, Missouri 64108 BY: JAMES MUEHLBERGER, ESQ. (via phone) 16 VIDEOTAPED DEPOSITION OF DANIEL ARENSON New York, New York Friday, March 14, 2014 17 18 20 19 20 21 22 21 22 23 24 23 24 25 BRYAN CAVE, LLP Attorneys for Merck & Co., Inc.; Merck, Sharp & Dohme Corp.; and PraSco, LLC 211 N. Broadway, Suite 3600 St. Louis, Missouri 63102 BY: TIMOTHY HASKEN, ESQ. (via phone) ALSO PRESENT: MATTHEW SMITH, Legal Video Specialist Reported by: JOMANNA DeROSA, CSR Page 4 Page 2 1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18 19 20 21 22 23 24 25 2. 12 ) 11 13 14 15 16 17 GREENBERG TRAURIG, LLP Attorneys for Alcon Laboratories, Alcon Research, Ltd.; Falcon Pharmaceuticals, Ltd; and Sandoz, Inc. 3333 Piedmont Road, NE, Suite 2500 Atlanta, Georgia 30305 BY: FLMJ KELOTRA, ESQ. (via video) 9 ) 9 LAW OFFICE OF RICHARD S. CORNFELD Attorneys for the Plaintiffs 1010 Market Street, Suite 1605 St. Louis, Missouri 63101 BY: RICHARD S. CORNFELD, ESQ. (via phone) 5 ) 8 APPEARANCES: March 14, 2014 9:38 a.m. CONFIDENTIAL VIDEOTAPED DEPOSITION OF DANIEL ARENSON, held at the offices of Kirkland & Ellis, LLP, 601 Lexington Avenue, New York, New York, before Jomanna DeRosa, a Certified Shorthand Reporter and Notary Public of the States of New York, New Jersey, California and Arizona. 1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18 19 20 21 22 23 24 25 INDEX WITNESS D. Arenson EXAM BY: Mr. Cornfeld PAGE: 7 EXHIBITS Page: Exhibit No. 6 Exhibit PL 4143 Notice of Deposition 32 Report Exhibit PL 378 37 Exhibit PL 4755 Xalatan Paper 46 Exhibit PL 1531 Letter 48 Exhibit PL 1547 Document 49 Exhibit PL 24902 Meeting Minutes Exhibit PL 24904 PowerPoint Presentation 50 56 Exhibit PL 24881 Meeting Minutes 57 Exhibit PL 24681 Meeting Minutes 75 Document Exhibit PL 97 Quality Overall Summary 75 Exhibit PL 108 80 Exhibit PL 24382 Meeting Agenda 83 Exhibit PL 2495 Document 88 Exhibit PL 24279 Published Data 90 Article Exhibit PL 437 95 Exhibit PL 24862 AS&T Report 1 (Pages 1 to 4) www.midwestlitigation.com MIDWEST LITIGATION SERVICES Phone: 1.800.280.3376 Fax: 314.644.1334 Case 3:12-cv-01141-SMY-DGW Document 176-28 *SEALED* Filed 12/01/14 Page 2 of 27 Page ID #2835 Case: 16-3334 Document: 55-9 02/08/2017 Pages: 27 (215 of 1511) DANIEL ARENSON Filed: 3/14/201 4 Page 5 1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18 19 20 21 22 23 24 25 LITIGATION SUPPORT INDEX DIRECTION TO WITNESS NOT TO ANSWER Page Line Page Line (NONE) REQUEST FOR PRODUCTION OF DOCUMENTS Page Line Page Line 67 19 77 13 INFORMATION TO BE FURNISHED Page Line Page Line (NONE) QUESTIONS MARKED FOR A RULING Page Line Page Line (NONE) Page 7 1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18 19 20 21 22 23 24 25 Allergan and the Bausch & Lomb defendants. MR. HASKEN: Tim Hasken from Bryan Cave, representing the Merck/Prasco defendants. MS. KELOTRA: Ritu Kelotra from Greenberg Traurig, representing the Alcon, Falcon, and Sandoz defendants. THE VIDEOGRAPHER: Thank you. And will the court reporter please swear in the witness? MR. CORNFELD: First can I ask, is there anyone else present in the deposition room? MS. BLADOW: No, Rick. MR. CORNFELD: Okay. You had mentioned a legal assistant, and that's why I was asking. Okay. We can swear the witness now. Thank you. DANIEL A R E N S 0 N, called as a witness, having been duly sworn by a Notary Public, was examined and testified as follows: EXAMINATION BY MR. CORNFELD: Q. Would you state your name please, Page 6 1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18 19 20 21 22 23 24 25 (Exhibit PL 4143 marked for identification.) THE VIDEOGRAPHER: We're on the record. Today's date is March 14th, 2014, and the time is 9:38 a.m. This is the videotaped deposition of Dan Arenson, in the matter of Charlene Eike, et al. v. Allergan, Incorporated, et al., Case No. 3:12-cv-01141, in the United States District Court, Southern District of Illinois. This deposition is being held at 601 Lexington Avenue in New York, New York. The reporter's name is Jomanna DeRosa. My name is Matthew Smith. I'm the certified legal videographer. We are with Midwest Litigation Services. Will the attorneys present please introduce yourself. MR. CORNFELD: Rick Cornfeld. I represent the plaintiffs. MS. BLADOW: Robyn Bladow for Pfizer, Inc. MR. MUEHLBERGER: This is Jim Muehlberger from Shook Hardy, representing Page 8 1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18 19 20 21 22 23 24 25 sir? A. My name is Daniel Arenson. Q. And I understand it's Dr. Arenson? A. Correct. Q. All right. And by whom are you employed, Dr. Arenson? A. I work for Pfizer, Inc. Q. What is your position? A. I am a research fellow. Q. We were provided information from your attorneys that described you as research fellow and also pharmaceutical sciences team leader. A. That's my role, yes. Q. Okay. I was going to say that was sometime last year and maybe it changed, but all right. And what is your business address? A. It's Groton, Connecticut, 06340. There is no road name. Q. Okay. I always try to start out with the toughest questions, so it will only get easier from asking your business address. Sir, I introduced myself to you before we started. My name is Rick Cornfeld, just as a reminder, and I represent the plaintiffs in 2 (Pages 5 to 8) www.midwestlitigation.com MIDWEST LITIGATION SERVICES Phone: 1.800.280.3376 Fax: 314.644.1334 Case 3:12-cv-01141-SMY-DGW Document 176-28 *SEALED* Filed 12/01/14 Page 3 of 27 Page Case: 16-3334 Document: 55-9 ID #2836 Filed: 02/08/2017 Pages: 27 (216 of 1511) DANIEL ARENSON 3/14/2014 Page 11 Page 9 1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18 19 20 21 22 23 24 25 the Eike litigation, and I will be asking you questions today. You understand that you are here testifying as a corporate representative of Pfizer, your employer. Correct? A. Yes. Q. All right. And you agree to fulfill that role on behalf of Pfizer. Is that right? A. Yes. Q. All right. And so, you understand that when I ask you questions, I'm asking you not just what you personally, Daniel Arenson, know, but what your employer, what Pfizer knows. Do you understand that? A. I understand. Q. All right. And if -- if I use the word "you" in a question, you understand that unless I specify that I am referring only to you personally, that I am asking you and using the word "you" to refer to Pfizer. Do you understand that? A. I understand. Q. Okay. And just -- I'd like you to know that if at any time when I ask you a question 1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18 19 20 21 22 23 24 25 about six years. Q. All right. How long have you been at Pfizer? A. 17 years. Q. So, you started at Pfizer around 1997. Would that be right? A. 1996, actually. Q. Okay. What are your responsibilities as a research fellow? A. A research fellow is a position on a salary grade. My actual role is a pharmaceutical science team leader. So, if you -if you meant to ask what do I do as a pharmaceutical science team leader -- is that what you were asking? Q. Well, what I'm asking is what do you do in your job? What are your responsibilities in your position at Pfizer? A. My job is to be the pharmaceutical science representative to project teams, and to coordinate all the activities that are done by the pharmaceutical science group, which is the development of the API synthesis, the drug product development, clinical manufacturing and supplies, and the CMC portion of regulatory filings. Page 12 Page 10 1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18 19 20 21 22 23 24 25 you don't understand the question, or maybe because of the video feed or audio feed or some other reason you think you maybe didn't hear the question correctly, I'd ask that you let me know and I'll rephrase or restate the question to make it audible and understandable. Is that agreeable? A. Yes. Thank you. Q. All right. And -- and also if -if at any time you want to take a break, that's fine. I understand from yesterday that the videographer can go about two hours without -without having to change, but we don't have to go two hours without taking a break. And if you'd like to take a break, just let me know. A. Thank you. Q. All right? Okay. How long have you been a research fellow at Pfizer? A. Are you asking how long I've been a research fellow or how long I've been at Pfizer? Q. Well, first, how long have you had your current position as research fellow, and then I'll ask you how long you've been at Pfizer. A. I've been a research fellow for 1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18 19 20 21 22 23 24 25 Q. All right. Let's -- let's even break that down, and help me understand this. You said you were the pharmaceutical representative to the project team? A. Uh-huh. Q. Can you explain what that means? A. The project team is the larger team across all of the research side at Pfizer that develops a given project from concept to commercialization. Q. By "given project" you mean a particular drug? A. Yes. Q. Pfizer has lots of drugs, I understand, so it must have lots of project teams. A. Correct. Q. Okay. Are you the pharmaceutical representative to all project teams or to some of them? A. I am one of many pharmaceutical science team leaders, so I am only to a few of them. Q. Okay. And when you say "pharmaceutical representative," what does it mean to be a pharmaceutical representative? 3 (Pages 9 to 12) www.midwestlitigation.com MIDWEST LITIGATION SERVICES Phone: 1.800.280.3376 Fax: 314.644.1334 Case 3:12-cv-01141-SMY-DGW Document 176-28 *SEALED* Filed 12/01/14 Page 4 of 27 Page ID #2837 Case: 16-3334 Document: 55-9 02/08/2017 Pages: 27 (217 of 1511) DANIEL ARENSON Filed: 3/14/2014 Page 13 1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18 19 20 21 22 23 24 25 A. I am the pharmaceutical science team leader, and as such I am the representative to the larger project teams, which means I represent all of our activities amongst all of the other activities that are required in order to be able to submit and get approval for a product. Q. Do I understand that as a -- that as a pharmaceutical team leader, you lead a team of people. Is that right? A. I lead a team. They all -- most of them don't report to me, but I am the team leader, yes. Q. All right. And you said a larger team. You are the representative to a larger team. And the larger team is the team that's in charge of the project of developing a drug? A. Correct. Q. What is the pharmaceutical team, as opposed to this larger team? A. The pharmaceutical team -- the pharmaceutical science team does a particular group of activities, which I listed earlier, in developing and manufacturing API and drug product, providing clinical supplies, and supporting the submissions. Page 15 1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18 19 20 21 22 23 24 25 Q. Okay. By "lines" you meant a reporting line? A. Correct. Q. All right. I was writing pretty fast when you were outlining your job responsibilities. I have written down coordinate activities, API synthesis. And I just don't remember, is that one thing or two things? A. API synthesis is -- is developing the synthetic route for the active pharmaceutical ingredient. Q. So, you coordinate that? A. I lead the team, and we have a -both a chemist and an analyst on the team that lead the sub-team that works specifically on that. Q. API stands for active pharmaceutical ingredient? A. Correct. Q. All right. And you said that this is developing the synthetic route. Do you mean how this active pharmaceutical ingredient will be manufactured? A. Correct. Q. And then another activity that your team coordinates is clinical manufacturing and Page 14 1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18 19 20 21 22 23 24 25 There are a lot of other functions that are required in order to develop a project; everything from understanding the biology, understanding the pharmacokinetics and pharmacodynamics, clinical, the greater regulatory, safety, drug safety, toxicology. There are a lot of other activities. So, there are many other departments and divisions that are represented at that greater team. Pharmaceutical science is just one. Q. All right. And you said you are a team leader, but the people on the team don't report to you. Can you explain what that means? A. We work in a matrix environment. So, I'm the team leader, but all of those people come from the individual lines. So, you can think of it that they have a dotted line to me, but when it comes to annual performance reviews, none of them work for me. Q. What do you mean when you say they come from individual lines? A. We have many lines within -- many reporting lines inside pharmaceutical science. And the teams pull people from individual lines to work on the project. Page 16 1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18 19 20 21 22 23 24 supplies. Is that right? A. Yes. Q. And can you explain what that involves? A. We have to manufacture both the active pharmaceutical ingredient. So, not only the development, which we touched on earlier, but the manufacturing as well. And then also the manufacture of the product itself that's going to be put into the clinical studies. Q. How is that different from the manufacture of the active pharmaceutical ingredient? A. The active pharmaceutical ingredient, since I work primarily in small molecules, is usually a powder. That's not a form that you want to give to the patient, so we turn it into tablets, capsules, injectables, oral liquids, et cetera, whatever is required for that particular study. Q. And then you said your team is also involved in the chemical manufacture and control area. Is that right? 25 A. For submissions of the IND and 4 (Pages 13 to 16) www.midwestlitigation.com MIDWEST LITIGATION SERVICES Phone: 1.800.280.3376 Fax: 314.644.1334 Case 3:12-cv-01141-SMY-DGW Document 176-28 *SEALED* Filed 12/01/14 Page 5 of 27 Page Case: 16-3334 Document: 55-9 ID #2838 Filed: 02/08/2017 Pages: 27 (218 of 1511) DANIEL ARENSON 3/14/2014 Page 19 Page 17 1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18 19 20 21 22 23 24 25 NDAs, yes. Q. What is an IND? A. Investigational New Drug. Q. Okay. A. It's the submission in order to run clinical studies. Q. I got you. All right. So, what -what is chemical, manufacturing, and controls? And I understand that is sometimes abbreviated CMC. Is that right? A. Correct. That's everything to -sorry. Q. All right. Go ahead. A. You were going to ask a question. Q. Yeah. My question is what is it, CMC? A. It's everything -- it's everything having to do with the technology and the manufacturing, the analytical testing of the -the product that goes into either the clinical studies or into the NDA. Q. Do we now have at least a general outline of what your responsibilities are as research fellow and pharmaceutical sciences team leader? 1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18 19 20 21 22 23 24 25 THE VIDEOGRAPHER: The time is 9:58 a.m. We're off the record. (Recess taken.) THE VIDEOGRAPHER: The time is 10:00 a.m. We're on the record. MS. BLADOW: Rick, I just want to designate the deposition transcript confidential, just as we -- as we proceed. There may be sections that are, and that are not, but recognizing some of the testimony that he's just given, I want to make sure that in the first instance I just have a preemptive designation. MR. CORNFELD: Okay. I believe under the protective order you have a certain amount of time. I think everything is considered confidential up until a certain date when you have to either say it is confidential or it's not, and designate which portions. So, I don't think you need to say that. I understand your concern, but I don't think you need to make that -- that designation at this time. And I'm sure all counsel on -- on Page 20 Page 18 1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18 19 20 21 22 23 24 25 A. That's -- that's my primary responsibility, yes, those that I've just told you. Q. All right. Is there anything else that we're missing of significance? A. No. MS. BLADOW: Object to the form. Q. All right. And you have done that for six years, meaning since approximately 2008. Is that right? A. I've been a research fellow since 2008. I've done this job since 2002. Q. Okay. In your position at Pfizer have you had involvement with Xalatan? A. Limited, yes. Q. What has that involvement been? A. My involvement was in two separate areas. One was a revision to the product for European submission for a room temperature product instead of a five-degree stored product. And the second one was an early development project, which was discontinued. And that was for a long-acting insertable device to go into the side of the eye to supply 60 days -- 60 to 180 days worth of drug. 1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18 19 20 21 22 23 24 25 the call who are facing similar issues with their clients are well-aware of that. And if what I said was incorrect, I'm sure somebody will say something. Q. All right. The involvement of Xalatan that you had in connection with Europe, you said that was to develop a form of Xalatan that was at a different temperature. Can you explain that? MS. BLADOW: And I just want to object that this is really outside the scope. I understand you're getting his background, but the "you" that you're using right now has to be with respect to Dr. Arenson only. MR. CORNFELD: All right. It is just -- it is just background. Q. Dr. Arenson, can you -- and I don't want a lot of detail here, but can you explain what that means, to be developing something at a different temperature, developing Xalatan at a different temperature? MS. BLADOW: Objection to form. A. Okay. So, we made some very minor adjustments to the formulation, primarily in the pH, that allowed it to be more chemically stable 5 (Pages 17 to 20) www.midwestlitigation.com MIDWEST LITIGATION SERVICES Phone: 1.800.280.3376 Fax: 314.644.1334 Case 3:12-cv-01141-SMY-DGW Document 176-28 *SEALED* Filed 12/01/14 Page 6 of 27 Page ID #2839 Case: 16-3334 Document: 55-9 02/08/2017 Pages: 27 (219 of 1511) DANIEL ARENSON Filed: 3/14/2014 Page 21 1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18 19 20 21 22 23 24 25 and, therefore, it could be stored at room temperature instead of five degree C. Q. Xalatan, as it's sold in the United States, is sold in refrigerated form. Is that right? A. Correct. Q. And it's at five degree C. Do you mean five degree centigrade? A. Yes. Q. Which would be roughly 40 or 41 degrees Fahrenheit. Is that right? A. Without doing the math in my head that sounds like it's close. It's refrigeration. Q. Okay. All right. When a patient buys Xalatan, are they supposed to keep it refrigerated? A. They do not have to. Q. But when they buy it from the pharmacy, the pharmacy keeps it in a refrigeration environment. Is that right? A. That's the -- that's the label of the product. MS. BLADOW: Lacks foundation. Outside the scope. Q. Xalatan is supposed to be shipped Page 23 1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18 19 20 21 22 23 24 25 Flexirene. Q. That was the -- the change in the resin? A. Correct. Q. Were you privy, at the time, to what was going on with that change? MS. BLADOW: Object to the form. Vague and ambiguous. Q. I mean, to the -- go ahead. A. My only knowledge of that was is the change was made, and that it was put into place for the current product prior to going forward with the room temperature product. Q. When was that change completed, as far as your being allowed to go forward with the room temperature project? A. I don't know specifically when the room -- the current product was completed. I can only tell you we were allowed to go forward with preparations for the submission in Europe, I believe, in 2011, after whatever decisions were made had been -- had been finalized, but I'm not aware of what the specific dates were around the current product or what -- the refrigerated product. Page 22 1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18 19 20 21 22 23 24 25 Page 24 1 and stored before being sold to the consumer, refrigerated to five degrees centigrade. Is that correct? MS. BLADOW: Same objection. A. That is my understanding, but that would be in the product label itself. Q. Were you involved in any of the -in any project related to the -- the container closure system for Xalatan? A. I was not directly involved in any of that work. Q. When you say not directly involved, were you indirectly involved in some way? A. The only way that I was involved in that is I am aware that there were some changes that were being made, and my room temperature product was held up until those changes were completed. Q. Which changes -- well, strike that. Were you privy to what was going on with the proposed and actual changes to the container closure system? A. I -- I knew about them, yes. Only the -- the change from the -- the one polymer, I 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18 19 20 21 22 23 24 think it was Escorene, to the final one of 25 Q. All right. We were provided with documents, and there was testimony yesterday that in the United States the change from Escorene to Flexirene went into effect in February or March of 2013. Did it go into effect in Europe before that point? A. I don't know the answer to that question. Q. All right. Will the witness please be handed Exhibit PL 004143? All right. Sir, do you see that this is the Notice of Deposition for this deposition? MS. BLADOW: I'm going to object to that question. It seems to lack foundation. A. I'm not sure what -- what's being asked. This is the -- I mean, I can read this, if you'd like me to. This is the first time I've seen it. Q. Nave you seen it before? A. No. Q. I'm sorry. Have you seen this before? A. No. 6 (Pages 21 to 24) www.midwestlitigation.com MIDWEST LITIGATION SERVICES Phone: 1.800.280.3376 Fax: 314.644.1334 I 1 s Case 3:12-cv-01141-SMY-DGW Document 176-28 *SEALED* Filed 12/01/14 Page 7 of 27 Page Case: 16-3334 Document: 55-9 ID #2840 Filed: 02/08/2017 Pages: 27 (220 of 1511) DANIEL ARENSON 3/14/2014 Page 27 Page 25 1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18 19 20 21 22 23 24 25 Q. For the record, this exhibit is on the caption of the Eike case, and it's entitled: "Plaintiffs First Amended Notice of Rule 30(b)(6) Deposition Duces Tecum of Corporate Representatives by a Video Conference Directed to Defendant, Pfizer, Inc." And it shows the deponent, Daniel Arenson, as corporate representative of defendant Pfizer, Inc. Sir, if you would look at -starting on the page with the Bates No. 4146, page 4 of this notice, do you see there's a section entitled "Testimony"? MS. BLADOW: Before you answer, I'm just going to object to your characterization of this document. It's obviously, I guess, how you would characterize this document. I sent you a letter on March 10th telling you what the witness would be designated for. MR. CORNFELD: I was just reading a title. Q. Sir, do you see that there's a section entitled "Testimony"? A. I see that on this page. 1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18 19 20 21 22 23 24 25 document last year that said that you are knowledgeable about issues related to dropper size and design. A. Correct. Q. Are you knowledgeable about issues related to dropper size and design? A. Yes. Q. Can you tell me what you mean by the term "dropper size"? A. So, dropper size would be the -what the overall primary packaging would be for a product, and how it relates to creating a drop. Q. The term "dropper," what does that mean? A. Something that creates a drop. Q. Are you knowledgeable about the size of the drop? MS. BLADOW: Objection to the form. Vague and ambiguous. The size of what? Q. Go ahead. Go ahead. A. What -- what specifically are you asking about, the size of what -Q. Do you have any knowledge of -A. -- the size of what drop and the size of the drop? How it's -- created how? I'm Page 28 Page 26 1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18 19 20 21 22 23 24 25 Q. And do you see that there are various numbered paragraphs on that page and the succeeding pages? A. I see the numbers. Q. Have you ever seen a document with those topics listed? A. I have not seen this specific list. Q. Have you seen a list of deposition topics -MS. BLADOW: Object to the form. Q. -- that would be similar -- that would be similar to this list? MS. BLADOW: Same objection. A. I have not seen this list. This is -- the only -- the only mention I saw was a much -- much narrower list than this. Q. What list did you see? Can you describe that? A. The only one I saw was that it would be around the -- and I don't remember the -the precise wording of it, but it was around the -- I think something to do with the container closure for the product. This appears to be a much broader list than I was informed about. Q. Sir, your attorneys sent us a 1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18 19 20 21 22 23 24 25 not -- I don't understand the question. Q. The size of Xalatan drops. A. I am aware of the size of Xalatan drops. Q. Could you tell me what you did to prepare for yourself for this deposition? MS. BLADOW: Without revealing any attorney-client communications. A. We had -- there were some discussions yesterday. Q. Discussions with whom? A. The attorneys. Q. Have you done anything else to prepare for this deposition? A. I have not done anything special to prepare for this, other than what was done yesterday. Q. Have you reviewed any documents? A. Only with the attorneys. Q. Tell me what documents you reviewed. MS. BLADOW: I'm just going to caution the witness. You know, the specific documents that we selected for him to review we believe would be work product. 7 (Pages 25 to 28) www.midwestlitigation.com MIDWEST LITIGATION SERVICES Phone: 1.800.280.3376 Fax: 314.644.1334 Case 3:12-cv-01141-SMY-DGW Document 176-28 *SEALED* Filed 12/01/14 Page 8 of 27 Page ID #2841 Case: 16-3334 Document: 55-9 Filed: 02/08/2017 Pages: 27 (221 of 1511) DANIEL ARENSON 3/14/2 014 Page 29 1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18 19 20 21 22 23 24 25 Do you want to ask a more general question, counsel? MR. CORNFELD: I'm entitled to know what the witness reviewed to prepare for this deposition. That's why I'm asking the question. So, go ahead. MS. BLADOW: You can answer generally with respect to the documents that you reviewed. A. These were a collection of some of the submissions that had been sent to the FDA, and I believe there were also some meeting minutes from internal Pfizer business. Q. From -- I'm sorry. You said from internal Pfizer what? A. Internal Pfizer business. Q. What submissions did you review? A. I believe the original NDA and a number of amendments. Q. What meeting minutes did you review? A. Without looking at them, I wouldn't be able to tell you specifically what they were. Q. Can you tell me what they related to? Page 31 1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18 19 20 21 22 23 24 25 A. I am not familiar with any -anything like that. Q. Are you familiar with any scientific literature regarding the drop size of ophthalmic pharmaceuticals generally? A. No. Q. Did you talk to anybody, other than your attorneys, in preparing for this deposition? A. No. Q. Were you involved in any search for documents in this case? A. The only knowledge I have about the search for documents was when I was asked for what documents I had. And as a policy, when that happens, Pfizer goes in and copies everything on my computer. So, that -- that's the limit to what I know about the search. Q. Did you have any documents relevant to this case? A. Not that I'm aware of. MS. BLADOW: I'm sorry. I should have objected. That calls for a legal conclusion. MR. CORNFELD: Robyn, would you hand the court reporter the document with the Page 30 Page 32 1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18 19 20 21 22 23 24 A. They, in general, related to changes in the polymer resin, and I think the change to the dropper design. Q. Prior to yesterday had you reviewed any of these documents? A. I had not seen these documents prior to getting the -- the package, to look at them. Q. When did you get the package to look at them? A. I think early this week, but I didn't really look at them until yesterday. Q. How did you become knowledgeable about the drop size of Xalatan? A. As part of the project I worked on for the room temperature, there was an evaluation to see if changing the pH, that the formulation had changed the drop size out of the -- what was the current bottle and dropper tip at the time. Q. Did you review any non-Pfizer documents in preparation for this deposition? A. No. Q. Are you familiar with any scientific literature regarding the drop size of 1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18 19 20 21 22 23 24 25 Xalatan? 25 Bates No. 378. It's a document we used yesterday. (Exhibit PL 378 marked for identification.) Q. Sir, you have been handed Exhibit Pfizer Xalatan 378. Are you familiar with this document? A. I am aware of this document, yes. Q. All right. Would you turn to page 422? Do you see that page 422 is a -- is the first page of a -- of an attachment 2.0, and is dated April 24, 1995, related to Xalatan eye drops, 50 micrograms per milliliter? A. Yes. Q. Do you see that? A. Yes. Q. Have you reviewed this document? MS. BLADOW: You took him to a specific page. You want to know if he reviewed the entire document? MR. CORNFELD: No, I'm sorry. The attachment 2.0, which this is just the cover page for that. MS. BLADOW: So, I'm sorry. Are 8 (Pages 29 to 32) www.midwestlitigation.com MIDWEST LITIGATION SERVICES Phone: 1.800.280.3376 Fax: 314.644.1334 Case 3:12-cv-01141-SMY-DGW Document 176-28 *SEALED* Filed 12/01/14 Page 9 of 27 Case: 16-3334 Document:Page 55-9 ID #2842 Filed: 02/08/2017 Pages: 27 (222 of 1511) DANIEL ARENSON 3/14/2014 Page 35 Page 33 1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18 19 20 21 22 23 24 25 you asking if he has reviewed attachment 2.0? MR. CORNFELD: Yes. Q. Attachment 2.0 that is -- that starts at page 422 of Exhibit Pfizer Xalatan 378. A. This does not look familiar. I don't believe I've -- I've reviewed this specific document. Q. All right. So I take it you're not knowledgeable about this report that's attachment 2.0. Is that right? And -- and here I'm not -here I'm referring to you as Dr. Arenson. A. I cannot claim to be knowledgeable of the entire document at this point in time. Q. Okay. Are you knowledgeable about any part of it? A. Some parts of it may have been reproduced in other documents that I am knowledgeable about, but I don't -Q. Well, take a look and tell me if there's -- tell me if there's anything that you have reviewed in here and that you are knowledgeable about. MS. BLADOW: I'm going to object to this question, the form of the question. You're asking him to read every page of this 1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18 19 20 21 22 23 24 25 Section 3.3, in the descriptions. Q. Which descriptions? A. The description of the materials of the bottle and dropper. Q. Can you show me where in the document -- if you can give me the page, the Bates numbered page that's on the lower right. A. So, the first one I gave you would have been 423, and the second one is 425. Q. All right. And what on page 425 have you -- have you seen before? A. In Section 3.3, the second paragraph, the description. Q. Any other part of section -- I'm sorry. A. Well, that's fine. Most of this covers -- a lot of this covers early development that I have not been familiar with. I'm only familiar with the final product. Q. Under packaging material, are you familiar with any part of this document, other than the second paragraph, the second paragraph under packaging material on 425? MS. BLADOW: Object to the form. A. I believe that in the third Page 36 Page 34 1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18 19 20 21 22 23 24 25 attachment and tell you if he is knowledgeable about anything contained in it? MR. CORNFELD: Robyn, if you have an objection to form, all you need to do is say "objection to form." It'll -- whatever your objection is will be preserved. And if you have any doubt about that, I'll stipulate to that. MS. BLADOW: I'm just trying to help move this along. A. There are portions of the formulation, packaging material process that I have seen in other documents. Q. You said the formulation and the packaging material. Was there anything else? A. Those are the ones that I can confirm that I have seen other places. The individual tables I can't -- can't guarantee are the same as tables in other documents, without comparing them directly. Q. All right. Show me what portion relates to the formulation that you believe you have seen in other documents. A. Section 2, the first part of Section 3, and then the packaging material in 1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18 19 20 21 22 23 24 25 paragraph a portion of that describes the final commercial product, the original commercial product. Q. Anything else? A. I'm not seeing anything else right now. Q. Do you understand that at the time Xalatan was originally developed it was developed by the Pharmacia Corporation? A. I understand that, yes. Q. And the Pharmacia Corporation was a predecessor of the current Pfizer. It merged with Pfizer in 2002. Correct? MS. BLADOW: Objection. Calls for a legal conclusion. Lacks foundation. Q. Go ahead. A. I am aware that Pfizer and -- and Pharmacia are now one company, yes. THE VIDEOGRAPHER: The time is 10:34 a.m. We're off the record. (Recess taken.) THE VIDEOGRAPHER: The time is 10:43 a.m. We're on the record. MR. CORNFELD: Would the court reporter hand the witness Exhibit Pfizer 9 (Pages 33 to 36) www.midwestlitigation.com MIDWEST LITIGATION SERVICES Phone: 1.800.280.3376 Fax: 314.644.1334 Case 3:12-cv-01141-SMY-DGW Document 176-28 *SEALED* Filed 12/01/14 Page 10 of 27 Page ID #2843 Case: 16-3334 Document: 55-9 Filed: 02/08/2017 Pages: 27 (223 of 1511) DANIEL ARENSON 3/14/2014 Page 37 1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18 19 20 21 22 23 24 25 Xalatan 4755. (Exhibit PL 4755 marked for identification.) MS. BLADOW: Are these all marked as one exhibit? MR. CORNFELD: I -- I don't remember, but if there's only an exhibit sticker on the first page, yes, they are. Q. Sir, do you have in front of you Exhibit Pfizer Xalatan 4755? A. Yes. Q. All right. Would you take a look at the second page of this exhibit, which bears the Bates No. 4894. Do you see that? A. Yes. Q. And do you see that this is a paper entitled: "Drop Size of Xalatan Eye Drops, 50 Micrograms Per Milliliter"? A. Yes. Q. Are you familiar with this paper? A. Yes. Q. All right. When did you review it? A. Yesterday. Q. In the meeting with your attorneys? Page 39 1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18 19 20 21 22 23 24 25 MS. BLADOW: Objection. Lacks foundation. A. All I can do is to read this document. And based on reading this document, that would be correct. Q. All right. And they found that -I'm sorry. Go ahead. A. Go ahead. Q. Sometimes there's a -- there's a lag in the video, and I don't mean to talk over you. If you didn't finish your answer, please do. A. Well, all I was going to do was to restate that I'm only able to read this document. I wasn't there. So -Q. All right. A. -- this is a written conclusion. I cant -Q. All right. A. -- I can't state for what was actually done. Q. And the written conclusion was that the difference in those two dropping methods was very small. Correct? MS. BLADOW: Object to the form. Vague and ambiguous. Page 38 1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18 19 20 21 22 23 24 25 A. Yes. Q. Have you reviewed any documents in preparation for this deposition, other than in the meeting with your attorneys? A. No. Q. You understand that in this paper, Pharmacia investigated the temperature drop angle, dropping method, and production batches for Xalatan. Correct? MS. BLADOW: Object to the form. A. Reading this document, that is my understanding, yes. Q. All right. And the dropping method that they looked at was the effect on pressure equalization, and the effect of pressure equalization depending on whether the bottle was returned to upright after the first drop or after two drops. Correct? MS. BLADOW: Object to the form of that question. A. That is the -- as I read it, that is the stated intention of this test, yes. Q. All right. And that is what they tested? Not just the intention, but they did the test. Correct? 1 Page 40 1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18 19 20 21 22 23 24 25 A. As this method and this test was conducted, there is a difference. How relative that difference is depends on how you want to use the data. Q. Well, they said that the difference was very small. Correct? They said that in this paper. MS. BLADOW: Same objection. A. Based on what they are trying to do, that appears to be correct. Q. They stated, on page 4899, the difference between using pressure equalization after each drop or after each second drop is very small. Correct? A. I'm sorry. Where was that? Q. If you look at page 4899, the caption to Figure 2. A. Yes, that's what it says. THE VIDEOGRAPHER: The time is 10:50 a.m. We're off the record. (Recess taken.) THE VIDEOGRAPHER: The time is 10:51 a.m. We're on the record. Q. Would you take a look at the paper that starts on page 4902? 10 (Pages 37 to 40) MIDWEST LITIGATION SERVICES www.midwestlitigation.com Phone: 1.800.280.3376 Fax: 314.644.1334 Case 3:12-cv-01141-SMY-DGW Document 176-28 *SEALED* Filed 12/01/14 Page 11 of 27 Page Case: 16-3334 Document: 55-9 ID #2844 Filed: 02/08/2017 Pages: 27 (224 of 1511) DANIEL ARENSON 3/14/2014 Page 43 Page 41 1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18 19 20 21 22 23 24 25 A. Yes. Q. Have you reviewed this paper? A. Yes. Q. Would you take a look at the summary section on page 4905? And do you see the sentence at the bottom of the first paragraph that says: "In other words, factors connected to surface tension have the largest effect on the drop size." Do you see that? A. I see that. Q. What factors are connected to surface tension? A. In -- in what circumstance? Q. What factors are connected to surface tension as is referred to here? MS. BLADOW: Objection. Lacks foundation. Vague and ambiguous. A. So, in this particular study -Q. What I'm talk -- what I'm -- what I'm asking about is what factors are connected to surface tension? MS. BLADOW: Same objections. A. I'm still -- if -- I'm not clear. 1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18 19 20 21 22 23 24 25 included in the documents that I've reviewed, but the other one is just by the definition of surface tension itself. Surface tension is a property of the liquid material in contact with another surface. As that other surface, whether it be another liquid, another solid, or a gas, the properties of that other -- other surface are going to affect drop size and surface tension and everything else. It's -- that's just inherent in the definition of surface tension. Q. What studies that were contained in the Pfizer documents that you reviewed in this case study the effect of the dropper tip materials on surface tension? A. This is the primary one that I am aware of. I am also aware that in materials that I've looked at of the change from one polymer to the other. Q. It was from Escorene to Flexirene? A. Correct. Q. All right. In this -- in this paper there was actually only one dropper tip in this paper that starts on page 4902. There was only one dropper tip studied. Correct? Page 44 Page 42 1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18 19 20 21 22 23 24 25 When you say what factors are -- are affecting surface tension, can you be more specific? Q. What -- what factors are -- are being referred to here as being connected to surface tension and having an effect on drop size? A. So, if you -- in the previous part of that paragraph they specifically say that the materials of the dropper itself have a great influence on the drop size than the design of these particular pipettes. So, the materials are going to have a large influence on the drop size based on surface tension. Q. Do materials affect -- the materials of the dropper tip affect surface tension? MS. BLADOW: Object to the form. A. Yes. Q. Does benzalkonium chloride affect surface tension? MS. BLADOW: Same objection. A. Yes. Q. What studies are you aware of that show that the materials in the dropper tip affect surface tension? A. I am aware of those that have been 1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18 19 20 21 22 23 24 25 MS. BLADOW: Lacks foundation. A. Yes. Q. Did you answer? A. Yes, that's correct. Q. Okay. So, they didn't study other materials in the dropper tip. Correct? MS. BLADOW: Objection. Misstates testimony. A. What I answered was there was only one tip that studied more than one material. Q. Well, they studied glass in a pipette. Correct? A. Yes. Q. And they studied polyethylene in a pipette. Correct? A. Yes. Q. And that's not material that's used in a -- in a dropper tip. Correct? A. That is not the material used in this particular dropper tip. That is correct. Q. That's not a material that's been used in any dropper tip that Pfizer has studied. Correct? MS. BLADOW: Objection. Outside the scope. Lacks foundation. 11 (Pages 41 to 44) www.midwestlitigation.com MIDWEST LITIGATION SERVICES Phone: 1.800.280.3376 Fax: 314.644.1334 Case 3:12-cv-01141-SMY-DGW Document 176-28 *SEALED* Filed 12/01/14 Page 12 of 27 Page ID #2845 Case: 16-3334 Document: 55-9 Filed: 02/08/2017 Pages: 27 (225 of 1511) DANIEL ARENSON 3/14/2014 Page 45 1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18 19 20 21 22 23 24 25 A. I am not aware that Pfizer has ever used those particular materials in a dropper tip. Q. In a dropper tip study. Correct? MS. BLADOW: Same objection. A. I am only aware of the dropper tip studies that were included in these particular documents for Xalatan. Q. All right. And they did not study this particular polyethylene that was used in what they refer to as dropping pipette B in the paper that begins on page 4902. Correct? A. Based on what's written here, I can't say for sure that that was a different material, but it appears to be a different -- at least a different polymer. Q. A different polymer than Pfizer -A. It's at least a different resin type, but I cant say what the difference actually is because of the limited description of what polyethylene is. Q. All right. But it appears to be a different resin type from the ones that Pfizer has studied in dropper tips. Correct? A. Correct. Q. And as far as the change from one Page 47 1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18 19 20 21 22 23 24 25 documents that we reviewed. So, no, I would not have seen it before. Q. Would you take a look at page 1541? And do you see in the second paragraph there's a statement that says: "Concerning the volume per drop, the results from the sample can be considered as general for the population." Do you see that? A. I see the sentence. Q. All right. Have you seen a statement in any report of a drop size study by Pfizer, or by its predecessor, Pharmacia, that had a statement contrary to this, a statement that said that the results from the sample cannot be considered as general for the population? MS. BLADOW: Objection. Vague and ambiguous. Lacks foundation as to the meaning of this statement. A. I'm not sure how to interpret this statement. I can only -- I can only speculate about what is meant by that statement, and I would have to do that in order to come to any conclusions about whether there is anything contradictory to that. Page 46 1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18 19 20 21 22 23 24 25 polymer to another, the studies that were done in connection with the change from Escorene to Flexirene, did any of those studies that you are aware of relate to surface tension? Did they include surface tension as a variable? MS. BLADOW: Objection. Multiple questions are pending. A. I don't recall offhand specifically seeing surface tension being measured as part of those studies. Having said that, surface tension is a -- a liquid property, so it would be measured as part of the liquid, and not part of the resin. Q. Would you take a look at Exhibit Pfizer Xalatan 1531, which is an exhibit we used yesterday? (Exhibit PL 1531 marked for identification.) Q. Sir, you've been handed what's been marked as Exhibit Pfizer Xalatan 1531, which is -indicates on the first page that it's a letter to the FDA from Pharmacia and Upjohn, dated September 21, 1998. Have you seen this document before? A. I don't believe this is one of the Page 48 1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18 19 20 21 22 23 24 25 So, if -- if this is -- if this is referring to the way that the -- the testing is done, then I'm not aware of -- of anything contradictory, but as far as I know, that's as far as the statement can go. Q. All right. Would you take a look at Exhibit Pfizer Xalatan 1547? (Exhibit PL 1547 marked for identification.) Q. Do you see -- if you look at page 1573 -- and do you see the statement in the first paragraph that says: "The normal position when dropping is an inclined angle, 45 degrees." Do you see that? A. I see that statement. Q. Are you aware of any studies that Pfizer or Pharmacia did after the date of -- of this submission on January 25th, 2002 on what would be the normal position when using an eye dropper? MS. BLADOW: Objection. Lacks foundation. Outside the scope. A. I am not aware of any study that specifically defined what a normal position was. 12 (Pages 45 to 48) www.midwestlitigation.com MIDWEST LITIGATION SERVICES Phone: 1.800.280.3376 Fax: 314.644.1334 Case 3:12-cv-01141-SMY-DGW Document 176-28 *SEALED* Filed 12/01/14 Page 13 of 27 Case: 16-3334 Document:Page 55-9 ID #2846 Filed: 02/08/2017 Pages: 27 (226 of 1511) DANIEL ARENSON 3/14/2014 Page 51 Page 49 1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18 19 20 21 22 23 24 25 Q. Would you take a look at the document that is Exhibit Pfizer Xalatan 24902? This was used yesterday. (Exhibit PL 24902 marked for identification.) Q. All right. Sir, do you have Exhibit Pfizer Xalatan 24902 in front of you? A. Yes. Q. And do you see that these are meeting minutes dated August 5, 2009 of a meeting of the drug product technology, support, and transfer? A. Yes. Q. Do you see that? And do you see that there is attached to it a document entitled -- it looks like a PowerPoint presentation entitled: "BFS New Dropper Tip Versus Old Catalent Tip Design, Summary of Results." Do you see that? A. I only have one piece of paper. Q. Okay. It must have been marked as a separate exhibit then, Exhibit Pfizer Xalatan 24902. MS. BLADOW: That was 24902. 1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18 19 20 21 22 23 24 25 A. Yes. Q. And there's a box plot graph on this page. Correct? A. Yes. Q. Do any of the results for drop size measurements pertain to any product of Pfizer that was ever on the market in the United States? MS. BLADOW: Outside the scope. Lacks foundation. A. These are PowerPoint results slide. These don't provide enough information for me to tell you that these specific lots were on the market in the U.S. I can only speculate, based on -- on trying to interpret what is here, that a couple of them may have been on the -- on the market. MS. BLADOW: Don't speculate. I just said don't speculate. I assume you don't want his speculation either. Q. The abbreviation CT, do you see a table of abbreviations on Bates there's that page 24905? A. Yes. Q. And that refers to the current or old tip design, Catalent. Do you see that? Page 52 Page 50 1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18 19 20 21 22 23 24 25 MR. CORNFELD: I'm sorry. 24904, yes. (Exhibit PL 24904 marked for identification.) Q. All right. Do you have Exhibit Pfizer Xalatan 24904 in front of you? A. Yes. Q. Are you familiar with this document? A. I have seen this, yes. Q. Are you familiar with it? A. I saw this for the first time during our -- our preparation session. Q. Do you know what -- in the title of the document, where it says "BFS new dropper tip," what does BFS stand for? A. Blow fill seal. Q. That's a type of plastic manufacturing? A. It's a process. Q. Is that right? A. It's a manufacturing process. Q. Would you take a look at page 8, please. And do you see that this page is titled "3. Results Drop Size." Do you see that? 1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18 19 20 21 22 23 24 25 A. Q. Yes. Do you know what that is referring to? A. It refers to the tip design that Catalent produced. Q. And that was -- that tip design was on the market in the United States. Correct? A. That is my understanding. Q. And do you see also in abbreviations used the abbreviation RT-B refers to Xalatan RT, and RT stands for room temperature. Correct? A. According to the abbreviation table, yes. Q. It says "Xalatan RT or Room Temperature - Formula B, which is low BAC." Do you see that definition for the abbreviation RT-B? Do you see that? A. Yes. Q. What does low BAC stand for or what does that mean? A. That's a development product that was never commercialized. Q. Low BAC is the preservative in -or, excuse me, BAC is the preservative in Xalatan. 13 (Pages 49 to 52) www.midwestlitigation.com MIDWEST LITIGATION SERVICES Phone: 1.800.280.3376 Fax: 314.644.1334 Case 3:12-cv-01141-SMY-DGW Document 176-28 *SEALED* Filed 12/01/14 Page 14 of 27 Page ID #2847 Case: 16-3334 Document: 55-9 02/08/2017 Pages: 27 (227 of 1511) DANIEL ARENSON Filed: 3/14/2014 Page 53 1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18 19 20 21 22 23 24 25 Correct? A. Correct. Q. It refers to benzalchromium chloride [sic]? Am I close enough? A. Benzalkonium chloride. Q. Okay. But the amount of BAC in Xalatan that's on the market is not low -- it would not be a low BAC? A. The title of that is specifically referring to a product or a formulation that is not the commercial product. Q. That would have been a high surface tension, according to what's written on page 24910? MS. BLADOW: Objection. Misstates the document. A. I don't see where it says high -high surface tension on here. Oh, the high SF? Is that what that says? Q. I am looking at the middle portion of the box plot. The middle portion is you go across horizontally, where it says "RT-B" and then in parentheses "high SF"? A. Yes, that's correct. Q. All right. Would Xalatan, as it's Page 55 1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18 19 20 21 22 23 24 25 MS. BLADOW: Objection. Object to the form. A. The drop size is going to be dependent on a lot of different measurements. And, generally speaking, as you lower the surface tension, the drop size will get smaller. Q. Does Pfizer consider Xalatan to be a high or low BAC formulation? A. Pfizer considers Xalatan to have an adequate BAC formulation for the purpose of microbial control. Q. What does Pfizer consider a low BAC formulation to be? MS. BLADOW: Objection. Outside the scope. A. A low BAC formulation was trying to lower the -- the -- the level of BAC based on European requests to limit exposure to BAC. The project was stopped because it did not provide the adequate microbial control. Q. Would you take a look at Exhibit Pfizer Xalatan 24881? I believe this was not used yesterday? Page 54 1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18 19 20 21 22 23 24 25 on the market, be considered high surface tension? MS. BLADOW: Objection. Object to the form. A. Surface tension is always a relative measurement. That particular formulation was never commercialized and never put in the clinic. It was stopped for -Q. I understand that. I'm asking -I'm sorry. Go ahead. A. I was just going to say that project was stopped. Q. I -- I understand that. And it says that that project was high surface tension. I'm asking whether Xalatan on the market would have been considered high surface tension? MS. BLADOW: Lacks foundation. Outside the scope. Potentially calls for an expert opinion. A. It would be a lower -- the Xalatan on the market would be a lower surface tension than the low BAC formulation. As to the actual measured surface tension, I don't know the answer to that. Q. Does the drop size go up or down as the surface tension increases? Page 56 1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18 19 20 21 22 23 24 25 (Exhibit PL 24881 marked for identification.) Q. Do you have in front of you Exhibit Pfizer Xalatan 24881? A. Yes. Yes. Q. Are familiar with these meeting minutes -- do you see that these are meeting minutes dated May 12, 2010, minutes of the drug product technology, support, and transfer? Are you familiar with these? A. Yes. Q. And do you see on Bates page 24882, the second hollowed bullet point refers to a low BAC formulation? A. Yes. Q. Is that talking about what you just referred to, a development project that did not pan out? A. Correct. Q. Would you take a look at Exhibit Pfizer Xalatan 24641, please? MS. BLADOW: Is this new? MR. CORNFELD: I'm sorry? MS. BLADOW: Is this a new exhibit? MR. CORNFELD: No. This was from 14 (Pages 53 to 56) www.midwestlitigation.com MIDWEST LITIGATION SERVICES Phone: 1.800.280.3376 Fax: 314.644.1334 Case 3:12-cv-01141-SMY-DGW Document 176-28 *SEALED* Filed 12/01/14 Page 15 of 27 Case: 16-3334 Document:Page 55-9 ID #2848 Filed: 02/08/2017 Pages: 27 (228 of 1511) DANIEL ARENSON 3/14 /2014 Page 59 Page 57 1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18 19 20 21 22 23 24 25 yesterday. (Exhibit PL 24681 marked for identification.) A. Okay. Q. All right. You've been handed what's been marked as Exhibit Pfizer Xalatan 24641, which indicates on its first page that it is meeting minutes dated 3/28/2011 of drug product technology, support, and transfer. Do you see that? A. Yes. Q. Are you familiar with this document? A. Yes. Q. Well, what is drug technology, support, and transfer? A. The memo's author -Q. I'm sorry? A. It's the group that the memo's author belongs to. Q. And what is that group? A. What it says. It's a product support group. Q. What type of support does it provide the product? 1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18 19 20 21 22 23 24 25 And that's on Bates page 24642. Do you see that? A. I see that. Q. And do you see that indicates that this is a summary of Bernadette's discussion with Mike Lynch, Pfizer internal documents, and ophthalmic literature. Do you see that? A. I see that. Q. Who is Bernadette? A. Bernadette Mauser is a member of the -- what we call Global CMC. She's part of the group that manages submissions. Q. And who is Mike Lynch? A. Mike Lynch is also a member of that group. Q. All right. Do you see that there's a bullet point underneath this section on medical and regulatory implications, a bullet point on the top of 24643, entitled "Drop Size is Not a Medical Issue." Do you see that? A. Yes. Q. And then you see that there are three sub bullet points explaining that below that? A. Yes. Page 60 Page 58 1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18 19 20 21 22 23 24 25 A. They are a technical support group for any -- any technology with products that are already launched. I'm only passingly familiar with that group. Q. Who is part of that group? A. I'm really not all that familiar with that group. They are part of a different division of Pfizer. Q. What division are they a part of? A. They're part of the commercial manufacturing division. Q. And what division are you part of? A. Research and development. Q. John Wydila is the author of this memo. Correct? A. Yes, I'm reading the same -- same name. Q. Who is John Wydila? A. I don't know John. All I know is what I'm reading here, that he was part of this group, and he was working on this project. Q. All right. Do you see, on page 2 there's a bullet point that states: "Medical and regulatory implication of dispensing drops greater than 31 microliters." 1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18 19 20 21 22 23 24 25 And the first one says: "The human eye can absorb approximately seven microliters of fluid. The remaining drop fluid beyond seven microliters is not absorbed by the eye." Do you see that? A. Yes. Q. Is that a true statement? MS. BLADOW: Objection. Outside the scope. Potentially calls for an expert opinion. Q. Go ahead. A. So, I am not an opthalmologist. I can't state whether that seven microliters is correct or not. I think that there's another consideration there. This only talks about what's absorbed. In order to be absorbed you have to have that seven microliters covering the eye. Depending on how you drop -- you put the eye drop in, there's no guarantee that a seven microliter drop would actually cover the eye and be absorbed. Q. Are you aware of any studies that would indicate that there has to be more than seven microliters dropped on the eye in order for Q. 15 (Pages 57 to 60) MIDWEST LITIGATION SERVICES www.midwestlitigation.com Phone: 1.800.280.3376 Fax: 314.644.1334 Case 3:12-cv-01141-SMY-DGW Document 176-28 *SEALED* Filed 12/01/14 Page 16 of 27 Page ID #2849 Case: 16-3334 Document: 55-9 02/08/2017 Pages: 27 (229 of 1511) DANIEL ARENSON Filed: 3/14/2014 Page 61 1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18 19 20 21 22 23 24 25 seven microliters to be absorbed? A. I'm not personally aware of a study. I am personal aware of my own experience and descriptions from opthalmologists about all the various ways people put eye drops in, and why that requires a lot more fluid to be administered to the eye in order to make sure that there's adequate coverage amongst the general population who puts eye drops in, in a lot of different ways. MR. CORNFELD: Move to strike that part of the answer. Q. With respect, sir, that part of the answer about whether you're aware of any studies is not responsive to my question. MS. BLADOW: Objection to the motion. Q. Do you see the next sub bullet point that says: "Pharmacia reports no medical reason for accurate measurement of drop size." Do you see that? A. Yes. Q. Is that a true statement? MS. BLADOW: Lacks foundation. Outside the scope. Calls for an expert Page 63 1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18 19 20 21 22 23 24 25 different manner. I know it as -- I believe it's 50 microliters per mole -- or 50 micrograms per mole. Q. 50 micrograms. Correct? A. Yes. Q. 50 micrograms per 100 -A. I thought it was per milliliter. Q. All right. Let me ask the question. The concentration of Latanoprost in Xalatan, one way to express it is 50 micrograms per milliliter. Correct? A. I believe that is correct, without looking up the formulation. Q. All right. Is it a -- is it a correct statement that the concentration of Latanoprost in Xalatan is Xalatan's dosing critical parameter as stated on page 24643? A. Yes. THE VIDEOGRAPHER: The time is 11:41 a.m. We're off the record. (Recess taken.) THE VIDEOGRAPHER: The time is 11:51 a.m. We're on the record. Q. Sir, if you could look again at Page 62 1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18 19 20 21 22 23 24 25 opinion. A. I -- I am not aware of those particular reports, so I can't -- I can't say conclusively that it is true or not. Q. Okay. Do you see the next bullet point that says: "API concentration is the dosing critical parameter." Do you see that? A. Yes. Q. And API stands for active pharmaceutical ingredient. Correct? A. Correct. Q. For Xalatan that is Latanoprost. Correct? A. Correct. Q. And do you see that when it says "API concentration for Latanoprost" that is 0.002 percent. Correct? MS. BLADOW: Are you reading from somewhere? MR. CORNFELD: No. I'm just asking the witness. MS. BLADOW: Object to the form. A. I know it as -- I know it in a Page 64 1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18 19 20 21 22 23 24 25 Exhibit Pfizer Xalatan 24881. Oh, excuse me, I'm sorry, 24641, Exhibit Pfizer Xalatan 24641, which we've been referring to. And do you see that the discussion on the top of page 24643 that's headed "Drop Size is Not a Medical Issue." Do you see that that was part of the summary of Bernadette's discussion with Mike Lynch, Pfizer internal documents, and opthalmic literature? Do you see that? A. Yes. Q. What opthalmic literature is being referred to there? MS. BLADOW: Objection. Lacks foundation. A. I -- I don't know. I -- I wasn't part of this discussion. I wouldn't know what specifically was referred to. Q. Well, you're the witness who's here to talk about this. How -- how would I find out what opthalmic literature is being referred to there? MS. BLADOW: Objection. Argumentative. Lacks foundation. Q. How could anybody find that out? MS. BLADOW: Same objection. 16 (Pages 61 to 64) www.midwestlitigation.com MIDWEST LITIGATION SERVICES Phone: 1.800.280.3376 Fax: 314.644.1334 Case 3:12-cv-01141-SMY-DGW Document 176-28 *SEALED* Filed 12/01/14 Page 17 of 27 Page Case: 16-3334 Document: 55-9 ID #2850 Filed: 02/08/2017 Pages: 27 (230 of 1511) DANIEL ARENSON 3/14/2014 Page 67 Page 65 1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18 19 20 21 22 23 24 25 Argumentative. Calls for speculation. A. I don't have an answer to that. Q. Did you ask Bernadette or Mike Lynch what opthalmic literature they were referring to, or the author of the memo, John Wydila, what opthalmic literature they were referring to? MS. BLADOW: Object to the form. A. I have not asked any of them about what was in this document. Q. Okay. I asked your attorneys what opthalmic literature -- well, strike that. Do you know what Pfizer internal documents are being referred to here? A. Since they're not listed, and I was not part of this discussion, no, I don't. Q. And I take it you didn't make any attempt to find that out. Is that right? A. Not since I first saw this document yesterday. Q. And learned that you would be testifying about it. Correct? MS. BLADOW: Objection. This document is outside the scope of the witness' designation. I object to the assumption in 1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18 19 20 21 22 23 24 25 And, sir, you know that there is a vast amount of opthalmic literature that relates to the subject of drop size. Correct? A. I am -MS. BLADOW: Objection. Outside the scope of -- of the deposition. A. -- I am not an expert in opthalmic literature, so I can't tell you how much there is or is not available. Q. But you have no idea which specific opthalmic literature is being referred to as the basis for saying that drop size is not a medical issue in Pfizer Xalatan 24641. Correct? MS. BLADOW: Objection. Asked and answered. A. Because it's not specific here, and I wasn't present, I wouldn't know the answer to that. MR. CORNFELD: I will renew my request for the specific opthalmic literature that is being referred to here. Q. The statement in Exhibit Pfizer Xalatan 24641, the statement that the human eye can absorb approximately seven microliters of fluid, and the remaining drop fluid beyond seven Page 68 Page 66 1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18 19 20 21 22 23 24 25 the question. MR. CORNFELD: Go ahead. A. I did not attempt to contact any of those people to find out what was -- what was referred to in this document. Q. I asked your attorneys what Pfizer internal documents and opthalmic literature were being referred to so that they could produce it to me, and the only answer I got was that the opthalmic literature that is summarized in the minutes is a matter of public record and already in your possession. That was in a letter from Shaun Paisley, dated March 12, 2014. That would indicate that the opthalmic literature would be publicly published opthalmic literature. Correct? MS. BLADOW: Objection. Lacks foundation. A. That would be how I would assume it was meant. Q. And I didn't get any answer about what Pfizer internal documents are being referred to here. So, let -- I will renew my request that the Pfizer internal documents and -- that the Pfizer internal documents be produced to me. 1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18 19 20 21 22 23 24 25 microliters is not absorbed by the eye, that statement doesn't distinguish between different types of people. Correct? It just refers to the human eye. Correct? MS. BLADOW: Objection. Lacks foundation. A. I can only read that statement. I am not an opthalmologist. Q. I'm sorry? A. I can only read what it says in that statement. I am not an opthalmologist. Q. Speaking for Pfizer as the corporate representative here at the deposition, you can tell us that the statement in Pfizer's document simply refers to the human eye, and the amount that the human eye can absorb, and makes no distinction between human eyes of different types of people. Correct? MS. BLADOW: Outside the scope. Lacks foundation. A. Once again, I can read this statement. Where this statement came from, who made that statement, is -- is outside of my knowledge. Those types of statements would generally come from medical and clinical, those 17 (Pages 65 to 68) www.midwestlitigation.com MIDWEST LITIGATION SERVICES Phone: 1.800.280.3376 Fax: 314.644.1334 Case 3:12-cv-01141-SMY-DGW Document 176-28 *SEALED* Filed 12/01/14 Page 18 of 27 Page ID #2851 Case: 16-3334 Document: 55-9 02/08/2017 Pages: 27 (231 of 1511) DANIEL ARENSON Filed: 3/14/2014 Page 69 1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18 19 20 21 22 23 24 25 with ophthalmology specialties. That's not me. Q. My question had to do with what is stated here. It just refers to the human eye and doesn't make any distinction between different types of people and their eyes. Correct? MS. BLADOW: Lacks foundation. Outside the scope. A. I -- I can only read what is on the paper, and it does not specifically refer to any type of person there. Q. All right. And, of course, Pfizer does have specialists in ophthalmology on its staff. Correct? A. There are people who have studied ophthalmology working for Pfizer. Q. Tremendous specialists in ophthalmology. Correct? MS. BLADOW: Objection. Vague and ambiguous. A. I -- I -Q. I mean, they're experts in it. That's why Pfizer is -- is -- why Pfizer hired them. Correct? MS. BLADOW: Outside the scope. Lacks foundation. Page 71 1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18 19 20 21 22 23 24 25 was primarily just a CMC issue, which was -involved mostly around stability. Q. All right. Well, whatever their expertise, the opthalmologists at Pfizer write internal documents; don't they? MS. BLADOW: Objection. Lacks foundation. Outside the scope. A. I would assume that there are some internal documents written by the opthalmologists. Q. And this statement about -- this section about drop size not being a medical issue, and how much fluid the eye can absorb, and so forth, part of the basis of that section is Pfizer internal documents. Correct? MS. BLADOW: Lacks foundation. A. Once again, because there is not a specific citation next to this, I cannot tell you where this -- this piece of information came from. Q. Well, but we know that at least part of the basis was Pfizer internal documents. We know that because that's what it says on the memo. Correct? A. What it says on the memo is Pfizer internal documents around the entire section, which includes significantly more than just that Page 70 1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18 19 20 21 22 23 24 25 A. You're asking me about one of the 80,000 people or a small group of the 80,000 people who work for Pfizer worldwide. I do not know everybody at Pfizer. I do not know what level of ophthalmic experience exists in the company. Q. Well, those opthalmologists, whether they're leading experts, as I would expect, or some -- you know, had some lesser degree of expertise and experience, as you may be suggesting, they write documents, they write internal documents; don't they? MS. BLADOW: Objection. Argumentative. Misstates the witness' testimony. Lacks foundation. Outside the scope. It's a completely improper question. A. I did not say that they would be lesser ophthalmic experts. What I said is I don't know them. There very well may be some world class experts, but I don't know everybody at Pfizer. Pfizer is a large company. It's located in many locations. And the majority of my work is done on very specific projects. And in the case of the work that I did on Xalatan itself, it did not include any of the opthalmologists because it Page 72 1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18 19 20 21 22 23 24 25 statement. So, I don't know if that statement -Q. Well, of course. A. -- I don't know if that statement is specifically referenced by a Pfizer internal document or whether it's from publicly available opthalmic literature. Q. Do you think that it's just barely possible that when the people involved in this team decided to look at whether drop size is a medical issue, and how much the human eye can absorb, and how -- the implications of eye drop size, that they consulted internal documents by Pfizer's opthalmologists? MS. BLADOW: Lacks foundation. A. Once again, all things are possible, but I cannot state what was -- what was consulted or referenced on this particular statement. Q. Are you aware of any studies that Pfizer has done or anyone else has done that show the effect of temperature on drop size? MS. BLADOW: Outside the scope. A. The only studies that I'm aware of are ones that I think are referenced -- didn't we already have that document? There's one that -- 18 (Pages 69 to 72) www.midwestlitigation.com MIDWEST LITIGATION SERVICES Phone: 1.800.280.3376 Fax: 314.644.1334 Case 3:12-cv-01141-SMY-DGW Document 176-28 *SEALED* Filed 12/01/14 Page 19 of 27 Case: 16-3334 Document:Page 55-9 ID #2852 Filed: 02/08/2017 Pages: 27 (232 of 1511) 3/14/2014 DANIEL ARENSON Page 75 Page 73 1 that compared a drop at 5C versus a drop at room 1 2 3 temperature. 2 Q. Would you take a look at page -the Bates page 4894? We previously looked at it. It's the paper called: 3 4 5 "Drop Size of Xalatan Eye Drops, 50 6 7 8 9 10 11 12 13 14 15 16 17 18 19 20 21 22 23 24 25 4 5 6 7 Micrograms Per Milliliter." MS. BLADOW: Can you repeat the 8 9 10 11 12 page? MR. CORNFELD: Yeah. It was not -I don't think it was the first page of the exhibit, but it's page 4894. The first page of the exhibit may be 4755. Q. Do you have that paper which is part of Exhibit Pfizer Xalatan 4755? A. Yes. Q. Is that the paper you're talking about? A. I don't see mention of different 13 14 15 16 17 18 19 temperatures in here. Q.. Look at the summary at page 4897. And do you see that the first parameter they mention is variation and temperature of solution? A. Yes, I see that. Q. That's why I thought maybe this was 20 21 22 23 24 25 MS. BLADOW: Is this a new one? MR. CORNFELD: No. I'm sorry. This is from yesterday. I apologize for not clarifying that. (Exhibit PL 97 marked for identification.) Q. Have you seen this document before? A. Yes. MR. CORNFELD: I'm sorry. That's not the document I had in mind to ask you about. The one I'd like to ask you about is Exhibit Pfizer Xalatan 108. (Exhibit PL 108 marked for identification.) MS. BLADOW: I'm just going to object to the -- that this is marked as these individual pages. It just seems like -- I know these are all portions of bigger documents, but it may be kind of hard to follow where they come from. MR. CORNFELD: Where I have taken documents that are part of bigger documents, I specified that yesterday when -- when I first offered the exhibits. And I don't believe that's true for this -- for this paper, but if Page 76 Page 74 1 2 3 4 5 6 7 8 the paper you had in mind. A. Yes. So, looking at 4898, the definition, they did some combination with temperature. Q. Did they report any results at different temperatures? A. I don't see any results, which is why I missed that the first time around. 9 10 11 Q. All right. Are you aware of any report of results at Pfizer for a study of drop size at different temperatures? 12 13 14 15 16 A. I thought there was something in a document that I reviewed, but I could not specify it off the top of my head. Q. All right. So, you're -- you're not aware of what it is, I take it? A. No. Q. Are you aware of any studies by Pfizer, or anyone else, looking at the effectiveness of eye drops of different sizes? MS. BLADOW: Objection. Outside the scope. 17 18 19 20 21 22 23 24 25 A. No. Q. Would you take a look at Exhibit Pfizer Xalatan 97? 1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18 19 20 21 22 23 24 25 it's not -- let me just check. MS. BLADOW: You may have specified it yesterday, but obviously Dr. Arenson wasn't here yesterday, so -MR. CORNFELD: No, I -- I know. I know, but I don't believe this was one of them. I believe this is -- this is as it was produced to plaintiffs. Q. But there was testimony yesterday that this is the quality overall summary that was submitted by Pfizer in support of a submission to the FDA, but there's just one thing I'd like to ask Dr. Arenson about. Doctor, would you take a look at page 110? Actually, I don't think I asked you if you're familiar with this document. A. Yes. Q. All right. And you recognize this as the quality overall summary that Pfizer submitted to the FDA in support of a revised dropper tip. Correct? A. As stated, this is -- this does not look like it's a complete document. We normally don't submit just this one section, but -Q. The testimony yesterday was that 19 (Pages 73 to 76) www.midwestlitigation.com MIDWEST LITIGATION SERVICES Phone: 1.800.280.3376 Fax: 314.644.1334 Case 3:12-cv-01141-SMY-DGW Document 176-28 *SEALED* Filed 12/01/14 Page 20 of 27 Page ID #2853 Case: 16-3334 Document: 55-9 Filed: 02/08/2017 Pages: 27 (233 of 1511) DANIEL ARENSON 3/14/2014 Page 77 1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18 19 20 21 22 23 24 25 this is a revised quality overall summary and response to an inquiry by the FDA. I'm offering this to you as a complete document because that's how it is produced -- how it was produced to us by Pfizer. A. Okay. Q. But can you tell me what -- what is missing -- what you would think would be missing from this? A. There would normally be, at minimum, a cover page for sending in something like this. MR. CORNFELD: Well, I would request whatever is not contained here that would have been submitted with it, with Exhibit Pfizer Xalatan 108. Q. Dr. Arenson, the portion I'd like to ask you about is on page 110. Do you see the statement in the first paragraph, the last sentence of that paragraph: "To determine an indifference region for the equivalence test, a range of plus or minus two microliters was specified, which is approximately one-quarter of the qualification range." Page 79 1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18 19 20 21 22 23 24 25 Q. Has Pfizer ever tested the drop size when it's dosed in humans? MS. BLADOW: Outside the scope. A. I'm not privy to what was done for this particular product in human tests, but I'm not even sure how you could run that test. Q. Has -- has Pfizer -- you're not aware of any such -- any attempt to do that. Is that correct? MS. BLADOW: Outside the scope. Q. To test drop size as a performance test? MS. BLADOW: Outside the scope. A. I'm not aware of any attempt by anybody to do that because I'm not sure how you would measure the size of a drop once it's on the human eyeball. That's normally considered an ethical problem. Q. So, the best you could do to come up with the drop size would be the quality control type of test, such as Pfizer has done. Correct? MS. BLADOW: Objection. Outside the scope. Lacks foundation. Vague and ambiguous. A. A quality control test is different Page 78 Page 80 1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18 19 20 21 22 23 24 Do you see that? A. Yes. Q. What is meant by "indifference region"? MS. BLADOW: Lacks foundation. A. I am presuming that that is a statistical reference that these would be equivalent. Q. All right. So, statistically speaking, drops that are within two microliters of each other would be equivalent. Is that right? MS. BLADOW: Objection. Lacks foundation. A. As this QC test is performed, that is my interpretation of what is written here. Q. What does "QC" stand for, quality control? A. Quality control. These types of drop tests are all quality control tests. These are not performance tests. Q. What do you mean by that? A. Quality control is a way we test the product to make sure that it is consistent. It is not necessarily identical to the performance 1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18 19 20 21 22 23 24 25 of a product when it is dosed into humans. 25 than a use test. A quality control test is designed to be as reproducible as -- as possible, so that we can evaluate the product as it's manufactured. A use test, when you put it in the hands of a large group of people who could use it, is not the same and will give significantly more varied results. Q. One way you could do it would be to take drops of different sizes as measured in a quality control test and ask humans to use those drops and see how well they performed in controlling the patient's glaucoma. Correct? MS. BLADOW: Objection. Outside the scope. It calls for speculation. Argumentative. A. I don't know how clinical studies would specifically be designed to evaluate that, but it sounds theoretically possible. MR. CORNFELD: Would you take a look at the document with the Bates number that begins 24382? And I don't believe that was used yesterday. (Exhibit PL 24382 marked for identification.) 20 (Pages 77 to 80) www.midwestlitigation.com MIDWEST LITIGATION SERVICES Phone: 1.800.280.3376 Fax: 314.644.1334 Case 3:12-cv-01141-SMY-DGW Document 176-28 *SEALED* Filed 12/01/14 Page 21 of 27 Case: 16-3334 Document:Page 55-9 ID #2854 Filed: 02/08/2017 Pages: 27 (234 of 1511) DANIEL ARENSON 3/14/2014 Page 83 Page 81 1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18 19 20 21 22 23 24 25 Q. All right. Do you see this is a one-page document, Exhibit Pfizer Xalatan 24382, that is a meeting agenda dated September 12th, 2011? A. Yes. Q. For the drug product technical support and transfer. Correct? A. Yes. Q. And do you see there's a reference there that they were going to review the 1994 user study? A. I see that. Q. And I asked your attorneys to provide that user study, and the response I had was that that was the document that starts with the Bates No. 1335. And I believe we already looked at that today. So, would you please get that out? A. Is that the one that's marked 1531? Q. Yes. Yes. I'm having trouble finding it myself, but -- so, do you see the document that -- that begins at Bates No. 1535 is the paper we've looked at called: "Evaluation of Total Yield, Number of Drops and Drop Size Per Bottle Simulating 1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18 19 20 21 22 23 24 25 MR. CORNFELD: Would you take a look at the document that begins with 2495? I believe that was used yesterday, but I'm not certain of that. (Exhibit PL 2495 marked for identification.) Q. Do you have in front of you Exhibit Pfizer Xalatan 2495? A. Yes. Q. Are you familiar with this document? A. Yes. Q. Would you take a look at page 2503? Do you see the statement below the tables in the second line that states: "The manual drop size test is known to be prone to operator dependent variations." Do you see that? A. I see the statement. Q. All right. What operator dependent variations are being referred to there? A. I can't specifically say because I wasn't involved in the discussions or the work that was done here. Normally for this type of -of test it would be how you're holding the bottle, Page 84 Page 82 1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18 19 20 21 22 23 24 25 Practical Use of Over Five Milliliters AOP Bottles Filled With Approximately 2.8 Milliliter Eye Drops Latanoprost, 50 Micrograms Per Milliliter." Do you see that? A. Yes. Q. And so, in 2011 Pfizer was continuing to use that 1994 user study, the one that begins at Bates page 1535. Correct? MS. BLADOW: Outside the scope. Lacks foundation. And the witness already testified he hasn't seen this document before. MR. CORNFELD: Go ahead. A. I don't know that this document is specifically the one that's referred to there, but if so, then it appears to be, yes. Q. All right. And I'm just asking you to assume that when your attorneys told us that that is what's being referred to, that that's a true statement, and you have no reason to question that. Correct? A. Assuming they agree, then yes. Q. Okay. Do you know who Filja (phonetic) and Patrine (phonetic) are who are referred to on page 4382? A. I don't know either one of them. 1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18 19 20 21 22 23 24 25 how you're squeezing the bottle, where you're squeezing the bottle, how quickly you squeeze the bottle. All of those would be known to modify the way that the drops come out of the bottle, and, therefore, the drop size. Again, this is specifically done as a QC test, so the purpose of -- of this, as I read it here, is they're going to be using the Xal-Ease applicator in order to have a more consistent quality control test. Q. All right. When you say how you are holding the bottle, what are you referring to? A. When you want to orient a bottle, because this is not round, it has a defined shape, the pressure that the liquid has, which is -impacts the drop size, is going to depend on how you orient that bottle because the pressure is the top of the fluid to the tip of the dropper. So, as you change that -- that height between them, you will change the -- the pressure that the tip sees. Q. When you -- when you say how you orient, what do you mean? Are you talking about the angle that you're holding the bottle at or 21 (Pages 81 to 84) www.midwestlitigation.com MIDWEST LITIGATION SERVICES Phone: 1.800.280.3376 Fax: 314.644.1334 Case 3:12-cv-01141-SMY-DGW Document 176-28 *SEALED* Filed 12/01/14 Page 22 of 27 Page ID #2855 Case: 16-3334 Document: 55-9 Filed: 02/08/2017 Pages: 27 (235 of 1511) DANIEL ARENSON 3/14/2014 Page 85 1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18 19 20 21 22 23 24 25 something else? A. The best way I can describe it is this container has a three-dimensional orientation. So, if I use this water bottle as an example, imagine that this water bottle is flat like this, which is how our container is. If I hold it this way, I get one pressure. If I hold it this way, I get another pressure. If I hold it this way, I get a different pressure altogether. Because it's flat, as I rotate it this way, I change it again. So, all of those orientations will change the pressure that the fluid has at the tip, and, therefore, the drop size. Q. All right. What studies are you aware of that have shown the effect on drop size of how the bottle is held or oriented? A. Well, just for starters, right here on this page you're seeing the difference between a 90- and a 45-degree angle. Q. Other than the 90- and 45-degree angle, what studies have you seen that show a difference in what that difference is in how the bottle is oriented? A. I'm not aware of specific studies, Page 87 1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18 19 20 21 22 23 24 25 and 90 degrees? MS. BLADOW: Outside the scope. A. I am not aware of any other studies that are -- that address that specifically. Q. All right. How about where the bottle is squeezed? Are you aware of any studies that Pfizer or anyone else has done to show whether there is an effect on drop size, depending on where the bottle is squeezed, and if so, how much that effect is? MS. BLADOW: Same objection. A. So, the only information I have is the difference between when the operators did it in a less controlled way versus when they are doing it with the -- the more refined method that controls these parameters better. Q. My question is: You mentioned that there are differences between -- in drop size, depending on where the bottle is squeezed, how the bottle is squeezed, how quickly is it squeezed. And my question is as to those factors are you aware of any studies -A. I am not aware of -Q. -- that would show the effect -A. -- I'm not aware of a study. Page 86 1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18 19 20 21 22 23 24 25 but this is basic hydrodynamic. As you change -Q. Has Pfizer -- I'm sorry. Go ahead. A. No, go ahead. Q. Go ahead. A. I was going to say it's basic hydrodynamics. So, as you change the -- the -what they call the head pressure based on the height of the fluid, you change the pressure. Q. All right. Has Pfizer ever studied how much of an effect on drop size there is in how the bottle is oriented, other than a difference between 45 and 90 degrees? MS. BLADOW: Outside the scope. Lacks foundation. A. I only know about the studies that are in the documents that are the same ones that you've seen, because I was not part of this project. Q. Well, my question is -- I can't testify about what I have seen. Have you seen a study that Pfizer or anyone else has ever done to show how much effect on drop size there is by changing the orientation of the bottle, other than the difference -- other than the difference between 45 Page 88 1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18 19 20 21 22 23 24 25 Q. Are you aware of any studies showing such an effect, if any, and what it is? MS. BLADOW: Outside the scope. A. I am not aware of -- of any specific studies. MR. CORNFELD: Let's take a break. I will let you know what else I have or how much more, and we can decide about lunch. THE VIDEOGRAPHER: The time is 12:38 p.m. We're off the record. (Recess taken.) THE VIDEOGRAPHER: The time is 12:47 p.m. We're on the record. MR. CORNFELD: Robyn, would you hand the court reporter the document with the Bates number beginning 24279. (Exhibit PL 24279 marked for identification.) Q. Sir, you have been handed Exhibit Pfizer Xalatan 24279, which is a two-page document that says at the top "Introduction." There's another heading, "Published Data." Have you seen this document before? A. I don't believe I've seen this one. Q. Do you see that in the fourth 22 (Pages 85 to 88) www.midwestlitigation.com MIDWEST LITIGATION SERVICES Phone: 1.800.280.3376 Fax: 314.644.1334 Case 3:12-cv-01141-SMY-DGW Document 176-28 *SEALED* Filed 12/01/14 Page 23 of 27 Page Case: 16-3334 Document: 55-9 ID #2856 Filed: 02/08/2017 Pages: 27 (236 of 1511) DANIEL ARENSON 3/14/2014 Page 91 Page 89 1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18 19 20 21 22 23 24 25 paragraph the author states "as of November 15, 2010." Do you see that? A. I see it. Q. So, that would indicate that this document was written sometime either on or after November 15, 2010? MS. BLADOW: Lacks foundation. A. Apparently so. Q. All right. And do you see that the author states that as of November 15, 2010 a computerized search of the published medical literature has identified a relevant article published in 2003 that discusses the daily cost and the expected days of therapy per Latanoprost bottle. Do you see that? A. I see it. Q. And then the author summarizes that article. Do you see that? A. Yes. Q. All right. And if you would look at the references, do you see that Reference 4 is that 2003 article? A. I see that. Q. That's an article by Fiscella, Green, Patuszynski, et al. called "Medical Therapy 1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18 19 20 21 22 23 24 25 A. Yes. Q. And do you see that this is a paper by Fiscella, et al., entitled "Medical Therapy Cost Considerations For Glaucoma"? A. Yes. Q. All right. And would you confirm that that is the same paper that was referred to in Exhibit Pfizer Xalatan 24279? A. That appears to be correct. Q. And do you see that in the paper, Exhibit Pfizer Xalatan 24279, the author looked at -- strike that. If you'd look at the Fiscella paper Exhibit, Exhibit PL 437, and you look at the second column of the first -- of the first page -by the way, have you ever seen this paper before? A. No. Q. You're not familiar with it at all? A. No. Q. Other than seeing a reference to it in Exhibit Pfizer Xalatan 4279, have you ever even heard about this paper? A. No. Q. Do you see that in the second column of the first page there's a reference to: Page 92 Page 90 1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18 19 20 21 22 23 24 25 Cost Considerations For Glaucoma," published in the American Journal of Ophthalmology in 2003, in Volume 136, pages 18 to 25. Do you see that? A. I see that. Q. And so, apparently the author of this -- of this paper for Pfizer was accepting that data as valid -- that 2003 study as valid in 2010 or later. Correct? MS. BLADOW: Objection. Lacks foundation. Vague and ambiguous. Outside the scope. A. I can't draw that conclusion. All I can draw is there was a search for a relevant article, an article was found, and the article was summarized. I -- I cannot speak to there being a Pfizer agreement that the article is correct. MR. CORNFELD: Would you take a look at the document that begins with the Bates No. PL 437? Robyn, would you hand that to the court reporter? (Exhibit PL 437 marked for identification.) Q. Do you have in front of you Exhibit 437? PL 1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18 19 20 21 22 23 24 25 "The calculated daily patient cost or cost minimization of medical glaucoma therapy is one way of starting at a baseline for comparison and has been studied by other investigators." Do you see that? A. Where? Q. The second column on the first page, towards the bottom. I'm sorry. The sentence that starts "the calculated daily cost -daily patient cost." A. Okay. Q. And then it says: "In the last few years new products and more ergonomic and efficient ophthalmic bottles have required reexamination of the cost per day." Do you see that? A. Yes. Q. And if you look up at the second page with the Bates No. 438, at the top of the page there's a sentence that says: "Latanoprost 0.005 percent (Xalatan; Pharmacia and Upjohn, Kalamazoo, Michigan, U.S.A.) was also recalculated because of 23 (Pages 89 to 92) www.midwestlitigation.com MIDWEST LITIGATION SERVICES Phone: 1.800.280.3376 Fax: 314.644.1334 Case 3:12-cv-01141-SMY-DGW Document 176-28 *SEALED* Filed 12/01/14 Page 24 of 27 Page ID #2857 Case: 16-3334 Document: 55-9 Filed: 02/08/2017 Pages: 27 (237 of 1511) DANIEL ARENSON 3/14/2014 Page 93 1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18 19 20 21 22 23 24 25 a new dropper tip design." Do you see that? A. Yes. Q. And are you aware that shortly before this paper was published in 2003 Pfizer did introduce a new dropper tip design for Xalatan? A. I know that a new dropper tip design was introduced, but I don't recall the timing for that. Q. All right. And I said Pfizer, but actually it was Pharmacia. And there was testimony that that was introduced in 2002. There was testimony yesterday. A. Okay. Q. If you would accept that. Okay. Now, would you take a look at Table 1 on page 441? A. Okay. Q. And do you see there's a reference to Xalatan on that page, in the table? A. I'm sorry. I had to find the bottom of the table. Yes. Q. All right. And in this table the authors presented a number of categories of results, and one of those was average drops per Page 95 1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18 19 20 21 22 23 24 25 MS. BLADOW: Outside the scope. A. I -- I don't have a calculator, so, go ahead. Q. Okay. Will you accept that I did the calculation correctly, and rounded to the nearest microliter it's 36 microliters? A. Okay. MS. BLADOW: Same objection. This is silly. Q. All right. Are you familiar -- I'm not sure. I may have asked you this, and if I did, I apologize, but I just want to make sure. Other than what we just looked at in that paper by Fiscella from 2003, Exhibit PL 437, are you aware of any other drop size measurements by any investigators outside Pfizer? MS. BLADOW: Object to the form. Q. Drop size measurements of Xalatan? A. No. MR. CORNFELD: Would you take a look at -- and, Robyn, would you hand the court reporter the document that begins with page 24862? (Exhibit PL 24862 marked for identification.) Page 94 1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18 19 20 21 22 23 24 25 milliliter. Do you see that? A. Yes. Q. And for Xalatan they present results, and then they present results for the new bottle in parentheses. Do you see that? MS. BLADOW: Objection. Lacks foundation for any testimony about this document. A. I see -- I see where it says that, yes. Q. All right. And so, for Xalatan the original results were 32 drops per milliliter, and for the new bottle, the new dropper tip design, it was 28 drops per milliliter. Do you see that result being reported there? MS. BLADOW: Lacks foundation. Outside the scope. A. I see -- yes, I see where it says that. Q. A dropper tip of 28 drops per milliliter would correspond to a drop size of -if you have a calculator, I guess you can do it. Will you accept my calculation that that corresponds to 36 microliters? Page 96 1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18 19 20 21 22 23 24 25 Q. You've been handed Exhibit Pfizer Xalatan 24862, which is a document on the letterhead of Pfizer Global Manufacturing that's titled "AS&T Report," and dated November 20, 2009, according to the signature line. Are you familiar with this document? A. I have not seen this document before. Q. If you would look at the document with the Bates No. 24864, under "Backgrounds and Objectives." Strike that. Are you familiar with any studies looking at the degradation or absorption of Xalatan over time? MS. BLADOW: Outside the scope. Vague. A. I am only peripherally aware of those as they related to the change in the resin that was used for the room temperature development. Q. It is -- it is true that a certain amount of Latanoprost will either degrade over time or be absorbed into the bottle. Correct? MS. BLADOW: Lacks foundation. 24 (Pages 93 to 96) www.midwestlitigation.com MIDWEST LITIGATION SERVICES Phone: 1.800.280.3376 Fax: 314.644.1334 Case 3:12-cv-01141-SMY-DGW Document 176-28 *SEALED* Filed 12/01/14 Page 25 of 27 Case: 16-3334 Document:Page 55-9 ID #2858 Filed: 02/08/2017 Pages: 27 (238 of 1511) 3/14/2014 DANIEL ARENSON Page 99 Page 97 1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18 19 20 21 22 23 24 25 Outside the scope. A. That's my understanding. Q. All right. And you see that the objective of this study, according to the background and objectives section on page 24864, if you look at the second sentence it was: "To evaluate the absorption rate of Latanoprost into containers, including tips manufactured from the proposed resins against the absorption rate into the current containers with tips made from the Escorene resin." Do you see that? A. Yes. Q. And if you would look at Xalatan 24865, do you see under study rationale, No. 1 says: "Latanoprost degrades at elevated temperatures"? A. Yes. Q. Do you see that? That's not something you would expect to see normally since Xalatan is ship refrigerated. Correct? MS. BLADOW: Argumentative. Outside the scope. A. I wouldn't expect to see that at 1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18 19 20 21 22 23 24 25 A. Yes. Q. Is that acid of Latanoprost in the bottle an active pharmaceutical ingredient when it is dispensed into the eye from the bottle? MS. BLADOW: Same objection. A. The acid of Latanoprost will not absorb into the eye. Q. Okay. So, by measuring the acid of Latanoprost and -- well, strike that. If you would look at the -- at page 24866, do you see that they indicate, in the third paragraph, that they -- in order to accelerate the study to see how rapidly Latanoprost would be absorbed into the bottle that they used an accelerated condition of 50 degrees centigrade? A. Yes. MS. BLADOW: Lacks foundation. Outside the scope. Q. All right. 50 degrees centigrade is obviously a lot warmer than four degrees centigrade, at which Xalatan is shipped. Correct? MS. BLADOW: Object to the form. A. Yes. Q. Okay. So, that would cause some of Page 100 Page 98 1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18 19 20 21 22 23 24 25 5C. Elevated -Q. All right. Did you finish your answer? A. Yes. Q. All right. 5C is the temperature at which Xalatan is shipped. Correct? A. Yes. Q. Do you see in Paragraph 1 at the bottom of page 24865 the sentence that refers to: "Latanoprost's major degradation product, acid of Latanoprost." A. Yes. Q. What is "acid of Latanoprost"? MS. BLADOW: Outside the scope. A. Latanoprost is a pro drug, and it's dosed that way because the Latanoprost pro drug itself will absorb into the eye. Inside the eye it enzymatically degrades to the acid of Latanoprost, which is the truly active ingredient. Q. Well, in -- in this study they say they measured both Latanoprost and acid of Latanoprost. So, does it degrade into acid of Latanoprost in the bottle also? MS. BLADOW: Lacks foundation. Outside the scope. 1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18 19 20 21 22 23 24 25 the -- some of the Latanoprost to degrade into acid of Latanoprost in the bottle, simply because of the temperature. Correct? MS. BLADOW: Lacks foundation. Outside the scope. A. Presumably, yes. Q. All right. And do you see that if you look at page 24867, in Table 2 they -- they measured the amount of Latanoprost and acid of Latanoprost together. Correct? MS. BLADOW: Same objections. A. They have measured both of them in the two tables, yes. Q. Okay. And that's -- and that's to account for the fact that some of that Latanoprost is being degraded into acid of Latanoprost simply because of the temperature at which they're storing it, but it wouldn't happen when Latanoprost was actually being shipped and -- and stored at four degrees centigrade. Correct? MS. BLADOW: Object to form. Foundation. And scope. A. That's actually an incorrect statement. The only difference would be the rate at which it forms. 25 (Pages 97 to 100) www.midwestlitigation.com MIDWEST LITIGATION SERVICES Phone: 1.800.280.3376 Fax: 314.644.1334 Case 3:12-cv-01141-SMY-DGW Document 176-28 *SEALED* Filed 12/01/14 Page 26 of 27 Page ID #2859 Case: 16-3334 Document: 55-9 02/08/2017 Pages: 27 (239 of 1511) DANIEL ARENSON Filed: 3/14/2014 Page 101 1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18 19 20 21 22 23 24 25 Q. There would be a lot more at 50 degrees than there would be at four degrees, a lot more acid of Latanoprost. Correct? MS. BLADOW: Same objection. A. Correct. Q. All right. And so, they're measuring both Latanoprost and acid of Latanoprost to try to account for that. Correct? MS. BLADOW: Same objections. A. Yes. MR. CORNFELD: That's all the questions I have. Thank you. And enjoy your spring vacation. THE WITNESS: Thank you. THE VIDEOGRAPHER: This concludes today's deposition. The time is 1:13 p.m. We are off the record. (Time Ended: 1:13 p.m.) Page 103 1 MIDWEST LITIGATION SERVICES 2 March 28, 2014 3 ROBYN BLADOW, ESQ. KIRKLAND & ELLIS, LLP 333 S. Hope Street Los Angeles, California 90071 4 5 6 IN RE: CHARLENE EIKE, et al., on behalf of themselves and all others similarly situated vs. ALLERGAN, INC., et al. 7 Dear MS. BLADOW, 8 9 10 11 12 13 14 15 16 17 18 19 20 21 22 23 24 Please find enclosed your copies of the deposition of DANIEL ARENSON taken on March 14, 2014 in the above-referenced case. Also enclosed is the original signature page and errata sheets. Please have the witness read your copy of the transcript, indicate any changes and/or corrections desired on the errata sheets, and sign the signature page before a notary public. Please return the errata sheets and notarized signature page to RICHARD S. CORNFELD for filing prior to trial date. Sincerely, JOMANNA DeROSA, CSR Enclosures 25 Page 102 1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18 19 20 21 22 23 24 25 CERTIFICATE STATE OF NEW YORK) )ss: COUNTY OF NEW YORK) Page 104 1 2 3 I, JOMANNA DeROSA, a Certified Shorthand Reporter and Notary Public within and for the States of New York, New Jersey, California and Arizona, do hereby certify: That DANIEL ARENSON, the witness whose deposition is hereinbefore set forth, was duly sworn by me and that such deposition is a true record of the testimony given by such witness. I further certify that I am not related to any of the parties to this action by blood or marriage, and that I am in no way interested in the outcome of this matter. In witness whereof, I have hereunto set my hand this 26th day of March, 2014. JOMANNA DeROSA ERRATA SHEET Witness Name: DANIEL ARENSON Case Name: CHARLENE EIKE, et al., on behalf of themselves and all others similarly situated vs. ALLERGAN, INC., et al. Date Taken: MARCH 14, 2014 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18 19 20 21 22 23 24 25 Page # Line # Should read: Reason for change: Page # Line # Should read: Reason for change: Page # Line # Should read: Reason for change: Page # Line # Should read: Reason for change: Page # Line # Should read: Reason for change: Witness Signature: 26 (Pages 101 to 104) www.midwestlitigation.com MIDWEST LITIGATION SERVICES Phone: 1.800.280.3376 Fax: 314.644.1334 Case 3:12-cv-01141-SMY-DGW Document 176-28 *SEALED* Filed 12/01/14 Page 27 of 27 Case: 16-3334 Document:Page 55-9 ID #2860 Filed: 02/08/2017 Pages: 27 (240 of 1511) DANIEL ARENSON 3/14/2014 Page 105 1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18 19 20 21 22 23 24 25 ) STATE OF ) COUNTY OF I, DANIEL ARENSON, do hereby certify: That I have read the foregoing deposition; That I have made such changes in form and/or substance to the within deposition as might be necessary to render the same true and correct; That having made such changes thereon, I hereby subscribe my name to the deposition. I declare under penalty of perjury that the foregoing is true and correct. day of , Executed this ,at 20 DANIEL ARENSON NOTARY PUBLIC My Commission Expires: 27 (Page 105) www.midwestlitigation.com MIDWEST LITIGATION SERVICES Phone: 1.800.280.3376 Fax: 314.644.1334 Case 3:12-cv-01141-SMY-DGW Document 176-4 *SEALED* Filed 12/01/14 Page 1 of 10 Page ID #2253 Case: 16-3334 Document: 55-10 Filed: 02/08/2017 Pages: 10 (241 of 1511) REVIEW ARTICLE Barriers to Glaucoma Drug Delivery Deepta Ghate, MD and Henry F. Edelhauser, PhD Abstract: Topical medications remain the mainstay of glaucoma treatment. This review will aim to cover the pharmacokinetics of topically applied drops, the ocular barriers to drug delivery, and the role of ophthalmic drug formulation in enhancing drug delivery to the target tissue while minimizing side effects and increasing patient compliance. Recent advances in surgical techniques, therapeutic approaches, and material sciences have produced exciting new therapies for ocular diseases. The development of new vehicles and drug formulations that require less patient compliance is also discussed, as are the routes of drug delivery for neuroprotection. Key Words: glaucoma drug delivery, topical medications (J Glaucoma 2008;17:147–156) G laucoma refers to a group of disorders with diverse pathophysiology and clinical manifestations and a common end point, optic neuropathy. The most frequent causative risk factor for this optic neuropathy is high intraocular pressure (IOP). IOP is not only the most important risk factor, but as of now it is also the only risk factor we can treat to prevent disease progression. Glaucoma drugs reduce the IOP by decreasing the aqueous humor inflow (b-blockers, a-adrenergic agonists, carbonic anhydrase inhibitors) or by increasing the aqueous humor outflow, by either the conventional route (muscarinic agonists) or by the nonconventional pathway (prostaglandin agonists). The b-blockers act on the b-adrenergic receptors in the ciliary processes and reduce aqueous humor production. Latanoprost, which is a prostaglandin analog, binds and activates the FP receptors in the ciliary smooth muscle and improves uveoscleral outflow. The a-adrenergic agonists (apraclonidine and brimonidine) suppress aqueous production and brimonidine also lowers IOP by increasing the uveoscleral outflow. The carbonic anhydrase inhibitors inhibit carbonic anhydrase in the ciliary epithelium and decrease aqueous humor synthesis. All these drugs target the ciliary body. Drug delivery to the Received for publication September 11, 2006; accepted June 30, 2007. From the Emory University Eye Center, Atlanta, GA. Supported by NIH grants P-30-EY06360 and R24-EY017045 and an unrestricted grant from Research to Prevent Blindness. Reprints: Henry F. Edelhauser, PhD, Emory University Eye Center, 1365B Clifton Road, Atlanta, GA 30322 (e-mail: ophthfe@emory.edu). Copyright r 2008 by Lippincott Williams & Wilkins J Glaucoma Volume 17, Number 2, March 2008 glaucoma patient thus consists of delivering the IOP reducing drugs to the ciliary body, while minimizing the systemic drug levels. Neuroprotective drugs are a different class of drugs that prevent or delay neuronal cell death. These drugs target the posterior segment, retinal ganglion cells, and optic nerve. Glaucoma drug treatment is long term, often lifelong. The development of new vehicles and drug formulations that require less patient effort is thus an important aspect in controlling the disease process. This review will aim to cover the pharmacokinetics of topically applied drops, the ocular barriers to drug delivery and the role of ophthalmic drug formulation in enhancing drug delivery to the target tissue while minimizing side effects and increasing patient compliance. TOPICAL DRUG DELIVERY TO THE EYE Topical drug delivery is the most convenient and efficacious method of ocular drug delivery to the anterior segment. The advantages of this route are obvious. It avoids first pass metabolism of drugs in the liver; it allows the drug to selectively target the anterior chamber and it is noninvasive. However, on a practical note, only 1% to 7% (Fig. 1) of the instilled drug reaches the aqueous humor. The inefficiency of this route stems mainly from the precorneal tear clearance mechanism, the highly selective corneal epithelial barrier and the one factor that is the most unpredictable and difficult to control, patient compliance. Precorneal Tear Drainage Under normal conditions, the tear volume in the conjunctival cul-de-sac is 7 to 9 mL in humans with a turnover rate of 0.5 to 2.2 mL/min and the maximum volume that the conjunctival cul-de-sac can contain is estimated to be 30 mL.1 Commercial eyedroppers typically deliver between 25.1 and 56.4 mL; with an average drop volume of 39 mL.2 This sudden increase in volume in the conjunctival cul-de-sac and the irritant properties of the drug cause rapid reflex blinking and increased tear secretion. Most of the drug leaves the conjunctival cul-de-sac through the lacrimal drainage system and the excess is spilled onto the cheeks.3 The drug thus resides in the conjunctival cul-de-sac for only 3 to 5 minutes.4,5 Reducing the drop size to 5-15 mL would reduce overflow, decrease systemic absorption, reduce cost of therapy while maintaining equivalent or even enhanced ocular bioavailability.6,7 The corollary to this low bioavailability after topical therapy is that the drug lost is absorbed into the systemic 147 PL-000514 Case 3:12-cv-01141-SMY-DGW Document 176-4 *SEALED* Filed 12/01/14 Page 2 of 10 Page ID #2254 Case: 16-3334 Document: 55-10 Filed: 02/08/2017 Pages: 10 (242 of 1511) Ghate and Edelhauser J Glaucoma Volume 17, Number 2, March 2008 FIGURE 1. Typical profile of a topically applied drug: only 1% to 7% of the topically applied drug reaches the anterior segment. circulation by the nasal mucosa. A drop of timolol used topically in aqueous solution resulted in an average plasma timolol concentration varying from 0.46 to 1.38 ng/mL8–11 up to 2 hours after instillation. In comparison, the mean plasma concentration after oral administration of 0.4 mg/kg of timolol was 123 ± 14 ng/mL12 at 2 hours. The clinical significance of these small systemic doses will depend on the pathways being studied and the dose-response curve. Hemodynamic changes in several cardiovascular parameters have been observed after topical timolol therapy in patients with no known systemic disease.13 Patients with asthma have a heightened response to bronchoconstrictors14 and severe, sometimes fatal effects of topical b-blocker therapy have been reported.15–17 The role of the nasal mucosa in systemic absorption of timolol is much larger than that of the conjunctival vasculature.18 Any pharmacologic intervention that increases retention time in the conjunctival cul-de-sac should increase bioavailability of the drug and decrease systemic absorption. Nasolacrimal duct occlusion by hand or by silicone plugs has been shown to increase the therapeutic index of several glaucoma drugs19 and decrease their systemic effects.20,21 Using timolol in a gel formulation allowed once daily dosing22 with decreased systemic absorption.23 the paracellular route (hydrophilic drugs or ions of small molecular weight).4 The presence or absence of an epithelium is thus an important factor to consider in drug absorption. Phenylephrine (2.5% and 10%) has been shown to cause dramatic drug-induced edema and endothelial vacuolation in corneas without the epithelium as opposed to corneas with the epithelium intact24 (Fig. 3). Similar results have been demonstrated with topical nonsteroidal anti-inflammatory drugs (unpublished data). Studies that demonstrate good corneal tolerability for glaucoma drugs in patients with normal corneas25 might not translate well for patients with a compromised epithelial surface and there have been case reports of irreversible corneal decompensation after dorzolamide therapy in patients with epithelial and endothelial compromise.26 Topical medications must therefore be used with particular care in patients with a compromised epithelium. The corneal stroma, as a barrier, can be considered to be an aqueous environment interspersed with glycosaminoglycans and collagen fibrils. Drugs diffuse through the stroma with relatively minor resistance. If the stroma is isolated, there is no dependence on lipophilicity, but Epithelium Bowmans membrane The Corneal Barrier The corneal epithelium (Fig. 2) is the most resistant component of the corneal barrier to drug penetration. It has 5 layers of tightly adherent cells with gap junctions and tight junctions. The epithelium is a lipophilic tissue and contributes 90% of the barrier to hydrophilic drugs and 10% of the barrier to lipophilic drugs. Drugs penetrate this layer by either partitioning through the cells by the intracellular route (predominantly lipophilic drugs), or by passing between the cells through 148 Stroma Descemets membrane Endothelium FIGURE 2. Structure of the human cornea: schematic diagram of the different histopathologic layers of the cornea. r 2008 Lippincott Williams & Wilkins PL-000515 Case 3:12-cv-01141-SMY-DGW Document 176-4 *SEALED* Filed 12/01/14 Page 3 of 10 Page ID #2255 Case: 16-3334 Document: 55-10 Filed: 02/08/2017 Pages: 10 (243 of 1511) J Glaucoma Volume 17, Number 2, March 2008 Phenylephrine 10% topical + Epithelium Epithelium intact Barriers to Glaucoma Drug Delivery − Epithelium Epithelium absent TEM of corneal endothelium after 1 drop of 10% phenylephrine (1 hr) FIGURE 3. Schematic diagram of topical 10% phenylephrine penetration. If the corneal epithelium is intact, the drug is restricted to the superficial layers of the cornea and the endothelium is healthy as seen in the transmission electron micrograph (TEM). If the corneal epithelial layer is absent, the drug penetrates all the way to the endothelium and damages it as seen in the TEM (endothelial layer swelling and vacuolation). Illustration from Arch Ophthalmol. 1979;97:937–947. a strong dependence on molecular radius, reflecting the aqueous intercellular route of drug diffusion.27 If a molecule is sufficiently lipophilic to rapidly cross the epithelium, the stroma becomes rate limiting. The Bowman’s and Descemet’s membrane do not provide significant resistance to drug penetration. The endothelium is a monolayer of cells with large intercellular junctions, which presents a leaky lipophilic barrier. The endothelium is definitely not rate limiting for hydrophilic compounds but it may play a small role in determining permeability for lipophilic compounds.4,27 The cornea can also act as a temporary drug depot; the drug is mostly stored in the corneal stroma.28,29 The enzymes in the epithelium can metabolize drugs; prodrugs like dipivefrin30 and bimatoprost31 are metabolized into their active forms in the cornea, mainly in the epithelium.32 Noncorneal Route of Absorption The ratio of corneal/conjunctival surface area is 1:17 in humans and 1:9.6 in rabbits.33 Although the corneal route is assumed to be the principle route of entry for topical drugs in the eye, studies have conclusively proved that the conjunctiva-scleral layer also plays a role in the drug absorption of large hydrophilic molecules like inulin,34 timolol maleate, carbonic anhydrase inhibitors; r 2008 Lippincott Williams & Wilkins and of peptides and proteins which can be used as drug carriers. The conjunctiva has a stratified squamous epithelium composed of 5 to 15 layers of cells with tight junctions at the apical end. The conjunctival stroma with nerves, lymphatics, and blood vessels loosely attaches to the underlying sclera. The permeability of the conjunctiva to large hydrophilic molecules is twice that of the sclera and higher than the cornea.35,36 The conjunctival epithelial tight junctions are by comparison leakier than the tight junctions in the corneal epithelium.37–40 In rabbit studies with the iris/ciliary body as the target organ, the ratio of corneal+conjunctival/scleral versus conjunctival/ scleral route absorption of drug was 40:1 for hydrocortisone41 and 5:1 for pilocarpine,41 8:1 for timolol,34 and 1.3:1 for inulin.34 In a study on cadaveric human eyes,42 the mean human scleral thickness was 0.53 ± 0.14 mm at the limbus and 0.9 mm near the optic nerve and the mean total scleral surface area was 16.3 ± 1.8 cm2. The ciliary body is said to be the zone of least resistance to transscleral drug delivery.43 Scleral permeability shows a strong dependence on molecular radius27 and no dependence on lipophilicity. Like the corneal stroma, the sclera is composed of collagen fibers and proteoglycan fibers with few protein binding sites. Drugs permeate through the aqueous intercellular media of the sclera occupying the 149 PL-000516 Case 3:12-cv-01141-SMY-DGW Document 176-4 *SEALED* Filed 12/01/14 Page 4 of 10 Page ID #2256 Case: 16-3334 Document: 55-10 Filed: 02/08/2017 Pages: 10 (244 of 1511) Ghate and Edelhauser spaces between the collagen fibers.27 Thus, pore diameter and intracellular space are important determinants of transscleral drug delivery. The cornea is relatively impermeable to solutes with a molecular size more than 1 kd; however, dextran (40 kd) and albumin (69 kd) readily penetrate the sclera.44,45 Scleral permeability is affected by an increase in IOP but the effect seems to be minimal at 15 mm Hg pressure.46 Increasing the IOP can decrease drug diffusion across the sclera.46 Subconjunctival Drug Delivery The subconjunctival route of drug delivery should theoretically provide a drug depot that would reduce dosing frequency while maintaining sustained drug delivery to the anterior and posterior segment. However, the morbidity of repeated subconjunctival injections particularly in inflamed eyes has reduced the popularity of this route for anterior segment drug delivery. In a corneal ulcer study comparing the subconjunctival and topical application for gentamicin and cefazolin, subconjunctival injections produced high but transient peaks in the aqueous humor followed by persistent low troughs.47 In contrast, eye drops produced moderate but sustained concentrations in the aqueous humor throughout the treatment period with equal efficacy for both routes. Other studies have demonstrated a sustained therapeutically effective drug concentration after subconjunctival gentamicin.48 In general, hydrophilic drugs, which penetrate through the sclera, are more effective when given by the subconjunctival route because these drugs do not need to diffuse across the conjunctival epithelium which is a significant rate-limiting barrier for water-soluble drugs. With the recent interest in implants and sustained release drug delivery vehicles and particles, interest in the subconjunctival route for anterior segment drug delivery has increased. Ocular Factors Influencing Drug Concentrations As mentioned above, the presence of an intact or a compromised epithelium is an important factor influencing transcorneal drug delivery. Other ocular factors that affect drug delivery include drug-tissue binding, drug metabolism, and drug clearance. Once the drug reaches the anterior chamber, it is cleared by aqueous outflow, the vasculature, or by tissue binding. Pilocarpine and timolol bind to melanin in the eye whereas prostaglandins do not.49,50 This presumably causes the higher IOP lowering effect of timolol in nonpigmented irides versus pigmented irides in rabbits and humans49,51 and causes the slow release of timolol from ocular tissues after with drawl, with timolol detected in the pigmented tissue of the iris for up to 42 days.52 A large multicenter study with pooled data from 8 countries found that the difference in mean IOP reduction between latanoprost and timolol was larger in Asian and Mexican patients than in US and European patients.53 This difference could be attributed to eye color or ethnic differences between populations. 150 J Glaucoma Volume 17, Number 2, March 2008 Rabbit Versus Human Anatomy The rabbit model is commonly used in ocular pharmacokinetics because of its large cornea, similar corneal architecture to humans, its protruding eye, and ease of handling. As has been previously mentioned, the ratio of corneal/conjunctival surface area is 1:17 in humans and 1:9.6 in rabbits.33 The rabbit cornea (1.5 cm2) is slightly larger in surface area than the human cornea (1 cm2) and the central corneal thickness in rabbit corneas is 407 ± 20 mm.54 The rabbit scleral thickness is 0.25 mm at the equator and the vitreous volume is about 1.5 to 2.5 mL55 as compared with the mean human scleral thickness of 0.53, 0.39, and 0.9 mm at the corneoscleral limbus, the equator, and the optic nerve,42 respectively and vitreous volume of 4 mL. However, the rabbit has similar scleral permeability to several compounds.56,57 The rabbit also has a communicating blood vessel between the 2 orbits,58 which may lead to higher contralateral eye drug levels than humans. The rabbit cornea is more sensitive than the human cornea to several irritants and the rabbit blood aqueous barrier is very unstable. Corneal irritation or any ocular manipulation leads to a severe anterior chamber inflammatory response.59 Patient Compliance in Glaucoma Drug Therapy Glaucoma is a disease that is chronic and mostly asymptomatic. If topical medications are prescribed, long-term patient compliance is needed to prevent disease progression. Studies document better visual field preservation with lower IOP60,61 and some studies have indicated that fluctuations in IOP may be an independent risk factor for disease progression.62 Nonadherence in glaucoma is a significant problem and figures ranging from 24% to 59% have been reported.63–65 Tsai66 conducted structured interviews with glaucoma patients and reported 71 barriers to adherence, these were grouped into 4 areas, situational/environmental (49%), regimen factors (32%), individual patient factors, and medical provider factors (19%). Simplifying the drug regimen does help improve adherence67 but a drug delivery system that would provide long-term drug delivery with minimal patient compliance would be ideal. Improving Drug Absorption After Topical Therapy Drug Formulations In an intact cornea, drug penetration depends primarily on the partitioning properties of the therapeutic agent. A lipophilic molecule will reach the target intraocular tissues transcorneally far easier than a hydrophilic one, because it is better able to cross the corneal epithelial barrier. Similarly, a drug that is unionized will be better able to cross the epithelial barrier than an ionized drug. The physicochemical properties of the drug had to be considered when topical carbonic anhydrase inhibitors were in development. Acetazolamide reduced IOP after systemic administration but was unable to cross the r 2008 Lippincott Williams & Wilkins PL-000517 Case 3:12-cv-01141-SMY-DGW Document 176-4 *SEALED* Filed 12/01/14 Page 5 of 10 Page ID #2257 Case: 16-3334 Document: 55-10 Filed: 02/08/2017 Pages: 10 (245 of 1511) J Glaucoma Volume 17, Number 2, March 2008 corneal epithelial barrier after topical administration.68 Several changes were made chemically to the carbonic anhydrase inhibitors, the aim being to create a drug that combined good lipid solubility, low pKa, and high activity against the enzyme. Trifluormethazolamide fulfilled all these criteria and diffused transcorneally into the anterior chamber to lower the IOP in vivo.69 Although this drug was too unstable to be used clinically, it proved that drug modification could improve drug bioavailability while retaining efficacy and led to the development of the topical carbonic anhydrase inhibitors. The prostaglandin analogs were another class of drug that needed chemical modification to improve drug bioavailability and efficacy. Although prostaglandins were known to decrease IOP in animal studies,70–72 the naturally occurring prostaglandins caused severe ocular irritation.73,74 Development of the isopropyl ester of PGF2a allowed dosing with a considerably lower concentration with correspondingly fewer ocular side effects.75,76 Stjernschantz77 found that a terminal phenyl ring attached to carbon 17 in PGF2a and the presence of a double saturated bond between C13 and C14 improved the receptor selectivity of the compound, reduced the hyperemic effect, and resulted in a more chemically stable drug, which resulted in the development and ultimate clinical usage of latanoprost (13,14-dihydro17-phenyl-18,19,20-trinor-PGF2a isopropyl ester). The pH of the medium determines the degree of ionization (besides drug properties such as pKa). A higher proportion of the nonionized species results in higher transcorneal permeability as shown by Mitra and Mikkelson 78 for pilocarpine. Pilocarpine is a weak base, but for stability and solubility, it is dispensed in an acidic eyedrop vehicle. On the other hand, carbonic anhydrase inhibitors paradoxically have greater IOP reduction in the ionized form than in the unionized,79,80 because the ionized species of the drug is able to sequester itself in the corneal epithelium and is converted to the unionized active form in the aqueous. Most glaucoma drug formulations are weak bases and exist predominantly in the nonionized form.81 Variations in osmolality between 220 and 640 mOsm/kg in the tears seem to be well tolerated; the eye tolerates hypotonic solutions (which increase epithelial permeability) better than hypertonic solutions, which cause an immediate dilution as the drug osmotically draws out fluid from the conjunctiva and cornea.5 Increasing the topical drug concentration and dosage frequency should theoretically increase the drug delivered to the anterior chamber. In practice, it does so but only to a certain level, beyond that the percentage of drug reaching the target tissue decreases and the risk for systemic side effects increases. In a study on IOP in normal human volunteers with 0.5%, 1%, and 1.5% timolol solution, Katz et al82 found that the 0.5% concentration caused the maximal IOP lowering at 2 hours. Twice daily dosing of bimatoprost decreased the IOP reducing efficacy as compared with once daily dosing.83 The prostaglandin analogs have a short half-life (latanoprost has a half-life of 2 to 3 h in the aqueous r 2008 Lippincott Williams & Wilkins Barriers to Glaucoma Drug Delivery humor84), but function at extremely small concentrations in the target tissue and are therefore effective at a once daily dosing frequency. Drug solubility affects ocular absorption in 2 ways. The presence of insoluble deposits of the drugs in the culde-sac, as occurs with topical ciprofloxacin, leads to a sustained drug effect. Poorly soluble drugs can be delivered to the eye in suspension. Glaucoma drugs including betaxolol and brinzolamide are available commercially as suspensions. For maximum drug bioavailability, a suspension needs to have a rapid rate of dissolution of the suspended particles in the tear film during the contact time. But, ocular bioavailability is inversely related to particle size,85 which is directly related to the potential for irritation. Drugs in suspension have the added disadvantage of poor patient compliance because they need to be resuspended before each use by shaking.86,87 Cyclodextrins are used to solubilize complex drugs that are poorly soluble, unstable, or difficult to formulate. The cyclodextrin-drug complex improves wettability, dissolution, solubility, and stability in solution and preserves the intrinsic ability of the drug to penetrate biologic membranes.88 Cyclodextrin formulations have been shown to improve penetration of pilocarpine89 and carbonic anhydrase inhibitors.90 Solutions in multiple dose containers must have a preservative to prevent the growth of microorganisms. Benzalkonium chloride (BAC), the most commonly used preservative also enhances the corneal permeability of various drugs.91,92 However, epithelial toxicity can occur when the dosing schedule requires multiple administrations in a day.93,94 After the topical administration of 1 drop of 0.01% BAC in rabbit eyes, significant BAC amounts could be found in ocular surface tissues up to 168 hours after application.95 Newer drug formulations with Purite in place of BAC have been shown to decrease the ocular surface damage.96 A new multidose bottle has been introduced with an Airless Antibacterial Dispensing System (AADS, Pfizer Inc, USA) with a valve system and an airless pump with a silver antibacterial coil that allows for preservative free eye drops. In a recent study comparing different preservatives [BAC/ethylenediamine tetraacetic acid (EDTA), parabens, chlorobutanol, silver chloride complex, and Purite-stabilized oxychloro complex], only BAC/EDTA met the European Pharmacopoeia major criteria for preservative efficacy.97 Preservatives can never replace proper handling instructions for eyedrop dispensers. Drug Vehicle The vehicle in which the drug is delivered determines the retention time in the conjunctival cul-de-sac. Increasing the retention time allows for greater transcorneal diffusion and lower systemic drug levels. The viscosity of ophthalmic solutions can be increased by several compounds including hydroxypropylmethycellulose and polyvinyl alcohol. They increase the residence time of the drug in the conjunctival cul-de-sac and slow clearance resulting in enhanced absorption.4 151 PL-000518 Case 3:12-cv-01141-SMY-DGW Document 176-4 *SEALED* Filed 12/01/14 Page 6 of 10 Page ID #2258 Case: 16-3334 Document: 55-10 Filed: 02/08/2017 Pages: 10 (246 of 1511) Ghate and Edelhauser Patton and Robinson98 suggest that the optimal viscosity of solutions should be 12 to 15 cps. Higher viscosity ranges cause ocular surface irritation, along with visual blurring and blockage of the puncti and canaliculi. Gels are semisolid systems with particles or macromolecules distributed in a liquid. They increase retention time. Both timolol and pilocarpine have gel formulations which allow once daily dosing.99,100 In situ gel forming systems are formulations that undergo gellation on contact with the ocular system. Gels that are activated by ions,101 pH,102 and temperature103 have also been developed. Ocular side effects, including blurring on instillation, are higher with the gel formulation than with topical medication in solution.99 These gellation systems combine the advantages of dispensing an aqueous solution with the increased retention time of a high viscosity formulation.103 Ophthalmic ointments are emulsions of aqueous drugs and ointment bases (eg, white petroleum). The major advantage is their tendency to serve as a drug depot in the conjunctival cul-de-sac, resulting in enhanced and sustained drug absorption. The disadvantages include blurring of vision on instillation, difficulty in applying the exact dose, and sensitivity of the base to temperature. Interest in emulsions has been renewed by the submicron emulsion (0.1 to 0.3 mm) with nonionic surfactants for long-term formulation stability.104 Increased ocular retention time and increased bioavailability of pilocarpine and other drugs have been reported with submicron emulsion formulations.104 Cyclosporin A in a topical formulation was known to suppress inflammation, have an antiapoptotic effect and a role in restoring tear function and ocular integrity.105–107 Owing to its hydrophobicity, the initial topical formulations of cyclosporine A were in oils or ointments. These formulations were messy, inconvenient, and had poor tissue partitioning properties.108 The development of a lipid emulsion formulation in castor oil that also included glycerin, polysorbate 80, and sodium hydroxide (to adjust the pH), marketed as Restasis (Allergan Inc) was a major advance. The cyclosporine emulsion, Restasis is now a standard of care for the management of moderately severe dry eye.109 Mucoadhesive Formulations Mucoadhesion refers to the process of attachment of the drug carrier system to the mucin coat covering the conjunctiva and cornea. Mucoadhesives increase drug residence time and provide intimate contact between the drug and the absorbing tissue, which results in a high drug concentration in the local area and a high drug flux through the absorbing tissue. The most commonly used mucoadhesives are macromolecular hydrocolloids that cannot cross biologic membranes.88 Hyaluronic acid is a mucoadhesive biologic polymer that also has the advantages of having a high water binding capacity, nonirritancy, increased viscosity, and pseudoplastic behavior. Other mucoadhesives include carboxymethycellulose, polyacrylic derivatives, xanthan gum, and carrageenan.88 152 J Glaucoma Volume 17, Number 2, March 2008 Chitosan is a biodegradable, nontoxic, and biocompatible polymer besides being pseudoplastic and viscoelastic in solution.110 Chitosan microspheres enhance ocular delivery of several drugs including acyclovir,111 ofloxacin,112 and pilocarpine.113 Microparticles Liposomes are microscopic structures (0.01 to 10 mm) consisting of spheres (vesicles) of lipid bilayers separated by water or an aqueous buffer compartment. The major advantage ascribed to liposomal formulations is the ability to circumvent cell membrane barriers and enhance the therapeutic effect of the drug. Almost every class of topically or subconjunctivally applied ophthalmic drug has been studied in liposomal form, including antibiotics, antifungals, and steroids114 with promising corneal penetration and pharmacokinetics, although these results are preliminary. Nanoparticles are polymeric colloidal particles ranging in size from 10 to 1000 nm. They consist of macromolecular materials in which the drug is dissolved, entrapped, encapsulated, and/or to which the drug is adsorbed or attached. Nanospheres are solid matricial spheres with drug in the matrix or adsorbed on the surface of the colloidal carrier. Nanocapsules are small capsules with a central cavity surrounded by a polymeric membrane. Nanoparticle formulations of several ophthalmic drugs have been studied which have demonstrated increased corneal permeability.115–117 The proposed mechanism is an enhanced retention time in the cul-de-sac and enhanced penetration through the conjunctival and corneal barriers possibly because of the bioadhesive properties. Nanoparticle suspensions of inert polymer resins have also been used to enhance drug delivery to the anterior chamber.117 Increasing Drug Penetration Through the Epithelium The epithelium is the major barrier for most ocular drugs as has been explained previously. The penetration enhancers are a class of vehicles that transiently change the permeability of the cornea. BAC is one of the commonest additives to topical medications due to its epitheliotoxic effect,95,96 which also increases the permeability of the epithelium to various drugs.94 BAC increases the corneal permeability by widening the intercellular spaces92 by making the corneal epithelial barrier leaky.118 Calcium chelators like EDTA are reported to loosen the tight junctions between the superficial epithelial cells; increasing paracellular transport119; whereas surface enhancers are another class of vehicles that get incorporated into the lipid bilayer and change membrane properties, increasing transcellular transport.88 Iontophoresis is a technique of introducing drugs into tissues noninvasively, by imposing electric currents across the cornea or sclera. Transcorneal iontophoresis has shown enhanced drug penetration into the aqueous.120 Recent studies in human volunteers have demonstrated that iontophoresis increases the diffusion of anti-inflammatory drugs.121 However, this technique can also result r 2008 Lippincott Williams & Wilkins PL-000519 Case 3:12-cv-01141-SMY-DGW Document 176-4 *SEALED* Filed 12/01/14 Page 7 of 10 Page ID #2259 Case: 16-3334 Document: 55-10 Filed: 02/08/2017 Pages: 10 (247 of 1511) J Glaucoma Volume 17, Number 2, March 2008 in corneal epithelial and endothelial damage.122 Further studies are needed to establish the safety and efficacy profile of this technique. Iontophoresis also holds promise for gene therapy and enhanced posterior segment drug delivery transsclerally. Ocular delivery of several glaucoma medications has been enhanced in isolated rabbit corneas by application of 20 kHz ultrasound,123 although the parameters used by authors caused significant structural damage to the cornea. Ophthalmic Inserts Ophthalmic inserts are solid devices, which are placed in the conjunctival cul-de-sac. These devices are designed to release the drug at a constant rate for a prolonged duration of time while minimizing systemic absorption through the nasal mucosa and improving patient compliance. Another potential advantage of insert therapy is the possibility of promoting noncorneal diffusion, especially of hydrophilic drugs that are poorly absorbed through the cornea. The pilocarpine Ocusert (Alza Corp) was the first marketed device to achieve zero order kinetics.124 Other inserts include medicated contact lenses,125 collagen shields,126 calcium alginate based inserts,127 and erodible inserts based on different polymers.128 To be clinically acceptable, ocular inserts need to cause minimal foreign body sensation, minimal extrusion. They should be easy to instill in the eye, and allow for slow release of a drug, possibly formulated with other penetration enhancers, mucoadhesives, microparticles, or all of the above. The inserts could be designed for the conjunctival cul-de-sac or for the subconjunctival or posterior subtenon space and could potentially allow continuous long-term anterior segment drug delivery with minimal patient compliance. Drug Delivery to the Optic Nerve As mentioned before, neuroprotection for the optic nerve in a glaucoma patient is targeted toward preventing the loss of neuronal tissue, rather than targeting the causative risk factors for the disease. The drug delivery has to be targeted to the retinal ganglion cell body and the axons in the optic nerve. There have been several studies about the effect of topical medications on optic nerve blood flow. Maurice129 reviewed the methodology of several of these studies. He found that many of the investigators had conflicting findings, which reduced the confidence that can be placed in many such studies. The measurement techniques were different and the animal and human experiments often did not consider sources of error like systemic absorption of the instilled drop, globe contamination, and the inaccuracy of vitreous sampling. Conventional ocular pharmacokinetics downplays the idea that a drug delivered from an eyedrop can affect the optic nerve. The concentration of drug in the vitreous rises to only about one-millionth of that in the eye drop after one instillation.129 There are 2 ways in which a drug can reach the optic nerve after topical instillation; via the r 2008 Lippincott Williams & Wilkins Barriers to Glaucoma Drug Delivery cornea, anterior chamber, pupil, lens, vitreous or by the conjunctival route, through the sclera, choroid, retinal pigment epithelium to the retina or indirectly to the retrobulbar space and the optic nerve. Brimonidine has been claimed to be pharmacologically active at such low concentrations. Topical instillation of 0.2% brimonidine tartrate results in vitreous concentrations of 185 ± 500 nM (4.625 10 5 times the concentration of the instilled drug).130 This is higher than the 2 nM concentration required to maximally activate a-2-adrenergic receptors.131 Further studies are eagerly awaited. As of now, the posterior segment diseases can be treated by 1 of 3 routes; intravenous or oral, which has low bioavailability and high systemic side effects; intravitreal, which has excellent bioavailability but is also the most invasive and has the highest ocular complication rates or by periocular injection. In a recent study using ocular fluorophotometry to study the pharmacokinetics of sodium fluorescein after periocular injections, we found that the posterior subtenon injection was a better periocular route to deliver drugs to the vitreous than the retrobulbar and subconjunctival route. It had the highest and most prolonged vitreous concentrations with the least systemic drug levels, because of its relative isolation from the conjunctival and orbital vasculature and lymphatics.132 In summary, topical glaucoma medications are easy to prescribe and instill, but require a high degree of patient compliance and have low bioavailability. An ideal glaucoma drug formulation would eliminate the need for daily instillation of drops; it would be a drug depot in the conjunctival cul-de-sac or subconjunctival space if the drug is targetted to the anterior segment or in the posterior subtenon space if the drug is targeted to the posterior segment. The drug depot would allow gradual and continuous release of the drug over a prolonged period of time. Microparticles with slow release characteristics packaged in ocular inserts may be the drug delivery vehicles of the future. REFERENCES 1. Mishima S, Gasset A, Klyce SD Jr, et al. Determination of tear volume and tear flow. Invest Ophthalmo. 1966;5:264–276. 2. Lederer CM Jr, Harold RE. Drop size of commercial glaucoma medications. Am J Ophthalmol. 1986;101:691–694. 3. Patton TF, Francoeur M. Ocular bioavailability and systemic loss of topically applied ophthalmic drugs. Am J Ophthalmol. 1978;85: 225–229. 4. Schoenwald RW. Ocular Pharmakokinetics. In: Zimmerman TJ, Ed. Textbook of Ocular Pharmacology. Philadelphia: LippincottRaven Publishers; 1997:119–138. 5. Wilson CG, Zhu YP, Kurmala P, et al. Ophthalmic drug delivery. In: Hillery AM, Lloyd AW, eds. Drug Delivery and Targeting for Pharmacists and Pharmaceutical Scientists. New York: Taylor and Francis; 2001:329–354. 6. Van Santvliet L, Ludwig A. Determinants of eye drop size. Surv Ophthalmol. 2004;49:197–213. 7. Shell JW. Pharmacokinetics of topically applied ophthalmic drugs. Surv Ophthalmol. 1982;26:207–218. 8. Dickstein K, Aarsland T. Comparison of the effects of aqueous and gellan ophthalmic timolol on peak exercise performance in middleaged men. Am J Ophthalmol. 1996;121:367–371. 153 PL-000520 Case 3:12-cv-01141-SMY-DGW Document 176-4 *SEALED* Filed 12/01/14 Page 8 of 10 Page ID #2260 Case: 16-3334 Document: 55-10 Filed: 02/08/2017 Pages: 10 (248 of 1511) Ghate and Edelhauser 9. Korte JM, Kaila T, Saari KM. Systemic bioavailability and cardiopulmonary effects of 0.5% timolol eyedrops. Graefes Arch Clin Exp Ophthalmol. 2002;240:430–435. 10. Vuori ML, Kaila T. Plasma kinetics and antagonist activity of topical ocular timolol in elderly patients. Graefes Arch Clin Exp Ophthalmol. 1995;233:131–134. 11. Shedden AH, Laurence J, Barrish A, et al. Plasma timolol concentrations of timolol maleate: timolol gel-forming solution (TIMOPTIC-XE) once daily versus timolol maleate ophthalmic solution twice daily. Doc Ophthalmol. 2001;103:73–79. 12. Wilson TW, Firor WB, Johnson GE, et al. Timolol and propranolol: bioavailability, plasma concentrations, and beta blockade. Clin Pharmacol Ther. 1982;32:676–685. 13. Nieminen T, Uusitalo H, Turjanmaa V, et al. Association between low plasma levels of ophthalmic timolol and haemodynamics in glaucoma patients. Eur J Clin Pharmacol. 2005;61:369–374. 14. Belvisi M. Beta-blocker induced asthma: a role for sensory nerve hyperresponsiveness? Clin Exp Allergy. 1996;26:1343–1346. 15. Lama PJ. Systemic adverse effects of beta-adrenergic blockers: an evidence-based assessment. Am J Ophthalmol. 2002;134:749–760. 16. Malnick SD, Gelzer G, Attali M. Fatal respiratory arrest following timolol ophthalmic solution. MedGenMed. 2001;3:12. 17. Prince DS, Carliner NH. Respiratory arrest following first dose of timolol ophthalmic solution. Chest. 1983;84:640–641. 18. Chang SC, Lee VH. Nasal and conjunctival contributions to the systemic absorption of topical timolol in the pigmented rabbit: implications in the design of strategies to maximize the ratio of ocular to systemic absorption. J Ocul Pharmacol. 1987;3: 159–169. 19. Zimmerman TJ, Sharir M, Nardin GF, et al. Therapeutic index of pilocarpine, carbachol, and timolol with nasolacrimal occlusion. Am J Ophthalmol. 1992;114:1–7. 20. Hepsen IF, Yildirim Z, Yilmaz H, et al. Preventive effect of lacrimal occlusion on topical timolol-induced bronchoconstriction in asthmatics. Clin Exp Ophthalmol. 2004;32:597–602. 21. Yamada Y, Takayanagi R, Tsuchiya K, et al. Assessment of systemic adverse reactions induced by ophthalmic beta-adrenergic receptor antagonists. J Ocul Pharmacol Ther. 2001;17:235–248. 22. Rosenlund EF. The intraocular pressure lowering effect of timolol in gel-forming solution. Acta Ophthalmol Scand. 1996;74: 160–162. 23. Ohno Y, Iga T, Yamada Y, et al. Pharmacokinetic and pharmacodynamic analysis of systemic effect of topically applied timolol maleate ophthalmic gelling vehicle (Rysmon TG). Curr Eye Res. 2005;30:319–328. 24. Edelhauser HF, Hine JE, Pederson H, et al. The effect of phenylephrine on the cornea. Arch Ophthalmol. 1979;97:937–947. 25. Lass JH, Khosrof SA, Laurence JK, et al. A double-masked, randomized, 1-year study comparing the corneal effects of dorzolamide, timolol, and betaxolol. Dorzolamide Corneal Effects Study Group. Arch Ophthalmol. 1998;116:1003–1010. 26. Konowal A, Morrison JC, Brown SV, et al. Irreversible corneal decompensation in patients treated with topical dorzolamide. Am J Ophthalmol. 1999;127:403–406. 27. Prausnitz MR, Noonan JS. Permeability of cornea, sclera, and conjunctiva: a literature analysis for drug delivery to the eye. J Pharm Sci. 1998;87:1479–1488. 28. Mindel JS, Smith H, Jacobs M, et al. Drug reservoirs in topical therapy. Invest Ophthalmol Vis Sci. 1984;25:346–350. 29. Maren TH, Jankowska L. Ocular pharmacology of sulfonamides: the cornea as barrier and depot. Curr Eye Res. 1985;4:399–408. 30. Anderson JA, Davis WL, Wei CP. Site of ocular hydrolysis of a prodrug, dipivefrin, and a comparison of it ocular metabolism with that of the parent compound, epinephrine. Invest Ophthalmol Vis Sci. 1980;19:817–823. 31. Maxey KM, Johnson JL, LaBrecque J. The hydrolysis of bimatoprost in corneal tissue generates a potent prostanoid FP receptor agonist. Surv Ophthalmol. 2002;47:S34–S40. 32. Lee VH, Morimoto KW, Stratford RE Jr. Esterase distribution in the rabbit cornea and its implications in ocular drug bioavailability. Biopharm Drug Dispos. 1982;3:291–300. 154 J Glaucoma Volume 17, Number 2, March 2008 33. Watsky MA, Jablonski MM, Edelhauser HF. Comparison of conjunctival and corneal surface areas in rabbit and human. Curr Eye Res. 1988;7:483–486. 34. Ahmed I, Patton TF. Importance of the noncorneal absorption route in topical ophthalmic drug delivery. Invest Ophthalmol Vis Sci. 1985;26:584–587. 35. Ahmed I, Gokhale RD, Shah MV, et al. Physicochemical determinants of drug diffusion across the conjunctiva, sclera, and cornea. J Pharm Sci. 1987;76:583–586. 36. Sasaki H, Igarashi Y, Nagano T, et al. Different effects of absorption promoters on corneal and conjunctival penetration of ophthalmic beta-blockers. Pharm Res. 1995;12:1146–1150. 37. Kompella UB, Kim KJ, Lee VH. Active chloride transport in the pigmented rabbit conjunctiva. Curr Eye Res. 1993;12:1041–1048. 38. Shi XP, Candia OA. Active sodium and chloride transport across the isolated rabbit conjunctiva. Curr Eye Res. 1995;14: 927–935. 39. Marshall WS, Klyce SD. Cellular and paracellular pathway resistances in the ‘‘tight’’ Cl-secreting epithelium of rabbit cornea. J Membr Biol. 1983;73:275–282. 40. Maurice DM. Electrical potential and ion transport across the conjunctiva. Exp Eye Res. 1973;15:527–532. 41. Doane MG, Jensen AD, Dohlman CH. Penetration routes of topically applied eye medications. Am J Ophthalmol. 1978;85: 383–386. 42. Olsen TW, Aaberg SY, Geroski DH, et al. Human sclera: thickness and surface area. Am J Ophthalmol. 1998;125:237–241. 43. Li SK, Molokhia SA, Jeong EK. Assessment of subconjunctival delivery with model ionic permeants and magnetic resonance imaging. Pharm Res. 2004;21:2175–2184. 44. Bill A. Movement of albumin and dextran throughout the sclera. Arch Ophthalmol. 1965;74:248–252. 45. Olsen TW, Edelhauser HF, Lim JI, et al. Human scleral permeability. Effects of age, cryotherapy, transscleral diode laser, and surgical thinning. Invest Ophthalmol Vis Sci. 1995;36: 1893–1903. 46. Rudnick DE, Noonan JS, Geroski DH, et al. The effect of intraocular pressure on human and rabbit scleral permeability. Invest Ophthalmol Vis Sci. 1999;40:3054–3058. 47. Baum J, Barza M. Topical vs subconjunctival treatment of bacterial corneal ulcers. Ophthalmology. 1983;90:162–168. 48. Jain MR, Goyal M, Jain V. Ocular penetration of subconjunctivally injected gentamicin, sisomicin and cephaloridine. Jpn J Ophthalmol. 1988;32:392–400. 49. Nagata A, Mishima HK, Kiuchi Y, et al. Binding of antiglaucomatous drugs to synthetic melanin and their hypotensive effects on pigmented and nonpigmented rabbit eyes. Jpn J Ophthalmol. 1993;37:32–38. 50. Menon IA, Trope GE, Basu PK, et al. Binding of timolol to irisciliary body and melanin: an in vitro model for assessing the kinetics and efficacy of long-acting antiglaucoma drugs. J Ocul Pharmacol. 1989;5:313–324. 51. Katz IM, Berger ET. Effects of iris pigmentation on response of ocular pressure to timolol. Surv Ophthalmol. 1979;23:395–398. 52. Trope GE, Menon IA, Liu GS, et al. Ocular timolol levels after drug withdrawal: an experimental model. Can J Ophthalmol. 1994; 29:217–219. 53. Hedman K, Larsson LI. The effect of latanoprost compared with timolol in African-American, Asian, Caucasian, and Mexican open-angle glaucoma or ocular hypertensive patients. Surv Ophthalmol. 2002;47:S77–S89. 54. Chan T, Payor S, Holden BA. Corneal thickness profiles in rabbits using an ultrasonic pachometer. Invest Ophthalmol Vis Sci. 1983; 24:1408–1410. 55. Killey FP, Edelhauser HF, Aaberg TM. Intraocular sulfur hexafluoride and octofluorocyclobutane. Effects on intraocular pressure and vitreous volume. Arch Ophthalmol. 1978;96: 511–515. 56. Ambati J, Canakis CS, Miller JW, et al. Diffusion of high molecular weight compounds through sclera. Invest Ophthalmol Vis Sci. 2000;41:1181–1185. r 2008 Lippincott Williams & Wilkins PL-000521 Case 3:12-cv-01141-SMY-DGW Document 176-4 *SEALED* Filed 12/01/14 Page 9 of 10 Page ID #2261 Case: 16-3334 Document: 55-10 Filed: 02/08/2017 Pages: 10 (249 of 1511) J Glaucoma Volume 17, Number 2, March 2008 57. Cruysberg LP, Nuijts RM, Geroski DH, et al. In vitro human scleral permeability of fluorescein, dexamethasone-fluorescein, methotrexate-fluorescein and rhodamine 6G and the use of a coated coil as a new drug delivery system. J Ocul Pharmacol Ther. 2002;18:559–569. 58. Forster S, Mead A, Sears M. An interophthalmic communicating artery as explanation for the consensual irritative response of the rabbit eye. Invest Ophthalmol Vis Sci. 1979;18:161–165. 59. Bito LZ. Species differences in the responses of the eye to irritation and trauma: a hypothesis of divergence in ocular defense mechanisms, and the choice of experimental animals for eye research. Exp Eye Res. 1984;39:807–829. 60. Heijl A, Leske MC, Bengtsson B, et al. Early Manifest Glaucoma Trial Group. Reduction of intraocular pressure and glaucoma progression: results from the Early Manifest Glaucoma Trial. Arch Ophthalmol. 2002;120:1268–1279. 61. Anderson DR. Normal Tension Glaucoma Study. Collaborative normal tension glaucoma study. Curr Opin Ophthalmol. 2003;14: 86–90. 62. Asrani S, Zeimer R, Wilensky J, et al. Large diurnal fluctuations in intraocular pressure are an independent risk factor in patients with glaucoma. J Glaucoma. 2000;9:134–142. 63. Rotchford AP, Murphy KM. Compliance with timolol treatment in glaucoma. Eye. 1998;12:234–236. 64. Gurwitz JH, Glynn RJ, Monane M, et al. Treatment for glaucoma: adherence by the elderly. Am J Public Health. 1993;83: 711–716. 65. Patel SC, Spaeth GL. Compliance in patients prescribed eyedrops for glaucoma. Ophthalmic Surg. 1995;26:233–236. 66. Tsai JC. Medication adherence in glaucoma: approaches for optimizing patient compliance. Curr Opin Ophthalmol. 2006;17: 190–195. 67. Nordstrom BL, Friedman DS, Mozaffari E, et al. Persistence and adherence with topical glaucoma therapy. Am J Ophthalmol. 2005;140:598–606. 68. Edelhauser HF, Maren TH. Permeability of human cornea and sclera to sulfonamide carbonic anhydrase inhibitors. Arch Ophthalmol. 1988;106:1110–1115. 69. Maren TH, Jankowska L, Sanyal G, et al. The transcorneal permeability of sulfonamide carbonic anhydrase inhibitors and their effect on aqueous humor secretion. Exp Eye Res. 1983;36: 457–479. 70. Camras CB, Bito LZ, Eakins KE. Reduction of intraocular pressure by prostaglandins applied topically to the eyes of conscious rabbits. Invest Ophthalmol Vis Sci. 1977;16:1125–1134. 71. Starr MS. Further studies on the effect of prostaglandin on intraocular pressure in the rabbit. Exp Eye Res. 1971;11: 170–177. 72. Camras CB, Alm A. Initial clinical studies with prostaglandins and their analogues. Surv Ophthalmol. 1997;41:S61–S68. 73. Giuffre G. The effects of prostaglandin F2 alpha in the human eye. Graefes Arch Clin Exp Ophthalmol. 1985;222:139–141. 74. Prostaglandins and hypotensive lipids. In: Allingham RR, Damji K, Freedman S, et al., eds. Shields Textbook of Glaucoma. Philadelphia: Lippincott-Raven Publishers; 2005:471–483. 75. Bito LZ, Baroody RA. The ocular pharmacokinetics of eicosanoids and their derivatives. 1. Comparison of ocular eicosanoid penetration and distribution following the topical application of PGF2 alpha, PGF2 alpha-1-methyl ester, and PGF2 alpha-1-isopropyl ester. Exp Eye Res. 1987;44:217–226. 76. Wang RF, Camras CB, Lee PY, et al. Effects of prostaglandins F2 alpha, A2, and their esters in glaucomatous monkey eyes. Invest Ophthalmol Vis Sci. 1990;31:2466–2470. 77. Stjernschantz JW. From PGF(2alpha)-isopropyl ester to latanoprost: a review of the development of xalatan: the Proctor Lecture. Invest Ophthalmol Vis Sci. 2001;42:1134–1145. 78. Mitra AK, Mikkelson TJ. Mechanism of transcorneal permeation of pilocarpine. Pharm Sci. 1988;77:771–775. 79. Brechue WF, Maren TH. pH and drug ionization affects ocular pressure lowering of topical carbonic anhydrase inhibitors. Invest Ophthalmol Vis Sci. 1993;34:2581–2587. r 2008 Lippincott Williams & Wilkins Barriers to Glaucoma Drug Delivery 80. Conroy CW, Maren TH. Effect of pH on the ocular distribution of a topical carbonic anhydrase inhibitor. Exp Eye Res. 1995;61: 213–222. 81. Prinicples of pharmacology in glaucoma. In: Allingham RR, Damji K, Freedman S, et al., eds. Shields Textbook of Glaucoma. Philadelphia: Lippincott-Raven Publishers; 2005:444–456. 82. Katz IM, Hubbard WA, Getson AJ, et al. Intraocular pressure decrease in normal volunteers following timolol ophthalmic solution. Invest Ophthalmol. 1976;15:489–492. 83. Brandt JD, VanDenburgh AM, Chen K, et al, Bimatoprost Study Group. Comparison of once- or twice-daily bimatoprost with twice-daily timolol in patients with elevated IOP: a 3-month clinical trial. Ophthalmology. 2001;108:1023–1031. 84. Sjoquist B, Stjernschantz J. Ocular and systemic pharmacokinetics of latanoprost in humans. Surv Ophthalmol. 2002;47:S6–S12. 85. Schoenwald RD, Stewart P. Effect of particle size on ophthalmic bioavailability of dexamethasone suspensions in rabbits. J Pharm Sci. 1980;69:391–394. 86. Apt L, Henrick A, Silverman LM. Patient compliance with use of topical ophthalmic corticosteroid suspensions. Am J Ophthalmol. 1979;87:210–214. 87. Diestelhorst M, Kwon KA, Suverkrup R. Dose uniformity of ophthalmic suspensions. J Cataract Refract Surg. 1998;24:672–677. 88. Kaur IP, Smitha R. Penetration enhancers and ocular bioadhesives: two new avenues for ophthalmic drug delivery. Drug Dev Ind Pharm. 2002;28:353–369.a. 89. Aktas Y, Unlu N, Orhan M, et al. Influence of hydroxypropyl beta-cyclodextrin on the corneal permeation of pilocarpine. Drug Dev Ind Pharm. 2003;29:223–230. 90. Maestrelli F, Mura P, Casini A, et al. Cyclodextrin complexes of sulfonamide carbonic anhydrase inhibitors as long-lasting topically acting antiglaucoma agents. J Pharm Sci. 2002;91:2211–2219. 91. Keller N, Moore D, Carper D, et al. Increased corneal permeability induced by the dual effects of transient tear film acidification and exposure to benzalkonium chloride. Exp Eye Res. 1980;30:203–210. 92. Green K, Tonjum A. Influence of various agents on corneal permeability. Am J Ophthalmol. 1971;72:897–905. 93. Pfister RR, Burstein N. The effects of ophthalmic drugs, vehicles, and preservatives on corneal epithelium: a scanning electron microscope study. Invest Ophthalmol. 1976;15:246–259. 94. Gasset AR, Ishii Y, Kaufman He, et al. Cytotoxicity of ophthalmic preservatives. Am J Ophthalmol. 1974;78:98–105. 95. Champeau EJ, Edelhauser HF. The effect of ophthalmic preservatives on the ocular surface: conjunctival and corneal uptake and distribution of Benzalkonium chloride and chlorhexidine digluconate. In: Holly FJ, ed. The Preocular Tear Film in Health, Disease and Contact Lens Wear. Lubbock, TX: Dry eye Institute, Inc; 1986. 96. Noecker RJ, Herrygers LA, Anwaruddin R. Corneal and conjunctival changes caused by commonly used glaucoma medications. Cornea. 2004;23:490–496. 97. Charnock C. Are multidose over-the-counter artificial tears adequately preserved? Cornea. 2006;25:432–437. 98. Patton TF, Robinson JR. Ocular evaluation of polyvinyl alcohol vehicle in rabbits. J Pharm Sci. 1975;64:1312–1316. 99. Schenker H, Maloney S, Liss C, et al. Patient preference, efficacy, and compliance with timolol maleate ophthalmic gel-forming solution versus timolol maleate ophthalmic solution in patients with ocular hypertension or open-angle glaucoma. Clin Ther. 1999; 21:138–147. 100. March WF, Stewart RM, Mandell AI, et al. Duration of effect of pilocarpine gel. Arch Ophthalmol. 1982;100:1270–1271. 101. Roziere A, Mazuel C, Grove J, et al. Gtelrite: a novel ion activated, in situ gelling polymer for ophthalmic vehicles: effect on bioavailability of Timolol. Int J Pharm. 1989;57:163–168. 102. Ibrahim H, Gurny R, Buri P, et al. Ocular bioavailability of Pilocarpine from phase transition latex system triggered by pH. Eur J Drug Metab Pharmacokinet.1990;15:206. 103. Ishibashi T, Yokoi N, Bron AJ, et al. Retention of reversibly thermo-gelling timolol on the human ocular surface studied by video meniscometry. Curr Eye Res. 2003;27:117–122. 155 PL-000522 Case 3:12-cv-01141-SMY-DGW Document 176-4 *SEALED* Filed 12/01/14 Page 10 of 10 Page ID #2262 Case: 16-3334 Document: 55-10 Filed: 02/08/2017 Pages: 10 (250 of 1511) Ghate and Edelhauser 104. Naveh N, Muchtar S, Benita S. Pilocarpine incorporated into a submicron emulsion vehicle causes an unexpectedly prolonged ocular hypotensive effect in rabbits. J Ocul Pharmacol. 1994;10:509–520. 105. Kaswan R. Characteristics of a canine model of KCS: effective treatment with topical cyclosporine. Adv Exp Med Biol. 1994;350: 583–594. 106. Gao J, Schwalb TA, Addeo JV, et al. The role of apoptosis in the pathogenesis of canine keratoconjunctivitis sicca: the effect of topical Cyclosporin A therapy. Cornea. 1998;17:654–663. 107. Pflugfelder SC, Solomon A, Stern ME. The diagnosis and management of dry eye: a twenty-five-year review. Cornea. 2000;19: 644–649. 108. Tang-Liu DD, Acheampong A. Ocular pharmacokinetics and safety of ciclosporin, a novel topical treatment for dry eye. Clin Pharmacokinet. 2005;44:247–261. 109. Pflugfelder SC. Integrating restasis into the management of dry eye. Int Ophthalmol Clin. 2006;46:101–103. 110. De Campos AM, Diebold Y, Carvalho EL, et al. Chitosan nanoparticles as new ocular drug delivery systems: in vitro stability, in vivo fate, and cellular toxicity. Pharm Res. 2004;21:803–810. 111. Genta I, Conti B, Perugini P, et al. Bioadhesive microspheres for ophthalmic administration of acyclovir. J Pharm Pharmacol. 1997;49:737–742. 112. Di Colo G, Zambito Y, Burgalassi S, et al. Effect of chitosan on in vitro release and ocular delivery of ofloxacin from erodible inserts based on polyethylene oxide. Int J Pharm. 2002;248:115–122. 113. Kao HJ, Lin HR, Lo YL, et al. Characterization of pilocarpineloaded chitosan/Carbopol nanoparticles. J Pharm Pharmacol. 2006;58:179–186. 114. Ebrahim S, Peyman GA, Lee PJ. Applications of liposomes in ophthalmology. Surv Ophthalmol. 2005;50:167–182. 115. Vega E, Egea MA, Valls O, et al. Flurbiprofen loaded biodegradable nanoparticles for ophthalmic administration. J Pharm Sci. 2006. [Epub ahead of print August 2.] 116. Irache JM, Merodio M, Arnedo A, et al. Albumin nanoparticles for the intravitreal delivery of anticytomegaloviral drugs. Mini Rev Med Chem. 2005;5:293–305. 117. Zimmer A, Mutschler E, Lambrecht G, et al. Pharmacokinetic and pharmacodynamic aspects of an ophthalmic pilocarpin nanoparticle-delivery-system. Pharm Res. 1994;11:1435–1442. 156 J Glaucoma Volume 17, Number 2, March 2008 118. Chang SW, Chi RF, Wu CC, et al. Benzalkonium chloride and gentamicin cause a leak in corneal epithelial cell membrane. Exp Eye Res. 2000;71:3–10. 119. Grass GM, Wood RW, Robinson JR. Effects of calcium chelating agents on corneal permeability. Invest Ophthalmol Vis Sci. 1985;26: 110–113. 120. Sarraf D, Lee DA. The role of iontophoresis in ocular drug delivery. J Ocul Pharmacol. 1994;10:69–81. 121. Halhal M, Renard G, Courtois Y, et al. Iontophoresis: from the lab to the bed side. Exp Eye Res. 2004;78:751–757. 122. Rootman DS, Jantzen JA, Gonzalez JR, et al. Pharmacokinetics and safety of transcorneal iontophoresis of tobramycin in the rabbit. Invest Ophthalmol Vis Sci. 1988;29:1397–1401. 123. Zderic V, Vaezy S, Martin RW, et al. Ocular drug delivery using 20-kHz ultrasound. Ultrasound Med Biol. 2002;28:823–829. 124. Dohlman CH, Pavan-Langston D, Rose J. A new ocular insert device for continuous constant-rate delivery of medication to the eye. Ann Ophthalmol. 1972;4:823–832. 125. Maddox YT, Bernstein HN. An evaluation of the Bionite hydrophilic contact lens for use in a drug delivery system. Ann Ophthalmol. 1972;4:789–790. 126. Sawusch MR, O’Brien TP, Dick JD, et al. Use of collagen corneal shields in the treatment of bacterial keratitis. Am J Ophthalmol. 1988;106:279–281. 127. Tonnesen HH, Karlsen J. Alginate in drug delivery systems. Drug Dev Ind Pharm. 2002;28:621–630. 128. Mundada AS, Shrikhande BK. Design and evaluation of soluble ocular drug insert for controlled release of ciprofloxacin hydrochloride. Drug Dev Ind Pharm. 2006;32:443–448. 129. Maurice DM. Drug delivery to the posterior segment from drops. Surv Ophthalmol. 2002;47:S41–S52. 130. Kent AR, Nussdorf JD, David R, et al. Vitreous concentration of topically applied brimonidine tartrate 0.2%. Ophthalmology. 2001;108: 784–787. 131. Wheeler L, WoldeMussie E, Lai R. Role of alpha-2 agonists in neuroprotection. Surv Ophthalmol. 2003;48:S47–S51. 132. Ghate D, Brooks W, McCarey B, et al. Pharmacokinetics of intraocular drug delivery by periocular injections using ocular fluorophotometry. Invest Ophthalmol Vis Sci. 2007;48: 2230–2237. r 2008 Lippincott Williams & Wilkins PL-000523 Case 3:12-cv-01141-SMY-DGW Document 176-29 *SEALED* Filed 12/01/14 Page 1 of 26 Page ID #2861 Case: 16-3334 Document: 55-11 Filed: 02/08/2017 Pages: 26 (251 of 1511) Confidential, Subject to Protective Order, Produced by Merck & Co., Inc., in Case 3:12-cv-01141-DRH-DGW (S.D. ILL.) NDA_Merck_Prasco 00000328 Case 3:12-cv-01141-SMY-DGW Document 176-29 *SEALED* Filed 12/01/14 Page 2 of 26 Page ID #2862 Case: 16-3334 Document: 55-11 Filed: 02/08/2017 Pages: 26 (252 of 1511) Confidential, Subject to Protective Order, Produced by Merck & Co., Inc., in Case 3:12-cv-01141-DRH-DGW (S.D. ILL.) NDA_Merck_Prasco 00000329 Case 3:12-cv-01141-SMY-DGW Document 176-29 *SEALED* Filed 12/01/14 Page 3 of 26 Page ID #2863 Case: 16-3334 Document: 55-11 Filed: 02/08/2017 Pages: 26 (253 of 1511) Confidential, Subject to Protective Order, Produced by Merck & Co., Inc., in Case 3:12-cv-01141-DRH-DGW (S.D. ILL.) NDA_Merck_Prasco 00000330 Case 3:12-cv-01141-SMY-DGW Document 176-29 *SEALED* Filed 12/01/14 Page 4 of 26 Page ID #2864 Case: 16-3334 Document: 55-11 Filed: 02/08/2017 Pages: 26 (254 of 1511) Confidential, Subject to Protective Order, Produced by Merck & Co., Inc., in Case 3:12-cv-01141-DRH-DGW (S.D. ILL.) NDA_Merck_Prasco 00000331 Case 3:12-cv-01141-SMY-DGW Document 176-29 *SEALED* Filed 12/01/14 Page 5 of 26 Page ID #2865 Case: 16-3334 Document: 55-11 Filed: 02/08/2017 Pages: 26 (255 of 1511) Confidential, Subject to Protective Order, Produced by Merck & Co., Inc., in Case 3:12-cv-01141-DRH-DGW (S.D. ILL.) NDA_Merck_Prasco 00000332 Case 3:12-cv-01141-SMY-DGW Document 176-29 *SEALED* Filed 12/01/14 Page 6 of 26 Page ID #2866 Case: 16-3334 Document: 55-11 Filed: 02/08/2017 Pages: 26 (256 of 1511) Confidential, Subject to Protective Order, Produced by Merck & Co., Inc., in Case 3:12-cv-01141-DRH-DGW (S.D. ILL.) NDA_Merck_Prasco 00000333 Case 3:12-cv-01141-SMY-DGW Document 176-29 *SEALED* Filed 12/01/14 Page 7 of 26 Page ID #2867 Case: 16-3334 Document: 55-11 Filed: 02/08/2017 Pages: 26 (257 of 1511) Confidential, Subject to Protective Order, Produced by Merck & Co., Inc., in Case 3:12-cv-01141-DRH-DGW (S.D. ILL.) NDA_Merck_Prasco 00000334 Case 3:12-cv-01141-SMY-DGW Document 176-29 *SEALED* Filed 12/01/14 Page 8 of 26 Page ID #2868 Case: 16-3334 Document: 55-11 Filed: 02/08/2017 Pages: 26 (258 of 1511) Confidential, Subject to Protective Order, Produced by Merck & Co., Inc., in Case 3:12-cv-01141-DRH-DGW (S.D. ILL.) NDA_Merck_Prasco 00000335 Case 3:12-cv-01141-SMY-DGW Document 176-29 *SEALED* Filed 12/01/14 Page 9 of 26 Page ID #2869 Case: 16-3334 Document: 55-11 Filed: 02/08/2017 Pages: 26 (259 of 1511) Confidential, Subject to Protective Order, Produced by Merck & Co., Inc., in Case 3:12-cv-01141-DRH-DGW (S.D. ILL.) NDA_Merck_Prasco 00000336 Case 3:12-cv-01141-SMY-DGW Document 176-29 *SEALED* Filed 12/01/14 Page 10 of 26 Page ID #2870 Case: 16-3334 Document: 55-11 Filed: 02/08/2017 Pages: 26 (260 of 1511) Confidential, Subject to Protective Order, Produced by Merck & Co., Inc., in Case 3:12-cv-01141-DRH-DGW (S.D. ILL.) NDA_Merck_Prasco 00000337 Case 3:12-cv-01141-SMY-DGW Document 176-29 *SEALED* Filed 12/01/14 Page 11 of 26 Page ID #2871 Case: 16-3334 Document: 55-11 Filed: 02/08/2017 Pages: 26 (261 of 1511) Confidential, Subject to Protective Order, Produced by Merck & Co., Inc., in Case 3:12-cv-01141-DRH-DGW (S.D. ILL.) NDA_Merck_Prasco 00000338 Case 3:12-cv-01141-SMY-DGW Document 176-29 *SEALED* Filed 12/01/14 Page 12 of 26 Page ID #2872 Case: 16-3334 Document: 55-11 Filed: 02/08/2017 Pages: 26 (262 of 1511) Confidential, Subject to Protective Order, Produced by Merck & Co., Inc., in Case 3:12-cv-01141-DRH-DGW (S.D. ILL.) NDA_Merck_Prasco 00000339 Case 3:12-cv-01141-SMY-DGW Document 176-29 *SEALED* Filed 12/01/14 Page 13 of 26 Page ID #2873 Case: 16-3334 Document: 55-11 Filed: 02/08/2017 Pages: 26 (263 of 1511) Confidential, Subject to Protective Order, Produced by Merck & Co., Inc., in Case 3:12-cv-01141-DRH-DGW (S.D. ILL.) NDA_Merck_Prasco 00000340 Case 3:12-cv-01141-SMY-DGW Document 176-29 *SEALED* Filed 12/01/14 Page 14 of 26 Page ID #2874 Case: 16-3334 Document: 55-11 Filed: 02/08/2017 Pages: 26 (264 of 1511) Confidential, Subject to Protective Order, Produced by Merck & Co., Inc., in Case 3:12-cv-01141-DRH-DGW (S.D. ILL.) NDA_Merck_Prasco 00000341 Case 3:12-cv-01141-SMY-DGW Document 176-29 *SEALED* Filed 12/01/14 Page 15 of 26 Page ID #2875 Case: 16-3334 Document: 55-11 Filed: 02/08/2017 Pages: 26 (265 of 1511) Confidential, Subject to Protective Order, Produced by Merck & Co., Inc., in Case 3:12-cv-01141-DRH-DGW (S.D. ILL.) NDA_Merck_Prasco 00000342 Case 3:12-cv-01141-SMY-DGW Document 176-29 *SEALED* Filed 12/01/14 Page 16 of 26 Page ID #2876 Case: 16-3334 Document: 55-11 Filed: 02/08/2017 Pages: 26 (266 of 1511) Confidential, Subject to Protective Order, Produced by Merck & Co., Inc., in Case 3:12-cv-01141-DRH-DGW (S.D. ILL.) NDA_Merck_Prasco 00000343 Case 3:12-cv-01141-SMY-DGW Document 176-29 *SEALED* Filed 12/01/14 Page 17 of 26 Page ID #2877 Case: 16-3334 Document: 55-11 Filed: 02/08/2017 Pages: 26 (267 of 1511) Confidential, Subject to Protective Order, Produced by Merck & Co., Inc., in Case 3:12-cv-01141-DRH-DGW (S.D. ILL.) NDA_Merck_Prasco 00000344 Case 3:12-cv-01141-SMY-DGW Document 176-29 *SEALED* Filed 12/01/14 Page 18 of 26 Page ID #2878 Case: 16-3334 Document: 55-11 Filed: 02/08/2017 Pages: 26 (268 of 1511) Confidential, Subject to Protective Order, Produced by Merck & Co., Inc., in Case 3:12-cv-01141-DRH-DGW (S.D. ILL.) NDA_Merck_Prasco 00000345 Case 3:12-cv-01141-SMY-DGW Document 176-29 *SEALED* Filed 12/01/14 Page 19 of 26 Page ID #2879 Case: 16-3334 Document: 55-11 Filed: 02/08/2017 Pages: 26 (269 of 1511) Confidential, Subject to Protective Order, Produced by Merck & Co., Inc., in Case 3:12-cv-01141-DRH-DGW (S.D. ILL.) NDA_Merck_Prasco 00000346 Case 3:12-cv-01141-SMY-DGW Document 176-29 *SEALED* Filed 12/01/14 Page 20 of 26 Page ID #2880 Case: 16-3334 Document: 55-11 Filed: 02/08/2017 Pages: 26 (270 of 1511) Confidential, Subject to Protective Order, Produced by Merck & Co., Inc., in Case 3:12-cv-01141-DRH-DGW (S.D. ILL.) NDA_Merck_Prasco 00000347 Case 3:12-cv-01141-SMY-DGW Document 176-29 *SEALED* Filed 12/01/14 Page 21 of 26 Page ID #2881 Case: 16-3334 Document: 55-11 Filed: 02/08/2017 Pages: 26 (271 of 1511) Confidential, Subject to Protective Order, Produced by Merck & Co., Inc., in Case 3:12-cv-01141-DRH-DGW (S.D. ILL.) NDA_Merck_Prasco 00000348 Case 3:12-cv-01141-SMY-DGW Document 176-29 *SEALED* Filed 12/01/14 Page 22 of 26 Page ID #2882 Case: 16-3334 Document: 55-11 Filed: 02/08/2017 Pages: 26 (272 of 1511) Confidential, Subject to Protective Order, Produced by Merck & Co., Inc., in Case 3:12-cv-01141-DRH-DGW (S.D. ILL.) NDA_Merck_Prasco 00000349 Case 3:12-cv-01141-SMY-DGW Document 176-29 *SEALED* Filed 12/01/14 Page 23 of 26 Page ID #2883 Case: 16-3334 Document: 55-11 Filed: 02/08/2017 Pages: 26 (273 of 1511) Confidential, Subject to Protective Order, Produced by Merck & Co., Inc., in Case 3:12-cv-01141-DRH-DGW (S.D. ILL.) NDA_Merck_Prasco 00000350 Case 3:12-cv-01141-SMY-DGW Document 176-29 *SEALED* Filed 12/01/14 Page 24 of 26 Page ID #2884 Case: 16-3334 Document: 55-11 Filed: 02/08/2017 Pages: 26 (274 of 1511) Confidential, Subject to Protective Order, Produced by Merck & Co., Inc., in Case 3:12-cv-01141-DRH-DGW (S.D. ILL.) NDA_Merck_Prasco 00000351 Case 3:12-cv-01141-SMY-DGW Document 176-29 *SEALED* Filed 12/01/14 Page 25 of 26 Page ID #2885 Case: 16-3334 Document: 55-11 Filed: 02/08/2017 Pages: 26 (275 of 1511) Confidential, Subject to Protective Order, Produced by Merck & Co., Inc., in Case 3:12-cv-01141-DRH-DGW (S.D. ILL.) NDA_Merck_Prasco 00000352 Case 3:12-cv-01141-SMY-DGW Document 176-29 *SEALED* Filed 12/01/14 Page 26 of 26 Page ID #2886 Case: 16-3334 Document: 55-11 Filed: 02/08/2017 Pages: 26 (276 of 1511) Confidential, Subject to Protective Order, Produced by Merck & Co., Inc., in Case 3:12-cv-01141-DRH-DGW (S.D. ILL.) NDA_Merck_Prasco 00000353 Case 3:12-cv-01141-SMY-DGW Document 176-5 *SEALED* Filed 12/01/14 Page 1 of 4 Case: 16-3334 Document:Page 55-12ID #2263 Filed: 02/08/2017 Pages: 4 (277 of 1511) Case 3:12-cv-01141-SMY-DGW Document 176-5 *SEALED* Filed 12/01/14 Page 2 of 4 Case: 16-3334 Document:Page 55-12ID #2264 Filed: 02/08/2017 Pages: 4 (278 of 1511) Case 3:12-cv-01141-SMY-DGW Document 176-5 *SEALED* Filed 12/01/14 Page 3 of 4 Case: 16-3334 Document:Page 55-12ID #2265 Filed: 02/08/2017 Pages: 4 (279 of 1511) Case 3:12-cv-01141-SMY-DGW Document 176-5 *SEALED* Filed 12/01/14 Page 4 of 4 Case: 16-3334 Document:Page 55-12ID #2266 Filed: 02/08/2017 Pages: 4 (280 of 1511) Case 3:12-cv-01141-SMY-DGW Document 176-30 *SEALED* Filed 12/01/14 Page 1 of 2 Case: 16-3334 Document:Page 55-13ID #2887 Filed: 02/08/2017 Pages: 2 (281 of 1511) COSOPT® (dorzolamide hydrochloride–timolol maleate ophthalmic solution) 9098902 with respiratory distress; Body as a Whole: Extremity pain, decreased exercise tolerance, weight loss; Cardiovascular: Worsening of arterial insufficiency, vasodilatation; Digestive: Gastrointestinal pain, hepatomegaly, mesenteric arterial thrombosis, ischemic colitis; Hematologic: Nonthrombocytopenic purpura; thrombocytopenic purpura, agranulocytosis; Endocrine: Hyperglycemia, hypoglycemia; Skin: Pruritus, skin irritation, increased pigmentation, sweating; Musculoskeletal: Arthralgia; Nervous System/Psychiatric: Vertigo, local weakness, diminished concentration, reversible mental depression progressing to catatonia, an acute reversible syndrome characterized by disorientation for time and place, emotional lability, slightly clouded sensorium, and decreased performance on neuropsychometrics; Respiratory: Rales, bronchial obstruction; Urogenital: Urination difficulties. OVERDOSAGE There are no human data available on overdosage with COSOPT. Symptoms consistent with systemic administration of beta-blockers or carbonic anhydrase inhibitors may occur, including electrolyte imbalance, development of an acidotic state, dizziness, headache, shortness of breath, bradycardia, bronchospasm, cardiac arrest and possible central nervous system effects. Serum electrolyte levels (particularly potassium) and blood pH levels should be monitored (see also ADVERSE REACTIONS). A study of patients with renal failure showed that timolol did not dialyze readily. DOSAGE AND ADMINISTRATION The dose is one drop of COSOPT in the affected eye(s) two times daily. If more than one topical ophthalmic drug is being used, the drugs should be administered at least ten minutes apart (see also PRECAUTIONS, Drug Interactions). HOW SUPPLIED COSOPT Ophthalmic Solution is a clear, colorless to nearly colorless, slightly viscous solution. ® No. 3628 — COSOPT Ophthalmic Solution is supplied in an OCUMETER * Plus container, a white, opaque, plastic ophthalmic dispenser with a controlled drop tip as follows: NDC 0006-3628-35, 5 mL NDC 0006-3628-36, 10 mL. Storage Store COSOPT between 15 and 25°C (59-77°F). Protect from light. By: Laboratories Merck Sharp & Dohme-Chibret 63963 Clermont-Ferrand Cedex 9, France Issued April 1999 Confidential, Subject to Protective Order, Produced by Merck & Co., Inc., in Case 3:12-cv-01141-DRH-DGW (S.D. ILL.) 8 NDA_Merck_Prasco 00009193 Case 3:12-cv-01141-SMY-DGW Document 176-30 *SEALED* Filed 12/01/14 Page 2 of 2 Case: 16-3334 Document:Page 55-13ID #2888 Filed: 02/08/2017 Pages: 2 CURRENT CIRCULAR SHOWING REVISIONS COSOPT® (dorzolamide hydrochloride–timolol maleate ophthalmic solution) (282 of 1511) COMMENTS/SUPPORT 9098902 mental depression progressing to catatonia, an acute reversible syndrome characterized by disorientation for time and place, emotional lability, slightly clouded sensorium, and decreased performance on neuropsychometrics; Respiratory: Rales, bronchial obstruction; Urogenital: Urination difficulties. OVERDOSAGE There are no human data available on overdosage with COSOPT. Symptoms consistent with systemic administration of beta-blockers or carbonic anhydrase inhibitors may occur, including electrolyte imbalance, development of an acidotic state, dizziness, headache, shortness of breath, bradycardia, bronchospasm, cardiac arrest and possible central nervous system effects. Serum electrolyte levels (particularly potassium) and blood pH levels should be monitored (see also ADVERSE REACTIONS). A study of patients with renal failure showed that timolol did not dialyze readily. DOSAGE AND ADMINISTRATION The dose is one drop of COSOPT in the affected eye(s) two times daily. If more than one topical ophthalmic drug is being used, the drugs should be administered at least ten minutes apart (see also PRECAUTIONS, Drug Interactions). HOW SUPPLIED COSOPT Ophthalmic Solution is a clear, colorless to nearly colorless, slightly viscous solution. ® No. 3628 — COSOPT Ophthalmic Solution is supplied in an OCUMETER * Plus container, a white, opaque, plastic ophthalmic dispenser with a controlled drop tip as follows: NDC 0006-3628-3503, 5 mL NDC 0006-3628-3610, 10 mL. Storage Store COSOPT between 15 and 25°C (59-77°F). Protect from light. • New information for the OCUMETER Plus image. 13 Confidential, Subject to Protective Order, Produced by Merck & Co., Inc., in Case 3:12-cv-01141-DRH-DGW (S.D. ILL.) NDA_Merck_Prasco 00009227 Case 3:12-cv-01141-SMY-DGW Document 176-6 *SEALED* Filed 12/01/14 Page 1 of 52 Page ID #2267 Case: 16-3334 Document: 55-14 Filed: 02/08/2017 Pages: 52 (283 of 1511) IN THE UNITED STATES DISTRICT COURT FOR THE EAST ST. LOUIS DIVISION CHARLENE EIKE, SHIRLEY FISHER, JORDAN PITLER AND ALAN RAYMOND, on behalf of themselves and all others similarly situated, No. 3:12-cv-01141-DRH-DGW Plaintiff, v. ALLERGAN, INC.; ALLERGAN USA, INC.; ALLERGAN SALES, LLC; ALCON LABORATORIES, INC.; ALCON RESEARCH, LTD.; FALCON PHARMACEUTICALS, Ltd.; SANDOZ, INC.; BAUSCH AND LOMB INCORPORATED; PFIZER INC., MERCK & CO., INC.; MERCK, SHARP & DOHME CORP., and PRASCO, LLC, Defendants. EXPERT REPORT OF BRIAN KRIEGLER, PH.D. Econ ONE Research, Inc. May 30, 2014 CONTAINS CONFIDENTIAL INFORMATION SUBJECT TO PROECTIVE ORDER IN ABOVE-CAPTIONED CASE Suite 800 550 South Hope Street Los Angeles, California 90071 i Eike et al. v. Allergan, Inc. et al. • Expert Report of Brian Kriegler, Ph.D. Case 3:12-cv-01141-SMY-DGW Document 176-6 *SEALED* Filed 12/01/14 Page 2 of 52 Page ID #2268 Case: 16-3334 Document: 55-14 Filed: 02/08/2017 Pages: 52 (284 of 1511) TABLE OF CONTENTS I. Introduction and Qualifications .................................................1 A. Fee Statement ................................................................................. 1 B. Selected Relevant Experience ............................................................ 1 II. Overview ...................................................................................3 III. Assignment, Summary of Conclusions, and Materials Relied Upon .........................................................................................4 IV. Document Review .....................................................................5 A. Identification of Relevant Eye Drop Products ........................................ 5 B. Extent to which Defendants Purport that Test Results Emulate Patient Usage ............................................................................................. 6 1. Alcon .......................................................................................... 7 2. Allergan ...................................................................................... 8 3. Bausch & Lomb............................................................................ 9 4. Merck/Prasco............................................................................... 9 5. Pfizer ....................................................................................... 11 C. Extent to which Defendants Purport that There Is Consistency in Eye Drop Sizes ..................................................................................... 11 1. Alcon ........................................................................................ 12 2. Allergan .................................................................................... 13 ii Eike et al. v. Allergan, Inc. et al. • Expert Report of Brian Kriegler, Ph.D. Case 3:12-cv-01141-SMY-DGW Document 176-6 *SEALED* Filed 12/01/14 Page 3 of 52 Page ID #2269 Case: 16-3334 Document: 55-14 Filed: 02/08/2017 Pages: 52 (285 of 1511) 3. Bausch & Lomb.......................................................................... 13 4. Merck/Prasco............................................................................. 15 5. Pfizer ....................................................................................... 16 D. Factors that Can Affect the Magnitude of Drop Sizes ........................... 16 1. Patient-to-Patient Variation ......................................................... 17 2. Angle ....................................................................................... 21 V. Analysis of Drop Size Studies (Class-wide Proof of Injury) .....22 VI. Estimation of Alleged Class-wide Losses .................................24 A. Proposed Methodology .................................................................... 24 B. Potential Data Sources for Quantifying the Total Purchase Amount ....... 26 VII. Concluding Remarks ................................................................27 iii Eike et al. v. Allergan, Inc. et al. • Expert Report of Brian Kriegler, Ph.D. Case 3:12-cv-01141-SMY-DGW Document 176-6 *SEALED* Filed 12/01/14 Page 4 of 52 Page ID #2270 Case: 16-3334 Document: 55-14 Filed: 02/08/2017 Pages: 52 (286 of 1511) CONFIDENTIAL 5/30/2014 SUBJECT TO PROTECTIVE ORDER I. Introduction and Qualifications 1. I am a Statistician employed by Econ One Research, Inc (“Econ One”), an economic and statistical consulting firm with offices in Berkeley, Houston, Los Angeles, Memphis, Sacramento, and Washington, D.C. I have master‟s and doctoral degrees in statistics from UCLA, and I have a bachelor‟s degree in mathematics/economics from Claremont McKenna College. 2. As a statistician, I routinely work with complex data files, I conduct statistical analyses, and if appropriate, I construct sampling and survey designs. In a litigation context, among other things, I have opined on the feasibility of and developed methodologies for estimating damages/restitution in a wide range of class action lawsuits, including civil rights, antitrust, wage & hour, and consumer products. I have testified as an expert statistician in both State and Federal courts, and I have published several articles in peer-reviewed journals. A summary of my education, experience, and prior testimony is attached hereto as Exhibit A. 3. I have been retained by the Plaintiffs in Charlene Eike et al. v. Allergan, Inc. et al. (Case No. 3:12-cv-01141-DRH-DGW). A. Fee Statement 4. Econ One is being compensated for the time I spend on this matter at $275 per hour (including deposition and trial testimony). Econ One is being compensated for the time spent by other Econ One employees who perform work under my supervision and direction at their normal and customary hourly rates. B. Selected Relevant Experience 5. I have worked on numerous cases entailing an analysis of data comparable to the analysis I have employed and expect to employ in this case. As a statistician in a legal setting, it is standard practice for me to rely on counsel and/or industry experts to provide data and/or working assumptions, similar to my reliance on materials that Plaintiffs‟ counsel provided in this case and on the opinions of Alan Robin, M.D. Conversely, decisions regarding the analytical approach, sampling design, and computational implementation are my responsibility. I have a consistent track record of implementing these protocols. Below I describe some aspects of ongoing and finalized cases that resemble aspects of this class action lawsuit. Page 1 Eike et al. v. Allergan, Inc. et al. • Expert Report of Brian Kriegler, Ph.D. Case 3:12-cv-01141-SMY-DGW Document 176-6 *SEALED* Filed 12/01/14 Page 5 of 52 Page ID #2271 Case: 16-3334 Document: 55-14 Filed: 02/08/2017 Pages: 52 (287 of 1511) CONFIDENTIAL 5/30/2014 SUBJECT TO PROTECTIVE ORDER a. Barnes et al. v. District of Columbia (Case No. 06-315 (RCL)) is a settled civil rights class action lawsuit in which plaintiffs allege that the District of Columbia held individuals in custody and/or conducted full body-cavity searches of individuals after their respective sentences had expired. Using the inmate accounting database (consisting of data on hundreds of thousands of inmates), I constructed a stratified random sampling design for selecting hardcopy documents of former inmates. The strata were based on the time period and type of release, as well as the length of potential overdetention. The hardcopy documents were analyzed by a criminal justice expert, and based on his analysis of the sample of inmate files, I estimated the numbers of actual overdetentions and post-release strip searches. I testified in two depositions and at trial. The Court relied on my testimony as an expert in summary judgment with respect to the issues described above. Barnes v. District of Columbia (D.D.C. 2011) 793 F.Supp.2d 260, 269. b. Marchbanks et al. v. Comdata et al. (Case No. 07-1078-.JKG) is a settled antitrust class action lawsuit in which plaintiffs were a class of independent truck stops offering services primarily to class 7 and 8 (long-haul) truck drivers. The plaintiffs alleged that Comdata, the dominant issuer of proprietary fleet cards for long-haul truck drivers, entered into a scheme with the four largest national truck stop chains. The purpose and effect of the alleged scheme was to maintain Comdata‟s dominance of the fleet card market, while at the same time maintaining the largest truck stop chains‟ market power in the long haul fueling market. Plaintiffs alleged that Comdata imposed several anticompetitive contractual clauses on independent truck stop owners, charged Class members supracompetitive transaction fees, and steered trucking business away from the Class and towards its co-conspirators (the largest truck stop chains). During the litigation and settlement proceedings, I analyzed and managed the electronic transactional data, which consisted of millions of transactions per month from the late 1990s through 2013, and I constructed several damages models. At merits stage, I was responsible for calculating class-wide damages subject to three benchmark methodologies proposed by the plaintiffs at class certification. During settlement proceedings, I was responsible for identifying class members, pulling their contact information, and calculating their respective settlement awards using one of the methodologies proposed during litigation. c. United States of America ex rel. Misty Wall v. VistaCare et al. (Case No. 3-07-CV0604-M) is an ongoing qui tam case in which the plaintiff alleges that the Page 2 Eike et al. v. Allergan, Inc. et al. • Expert Report of Brian Kriegler, Ph.D. Case 3:12-cv-01141-SMY-DGW Document 176-6 *SEALED* Filed 12/01/14 Page 6 of 52 Page ID #2272 Case: 16-3334 Document: 55-14 Filed: 02/08/2017 Pages: 52 (288 of 1511) CONFIDENTIAL 5/30/2014 SUBJECT TO PROTECTIVE ORDER defendant violated the False Claims Act by having a widespread practice of enrolling individuals on hospice care who did not qualify for such care. The plaintiff also alleges that the defendant made fraudulent representations to the United States government concerning the medical conditions of many of its patients so that the defendant could receive per diem payments from Medicare. I am tasked with constructing a sampling design for reviewing patient files. Such sample of patient files will be analyzed by a doctor with expertise in the area of hospice care. With the analysis of that sample, I will extrapolate the total number of ineligible per diem payments in the population, along with the margin of error. d. O’Shea et al. v. Epson America, Inc. et al. (Case No. CV09-8063 PSG (CWx)) is an ongoing consumer class action lawsuit in which plaintiffs alleged that Epson knew but did not disclose that certain printer models utilized more ink than advertised. I submitted a declaration regarding the feasibility of several methodologies for calculating money lost by the proposed class members on a class-wide basis. II. Overview 6. I understand from the First Amended Class Action Complaint that Plaintiffs seek to represent a number of similarly defined classes, which differ only based on the state (Illinois or Missouri) and the company that manufactured the product. For example, the Allergan Illinois Class is defined as follows:1 All persons who, in the State of Illinois, purchased prescription eye drops manufactured and sold by Allergan in multi-dose dispensers within the period of the applicable statute of limitations prior to the filing of this lawsuit and up to the date of certification. 7. 1 I also understand that Plaintiffs are seeking, on behalf of themselves and similarly situated Illinois and Missouri consumers of multi-dose bottles of prescription eye Complaint, ¶105. The other classes are similarly defined. Page 3 Eike et al. v. Allergan, Inc. et al. • Expert Report of Brian Kriegler, Ph.D. Case 3:12-cv-01141-SMY-DGW Document 176-6 *SEALED* Filed 12/01/14 Page 7 of 52 Page ID #2273 Case: 16-3334 Document: 55-14 Filed: 02/08/2017 Pages: 52 (289 of 1511) CONFIDENTIAL 5/30/2014 SUBJECT TO PROTECTIVE ORDER drops manufactured by Defendants, “to recover as damages their excessive costs for inherently wasted medication manufactured and sold by Defendants.”2 8. I further understand that Plaintiffs are claiming to have suffered “actual damage measured by the allocated purchase price for the portion of their eye drops in excess of 15 µL.”3 However, I also understand that Dr. Robin has stated that “to be conservative my recommendation would be that drops be no larger than 16 µL on average.”4 III. Assignment, Summary of Conclusions, and Materials Relied Upon 9. Broadly speaking, Plaintiffs have given me the following assignments to date: a. First, I have been asked by Plaintiffs‟ counsel to address whether the drop size results in the eye drop studies discussed herein can be projected onto the class. Based on the documents I have reviewed to date, my understanding is that in terms of the size of eye drops, such studies were typically performed to emulate patient usage. It follows that my analysis of the drop size results is representative of the subclasses in this case. (¶¶12-19) b. Second, using the documents made available to me, I have been asked to identify characteristics that purportedly drive the size of eye drops. While a number of characteristics purportedly come into play (e.g., user technique, bottle angle, room temperature), defendants‟ documents generally purport to show “consistent” and “uniform” drop sizes. (¶¶20-44) c. Third, I have been asked by Plaintiffs‟ counsel to analyze the distributions of the eye drop sizes that were reported in defendants‟ documents and to assess whether patients were statistically likely to have dispensed eye drops that went to waste using the existing bottles. Based on my analysis discussed herein, with reliance on the opinions of Dr. Robin concerning the quantity that the eye is capable of receiving, I have concluded that virtually all persons in each 2 Complaint, ¶14. 3 Complaint, ¶¶141, 151. 4 Expert Report of Alan Robin, M.D., dated May 30, 2014, at ¶17. Page 4 Eike et al. v. Allergan, Inc. et al. • Expert Report of Brian Kriegler, Ph.D. Case 3:12-cv-01141-SMY-DGW Document 176-6 *SEALED* Filed 12/01/14 Page 8 of 52 Page ID #2274 Case: 16-3334 Document: 55-14 Filed: 02/08/2017 Pages: 52 (290 of 1511) CONFIDENTIAL 5/30/2014 SUBJECT TO PROTECTIVE ORDER subclass have dispensed eye drops that partially went to waste due to their excess size. (¶¶46-48) d. Finally, I have been asked by Plaintiffs‟ counsel to opine on the feasibility of implementing Plaintiffs‟ proposed methodology for calculating the cost to class members attributed to wasted eye drop medicine due to excessive eye drop size (“Alleged Class-wide Losses”). My opinion is that said methodology can be implemented on a class-wide basis with no need for individualized inquiry. I demonstrate how such methodology can be applied. (¶¶49-55) 10. A list of the materials that I or members of the staff at Econ One working under my supervision and direction have relied upon in connection with this assignment to date is attached as Exhibit B. Additional materials developed in the process of continuing discovery may lead me to revise or supplement my findings and conclusions. IV. Document Review A. Identification of Relevant Eye Drop Products 11. My first step was to determine the extent to which it was possible to estimate an average drop size for the eye drop products at issue. After reviewing produced documents and deposition transcripts of Defendant‟s 30(b)(6) witness(es), I determined that I had drop size data on the products listed in Table 1 below.5 In the case of brand-name drugs, Table 1 shows the products‟ generic names; in the case of generic products, Table 1 shows the equivalent brand-name product or Reference Listed (“RLD”), The column headed “Date of Approval” shows the product‟s date of initial approval by the United States Food & Drug Administration (“FDA”). I obtained those dates from the FDA‟s website, Drugs@FDA: FDA Approved Drug Products.6 At the outset, all of these medications are for treating glaucoma. However, my approach for reviewing documents, analyzing drop size data, assessing whether a class-wide injury occurred, and calculating Alleged Class-wide Losses is applicable to eye drop medications covered in the class definitions but not listed in Table 1. 5 6 URL: http://www.accessdata.fda.gov/Scripts/cder/drugsatfda/index.cfm Page 5 Eike et al. v. Allergan, Inc. et al. • Expert Report of Brian Kriegler, Ph.D. Case 3:12-cv-01141-SMY-DGW Document 176-6 *SEALED* Filed 12/01/14 Page 9 of 52 Page ID #2275 Case: 16-3334 Document: 55-14 Filed: 02/08/2017 Pages: 52 (291 of 1511) CONFIDENTIAL 5/30/2014 SUBJECT TO PROTECTIVE ORDER Manufacturer Alcon Alcon Alcon Alcon Alcon Alcon Alcon Alcon Alcon Alcon Allergan Allergan Allergan Allergan Allergan Bausch & Lomb Merck Merck Merck Merck Pfizer Table 1: List of Eye Drop Medications Discussed Herein Product Date of Approval Azopt 1% (Brinzolamide Hydrochloride) 04/01/1998 Dorzolamide (generic equivalent to Trusopt7) 04/13/2009 Dorzolamide Timolol (generic equivalent to Cosopt) 11/18/2009 Latanoprost (generic equivalent to Xalatan) 03/22/2011 Timolol GFS 0.25% 10/21/1998 (generic equivalent to Timoptic-XE8) Timolol GFS 0.5% 10/21/1998 (generic equivalent to Timoptic-XE9) Timolol or Timolol Maleate 0.5% 04/28/1995 (generic equivalent to Timoptic 0.5%) Travatan (Travoprost) 03/16/2001 Travatan Z (Travoprost [BAC-free]) 09/21/2006 Vigamox (Moxifloxicin) 04/15/2003 Alphagan P 0.1% (Brimonidine Tartrate 0.1%) 08/19/2005 Alphagan P 0.15% (Brimonidine Tartrate 0.15%) 03/16/2001 Combigan (Brimonidine Tartrate Timolol Maleate) 10/30/2007 Lumigan 0.01% (Bimatoprost 0.01%) 08/31/2010 Lumigan 0.03% (Bimatoprost 0.03%) 03/16/2001 Brimonidine Tartrate 0.2% 05/28/2003 (generic equivalent to Alphagan P) Cosopt (Dorzolamide Hydrochloride-Timolol Maleate) 04/07/1998 Timoptic (Timolol Maleate) 08/17/1978 Trusopt (Dorzolamide) 12/09/1994 Timoptic XE (Timolol GFS) 11/04/1993 Xalatan (Latanoprost) 06/05/1996 B. Extent to which Defendants Purport that Test Results Emulate Patient Usage 12. Numerous produced documents support the notion that the companies‟ eye drop tests were designed to emulate patient usage. In short, it is my understanding that the studies were designed to provide information regarding the drop size during patients‟ actual usage of the products listed in Table 1. To date, I have not seen any eye drop studies or statements indicating that said studies were not designed to emulate patient 7 Generic Trusopt was also manufactured by Merck. 8 Generic Timoptic-XE was also manufactured by Merck. 9 Generic Timoptic-XE was also manufactured by Merck. Page 6 Eike et al. v. Allergan, Inc. et al. • Expert Report of Brian Kriegler, Ph.D. Case 3:12-cv-01141-SMY-DGW Document 176-6 *SEALED* Filed 12/01/14 Page 10 of 52 Page ID #2276 Case: 16-3334 Document: 55-14 Filed: 02/08/2017 Pages: 52 (292 of 1511) CONFIDENTIAL 5/30/2014 SUBJECT TO PROTECTIVE ORDER usage. Thus, I have concluded that it is reasonable to use the defendants‟ testing results to estimate the drop size distribution (e.g., mean, standard deviation, range, etc.) consumed by members of each subclass. 1. Alcon 13. Alcon repeatedly stated that its drop size studies simulated patient usage. For example, Alcon‟s submission to the FDA,10 dated May 4, 2007, regarding Dorzolamide Hydrochloride states: The LDPE bottle is easy to squeeze due to its geometry and choice of resin material. A drop size study to simulate patient use of the product was conducted for Dorzolamide Hydrochloride Ophthalmic Solution, 2%. The drop size data indicate an average drop size of 48.1 mg (47.3 µL) with a standard deviation of ± 3 mg (2.9 µL). 14. Additionally, Alcon Technical Report No. 004:89:0102, titled “Measurement of Drop Size and Doses per Container During an In-Use Simulation of Ophthalmic Products,” dated February 6, 2002, is a study of Travatan, Pfizer‟s Xalatan, and two products, the identity of which were redacted from the copy of the document I was provided.11 The report states: This limited in-use laboratory study was intended to mimic actual patient use of these products with two drops being dispensed and measured daily to simulate a QD [i.e., four times a day] dosing regimen with Travatan, [redacted] and Xalatan, [redacted].…The results indicated that Travatan delivered an overall average drop size of 27.63 mg, with an average of 104 drops per container. [Redacted] with an average of 102 drops per container. Xalatan delivered an overall average drop size of AD_DORZOLAMIDE_EIKE000603 at 624 (emphasis added). See also similar statements made for the products Vigamox (AD_VIGAMOX_EIKE16359 at 16364); Dorzolamide Timolol (AD_ DORZ-TIM_ EIKE001214 at 1217); and Latanoprost (AD LATANOPROST EIKE000121 at 125). 10 11 AD_EIKE001281-1282. Page 7 Eike et al. v. Allergan, Inc. et al. • Expert Report of Brian Kriegler, Ph.D. Case 3:12-cv-01141-SMY-DGW Document 176-6 *SEALED* Filed 12/01/14 Page 11 of 52 Page ID #2277 Case: 16-3334 Document: 55-14 Filed: 02/08/2017 Pages: 52 (293 of 1511) CONFIDENTIAL 5/30/2014 SUBJECT TO PROTECTIVE ORDER 30.88 mg, with an average of 70 drops per container. [Redacted].12 2. Allergan 15. An Allergan Technical Memorandum13 states that the “hand” method of drop size testing (as opposed to using a robotic arm14) “has a person delivering drops in the same way as someone using the product.”15 Several Allergan technical memoranda indicate that the MP500 series container closure system provides the correct drop size when the container is used by patients, not just in laboratory tests, and that the drop weight as determined in these tests is one of the factors that, according to Allergan‟s scientists, makes it suitable for ophthalmic pharmaceutical products. For example, Technical Memorandum TPC-TM-2001-018, dated 9/25/2001,16 states in its Summary: The MP500/500W container closure system was tested to assure that it is suitable for ophthalmic pharmaceutical products…. Sixteen different tests were performed to test the safety, performance, and usability of the container closure system. The results show that the MP500/500W container closure system adequately protects the contents of the bottle from contamination, excessive water loss, leakage, and tampering. The system provides the correct drop weight and is easy to use.17 Id. at 1281 (emphasis added). In terms of microliters, the average drop size for Travatan and Xalatan are 27.65 μL and 30.60 μL, respectively. Such conversions to microliters are based on AD_EIKE001283 at 1286 and PFIZER_XALATAN_000000097, respectively. 12 13 PDD-TM-2002-164, Ex. ARGN_0002642. “The robotic arm essentially acts as another user, but with a very slow, consistent delivery technique.” ARGN_0002642 at 2658. 14 15 Ex. ARGN_0002642 at 2655. 16 ARGN_LUM03_0005644 at 5878. ARGN_LUM03_0005644 at 5879 (emphasis added). See identical statements regarding other configurations within the MP500 series at 5995, 5996 (Technical Memorandum TPC-TM-2002-023, dated 4/29/2002, regarding MP503/MP503W); 6106, 6107 (Technical Memorandum TPC-TM-2002-002, dated 17 Page 8 Eike et al. v. Allergan, Inc. et al. • Expert Report of Brian Kriegler, Ph.D. Case 3:12-cv-01141-SMY-DGW Document 176-6 *SEALED* Filed 12/01/14 Page 12 of 52 Page ID #2278 Case: 16-3334 Document: 55-14 Filed: 02/08/2017 Pages: 52 (294 of 1511) CONFIDENTIAL 5/30/2014 SUBJECT TO PROTECTIVE ORDER 3. Bausch & Lomb 16. Bausch & Lomb (“B&L”) Study Design Number FDSD-2000-024 (dated December 4, 2000) is a protocol for a study to assess B&L‟s proposed container closure system for Brimonidine Tartrate Ophthalmic Solution.18 The document states: “The purpose of the study is to „demonstrate uniformity of drops delivered from the container under conditions of normal patient use and to determine minimum required fill volume to deliver product label claim….‟ ”19 Similarly, a drop size study of B&L‟s Brimonidine Tartrate (incidentally, Allergan‟s Alphagan P as well), B&L Report Number FD-2003-003 (dated July 24, 2003), states: “Data was collected using both marketed drug products allowing for a direct comparison of the uniformity of drops delivered, number of drops (dose) delivered and number of days of medication, as well as fill volume and product consistency from the container under normal conditions of patient use.”20 4. Merck/Prasco 17. I have been provided one Merck study from which the drop sizes of Cosopt and Trusopt can be determined. This was a study to determine the number of drops per bottle and was conducted “in order to mimic, as close as possible, the instructions for use ….”21 This study found that a 10 mL bottle of Cosopt delivered an actual volume between 10.98 mL and 11.42 mL (though the average volume is not provided), with an average of 235 drops per bottle lasting 58 days (assuming one drop per eye two times daily); 235 drops would last between 58 and 59 days (235 drops / 4 drops per day = 58.75 days, or approximately 8 weeks). In addition, the maximum number of drops was 253.22 Thus, the average drop size is at least 43.3 L (10.98 mL 4/29/2002, regarding MP503/MP503W). My understanding is that the MP500 series has been employed on Allergan prescription eye drop products since approximately 2003. See Deposition of Lon Spada (March 26, 2014), 120:5-12. 18 BHLB BRIM_0001052. 19 BHLB BRIM_0001052 at 1053 (emphasis added). 20 BHLB_ BRIM-0000900 at 901 (emphasis added). 21 NDA_Merck_Prasco 00010421-10426 at 10421. 22 Id. at 10422 and 10423. Page 9 Eike et al. v. Allergan, Inc. et al. • Expert Report of Brian Kriegler, Ph.D. Case 3:12-cv-01141-SMY-DGW Document 176-6 *SEALED* Filed 12/01/14 Page 13 of 52 Page ID #2279 Case: 16-3334 Document: 55-14 Filed: 02/08/2017 Pages: 52 (295 of 1511) CONFIDENTIAL 5/30/2014 SUBJECT TO PROTECTIVE ORDER / 253 drops = 0.0433 mL or 43.3 L). This same study also found that a 10 mL bottle of Trusopt delivered an actual volume between 10.62 mL and 10.97 mL, with an average of 228 drops per bottle lasting 38 days (also assuming one drop per eye two times daily). Here, the maximum number of drops was 240.23 Thus, the average Trusopt drop size is at least 44.3 L.24 18. My understanding is that this test was the basis for a statement by a Prasco representative about the number of days that a 10 mL bottle of generic Cosopt (Brimonidine Tartrate) would be expected to last. I further understand that Merck‟s generic Cosopt is an identical drug to Cosopt and marketed in the same bottles as Cosopt.25 A Prasco report of a response to a consumer inquiry (hereinafter, “Consumer X” to protect the consumer‟s identity) indicates that Merck‟s drop size tests were used to determine how long a bottle would last a consumer. The Prasco representative stated to the consumer based on information supplied by Merck26 as follows: We cannot determine the exact number of drops per bottle dispenser or the exact number of days of therapy per bottle because usage may vary with individual patients. However, I can provide you with approximately how many days of therapy a bottle should last based on the recommended dose stated in the product insert. Per the product insert for Dorzolamide HCI-Timolol Maleate ophthalmic solution in a 10 mL bottle, putting one (1) drop in each eye two (2) times daily, the number of days of therapy should last approximately 59 days (~ 8 weeks). Thus, it appears that Merck and Prasco used this drop size test to estimate the number of days that a bottle would last a customer. 23 Id. at 10422 and 10424. 24 The underlying data is included in this document, but at least in the copy I have reviewed, it is illegible. 25 Deposition of David Walker (February 18, 2014), 38:22-39:2. 26 Prasco 000001 at 93 (emphasis added). Page 10 Eike et al. v. Allergan, Inc. et al. • Expert Report of Brian Kriegler, Ph.D. Case 3:12-cv-01141-SMY-DGW Document 176-6 *SEALED* Filed 12/01/14 Page 14 of 52 Page ID #2280 Case: 16-3334 Document: 55-14 Filed: 02/08/2017 Pages: 52 (296 of 1511) CONFIDENTIAL 5/30/2014 SUBJECT TO PROTECTIVE ORDER 5. Pfizer 19. In 1998, Pharmacia (Pfizer‟s predecessor)27 conducted drop size testing on Xalatan, in which “[t]he purpose of this investigation was to simulate practical use and evaluate the total yield, number of drops and drop size from the oval 5 ml ALP bottles using Eye Drops Latanoprost 50 µg/ml.”28 In addition, the report states explicitly that “[c]oncerning the volume per drop, the results from the sample can be considered as general for the population.”29 A Pfizer document from November 15, 2010 or later30 refers to this 1998 Pharmacia study, stating: “Based on calculations derived from this study data, and assuming administration of one drop in each eye once daily, approximately 45.5 days of therapy could be expected per bottle of Latanoprost.”31 Thus, it appears that Pfizer was using these drop size results to estimate the length of therapy a bottle would provide for the general population of patients. C. Extent to which Defendants Purport that There Is Consistency in Eye Drop Sizes 20. Here, I summarize the extent to which the defendant companies have stated in their documents that their bottles deliver “uniform,” “consistent,” or “controlled” (conceptually, minimally varying) drop size and/or weight. Just as in Section IV.B, I provide a summary for each defendant company. Pfizer and Pharmacia merged and began operating as a unified company on April 16, 2003. See statement on Pfizer‟s web page, “2003: Pfizer and Pharmacia Merger.” http://www.pfizer.com/about/history/pfizer_pharmacia (“Pfizer Inc and Pharmacia Corporation began operating as a unified company on April 16, 2003”). 27 PFIZER_ XALATAN_ 00001531 at 1538 (emphasis added). Latanoprost 50 µg/ml is the generic name for Xalatan. 28 PFIZER_ XALATAN_ 00001531 at 1541. In contrast, the report also states that “[t]he yield and volume left in the bottles are influenced by technique when using the bottles, filling volume, formation of foam when the bottle is nearly empty and therefore it is impossible to draw any conclusion concerning the population based on the sample.” (emphasis added) 29 PFIZER_XALATAN_00024279. This document is undated, but it states: “As of November 15, 2010, a computerized search of the published medical literature has identified a relevant article published in 2003…” Thus, document must have been prepared on or after November 15, 2010. 30 31 PFIZER_XALATAN_00024279. Page 11 Eike et al. v. Allergan, Inc. et al. • Expert Report of Brian Kriegler, Ph.D. Case 3:12-cv-01141-SMY-DGW Document 176-6 *SEALED* Filed 12/01/14 Page 15 of 52 Page ID #2281 Case: 16-3334 Document: 55-14 Filed: 02/08/2017 Pages: 52 (297 of 1511) CONFIDENTIAL 5/30/2014 SUBJECT TO PROTECTIVE ORDER 1. Alcon 21. With respect to one of Alcon‟s glaucoma medicines, Travatan, Alcon developed a device called the “Travatan Dosing Aid” which, among other characteristics, could provide a more uniform drop size for some patients.32 However, according to an Alcon report on the device, “[t]he average drop size for TRAVATAN with and without the dosing aid are essentially identical with the slight reduction when the dosing aid is used.”33 The document goes on to state, “TDOC-0002284 demonstrates consistency of drop size with and without dosing aid.”34 22. Another document titled “Dorzolamide HCl and Timolol Maleate Ophthalmic Solution” contains a section under the heading, “What specific container closure attributes are necessary to ensure product performance?”35 Among other attributes, the answer states: “Performance studies included drop-size studies to confirm consistency of the drug product delivery …”36 Thus, according to Alcon, consistency of drug product delivery is a product attribute necessary to ensure product performance. 23. Alcon produced one set of results that, at a glance, suggests relatively wide variability. This was a test of Travatan‟s drop size when dispensed at 60 degrees.37 Such study suggests an average drop size of 27.96 μL and a standard deviation of 8.15 μL. The underlying drop size data reveal that the wide variation is attributed to three extremely large drops (out of 1,034 drops in total). Respectively, these three drops had sizes of 128.0 μL, 162.7 μL, and 171.3 μL. These drops, as reported in the study, are approximately 4-6 times as large as the average drop size. I have not been provided with a narrative report regarding this test to explain this odd result, but my 32 Deposition of Lisa Blackwell (March 27, 2014), 178:21-179:1. 33 Ex. AD_TRAVATAN_EIKE040560 at 40564. 34 Id. at 40577 (emphasis added). 35 AD DORZ-TIM_EIKE001234. 36 Id. at 1235 (emphasis added). 37 AD_EIKE001304-1305. Page 12 Eike et al. v. Allergan, Inc. et al. • Expert Report of Brian Kriegler, Ph.D. Case 3:12-cv-01141-SMY-DGW Document 176-6 *SEALED* Filed 12/01/14 Page 16 of 52 Page ID #2282 Case: 16-3334 Document: 55-14 Filed: 02/08/2017 Pages: 52 (298 of 1511) CONFIDENTIAL 5/30/2014 SUBJECT TO PROTECTIVE ORDER understanding is that these drop measurements are anomalies.38 Excluding these three drops, the standard deviation is approximately 4.4 μL (i.e., approximately half of the standard deviation including the three extreme values). Furthermore, 4 out of 1,034 (0.4 percent) drops in this study are less than 16 μL. 2. Allergan 24. In 2001, an Allergan document set forth the marketing rationale and scientific basis for its new container closure system. One of their desired objectives was to “provide an advantage to the consumer in terms of ergonomics, consistent drops and no leakage.”39 A few years later, Allergan purportedly met this objective. A 2002 Allergan Technical Memorandum on its MP500 series of container closure systems indicates that the purpose of Allergan‟s drop weight tests “was to show that the MP500 series bottles deliver a consistent drop weight when fitted with the 40979 (white) or 41351LH (natural) dropper tip.”40 The results showed, in the words of the report, that “[t]he container closure provides a consistent drop weight and is easy to use.”41 3. Bausch & Lomb 25. 38 A Bausch & Lomb memo dated 3/17/2002 has the subject line “Drop Size Technical Assessment Report for Approved ANDA/NDA Ophthalmic Drug Products.”42 The memo deals with “drop size delivery associated with ophthalmic drug products manufactured commercially by Bausch and Lomb, Tampa.”43 One of the listed factors considered in selection of a specific dropper tip is: “Delivers a consistent Robin Report, ¶79. ARGN_2858 at 2867 (the complete report, entitled, New Generation Container Closure Systems,” is contained in ARGN_00002865-2881. 39 40 Technical Memorandum 2002-023; ARGN_LUM03_0005995 at 6003 (emphasis added). 41 ARGN_LUM03_0005995 at 6024 (emphasis added). 42 BHLB BRIM 0001076. 43 Id. Page 13 Eike et al. v. Allergan, Inc. et al. • Expert Report of Brian Kriegler, Ph.D. Case 3:12-cv-01141-SMY-DGW Document 176-6 *SEALED* Filed 12/01/14 Page 17 of 52 Page ID #2283 Case: 16-3334 Document: 55-14 Filed: 02/08/2017 Pages: 52 (299 of 1511) CONFIDENTIAL 5/30/2014 SUBJECT TO PROTECTIVE ORDER drop size.”44 The memo explains that this factor applies to products considered to be chronic, such as anti-glaucoma drugs. 26. Additionally in 2000, Bausch & Lomb conducted a study titled “Assessment of drop uniformity of Alphagan 0.2% [Brimonidine Tartrate Ophthalmic Solution].”45 This document states: The ultimate objective of this study is to specify a container closure system which has comparable drop delivery characteristics as that of [Allergan‟s] Alphagan® 0.2% (Sterile); the reference listed drug product (RLD). The purpose of the study is to…demonstrate uniformity of drops delivered from the container under conditions of normal patient use…46 Bausch & Lomb‟s 30(b)(6) witness, Mr. Matthew Jonasse, was asked what is meant by “uniformity” in said study. Mr. Jonasse testified that it meant both whether Bausch‟s container “…provide[s] a uniform drop, as well as … provide[s] a drop that is uniform compared to the…Allergan reference listed drug container….”47 27. Recognizing that uniformity and consistency in drop size do not imply that every drop will be exactly the same size--and looking ahead to Section V below--I analyze the variability in drop sizes based on defendants‟ eye drop studies. For example, one Bausch & Lomb study found that their containers produce “drop delivery characteristics comparable to that of [Allergan‟s] Alphagan,”48 with an expected average of approximately 35 µL per drop49 and a “range of the drop volume estimated based on this study [of] 33 – 36 µL.”50 Mr. Jonasse testified that “[t]he range of 33 to 36 microliters was considered to be reasonably uniform so that it 44 Id. (emphasis added). 45 BHLB_BRIM_0001052. 46 Id. at 1053 (emphasis added). 47 Deposition of Matthew Jonasse (March 11, 2014), 72:8-12 (emphasis added). 48 BHLB_BRIM_0001070 at 1072. 49 Id. 50 Id. Page 14 Eike et al. v. Allergan, Inc. et al. • Expert Report of Brian Kriegler, Ph.D. Case 3:12-cv-01141-SMY-DGW Document 176-6 *SEALED* Filed 12/01/14 Page 18 of 52 Page ID #2284 Case: 16-3334 Document: 55-14 Filed: 02/08/2017 Pages: 52 (300 of 1511) CONFIDENTIAL 5/30/2014 SUBJECT TO PROTECTIVE ORDER would meet the objective of this container-closure system in providing uniformity of drop volume.”51 4. Merck/Prasco 28. In a 1997 document regarding Dorzolamide Hydrochloride and Timolol Maleate, the description of the packaging reads as follows: During the development of this product, the same packaging components used for other commercially available ophthalmic products marketed by Merck were also utilized. These components will also be used for the market product. 29. Clinical and stability preparations were packaged in white opaque low density polyethylene bottles referred to as the Boston Round OCUMETER® container….[t]hese OCU-METER® containers were composed of the same polyethylene resin as the market container, DuPont 20-6064. These tips are specially designed to deliver a controlled drop size.52 30. Mr. David Walker, Merck‟s 30(b)(6) witness, elaborated on what is meant by a “controlled drop size,” stating that “[B]y limiting how rapidly the medication could come out of the dropper tip, the drop size would be more reproducible by each use of the patient.”53 31. My understanding is that the Ocumeter® was the predecessor to the Ocumeter® Plus, the latter of which was used during the class period. In its product label for Cosopt,54 Merck states that the “COSOPT Ophthalmic Solution is supplied in an Ocumeter® Plus container, a white, opaque plastic ophthalmic dispenser with a controlled drop tip…”55 51 Jonasse Depo., 77:13-17. 52 NDA_Merck_Prasco 00000328 at 348-349. 53 Walker Depo., 57:13-19. 54 NDA_Merck_Prasco 00009185; NDA_Merck_Prasco 00009214. 55 NDA_Merck_Prasco 00009193; NDA_Merck_Prasco 9227. Page 15 Eike et al. v. Allergan, Inc. et al. • Expert Report of Brian Kriegler, Ph.D. Case 3:12-cv-01141-SMY-DGW Document 176-6 *SEALED* Filed 12/01/14 Page 19 of 52 Page ID #2285 Case: 16-3334 Document: 55-14 Filed: 02/08/2017 Pages: 52 (301 of 1511) CONFIDENTIAL 5/30/2014 SUBJECT TO PROTECTIVE ORDER 5. Pfizer 32. Pfizer developed a dosing aid for Xalatan called Xal-Ease. The Xal-Ease device has been available for well over a decade56 and, according to Pfizer 30(b)(6) witness Daniel Arenson, such device was used in Quality Control drop size tests to have a more consistent quality control test.57 However, based on Pfizer‟s drop size tests that included drop size results with and without Xal-Ease, such device yields marginally different results, at best. In a response to a November 10, 2010 FDA query concerning Latanoprost, the difference in average drop size (Xal-Ease versus manual) was less than 2 µL, both for “current” tips and “new” tips.58 That same document described a difference of 2 L as an “indifference region.”59 Separately, based on a 2012 study of Xalatan/Latanoprost, I computed the variation in drop sizes using XalEase to be comparable to the variation when administering drops manually, both at 45 and 90 degrees.60 Accordingly, my conclusion is that the variation due to human factors is substantively minimal compared to what would be expected when using the Xal-Ease device. D. Factors that Can Affect the Magnitude of Drop Sizes 33. Numerous statements have been made by defendants‟ witnesses in their deposition testimony indicating that drop size can be a function of various factors. These witnesses testified variously (though not consistently) that the drop size is a function of where and how a patient squeezes the bottle, where the patient holds the bottle, how long the patient squeezes the bottle (collectively, “patient squeezing technique”), See, e.g., http://www.accessdata.fda.gov/drugsatfda_docs/label/2002/20597s25lbl.pdf. The final page of this document shows a date of August 26, 2002. 56 57 Deposition of Daniel Arenson (March 14, 2014), 83:20-84:11. 58 This specific analysis is based on the data provided in PFIZER_XALATAN_00000097 at 105-106. 59 Id. at 101. PFIZER_XALATAN_00002495 at 2501-2505. Using Xal-Ease, I computed the standard deviation to be 2.13 μL, whereas manually at 45 and 90 degrees, I computed the standard deviation to be 1.69 μL and 2.00 μL, respectively. Thus, the variation was slightly higher when using Xal-Ease. 60 Page 16 Eike et al. v. Allergan, Inc. et al. • Expert Report of Brian Kriegler, Ph.D. Case 3:12-cv-01141-SMY-DGW Document 176-6 *SEALED* Filed 12/01/14 Page 20 of 52 Page ID #2286 Case: 16-3334 Document: 55-14 Filed: 02/08/2017 Pages: 52 (302 of 1511) CONFIDENTIAL 5/30/2014 SUBJECT TO PROTECTIVE ORDER temperature, and bottle angle.61 In these regards, I have formed the following opinions: a. To date I am unaware of any studies that quantify differences in terms of temperature or patient technique. And, to my knowledge none of defendants‟ 30(b)(6) witnesses are aware of such studies.62 b. To the extent that patient-to-patient variation was reported, it appears that such differences were generally inconsequential. c. Several studies examined the affect of different angles, namely 45 and 90 degrees. In each of these regards, I elaborate below. 1. Patient-to-Patient Variation 34. While it is my understanding that the studies which emulate patient usage encompass patient-to-patient variation (otherwise they would not emulate patient usage), two of the Defendant companies--namely Alcon and Allergan--examined this issue explicitly. 35. Alcon‟s 30(b)(6) witness, Lisa Blackwell, pointed to only one test (in AD_EIKE0001172, which outlined tests that were completed or initiated) where See, e.g., ARGN_0002642 at 2655 (“Previous drop-weight studies showed that most of the variation that occurs in drop weight is due to different delivery techniques among people.”); Arenson Depo., 72:19-74:4, 83:7-88:5; Blackwell Depo., 191:8-192:17. 61 Alcon‟s 30(b)(6) witness Lisa Blackwell stated that there were no formal studies done to compare these differences in factors. Blackwell Depo., 221:7-222:6; Allergan‟s 30(b)(6) witness Lon Spada stated that he believed that there were references to such studies in binders he produced. Spada Depo., 97:19-98:11; However, I have reviewed his deposition exhibits and have found no such references. Spada also testified such studies should have been “in technical packaging reports. Don‟t know if they still have – where those are. It was 14 years ago, whether those exist. But I think as I went through the binder, I saw a reference there to a chart that showed a big variability between, you know, four or five people…” Id. at 98:1-6; Pfizer‟s 30(b)(6) witness Diane Rocco identified how hard a person squeezes the bottle as a factor affecting drop size, but when asked for studies showing that effect, Rocco replied that she meant that it can result in multiple drops being emitted and then identified only temperature, type of liquid and angle as the main variables affecting drop size. Deposition of Diane Rocco (March 13, 2014), 145:2-146:15. Ms. Rocco stated that she believed that Pfizer had done “some development studies looking at drop size relative to temperature refrigerated versus room temperature.” Rocco Depo. 146:24-147:2. However, to my knowledge, Pfizer never produced reports of such studies in this litigation, so it is impossible to evaluate them or to determine what, if anything, those studies (assuming they exist) have to say about the effect of temperature on drop size. 62 Page 17 Eike et al. v. Allergan, Inc. et al. • Expert Report of Brian Kriegler, Ph.D. Case 3:12-cv-01141-SMY-DGW Document 176-6 *SEALED* Filed 12/01/14 Page 21 of 52 Page ID #2287 Case: 16-3334 Document: 55-14 Filed: 02/08/2017 Pages: 52 (303 of 1511) CONFIDENTIAL 5/30/2014 SUBJECT TO PROTECTIVE ORDER there were two different technicians but other conditions (e.g., product, bottle, tip, etc.) were the same. That was a test of Travatan in which one technician obtained an average of 25.38 mg, and the other obtained an average of 26.45 mg. Thus, the difference in weight was 1.07 mg (and 1.05 µL in terms of volume63). My understanding is that this difference is substantively insignificant. 36. Alcon produced another set of drop size results that compared results across multiple technicians.64 This was a comparison of drop sizes using a product called Ciloxan, an older product that may not have been sold in the United States.65 The differences in drop sizes across users were within 5 mg.66 37. Aside from these two studies and among the products in question--one of which is not in Table 1 and not part of my statistical analysis below--Ms. Blackwell could not recall any other Alcon tests comparing two different users of the same product.67 38. In May 2014--after Ms. Blackwell‟s deposition--Alcon produced another set of test results in which drop sizes for Travatan Z were compared across two types of plugs (“current” versus “proposed”).68 Table 1 of such study reports average drop sizes for the current and proposed plugs of 28.6 mg and 26.7 mg, respectively and states that there was a “[s]light difference in average drop size due to variability of dispensing technique.”69 Such document does not indicate how the dispensing technique varied. At most, the estimated average difference, referred to by Alcon as “slight,” is 1.9 mg (1.9 μL in terms of volume70). Indeed, some of the difference of 63 This is calculated based on Azopt‟s density of 1.016 g/mL. See AD_EIKE001283 at 1291. 64 AD EIKE0001167 at 1171. 65 Blackwell Depo., 128:22-130:6. Ms. Blackwell, Alcon‟s 30(b)(6) witness, could not say whether these differences were statistically significant from each other. Blackwell Depo., 130:21-24. 66 67 Blackwell Depo., 131:10-133:13. 68 AD_EIKE001312-1316. 69 Id. (emphasis added). 70 This is calculated based on Travatan Z‟s density of 1.0026 g/mL. See AD_EIKE001283 at 1286. Page 18 Eike et al. v. Allergan, Inc. et al. • Expert Report of Brian Kriegler, Ph.D. Case 3:12-cv-01141-SMY-DGW Document 176-6 *SEALED* Filed 12/01/14 Page 22 of 52 Page ID #2288 Case: 16-3334 Document: 55-14 Filed: 02/08/2017 Pages: 52 (304 of 1511) CONFIDENTIAL 5/30/2014 SUBJECT TO PROTECTIVE ORDER 1.9 μL may well be attributed to the difference in plugs and not have anything to do with dispensing technique. 39. Also in mid-May 2014, Alcon produced a drop size study of Travatan and Timolol GFS 0.5%, in which average drop sizes were compared among three groups of people: men who were at least 50 years old, women who were at least 50 years old, and people less than 40 years old.71 However, the underlying data for this study was not produced, and each subgroup‟s sample size was very small. Without such information, I cannot parse out whether the variation is attributed to the small sample sizes (one group included five individuals; all others included two or three people), a particular user, the method of use (for Timolol GFS 0.5%, two methods were studied), or a handful of statistical outliers.72 Furthermore, there are also a handful of suspicious-looking maximum drop sizes of Timolol GFS 0.5%; for example, among women who are at least 50 years old, the maximum drop size from current and modified use are 149.7 mg and 163.4 mg, respectively. My understanding is that with the existing dispensers, drops of this magnitude are impossible to obtain.73 Accordingly, I include the drop size calculations reported in this study, but I have reservations about what the reported standard deviations represent. 40. Allergan‟s 30(b)(6) witness, Mr. Lon Spada, testified that Allergan had conducted studies to determine the amount of variability in drop size between different consumers. He did not know if the reports of those studies still existed, but he thought there was a reference to a chart in his binder that showed “big variability” among four or five people.74 Mr. Spada produced the contents of two binders that were contained in three deposition exhibits.75 I have reviewed those exhibits, but 71 AD_EIKE001258-1267. Nevertheless, the differences between historical Alcon data and both men and women over 50 years old are 1.7 mg and 0.7 mg, respectively. In other words, these are within the range that, in the study discussed in paragraph 38, above, Alcon characterized as “slight.” See AD_EIKE001312-1316. While the difference between historical Alcon data and people under the age of 40 years old was relatively larger at 2.9 mg, my understanding is that such people are younger than typical glaucoma patients. 72 73 Robin Report, ¶79. 74 Spada Depo., 98:19-99:11. 75 Id., at 169:6-12, 176:11-17; Ex. ARGN_0002745, ARGN_0002858, ARGN_0003197. Page 19 Eike et al. v. Allergan, Inc. et al. • Expert Report of Brian Kriegler, Ph.D. Case 3:12-cv-01141-SMY-DGW Document 176-6 *SEALED* Filed 12/01/14 Page 23 of 52 Page ID #2289 Case: 16-3334 Document: 55-14 Filed: 02/08/2017 Pages: 52 (305 of 1511) CONFIDENTIAL 5/30/2014 SUBJECT TO PROTECTIVE ORDER they do not contain any charts or other information comparing drop sizes from different individuals. However, a number of pages appear to be redacted and state only, “Other Product.”76 These pages all appear after a tab that states, “Drop Size.”77 It is possible that these pages contain the results Mr. Spada was referring to, but at the outset that is something I cannot determine. Because I am unable to evaluate or verify Mr. Spada‟s statement about variability in drop sizes between different individuals, at present there is nothing more I can say about these purported studies and results. If those test results are provided to me, I will review them. 41. In 2005, Allergan conducted tests on Alphagan P using two users (named Anthony and Tung).78 My understanding is that this study entailed three types of bottles (30 µL, 35 µL, and 45 µL)--though Mr. Spada was uncertain if such bottles were sold commercially--and two angles (45 and 90 degrees).79 For the 30 µL bottle, average differences at 45 and 90 degrees across the two users were 6.1 µL and 6.3 µL, respectively. For the other bottles, all other differences across users were less than 2.0 µL. To put these differences in perspective, in at least one other Allergan study, differences of this magnitude were not considered significant.80 More broadly, Mr. Spada could not quantify variability from person to person, other than to say that drop size varies “quite a bit.”81 Without any test results to verify what is meant by “quite a bit,” currently there is nothing more I can say regarding this statement. 42. In summary, to the extent that defendants conducted studies in which they examined patient-to-patient variation, some studies include differences that I understand to be relatively small, some studies include differences that they characterize as slight or 76 Spada Depo., Ex. ARGN_0002745 at 2760-2775. 77 Id., at 2759. 78 ARGN_2428 at 2430. 79 Spada Depo., 121:20-124:13. “[A]n average drop-weight difference…of less than six milligrams is not significant.” (Allergan Technical Memorandum PDD-TM-2002-164, ARGN_002642 at 2658) Such weight equates to approximately 6 µL (Spada Depo., 16:24). The same Allergan Technical Memorandum also states that “a two-milligram difference in means is not practically significant.” ARGN_0002642 at 2658. 80 81 Spada Depo., at 46:18-47:5. Page 20 Eike et al. v. Allergan, Inc. et al. • Expert Report of Brian Kriegler, Ph.D. Case 3:12-cv-01141-SMY-DGW Document 176-6 *SEALED* Filed 12/01/14 Page 24 of 52 Page ID #2290 Case: 16-3334 Document: 55-14 Filed: 02/08/2017 Pages: 52 (306 of 1511) CONFIDENTIAL 5/30/2014 SUBJECT TO PROTECTIVE ORDER insignificant, some studies purportedly exist but to my knowledge have not been produced, and some studies provide incomplete information for me to conduct my own independent statistical analysis. 2. Angle 43. At least two of the defendant companies consider 45 degrees to be the usual position for administering eye drops. Pfizer stated in an application for a CBE-30 to the FTC: “The „normal‟ position when dropping is an inclined angle (45°).”82 Alcon‟s protocol for conducting drop size testing calls for dispensing at 45 degrees because “[i]t is not realistic in most instances to anticipate a patient will hold a bottle absolutely perpendicular to the delivery site while dosing (i.e., 90°).”83 To the extent that the Alcon drop studies did not signify the angle but simulated patient usage, my understanding is that the angle was 45 degrees. 44. That said, a handful of studies tested whether drop sizes varied when administering drops at 45 degrees versus 90 degrees. One Allergan study was expressly designed to show that the angle had no impact,84 and Allergan‟s 30(b)(6) witness agreed that it showed that the drop sizes at two angles were not statistically different. 85 Said report states the following: The drop size study was carried out at two different holding positions, at an inverted position (180 from the normal upright position)…and also at approximately 135 angle holding position to show that the drug position has no impact on the drop size. The different holding angles had no impact on the average drop size for either bottle configuration and the average drop sizes from two angle positions are statistically equivalent.86 82 Ex. Pfizer_Xalatan_00001547 at 1573. 83 AD_EIKE001012 at 1014. 84 ARGN_0003774-3779. 85 Spada Depo., 165:22-167:4. 86 ARGN_0003774 at 3777. Page 21 Eike et al. v. Allergan, Inc. et al. • Expert Report of Brian Kriegler, Ph.D. Case 3:12-cv-01141-SMY-DGW Document 176-6 *SEALED* Filed 12/01/14 Page 25 of 52 Page ID #2291 Case: 16-3334 Document: 55-14 Filed: 02/08/2017 Pages: 52 (307 of 1511) CONFIDENTIAL 5/30/2014 SUBJECT TO PROTECTIVE ORDER 45. As I demonstrate in the next section, the angle does not distinguish whether some of the eye drop would have been wasted using the existing bottles. Looking ahead to Section VI, I incorporate results at all angles into my calculations for estimating Alleged Class-wide Losses; to the extent results at different angles are provided, I use such results by providing a range of possible rates at which eye drops were wasted. V. Analysis of Drop Size Studies (Class-wide Proof of Injury) 46. Defendants‟ studies show a small amount of variability in drop size relative to the average drop size. Such studies suggest that, using the existing container closure systems (dispensers) for each of the products in Table 1, it is highly improbable to obtain a drop of 16 μL or less. Furthermore, Defendants‟ studies demonstrate that it is virtually impossible for a consumer to use a bottle that dispensed an average drop size of 16 μL or less, for any individual bottle. Given Dr. Robin‟s recommendation that “drops be no larger than 16 L on average,”87 it follows that all or virtually all class members paid for a portion of the eye drops that was wasted in every bottle that they purchased. 47. 87 My analysis of defendants‟ individual drop size studies is shown in Exhibit C. In Exhibit C, each row of results corresponds to a distinct analysis (e.g., a particular bottle size, tip, angle, etc.). Some of defendants‟ studies included multiple analyses, and those analyses are shown separately. Exhibit C reveals the following: a. Across all defendants and products, there were 139 distinct drop size analyses. At a minimum, all of defendants‟ drop size studies included an average drop size. b. Across all analyses and all products, the average drop size ranged from 21.9 μL to 60.0 μL. Thus, the differential between the average drop sizes in these analyses and 16 μL is between 5.9 μL and 44.0 μL. c. The standard deviation--a commonly accepted measure of spread of a data distribution--was available in 107 analyses. In such situations, I computed the probability that a single drop (as opposed to the average drop in the bottle) was less than or equal to 16 μL. For 90 of these 107 analyses, the probability Robin Report, ¶17. Page 22 Eike et al. v. Allergan, Inc. et al. • Expert Report of Brian Kriegler, Ph.D. Case 3:12-cv-01141-SMY-DGW Document 176-6 *SEALED* Filed 12/01/14 Page 26 of 52 Page ID #2292 Case: 16-3334 Document: 55-14 Filed: 02/08/2017 Pages: 52 (308 of 1511) CONFIDENTIAL 5/30/2014 SUBJECT TO PROTECTIVE ORDER that a single drop is less than or equal to 16 L is less than 0.0001 (i.e., 1 drop out of 10,000 drops). For the remaining 17 studies, 12 are analyses of Travatan, and 5 are analyses of Timolol GFS 0.5%. With respect to Travatan, the highest probability that a single drop is less than or equal to 16 μL is 7.5 percent. Likewise with respect to Timolol GFS 0.5%, the highest probability that a single drop is less than or equal to 16 μL is 6.8 percent. 48. Next, I combined analyses within each product, first irrespective of the angle (Exhibit D-1), and second for each of the angles separately, to the extent that such studies were performed and angles were specified (Exhibit D-2). Collectively, Exhibits D-1 and D-2 reveal the following: a. Across all defendants and products, the combined average drop size ranged from 24.1 μL to 48.3 μL. Thus, the differential between the combined average drop sizes and 16 μL ranged from 8.1 μL to 32.3 μL. b. When combining studies together, the probability that a single drop is less than or equal to 16 μL is less than 1 percent for all products and less than 0.01 percent for all but two products (Travatan and Timolol GFS 0.5%). c. The above analysis looks only at the likelihood that a single drop is less than or equal to 16 μL. That is different from whether the average drop from any bottle would ever be less than or equal to 16 μL. It is only this question that determines whether a consumer has suffered an injury because of using eye drops that went partially to waste because of their size. d. For each of the existing dispensers and products, the probability that the average drop per bottle is less than or equal to 16 μL is so small that it is virtually 0. Obtaining an average drop size of 16 μL or less would require approximately half of the drops in a bottle to be less than this amount. Even if there is a 10 percent probability that a single drop is less than or equal to 16 μL (which is higher than any of the probabilities shown in Exhibits C, D-1 and D-2), the probability that at least half of the drops are below this amount is less than one out of a trillion. e. Exhibit D-2 shows that for three products--Alphagan P 0.15%, Lumigan 0.03%, and Xalatan--drop sizes were analyzed at 45 and 90 degrees, and Travatan was analyzed at 45, 60, 75, and 90 degrees. With respect to the first three products, the respective average drop sizes at 45 degrees were 3.4 μL Page 23 Eike et al. v. Allergan, Inc. et al. • Expert Report of Brian Kriegler, Ph.D. Case 3:12-cv-01141-SMY-DGW Document 176-6 *SEALED* Filed 12/01/14 Page 27 of 52 Page ID #2293 Case: 16-3334 Document: 55-14 Filed: 02/08/2017 Pages: 52 (309 of 1511) CONFIDENTIAL 5/30/2014 SUBJECT TO PROTECTIVE ORDER lower, 2.5 μL higher,88 and 0.8 μL lower than the average drop sizes at 90 degrees. Thus for two products, estimates are lower at 45 degrees, and for one product, the estimate is lower at 90 degrees. With respect to Travatan, the lowest average drop size was at 45 degrees (25.0 μL) and the highest average drop size was at 90 degrees (30.3 μL). Drop sizes at 60 degrees and 75 degrees were 27.5 μL and 27.2 μL, respectively. None of these differences result in a substantive change in the probability that an eye drop (let alone an average drop per bottle) is less than or equal to 16 μL. VI. Estimation of Alleged Class-wide Losses A. Proposed Methodology 49. 50. For purposes of our calculation of the alleged class-wide losses by each of the proposed classes in the Complaint, Plaintiffs‟ counsel has asked me to consider the feasibility of implementing the following methodology: a. For each of the proposed classes in the Complaint and each product covered by the Complaint, calculate the total amount of sales of eye drops during the proposed class period. b. Use defendant‟s eye drop studies that estimate the difference between the average size of eye drops and a specified benchmark of 16 μL. The percentage difference between the two will represent the amount of medicine wasted, as a percentage of all medicine purchased by the class. c. The amount of money lost by each proposed Class member then will be computed as the total cost of the eye drops paid by Class members (described in 49(a)) multiplied by the amount of medicine wasted (described in 49(b)). For each of the products listed in Table 1, it stands to reason that the average drop size across the whole class falls within the distribution of average drop sizes reported in defendants‟ studies. The same is true about the percentage of medicine wasted because of excessive drop size. This percentage is a function of the average drop size. Thus, I offer three estimates of both the population average drop size and As explained in paragraph 44, above, Allergan found Lumigan 0.03% drop size at 45 (135) and 90 (180) degrees to be statistically equivalent. 88 Page 24 Eike et al. v. Allergan, Inc. et al. • Expert Report of Brian Kriegler, Ph.D. Case 3:12-cv-01141-SMY-DGW Document 176-6 *SEALED* Filed 12/01/14 Page 28 of 52 Page ID #2294 Case: 16-3334 Document: 55-14 Filed: 02/08/2017 Pages: 52 (310 of 1511) CONFIDENTIAL 5/30/2014 SUBJECT TO PROTECTIVE ORDER population percentage of medicine wasted, and such calculations are shown in Exhibit E. One estimate is the average (arithmetic mean) of averages (“Mean Percentage”). This is a natural starting point for purposes of making the class whole. To guard against outliers in each distribution of average percentage of medicine wasted, a second estimate is the median of such averages (“Median Percentage”). If one wished to be especially conservative in terms of making the class whole, one could utilize the minimum of averages (“Minimum Percentage”). At merits, all three of these can be used to assist a trier of fact in determining how best for a class to recover class-wide losses. If need be, a trier of fact is not precluded from applying, for example, a Median Percentage to some subclasses and the Minimum Percentage to other subclasses. 51. Based on the documents I have reviewed to date, my recommendation is to use either the Median Percentage or the Mean Percentage. Here, the Median Percentage and Mean Percentage are substantively similar for each product listed in Table 1, above. In addition, by definition the median is the midpoint of a numerical distribution; thus, the probability of being above or below such estimate is the same. At the outset, I have no basis for speculating that the studies I have relied upon herein should be weighted unevenly in terms of how well they the emulate the amount of medicine wasted among the population of class members. 52. Here I will provide an actual example using the results from Exhibit C. Exhibit C shows 5 analyses of Lumigan 0.01%. The average drop sizes (in microliters) for these five analyses are 23.6, 23.7, 23.9, 24.1, and 25.4. The arithmetic mean of these five averages is 24.1 μL, the median of these five averages is 23.9 μL, and the minimum of these five averages is 23.6 μL. Thus, the Mean Percentage of medicine wasted because of large drop sizes is 33.6 percent, the Median Percentage is 33.1 percent, and the Minimum Percentage is 32.2 percent. 53. Exhibit E includes said calculations in two ways: first irrespective of the angle (Exhibit E-1), and second for each of the angles separately, to the extent that such studies were performed and angles were specified (Exhibit E-2). In both Exhibits E1 and E-2, the Median Percentage and Mean Percentage are almost identical for each glaucoma product, except for two products: Timolol GFS 0.25% and Brimonidine Tartrate 0.2%. Those respective differences are approximately 4.0 percent and 1.6 Page 25 Eike et al. v. Allergan, Inc. et al. • Expert Report of Brian Kriegler, Ph.D. Case 3:12-cv-01141-SMY-DGW Document 176-6 *SEALED* Filed 12/01/14 Page 29 of 52 Page ID #2295 Case: 16-3334 Document: 55-14 Filed: 02/08/2017 Pages: 52 (311 of 1511) CONFIDENTIAL 5/30/2014 SUBJECT TO PROTECTIVE ORDER percent, where in both instances, the Median Percentage is less than the Mean Percentage. Thus, as a general matter, not only is the Median Percentage a reasonable estimate for the percentage of medicine wasted by the class, but in these instances, it is also a conservative estimate compared to the Mean Percentage. 54. As discussed above, for a handful of products, defendants reported average drop sizes at specified angles. For purposes of calculating and allocating class-wide losses, there are a handful of ways to utilize angle-specific results (depending on whether a trier of fact finds that the angle is an important factor). One way is to use estimated drop sizes at 45 degrees, as this is the angle that two companies (Alcon and Pfizer) consider typical.89 For three of the four products with drop size data at specified angles, the average drop size yields a lower, more conservative drop size at 45 degrees. Although drop sizes were higher at 45 degrees for Lumigan 0.03%, Allergan found insignificant differences in drop sizes with respect to angle. A second way is to treat all of the drop size analyses irrespective of the angle, as I have done in Exhibit E-1. A third way is to request patients to self-identify in their claim form the angle at which they instill eye drops, and to use such information as an input to a class member‟s calculated losses. B. Potential Data Sources for Quantifying the Total Purchase Amount 55. There are multiple data sources that would allow me to compute the total purchase amount at the state level. For example: a. 89 Data provided by IMS Health, Inc. (“IMS”) will allow me to compute the total purchase amounts for the various glaucoma drugs at issue. IMS is a company that compiles data relating to the pharmaceutical industry.90 The IMS National Prescription Audit (“NPA”) database contains monthly sales information by drug. This database is a widely-used source of information on retail prescription drug transactions and can be used to calculate both total retail dollars and total retail volume sold during the proposed class period. AD_EIKE001012 at 1014; Pfizer_Xalatan_00001547 at 1573. IMS provides market research on the pharmaceutical industry, including estimated sales of prescription drugs. See IMS Health, available at http://www.imshealth.com. 90 Page 26 Eike et al. v. Allergan, Inc. et al. • Expert Report of Brian Kriegler, Ph.D. Case 3:12-cv-01141-SMY-DGW Document 176-6 *SEALED* Filed 12/01/14 Page 30 of 52 Page ID #2296 Case: 16-3334 Document: 55-14 Filed: 02/08/2017 Pages: 52 (312 of 1511) CONFIDENTIAL 5/30/2014 SUBJECT TO PROTECTIVE ORDER b. Another possible data source is available from Symphony Health Solutions (“SHS”).91 SHS provides market research and analytics regarding pharmaceutical sales and prescription activity. SHS can provide data regarding total retail dollars and total retail volumes sold during the proposed class period. c. A third option is to allow class members to self-identify. Under this approach, the total purchase amount is based on the total purchase amount of class members who submit valid claim forms. VII. Concluding Remarks 56. With respect to the products listed in Table 1, if additional drop size results become available to me, it is a straightforward exercise for me to update my analyses and calculations discussed in Sections V and VI, above. 57. More broadly, my approach for assessing class-wide impact and calculating class-wide losses is transferrable to eye drop products in addition to those listed in Table 1 (e.g., allergy medicines). If drop size measurements and studies pertaining to additional products become available to me, I can conduct an analysis similar to that which I have done herein. 58. Should additional, relevant information become available to me in this litigation, I am open to incorporating it into future calculations and opinions. Brian Kriegler, Ph.D. May 30, 2014 91 See Symphony Health Solutions, available at http://symphonyhealth.com. Page 27 Eike et al. v. Allergan, Inc. et al. • Expert Report of Brian Kriegler, Ph.D. Case 3:12-cv-01141-SMY-DGW Document 176-6 *SEALED* Filed 12/01/14 Page 31 of 52 Page ID #2297 Case: 16-3334 Document: 55-14 Filed: 02/08/2017 Pages: 52 (313 of 1511) EXHIBIT A DR. BRIAN KRIEGLER Statistician Los Angeles, California Tel: 213 624 9600 BRIAN KRIEGLER is a statistician with expertise in statistics, sampling, surveying, econometrics, and data management. He has extensive experience collecting, maintaining, and analyzing data sets in both consulting and academic research capacities. He has authored and co-authored multiple papers and has presented his research to the American Statistical Association, of which he is a member. Dr. Kriegler has given expert testimony as a statistician in litigation proceedings involving civil rights, Medicare fraud, and various employment issues. He also has analyzed large transactional databases and constructed damage models in multiple antitrust class action lawsuits. Specifically in employment cases, Dr. Kriegler has testified about unpaid overtime, off-the-clock claims, punch card rounding, reimbursement, and misclassification. Recently, he consulted with a national restaurant chain to design and analyze a survey for its kitchen managers in order to assess the extent to which they were conducting supervisorial versus non-supervisorial tasks. Those survey results were relied upon for purposes of reaching a settlement in a class action lawsuit relating to misclassification. EDUCATION Ph.D., Statistics, University of California, Los Angeles M.S., Statistics, University of California, Los Angeles B.A., Mathematics-Economics, Claremont McKenna College WORK EXPERIENCE Econ One Research, Inc., Statistician, August 2008 to Date University of Pennsylvania Department of Statistics, Post Doctoral Researcher, 2007 - 2008 UCLA Department of Statistics, Lecturer Statistics 10, Introduction to Statistical Reasoning, Winter 2008 Statistics 130B, Statistical Analysis with SAS, Summer 2007 Case 3:12-cv-01141-SMY-DGW Document 176-6 *SEALED* Filed 12/01/14 Page 32 of 52 Page ID #2298 Case: 16-3334 Document: 55-14 Filed: 02/08/2017 Pages: 52 (314 of 1511) DR. BRIAN KRIEGLER Statistician Self-Employed Statistical Consultant, 2004 - 2008 Claremont McKenna College Reed Institute for Applied Statistics, Post Doctoral Researcher, 2007 RAND Corporation, Summer Associate, 2006 UCLA Department of Statistics, Graduate Student Researcher, 2004 - 2006 UCLA Department of Statistics, Technology Teaching Assistant Coordinator, 2004 - 2005 Lockheed Martin Missiles and Space, Associate Reliability Engineer, 2001 - 2003 INVITED PRESENTATIONS “Cost-Sensitive Boosting: An Estimation Procedure When the Average is Not the Gold Standard,” Claremont McKenna College, Claremont, CA, January 2007. “Counting the Homeless in Los Angeles County,” Joint Statistical Meetings, Seattle, WA, August 2006. “A Southpaw Secret: Are Their Salaries Consistent with Their Contributions to Team Performance?” Claremont McKenna College, Claremont, CA, March 2002. “Mixing Component and System Data in Reliability Assessment,” United States Navy Complex, Washington, DC, July 2001. PUBLISHED ARTICLES & PAPERS “Small Area Estimation of the Homeless Population in Los Angeles County: An Application of Cost-Sensitive Stochastic Gradient Boosting,” Annals of Applied Statistics. Vol. 4 (3), 1234-1255, with Berk, R. “Counting the Homeless in Los Angeles County.” IMS Collections. Probability and Statistics: Essays in Honor of David A. Freedman, Vol. 2. 127-141, with Berk, R. and Ylvisaker, D. “Cost-Sensitive Stochastic Gradient Boosting Within a Quantitative Regression Framework,” Ph.D. Dissertation, Committee Chair: Richard Berk. Portions of this research have been implemented into the “gbm” library in R (open source statistical software) available at www.r-project.org, June 2007. Case 3:12-cv-01141-SMY-DGW Document 176-6 *SEALED* Filed 12/01/14 Page 33 of 52 Page ID #2299 Case: 16-3334 Document: 55-14 Filed: 02/08/2017 Pages: 52 (315 of 1511) DR. BRIAN KRIEGLER Statistician “Forecasting Dangerous Inmate Misconduct: An Application of Ensemble Statistical Procedures.” Journal of Quantitative Criminology, 22(2). 131-145, with Berk, R. and Baek, J.H. “Comparison of Achievement of 8th Graders Who Used the MathScape Curriculum to Those Who Used a More Traditional Curriculum,” Creative Publications, July 2001. “Estimation of Component and System Reliabilities Using Binomial and Exponential Data and Various Test Methods,” Undergraduate Senior Thesis, Chair: Janet Myhre, May 2001. Case 3:12-cv-01141-SMY-DGW Document 176-6 *SEALED* Filed 12/01/14 Page 34 of 52 Page ID #2300 Case: 16-3334 Document: 55-14 Filed: 02/08/2017 Pages: 52 (316 of 1511) Econ One Research, Inc. Los Angeles, California DR. BRIAN KRIEGLER Prior Testimony/Reports Proceeding Court/Commission/Agency Docket or File Deposition/ Trial/Reports Date On Behalf Of Civil Rights 1. Dianna Johnson, et al., v. United States Marshals U.S. District Court, District of Columbia 02-2364 (RMC) Declaration Declaration July 2007 April 2010 Plaintiff 2. Thomas Lee Goldstein v. City of Long Beach, John Henry Miller, William Collette, and Logan Wren U.S. District Court, Central District of California CV 04-9692 AHM (Ex) Expert Report Deposition Declaration November 2009 February 2010 June 2010 Plaintiff 3. Carl A. Barnes, et al., v. District of Columbia U.S. District Court, District of Columbia 06-315 (RCL) Declaration Expert Report Expert Report Deposition Declaration Expert Report Declaration Expert Report Deposition Expert Report Trial March 2010 November 2010 December 2010 December 2010 November 2011 February 2012 March 2012 June 2012 October 2012 November 2012 March 2013 Plaintiff 4. Eric Jones, et al., v. Baltimore City Police Department, et al. U.S. District Court, District of Maryland CCB 05 CV 1287 Declaration Deposition Declaration July 2010 October 2010 January 2011 Plaintiff 5. Mary Amador, et al., v. Sheriff Leroy Baca, et al. U.S. District Court, Central District of California CV 10-1649 SVW (JEMx) Declaration Declaration Declaration Declaration October 2010 January 2011 June 2013 July 2013 Plaintiff Case 3:12-cv-01141-SMY-DGW Document 176-6 *SEALED* Filed 12/01/14 Page 35 of 52 Page ID #2301 Case: 16-3334 Document: 55-14 Filed: 02/08/2017 Pages: 52 (317 of 1511) Econ One Research, Inc. Los Angeles, California DR. BRIAN KRIEGLER Prior Testimony/Reports Docket or File Deposition/ Trial/Reports U.S. District Court, Northern District of Georgia, Atlanta Division 1:04-CV-1100 (RWS) Declaration October 2011 Plaintiff Proceeding Court/Commission/Agency 6. C. Alan Powell, et al., v. Jacqueline H. Barrett, et al. Date On Behalf Of Employment 7. Richard Fairfield, et al., v. Advantage Rent-A-Car Superior Court of the State of California, for the County of Los Angeles BC342461 Declaration Declaration Declaration Deposition Declaration December 2006 February 2007 March 2007 March 2007 May 2007 Plaintiff 8. Elveta Louise Francis, et al., v. State of California Department of Corrections Superior Court of the State of California, for the County of Los Angeles BC302856 Declaration Declaration January 2007 May 2010 Plaintiff 9. David Lubocki, et al., v. ZipRealty, Inc. U.S. District Court, Central District of California CV 07 2959 SJO (JCx) Declaration September 2007 Plaintiff 10. Eric Moore, et al., v. Roadway Express, Inc. et al. U.S. District Court, Central District of California 2:09-CV-01588 RBL (Opx) Declaration May 2010 Plaintiff 11. Maria Martinez, et al., v. Jatco, Inc. Superior Court of the State of California, for the County of Alameda RG08397316 Deposition Trial September 2011 December 2011 Defendant 12. Valerie Alberts, et al., v. Aurora Behavioral Health Care Superior Court of the State of California, for the County of Los Angeles BC419340 Declaration Deposition Deposition Declaration May 2012 July 2012 October 2012 April 2013 Plaintiff Case 3:12-cv-01141-SMY-DGW Document 176-6 *SEALED* Filed 12/01/14 Page 36 of 52 Page ID #2302 Case: 16-3334 Document: 55-14 Filed: 02/08/2017 Pages: 52 (318 of 1511) Econ One Research, Inc. Los Angeles, California DR. BRIAN KRIEGLER Prior Testimony/Reports Proceeding Court/Commission/Agency Docket or File Deposition/ Trial/Reports 13. U.S. District Court, Northern District of California 3:10-cv-04317 SI Declaration Deposition April 2013 May 2013 Plaintiff U.S. District Court, Middle District of Florida 6:10-CV-80628TBS Expert Report Deposition December 2012 February 2013 Plaintiff U.S. Civilian Board of Contract Appeals CBCA 2346FEMA Arbitration Hearing June 2012 Plaintiff Patrick Santiago, et al., v. Amdocs, Inc. Date On Behalf Of False Claims Act 14. U.S. ex rel. Santa Ana v. Winter Park Urology Associates, P.A., et al. Breach of Contract 15. In the Matter of City of Moss Point v. FEMA Consumer Class Actions 16. Christopher O’Shea, et al., v. Epson America, Inc., et al. U.S. District Court, Central District of California CV09-8063 PSG (CWx) Declaration February 2011 Plaintiff 17. Manny Villanueva v. Fidelity National Title Company Superior Court of the State of California, for the County of Santa Clara 1-10-CV173356 Deposition Declaration Deposition Trial March 2014 April 2014 April 2014 April 2014 Plaintiff Case 3:12-cv-01141-SMY-DGW Document 176-6 *SEALED* Filed 12/01/14 Page 37 of 52 Page ID #2303 Case: 16-3334 Document: 55-14 Filed: 02/08/2017 Pages: 52 (319 of 1511) Exhibit B List of Materials Relied Upon by Dr. Brian Kriegler In Eike et al. v. Allergan, Inc. et al. Pleadings and Motions First Amended Class Action Complaint for Damages, Punitive Damages, and Injunctive Relief, 2/22/2013 Expert Reports Expert Report of Alan Robin, M.D., 5/30/2014 Depositions and or Exhibits Arenson, Daniel - 3/14/2014 Blackwell, Lisa - 3/27/2014 Jonasse, Matthew - 3/11/2014 Rocco, Diane - 3/13/2014 Spada, Lon - 3/26/2014 Walker, David - 2/18/2014 Documents with AD_DORZOLAMIDE_EIKE prefix 000603 - 000626 Documents with AD_DORZ-TIM_EIKE prefix 001214 - 001221 001234 - 001235 Documents with AD_EIKE prefix 001012 - 001029 001065 - 001066 001067 - 001068 001069 - 001070 001074 - 001075 001076 - 001077 001078 - 001080 001081 - 001082 001083 - 001084 001085 - 001086 001167 - 001171 001172 - 001190 001250 - 001252 001253 - 001255 001256 - 001257 001258 - 001267 001281 - 001282 001283 - 001294 001295 - 001299 001300 - 001301 001302 - 001303 001304 - 001305 001306 - 001307 001308 - 001309 001310 - 001311 001312 - 001316 001317 - 001317 Page 1 of 3 Econ One 5/30/2014 Case 3:12-cv-01141-SMY-DGW Document 176-6 *SEALED* Filed 12/01/14 Page 38 of 52 Page ID #2304 Case: 16-3334 Document: 55-14 Filed: 02/08/2017 Pages: 52 (320 of 1511) Exhibit B List of Materials Relied Upon by Dr. Brian Kriegler In Eike et al. v. Allergan, Inc. et al. 001318 - 001320 001321 - 001322 001323 - 001324 001325 - 001326 001327 - 001328 001329 - 001330 001331 - 001333 001334 - 001335 Documents with AD_LATANOPROST_EIKE prefix 000121 - 000128 Documents with AD_TRAVATAN_EIKE prefix 000011 - 000015 037989 - 038032 039914 - 039920 041118 - 041123 040560 - 040581 Documents with AD_VIGAMOX_EIKE prefix 016359 - 016372 Documents with ARGN prefix 0000945 - 0001075 0001093 - 0001099 0002352 - 0002389 0002428 - 0002461 0002642 - 0002693 0002745 - 0002857 0002858 - 0002962 0003197 - 0003313 0003774 - 0003779 Documents with ARGN_ALP1 prefix 0001412 - 0004133 Documents with ARGN_COMB prefix 0005644 - 0006222 0010322 - 0010328 0010396 - 0010396 0020527 - 0022362 0022363 - 0029025 0029026 - 0029033 Documents with ARGN_LUM03_ prefix 0005644 - 0006222 Documents with BHLB_BRIM_ prefix Page 2 of 3 Econ One 5/30/2014 Case 3:12-cv-01141-SMY-DGW Document 176-6 *SEALED* Filed 12/01/14 Page 39 of 52 Page ID #2305 Case: 16-3334 Document: 55-14 Filed: 02/08/2017 Pages: 52 (321 of 1511) Exhibit B List of Materials Relied Upon by Dr. Brian Kriegler In Eike et al. v. Allergan, Inc. et al. 0000858 - 0000860 0000900 - 0000906 0001052 - 0001055 0001070 - 0001075 0001076 - 0001134 Documents with NDA_Merck_Prasco prefix 00000328 - 00000353 00009185 - 00009196 00009214 - 00009232 00009660 - 00009696 00010382 - 00010433 Documents with PFIZER_XALATAN_ prefix 00000038 - 00000040 00000093 - 00000096 00000097 - 00000106 00000378 - 00000442 00001531 - 00001546 00001547 - 00001600 00002144 - 00002169 00002495 - 00002512 00010382 - 00010433 00023573 - 00023577 00024279 - 00024280 Documents with Prasco prefix 000001 - 000094 Publicly Available Materials Pfizer Pharmaceutical Company, “2003: Pfizer and Pharmacia Merger,” www.pfizer.com/about/history/pfizer_pharmacia. Drugs@FDA, http://www.accessdata.fda.gov/Scripts/cder/drugsatfda/index.cfm Drugs@FDA, "NDA 20-597/S-025", http://www.accessdata.fda.gov/drugsatfda_docs/label/2002/20597s25lbl.pdf IMS Health, http://www.imshealth.com Symphony Health Solutions, http://symphonyhealth.com Page 3 of 3 Econ One 5/30/2014 Case 3:12-cv-01141-SMY-DGW Document 176-6 *SEALED* Filed 12/01/14 Page 40 of 52 Page ID #2306 Case: 16-3334 Document: 55-14 Filed: 02/08/2017 Pages: 52 Confidential Subject to Protective Order (322 of 1511) EXHIBIT C Analysis of Glaucoma Drop Size Studies and the Probability that a Drop Is Less Than or Equal to 16L Company Product (1) (2) Date of Study Angle of Bottle   or Document   (if available) (3) (4) Mean Drop Size Standard Deviation (if available)   (5) (6) Probability that Any One Drop Size Is ≤ 16 µL1 Source(s) (7) (8) (Microliters) 1. ALCON AZOPT 3/27/2007 45 36.2 2.2 0.0000 2. ALCON AZOPT 3/27/2007 45 34.5 2.9 0.0000 3. ALCON DORZOLAMIDE 2/13/2006 45 47.3 2.9 0.0000 4. ALCON DORZOLAMIDE 7/8/2011 45 36.9 3.1 0.0000 5. ALCON DORZOLAMIDE TIMOLOL 3/22/2007 45 43.8 3.6 0.0000 6. ALCON DORZOLAMIDE TIMOLOL 9/5/2007 45 45.3 3.7 0.0000 7. ALCON LATANOPROST 2/6/2002 45 30.6 N/A N/A 8. ALCON LATANOPROST 9/26/2007 45 28.1 2.2 0.0000 9. ALCON TIMOLOL GFS 0.25% 4/1/1997 45 42.9 4.5 0.0000 AD_EIKE001074; AD_EIKE0001172 AT 1181; BLACKWELL DEPO., 74:21-75:7, 76:22-78:7 AD_EIKE001081; BLACKWELL DEPO., 82:11-84:24 10. ALCON TIMOLOL GFS 0.25% 1/11/2001 45 32.0 3.5 0.0000 AD_EIKE001295 AT 1298 11. ALCON TIMOLOL GFS 0.25% 1/11/2001 45 32.2 2.2 0.0000 AD_EIKE001295 AT 1298 12. ALCON TIMOLOL GFS 0.5% 4/1/1997 45 42.3 5.1 0.0000 AD_EIKE001083; BLACKWELL DEPO., 85:3-85:12 13. ALCON TIMOLOL GFS 0.5% 7/7/2005 45 42.6 4.0 0.0000 14. ALCON TIMOLOL GFS 0.5% 3/2/2009 45 36.1 7.9 0.0057 AD_EIKE001085; AD_EIKE0001172 AT 1177; BLACKWELL DEPO., 85:25-88:10; AD_EIKE001258 AT 1264 15. ALCON TIMOLOL GFS 0.5% 3/2/2009 45 33.4 7.9 0.0145 AD_EIKE001258 AT 1264 16. ALCON TIMOLOL GFS 0.5% 3/2/2009 45 35.3 13.0 0.0678 AD_EIKE001258 AT 1264 17. ALCON TIMOLOL GFS 0.5% 3/2/2009 45 37.9 9.9 0.0136 AD_EIKE001258 AT 1263 18. ALCON TIMOLOL GFS 0.5% 3/2/2009 45 37.6 5.3 0.0000 AD_EIKE001258 AT 1264 19. ALCON TIMOLOL GFS 0.5% 3/2/2009 45 34.2 6.9 0.0039 AD_EIKE001258 AT 1263 Page 1 of 8 AD_EIKE001069; AD_EIKE0001172 AT 1180; AD_EIKE001308; BLACKWELL DEPO., 60:18-63:24 AD_EIKE001067; AD_EIKE0001172 AT 1180; AD_EIKE001323; BLACKWELL DEPO., 53:3-60:2 AD_EIKE0001172 AT 1178; BLACKWELL DEPO., 100:22-101:11 AD_EIKE0001172 AT 1188 AD_EIKE001078; AD EIKE0001172 AT 1180; BLACKWELL DEPO., 79:6-80:21, 102:16-103:14 AD EIKE0001172 AT 1180 AD_EIKE001281 AT 1282 Econ One 5/30/2014 Case 3:12-cv-01141-SMY-DGW Document 176-6 *SEALED* Filed 12/01/14 Page 41 of 52 Page ID #2307 Case: 16-3334 Document: 55-14 Filed: 02/08/2017 Pages: 52 Confidential Subject to Protective Order (323 of 1511) EXHIBIT C Analysis of Glaucoma Drop Size Studies and the Probability that a Drop Is Less Than or Equal to 16L Company Product (1) (2) Date of Study Angle of Bottle   or Document   (if available) (3) (4) Mean Drop Size Standard Deviation (if available)   (5) (6) Probability that Any One Drop Size Is ≤ 16 µL1 Source(s) (7) (8) (Microliters) 20. ALCON TIMOLOL MALEATE 0.5% 4/15/1997 45 30.9 1.8 0.0000 21. ALCON 22. TRAVATAN 2/1/2000 45 27.0 N/A N/A ALCON TRAVATAN 8/23/2001 90 30.3 4.7 0.0010 23. ALCON TRAVATAN 9/19/2001 60 27.5 8.0 0.0754 24. ALCON TRAVATAN 10/15/2001 75 27.2 3.9 0.0024 AD_EIKE001256; AD_EIKE001304; AD_EIKE001325; AD_EIKE0001172 AT 1172; AD_EIKE001306 25. ALCON TRAVATAN 1/11/2002 45 25.7 2.1 0.0000 AD_EIKE001250; AD_EIKE001302 26. ALCON TRAVATAN 2/6/2002 45 27.2 N/A N/A AD_EIKE001281 AT 1282 27. ALCON TRAVATAN 3/7/2002 45 26.0 N/A N/A AD_EIKE0001172 AT 1173 28. ALCON TRAVATAN 3/8/2002 45 25.0 N/A N/A AD_EIKE0001172 AT 1173 29. ALCON TRAVATAN 6/25/2003 45 26.0 N/A N/A 30. ALCON TRAVATAN 12/3/2003 45 26.0 3.8 0.0039 AD_TRAVATAN_EIKE000011 AT 12; BLACKWELL DEPO., 172:12-175:23 AD_EIKE001253 31. ALCON TRAVATAN 2/24/2004 45 25.0 N/A N/A 32. ALCON TRAVATAN 6/30/2004 45 25.8 3.2 0.0013 33. ALCON TRAVATAN 10/24/2007 45 25.5 1.2 0.0000 34. ALCON TRAVATAN 1/18/2008 45 23.7 2.6 0.0014 AD_EIKE001321; AD_EIKE0001172 AT 1181; BLACKWELL DEPO., 103:15-20 AD_EIKE001331 35. ALCON TRAVATAN 1/18/2008 45 22.7 3.1 0.0139 AD_EIKE001318 36. ALCON TRAVATAN 2/5/2008 45 26.0 1.7 0.0000 AD_EIKE001300; AD_EIKE1334 37. ALCON TRAVATAN 6/4/2008 45 21.9 3.2 0.0315 AD_EIKE001317 38. ALCON TRAVATAN 6/4/2008 45 23.7 2.6 0.0013 AD_EIKE001317 Page 2 of 8 AD_EIKE001076; BLACKWELL DEPO., 78:11-22 AD_TRAVATAN_EIKE037989 AT 37996; BLACKWELL DEPO., 162:9-164:4; WOOLDRIDGE AD_EIKE001310 AD_TRAVATAN_EIKE039914 AT 39918; BLACKWELL DEPO., 157:9-23 AD_EIKE001327 Econ One 5/30/2014 Case 3:12-cv-01141-SMY-DGW Document 176-6 *SEALED* Filed 12/01/14 Page 42 of 52 Page ID #2308 Case: 16-3334 Document: 55-14 Filed: 02/08/2017 Pages: 52 Confidential Subject to Protective Order (324 of 1511) EXHIBIT C Analysis of Glaucoma Drop Size Studies and the Probability that a Drop Is Less Than or Equal to 16L Company Product (1) (2) Date of Study Angle of Bottle   or Document   (if available) (3) (4) Mean Drop Size Standard Deviation (if available)   (5) (6) Probability that Any One Drop Size Is ≤ 16 µL1 Source(s) (7) (8) (Microliters) 39. ALCON TRAVATAN 3/2/2009 45 23.1 2.2 0.0005 AD_EIKE001258 AT 1262 40. ALCON TRAVATAN 3/2/2009 45 25.3 2.7 0.0002 AD_EIKE001258 AT 1262 41. ALCON TRAVATAN 3/2/2009 45 24.3 5.4 0.0622 AD_EIKE001258 AT 1262 42. ALCON TRAVATAN Z 8/11/2004 45 28.8 3.1 0.0000 AD_EIKE001329 43. ALCON TRAVATAN Z 6/13/2005 45 28.5 1.5 0.0000 AD_EIKE001312 AT 1313 44. ALCON TRAVATAN Z 9/21/2006 45 28.7 3.1 0.0000 AD_TRAVATAN_EIKE041118 AT 41122 45. ALCON TRAVATAN Z 3/21/2007 45 31.3 0.8 0.0000 46. ALCON TRAVATAN Z 10/24/2007 45 26.6 1.2 0.0000 47. ALCON VIGAMOX 11/15/2001 45 37.8 3.2 0.0000 48. ALLERGAN ALPHAGAN P 0.1% 5/24/2004 N/A 35.0 N/A N/A 49. ALLERGAN ALPHAGAN P 0.15% 4/4/2002 45 43.1 1.1 0.0000 50. ALLERGAN ALPHAGAN P 0.15% 4/4/2002 90 45.6 1.4 0.0000 51. ALLERGAN ALPHAGAN P 0.15% 11/7/2002 45 44.7 N/A N/A 52. ALLERGAN ALPHAGAN P 0.15% 11/7/2002 45 42.7 N/A N/A 53. ALLERGAN ALPHAGAN P 0.15% 11/7/2002 45 42.7 N/A N/A 54. ALLERGAN ALPHAGAN P 0.15% 11/7/2002 45 39.7 N/A N/A 55. ALLERGAN ALPHAGAN P 0.15% 11/7/2002 90 42.7 N/A N/A 56. ALLERGAN ALPHAGAN P 0.15% 11/7/2002 90 44.7 N/A N/A 57. ALLERGAN ALPHAGAN P 0.15% 11/7/2002 90 44.7 N/A N/A AD_EIKE0001172 AT 1180; BLACKWELL DEPO., 102:1-15 AD_EIKE001312 AT 1315; AD_EIKE0001172 AT 1181; BLACKWELL DEPO., 103:15-20 AD_EIKE001065; AD_EIKE0001172 AT 1173; BLACKWELL DEPO., 42:20-52:21; ARGN_ALP1_0001412 AT 1415; CHARBONNEAU DEPO., 73:3-74:24 ARGN_0001093 AT 1095; SPADA DEPO., 111:24114:21 ARGN_0001093 AT 1095; SPADA DEPO., 111:24114:21 ARGN_0002642 AT 2659; SPADA DEPO., 103:11111:23 ARGN_0002642 AT 2659; SPADA DEPO., 103:11111:23 ARGN_0002642 AT 2659; SPADA DEPO., 103:11111:23 ARGN_0002642 AT 2659; SPADA DEPO., 103:11111:23 ARGN_0002642 AT 2659; SPADA DEPO., 103:11111:23 ARGN_0002642 AT 2659; SPADA DEPO., 103:11111:23 ARGN_0002642 AT 2659; SPADA DEPO., 103:11111:23 Page 3 of 8 Econ One 5/30/2014 Case 3:12-cv-01141-SMY-DGW Document 176-6 *SEALED* Filed 12/01/14 Page 43 of 52 Page ID #2309 Case: 16-3334 Document: 55-14 Filed: 02/08/2017 Pages: 52 Confidential Subject to Protective Order (325 of 1511) EXHIBIT C Analysis of Glaucoma Drop Size Studies and the Probability that a Drop Is Less Than or Equal to 16L Company Product (1) (2) Date of Study Angle of Bottle   or Document   (if available) (3) (4) Mean Drop Size Standard Deviation (if available)   (5) (6) Probability that Any One Drop Size Is ≤ 16 µL1 Source(s) (7) (8) (Microliters) 58. ALLERGAN ALPHAGAN P 0.15% 11/7/2002 90 45.7 N/A N/A 59. ALLERGAN ALPHAGAN P 0.15% 4/16/2003 45 37.9 0.8 0.0000 60. ALLERGAN ALPHAGAN P 0.15% 4/16/2003 90 40.5 0.6 0.0000 61. ALLERGAN ALPHAGAN P 0.15% 8/29/2005 45 39.6 1.4 0.0000 62. ALLERGAN ALPHAGAN P 0.15% 8/29/2005 45 40.8 1.4 0.0000 63. ALLERGAN ALPHAGAN P 0.15% 8/29/2005 45 39.1 1.7 0.0000 64. ALLERGAN ALPHAGAN P 0.15% 8/29/2005 45 33.1 1.9 0.0000 65. ALLERGAN ALPHAGAN P 0.15% 8/29/2005 45 49.4 2.1 0.0000 66. ALLERGAN ALPHAGAN P 0.15% 8/29/2005 45 51.1 1.4 0.0000 67. ALLERGAN ALPHAGAN P 0.15% 8/29/2005 90 39.0 1.3 0.0000 68. ALLERGAN ALPHAGAN P 0.15% 8/29/2005 90 58.3 2.9 0.0000 69. ALLERGAN ALPHAGAN P 0.15% 8/29/2005 90 45.1 1.8 0.0000 70. ALLERGAN ALPHAGAN P 0.15% 8/29/2005 90 32.8 1.8 0.0000 71. ALLERGAN ALPHAGAN P 0.15% 8/29/2005 90 60.0 1.5 0.0000 72. ALLERGAN ALPHAGAN P 0.15% 8/29/2005 90 46.1 1.3 0.0000 73. ALLERGAN COMBIGAN 1/14/2000 N/A 35.0 N/A N/A 74. ALLERGAN COMBIGAN 8/9/2004 N/A 35.0 N/A N/A 75. ALLERGAN COMBIGAN 6/24/2006 N/A 35.0 N/A N/A 76. ALLERGAN COMBIGAN 4/27/2007 N/A 35.0 N/A N/A Page 4 of 8 ARGN_0002642 AT 2659; SPADA DEPO., 103:11111:23 ARGN_0002352 AT 2353; SPADA DEPO., 116:24120:5 ARGN_0002352 AT 2353; SPADA DEPO., 116:24120:5 ARGN_0002428 AT 2431; SPADA DEPO., 120:7123:13 ARGN_0002428 AT 2430; SPADA DEPO., 120:7123:13 ARGN_0002428 AT 2430; SPADA DEPO., 120:7123:13 ARGN_0002428 AT 2431; SPADA DEPO., 120:7123:13 ARGN_0002428 AT 2431; SPADA DEPO., 120:7123:13 ARGN_0002428 AT 2430; SPADA DEPO., 120:7123:13 ARGN_0002428 AT 2430; SPADA DEPO., 120:7123:13 ARGN_0002428 AT 2431; SPADA DEPO., 120:7123:13 ARGN_0002428 AT 2431; SPADA DEPO., 120:7123:13 ARGN_0002428 AT 2431; SPADA DEPO., 120:7123:13 ARGN_0002428 AT 2430; SPADA DEPO., 120:7123:13 ARGN_0002428 AT 2430; SPADA DEPO., 120:7123:13 ARGN_COMB_0029026 AT 29029; CHARBONNEAU DEPO., 120:23-122:20, 135:12-23 ARGN_COMB_0020527 AT 20531 CHARBONNEAU DEPO., 122:21-24:3, 135:12-23 ARGN_COMB_0010322 AT 10396; CHARBONNEAU DEPO., 124:4-126:10, 135:12-23 ARGN_COMB_0022363 AT 22434; CHARBONNEAU DEPO., 126:11-127:11, 135:12-23 Econ One 5/30/2014 Case 3:12-cv-01141-SMY-DGW Document 176-6 *SEALED* Filed 12/01/14 Page 44 of 52 Page ID #2310 Case: 16-3334 Document: 55-14 Filed: 02/08/2017 Pages: 52 Confidential Subject to Protective Order (326 of 1511) EXHIBIT C Analysis of Glaucoma Drop Size Studies and the Probability that a Drop Is Less Than or Equal to 16L Company Product (1) (2) Date of Study Angle of Bottle   or Document   (if available) (3) (4) Mean Drop Size Standard Deviation (if available)   (5) (6) Probability that Any One Drop Size Is ≤ 16 µL1 Source(s) (7) (8) (Microliters) 77. ALLERGAN LUMIGAN 0.01% 2/9/2007 N/A 23.6 1.3 0.0000 78. ALLERGAN LUMIGAN 0.01% 2/9/2007 N/A 23.7 1.2 0.0000 79. ALLERGAN LUMIGAN 0.01% 2/9/2007 N/A 23.9 1.1 0.0000 80. ALLERGAN LUMIGAN 0.01% 2/9/2007 N/A 24.1 1.1 0.0000 81. ALLERGAN LUMIGAN 0.01% 2/9/2007 N/A 25.4 1.0 0.0000 82. ALLERGAN LUMIGAN 0.03% 9/25/2001 45 30.0 1.0 0.0000 83. ALLERGAN LUMIGAN 0.03% 9/25/2001 90 26.2 0.4 0.0000 84. ALLERGAN LUMIGAN 0.03% 9/25/2001 90 26.3 0.4 0.0000 85. ALLERGAN LUMIGAN 0.03% 9/25/2001 90 25.5 0.6 0.0000 86. ALLERGAN LUMIGAN 0.03% 6/28/2002 45 27.4 1.6 0.0000 87. ALLERGAN LUMIGAN 0.03% 6/28/2002 90 26.7 1.4 0.0000 88. BRIMONIDINE TARTRATE 0.2% 4/26/2001 N/A 35.0 N/A N/A BRIMONIDINE TARTRATE 0.2% 7/14/2003 N/A 38.2 1.6 0.0000 BRIMONIDINE TARTRATE 0.2% 7/24/2003 N/A 32.4 N/A N/A BRIMONIDINE TARTRATE 0.2% 7/24/2003 N/A 32.0 N/A N/A BRIMONIDINE TARTRATE 0.2% 7/24/2003 N/A 30.7 N/A N/A 93. BAUSCH & LOMB BAUSCH & LOMB BAUSCH & LOMB BAUSCH & LOMB BAUSCH & LOMB MERCK COSOPT 7/9/2003 N/A 34.5 N/A N/A 94. MERCK COSOPT 9/28/2011 N/A 42.4 N/A N/A 95. MERCK TIMOPTIC 7/9/2003 N/A 34.5 N/A N/A 89. 90. 91. 92. Page 5 of 8 ARGN_0000945 AT 983-984; ARGN_LUM01_0000001 AT 11; SPADA DEPO., 148:24-151:16 ARGN_0000945 AT 983-984; ARGN_LUM01_0000001 AT 11; SPADA DEPO., 148:24-151:16 ARGN_0000945 AT 983-984; ARGN_LUM01_0000001 AT 11; SPADA DEPO., 148:24-151:16 ARGN_0000945 AT 983-984; ARGN_LUM01_0000001 AT 11; SPADA DEPO., 148:24-151:16 ARGN_0000945 AT 983-984; ARGN_LUM01_0000001 AT 11; SPADA DEPO., 148:24-151:16 ARGN_LUM03_0005644 AT 5900; SPADA DEPO., 153:13-158:2 ARGN_LUM03_0005644 AT 5900; SPADA DEPO., 153:13-158:2 ARGN_LUM03_0005644 AT 5900; SPADA DEPO., 153:13-158:2 ARGN_LUM03_0005644 AT 5900; SPADA DEPO., 153:13-158:2 ARGN_0003774 AT 3778; SPADA DEPO., 163:12168:5 ARGN_0003774 AT 3778; SPADA DEPO., 163:12168:5 BHLB_BRIM_0001070 AT 1072 BHLB_BRIM_0000858 BHLB_BRIM_0000900 AT 903; JONASSE DEPO., 85:4-102:23 BHLB_BRIM_0000900 AT 903; JONASSE DEPO., 85:4-102:23 BHLB_BRIM_0000900 AT 903; JONASSE DEPO., 85:4-102:23 NDA_MERCK_PRASCO 00009660 AT 9692; WALKER DEPO., 167:6-173:9; GROSSMAN DEPO., PRASCO 000001 AT 93; WALKER DEPO., 178:17196:21 NDA_MERCK_PRASCO 00009660 AT 9692 Econ One 5/30/2014 Case 3:12-cv-01141-SMY-DGW Document 176-6 *SEALED* Filed 12/01/14 Page 45 of 52 Page ID #2311 Case: 16-3334 Document: 55-14 Filed: 02/08/2017 Pages: 52 Confidential Subject to Protective Order (327 of 1511) EXHIBIT C Analysis of Glaucoma Drop Size Studies and the Probability that a Drop Is Less Than or Equal to 16L Company Product (1) (2) Date of Study Angle of Bottle   or Document   (if available) (3) (4) Mean Drop Size Standard Deviation (if available)   (5) (6) Probability that Any One Drop Size Is ≤ 16 µL1 Source(s) (7) (8) (Microliters) 96. MERCK TIMOPTIC XE 2/10/2006 N/A 48.3 6.4 0.0000 97. MERCK 98. TRUSOPT 7/9/2003 N/A 35.7 N/A N/A MERCK TRUSOPT 5/4/2007 N/A 46.4 5.9 0.0000 99. PFIZER XALATAN 11/2/1995 N/A 30.0 N/A N/A 100. PFIZER XALATAN 1/25/2002 45 29.1 0.7 0.0000 101. PFIZER XALATAN 1/25/2002 45 28.6 1.2 0.0000 102. PFIZER XALATAN 1/25/2002 45 25.4 1.4 0.0000 103. PFIZER XALATAN 1/25/2002 90 29.9 0.8 0.0000 104. PFIZER XALATAN 1/25/2002 90 29.4 0.8 0.0000 105. PFIZER XALATAN 1/25/2002 90 24.8 1.1 0.0000 106. PFIZER XALATAN 5/30/2002 N/A 28.3 1.0 0.0000 107. PFIZER XALATAN 5/30/2002 N/A 29.6 0.6 0.0000 108. PFIZER XALATAN 1/1/2008 N/A 30.0 N/A N/A PFIZER_XALATAN_00000378 AT 427; ROCCO DEPO., 30:11-33:5 PFIZER_XALATAN_00001547 AT 1576; ROCCO DEPO., 71:24-74:25 PFIZER_XALATAN_00001547 AT 1575; ROCCO DEPO., 71:24-74:25 PFIZER_XALATAN_00001547 AT 1577; ROCCO DEPO., 71:24-74:25 PFIZER_XALATAN_00001547 AT 1576; ROCCO DEPO., 71:24-74:25 PFIZER_XALATAN_00001547 AT 1575; ROCCO DEPO., 71:24-74:25 PFIZER_XALATAN_00001547 AT 1577; ROCCO DEPO., 71:24-74:25 PFIZER_XALATAN_00023573 AT 23575; ROCCO DEPO., 76:16-79:25 PFIZER_XALATAN_00023573 AT 23575; ROCCO DEPO., 76:16-79:25 PFLZER_XALATAN_00000038 AT 39 109. PFIZER XALATAN 1/1/2008 N/A 30.0 N/A N/A PFLZER_XALATAN_00000038 AT 39 110. PFIZER XALATAN 1/1/2008 N/A 30.0 N/A N/A PFLZER_XALATAN_00000038 AT 39 111. PFIZER XALATAN 5/7/2008 45 28.6 1.2 0.0000 112. PFIZER XALATAN 5/7/2008 45 29.1 1.1 0.0000 Page 6 of 8 AD_EIKE0001172 AT 1178; BLACKWELL DEPO., 99:8:100:3 NDA_MERCK_PRASCO 00009660 AT 9692 AD_DORZOLAMIDE_EIKE000603 AT 624 PFIZER_XALATAN_00000093 AT 95; PFIZER_XALATAN_00002144 AT 2160; ROCCO PFIZER_XALATAN_00000093 AT 94; PFIZER_XALATAN_00002144 AT 2160; ROCCO Econ One 5/30/2014 Case 3:12-cv-01141-SMY-DGW Document 176-6 *SEALED* Filed 12/01/14 Page 46 of 52 Page ID #2312 Case: 16-3334 Document: 55-14 Filed: 02/08/2017 Pages: 52 Confidential Subject to Protective Order (328 of 1511) EXHIBIT C Analysis of Glaucoma Drop Size Studies and the Probability that a Drop Is Less Than or Equal to 16L Company Product (1) (2) Date of Study Angle of Bottle   or Document   (if available) (3) (4) Mean Drop Size Standard Deviation (if available)   (5) (6) Probability that Any One Drop Size Is ≤ 16 µL1 Source(s) (7) (8) (Microliters) 113. PFIZER XALATAN 5/7/2008 90 29.4 0.8 0.0000 114. PFIZER XALATAN 5/7/2008 90 27.5 1.1 0.0000 115. PFIZER XALATAN 5/13/2011 N/A 28.1 0.2 0.0000 116. PFIZER XALATAN 5/13/2011 N/A 29.8 0.8 0.0000 117. PFIZER XALATAN 5/13/2011 N/A 28.5 0.3 0.0000 118. PFIZER XALATAN 5/13/2011 N/A 29.8 1.3 0.0000 119. PFIZER XALATAN 11/8/2012 N/A 27.7 1.0 0.0000 120. PFIZER XALATAN 11/8/2012 N/A 25.2 0.8 0.0000 121. PFIZER XALATAN 11/8/2012 N/A 28.1 0.3 0.0000 122. PFIZER XALATAN 11/8/2012 N/A 27.6 0.9 0.0000 123. PFIZER XALATAN 11/8/2012 N/A 27.5 0.5 0.0000 124. PFIZER XALATAN 11/8/2012 N/A 28.2 0.2 0.0000 125. PFIZER XALATAN 11/8/2012 N/A 25.9 1.3 0.0000 126. PFIZER XALATAN 11/8/2012 45 28.5 0.4 0.0000 127. PFIZER XALATAN 11/8/2012 45 27.6 0.4 0.0000 128. PFIZER XALATAN 11/8/2012 45 28.0 0.3 0.0000 129. PFIZER XALATAN 11/8/2012 45 28.1 0.7 0.0000 130. PFIZER XALATAN 11/8/2012 45 28.4 0.8 0.0000 131. PFIZER XALATAN 11/8/2012 45 29.9 0.7 0.0000 Page 7 of 8 PFIZER_XALATAN_00000093 AT 96; PFIZER_XALATAN_00002144 AT 2160; ROCCO PFIZER_XALATAN_00000093 AT 95; PFIZER_XALATAN_00002144 AT 2160; ROCCO PFIZER_XALATAN_00000097 AT 102; ROCCO DEPO., 117:2-120:4 PFIZER_XALATAN_00000097 AT 100; ROCCO DEPO., 117:2-120:4 PFIZER_XALATAN_00000097 AT 102; ROCCO DEPO., 117:2-120:4 PFIZER_XALATAN_00000097 AT 99; ROCCO DEPO., 117:2-120:4 PFIZER_XALATAN_0002495 AT 2504; ROCCO DEPO., 151:5-155:18 PFIZER_XALATAN_0002495 AT 2504; ROCCO DEPO., 151:5-155:18 PFIZER_XALATAN_0002495 AT 2504; ROCCO DEPO., 151:5-155:18 PFIZER_XALATAN_0002495 AT 2504; ROCCO DEPO., 151:5-155:18 PFIZER_XALATAN_0002495 AT 2504; ROCCO DEPO., 151:5-155:18 PFIZER_XALATAN_0002495 AT 2504; ROCCO DEPO., 151:5-155:18 PFIZER_XALATAN_0002495 AT 2504; ROCCO DEPO., 151:5-155:18 PFIZER_XALATAN_0002495 AT 2503; ROCCO DEPO., 151:5-155:18 PFIZER_XALATAN_0002495 AT 2503; ROCCO DEPO., 151:5-155:18 PFIZER_XALATAN_0002495 AT 2503; ROCCO DEPO., 151:5-155:18 PFIZER_XALATAN_0002495 AT 2503; ROCCO DEPO., 151:5-155:18 PFIZER_XALATAN_0002495 AT 2502; ROCCO DEPO., 151:5-155:18 PFIZER_XALATAN_0002495 AT 2502; ROCCO DEPO., 151:5-155:18 Econ One 5/30/2014 Case 3:12-cv-01141-SMY-DGW Document 176-6 *SEALED* Filed 12/01/14 Page 47 of 52 Page ID #2313 Case: 16-3334 Document: 55-14 Filed: 02/08/2017 Pages: 52 Confidential Subject to Protective Order (329 of 1511) EXHIBIT C Analysis of Glaucoma Drop Size Studies and the Probability that a Drop Is Less Than or Equal to 16L Company Product (1) (2) Date of Study Angle of Bottle   or Document   (if available) (3) (4) Mean Drop Size Standard Deviation (if available)   (5) (6) Probability that Any One Drop Size Is ≤ 16 µL1 Source(s) (7) (8) (Microliters) 132. PFIZER XALATAN 11/8/2012 45 29.0 0.9 0.0000 133. PFIZER XALATAN 11/8/2012 90 29.6 0.3 0.0000 134. PFIZER XALATAN 11/8/2012 90 29.8 0.8 0.0000 135. PFIZER XALATAN 11/8/2012 90 30.2 0.7 0.0000 136. PFIZER XALATAN 11/8/2012 90 30.6 0.6 0.0000 137. PFIZER XALATAN 11/8/2012 90 29.8 1.3 0.0000 138. PFIZER XALATAN 11/8/2012 90 30.1 0.5 0.0000 139. PFIZER XALATAN 11/8/2012 90 29.2 0.7 0.0000 1 PFIZER_XALATAN_0002495 AT 2502; DEPO., 151:5-155:18 PFIZER_XALATAN_0002495 AT 2503; DEPO., 151:5-155:18 PFIZER_XALATAN_0002495 AT 2503; DEPO., 151:5-155:18 PFIZER_XALATAN_0002495 AT 2503; DEPO., 151:5-155:18 PFIZER_XALATAN_0002495 AT 2503; DEPO., 151:5-155:18 PFIZER_XALATAN_0002495 AT 2503; DEPO., 151:5-155:18 PFIZER_XALATAN_0002495 AT 2504; DEPO., 151:5-155:18 PFIZER_XALATAN_0002495 AT 2503; DEPO., 151:5-155:18 ROCCO ROCCO ROCCO ROCCO ROCCO ROCCO ROCCO ROCCO This is the probability that any one single drop in a given bottle is ≤ 16 µL. This is not the probability that the average drop size for any given bottle is ≤ 16 µL. Page 8 of 8 Econ One 5/30/2014 Case 3:12-cv-01141-SMY-DGW Document 176-6 *SEALED* Filed 12/01/14 Page 48 of 52 Confidential Page ID #2314 Case: 16-3334 Document: 55-14 Filed: 02/08/2017 Pages: 52 (330Order of 1511) Subject to Protective EXHIBIT D-1 Analysis of Glaucoma Drop Size Studies and the Probability that a Drop Is Less Than or Equal to 16L For Each Combination of Company and Glaucoma Product Company Product Number of   Analyses   (1) (2) (3) Combined Drop Size Across Analyses Standard Deviation (if available) Mean   (4) Probability that Any One Drop Size Is ≤ 16 µL1 (5) (6) (Microliters) 1. 2. 3. 4. 5. 6. 7. 8. 9. 10. 11. 12. 13. 14. 15. 16. 17. 18. 19. 20. 21. ALCON ALCON ALCON ALCON ALCON ALCON ALCON ALCON ALCON ALCON ALLERGAN ALLERGAN ALLERGAN ALLERGAN ALLERGAN BAUSCH & LOMB MERCK MERCK MERCK MERCK PFIZER 1 1 AZOPT DORZOLAMIDE DORZOLAMIDE TIMOLOL LATANOPROST TIMOLOL GFS 0.25% TIMOLOL GFS 0.5% TIMOLOL MALEATE 0.5% TRAVATAN TRAVATAN Z VIGAMOX ALPHAGAN P 0.1% ALPHAGAN P 0.15% COMBIGAN LUMIGAN 0.01% LUMIGAN 0.03% BRIMONIDINE TARTRATE 0.2% COSOPT TIMOPTIC TIMOPTIC XE TRUSOPT XALATAN 2 2 2 2 3 8 1 21 5 1 1 24 4 5 6 5 2 1 1 2 41 35.3 42.1 44.5 29.4 35.7 37.4 30.9 25.5 28.8 37.8 35.0 43.7 35.0 24.1 27.0 33.7 38.5 34.5 48.3 41.1 28.7 2.6 3.0 3.7 2.2 3.5 8.0 1.8 3.7 2.2 3.2 N/A 1.6 N/A 1.1 1.0 1.6 N/A N/A 6.4 5.9 0.8 0.0000 0.0000 0.0000 0.0000 0.0000 0.0036 0.0000 0.0055 0.0000 0.0000 N/A 0.0000 N/A 0.0000 0.0000 0.0000 N/A N/A 0.0000 0.0000 0.0000 This is the probability that any one single drop in a given bottle is less than or equal to 16 µL. This is not the probability that the average drop size for a given bottle is less than or equal to 16 µL. Sources: See Exhibit C, Column 8. Econ One 5/30/2014 Case 3:12-cv-01141-SMY-DGW Document 176-6 *SEALED* Filed 12/01/14 Page 49 of 52 Confidential Page ID #2315 Case: 16-3334 Document: 55-14 Filed: 02/08/2017 Pages: 52 (331Order of 1511) Subject to Protective EXHIBIT D-2 Analysis of Glaucoma Drop Size Studies and the Probability that a Drop Is Less Than or Equal to 16L For Each Combination of Company, Glaucoma Product, and Angle Company Product (1) (2) Angle of Bottle   (if available) (3) Number of Analyses (4) Combined Drop Size Across Analyses Standard Deviation Mean (if available)   (5) (6) Probability that Any One Drop Size Is ≤ 16 µL1 (7) (Microliters) 1. 2. 3. 4. 5. 6. 7. 8. 9. 10. 11. 12. 13. 14. 15. 16. 17. 18. 19. 20. 21. 22. 23. 24. 25. ALCON ALCON ALCON ALCON ALCON ALCON ALCON ALCON ALCON ALCON ALCON ALCON ALCON ALLERGAN ALLERGAN ALLERGAN ALLERGAN ALLERGAN ALLERGAN ALLERGAN BAUSCH & LOMB MERCK MERCK MERCK MERCK AZOPT DORZOLAMIDE DORZOLAMIDE TIMOLOL LATANOPROST TIMOLOL GFS 0.25% TIMOLOL GFS 0.5% TIMOLOL MALEATE 0.5% TRAVATAN TRAVATAN TRAVATAN TRAVATAN TRAVATAN Z VIGAMOX ALPHAGAN P 0.1% ALPHAGAN P 0.15% ALPHAGAN P 0.15% COMBIGAN LUMIGAN 0.01% LUMIGAN 0.03% LUMIGAN 0.03% BRIMONIDINE TARTRATE 0.2% COSOPT TIMOPTIC TIMOPTIC XE TRUSOPT 45 45 45 45 45 45 45 45 60 75 90 45 45 N/A 45 90 N/A N/A 45 90 N/A N/A N/A N/A N/A 2 2 2 2 3 8 1 18 1 1 1 5 1 1 12 12 4 5 2 4 5 2 1 1 2 35.3 42.1 44.5 29.4 35.7 37.4 30.9 25.0 27.5 27.2 30.3 28.8 37.8 35.0 42.0 45.4 35.0 24.1 28.7 26.2 33.7 38.5 34.5 48.3 41.1 2.6 3.0 3.7 2.2 3.5 8.0 1.8 3.0 8.0 3.9 4.7 2.2 3.2 N/A 1.5 1.7 N/A 1.1 1.3 0.8 1.6 N/A N/A 6.4 5.9 0.0000 0.0000 0.0000 0.0000 0.0000 0.0036 0.0000 0.0013 0.0754 0.0024 0.0010 0.0000 0.0000 N/A 0.0000 0.0000 N/A 0.0000 0.0000 0.0000 0.0000 N/A N/A 0.0000 0.0000 Econ One 5/30/2014 Case 3:12-cv-01141-SMY-DGW Document 176-6 *SEALED* Filed 12/01/14 Page 50 of 52 Confidential Page ID #2316 Case: 16-3334 Document: 55-14 Filed: 02/08/2017 Pages: 52 (332Order of 1511) Subject to Protective EXHIBIT D-2 Analysis of Glaucoma Drop Size Studies and the Probability that a Drop Is Less Than or Equal to 16L For Each Combination of Company, Glaucoma Product, and Angle Company Product (1) (2) Angle of Bottle   (if available) (3) Number of Analyses Combined Drop Size Across Analyses Standard Deviation Mean (if available)   (4) (5) (6) Probability that Any One Drop Size Is ≤ 16 µL1 (7) (Microliters) 26. 27. 28. PFIZER PFIZER PFIZER XALATAN XALATAN XALATAN 1 1 N/A 45 90 17 12 12 28.5 28.4 29.2 0.8 0.9 0.8 0.0000 0.0000 0.0000 This is the probability that any one single drop in a given bottle is less than or equal to 16 µL. This is not the probability that the average drop size for a given bottle is less than or equal to 16 µL. Sources: See Exhibit C, Column 8. Econ One 5/30/2014 Case 3:12-cv-01141-SMY-DGW Document 176-6 *SEALED* Filed 12/01/14 Page 51 of 52 Page ID #2317 Case: 16-3334 Document: 55-14 Filed: 02/08/2017 Pages: 52 Confidential Subject to Protective (333Order of 1511) EXHIBIT E-1 Estimates of the Percentage of Medicine Wasted For Each Combination of Company and Glaucoma Product Summary Statistics of the Average Drop Size 1. 2. 3. 4. 5. 6. 7. 8. 9. 10. 11. 12. 13. 14. 15. 16. 17. 18. 19. 20. 21. Company Product (1) (2) ALCON ALCON ALCON ALCON ALCON ALCON ALCON ALCON ALCON ALCON ALLERGAN ALLERGAN ALLERGAN ALLERGAN ALLERGAN BAUSCH & LOMB MERCK MERCK MERCK MERCK PFIZER AZOPT DORZOLAMIDE DORZOLAMIDE TIMOLOL LATANOPROST TIMOLOL GFS 0.25% TIMOLOL GFS 0.5% TIMOLOL MALEATE 0.5% TRAVATAN TRAVATAN Z VIGAMOX ALPHAGAN P 0.1% ALPHAGAN P 0.15% COMBIGAN LUMIGAN 0.01% LUMIGAN 0.03% BRIMONIDINE TARTRATE 0.2% COSOPT TIMOPTIC TIMOPTIC XE TRUSOPT XALATAN Number of Averages Calculated   (3) 2 2 2 2 3 8 1 21 5 1 1 24 4 5 6 5 2 1 1 2 41 Percentage of Medicine Wasted Minimum Median Mean Minimum Median Mean (4) (5) (Microliters) (6) [(4) - 16] / (4) (7) [(5) - 16] / (5) (8) (Percent) [(6) - 16] / (6) (9) 34.5 36.9 43.8 28.1 32.0 33.4 30.9 21.9 26.6 37.8 35.0 32.8 35.0 23.6 25.5 30.7 34.5 34.5 48.3 35.7 24.8 35.3 42.1 44.5 29.4 32.2 36.8 30.9 25.7 28.7 37.8 35.0 42.9 35.0 23.9 26.5 32.4 38.5 34.5 48.3 41.1 29.0 35.3 42.1 44.5 29.4 35.7 37.4 30.9 25.5 28.8 37.8 35.0 43.7 35.0 24.1 27.0 33.7 38.5 34.5 48.3 41.1 28.7 53.6 % 56.6 63.5 43.2 50.0 52.0 48.2 26.8 39.9 57.7 54.3 51.2 54.3 32.2 37.3 47.9 53.6 53.6 66.9 55.2 35.5 54.7 % 61.4 64.1 45.5 50.3 56.6 48.2 37.8 44.3 57.7 54.3 62.7 54.3 33.1 39.6 50.6 57.9 53.6 66.9 60.3 44.8 54.7 % 61.4 64.1 45.5 54.3 56.9 48.2 36.9 44.3 57.7 54.3 62.7 54.3 33.7 40.6 52.2 57.9 53.6 66.9 60.3 44.0 Sources: See Exhibit C, Column 8. Econ One 5/30/2014 Case 3:12-cv-01141-SMY-DGW Document 176-6 *SEALED* Filed 12/01/14 Page 52 of 52 Page ID #2318 Case: 16-3334 Document: 55-14 Filed: 02/08/2017 Pages: 52 Confidential Subject to Protective (334Order of 1511) EXHIBIT E-2 Estimates of the Percentage of Medicine Wasted For Each Combination of Company, Glaucoma Product, and Angle Summary Statistics of the Average Drop Size 1. 2. 3. 4. 5. 6. 7. 8. 9. 10. 11. 12. 13. 14. 15. 16. 17. 18. 19. 20. 21. 22. 23. 24. 25. 26. 27. 28. Company Product (1) (2) ALCON ALCON ALCON ALCON ALCON ALCON ALCON ALCON ALCON ALCON ALCON ALCON ALCON ALLERGAN ALLERGAN ALLERGAN ALLERGAN ALLERGAN ALLERGAN ALLERGAN BAUSCH & LOMB MERCK MERCK MERCK MERCK PFIZER PFIZER PFIZER AZOPT DORZOLAMIDE DORZOLAMIDE TIMOLOL LATANOPROST TIMOLOL GFS 0.25% TIMOLOL GFS 0.5% TIMOLOL MALEATE 0.5% TRAVATAN TRAVATAN TRAVATAN TRAVATAN TRAVATAN Z VIGAMOX ALPHAGAN P 0.1% ALPHAGAN P 0.15% ALPHAGAN P 0.15% COMBIGAN LUMIGAN 0.01% LUMIGAN 0.03% LUMIGAN 0.03% BRIMONIDINE TARTRATE 0.2% COSOPT TIMOPTIC TIMOPTIC XE TRUSOPT XALATAN XALATAN XALATAN Angle of Bottle   (if available) (3) Number of Averages Calculated   (4) 45 45 45 45 45 45 45 45 60 75 90 45 45 N/A 45 90 N/A N/A 45 90 N/A N/A N/A N/A N/A N/A 45 90 2 2 2 2 3 8 1 18 1 1 1 5 1 1 12 12 4 5 2 4 5 2 1 1 2 17 12 12 Percentage of Medicine Wasted Minimum Median Mean Minimum Median Mean (5) (6) (Microliters) (7) [(5) - 16] / (5) (8) [(6) - 16] / (6) (9) (Percent) [(7) - 16] / (7) (10) 34.5 36.9 43.8 28.1 32.0 33.4 30.9 21.9 27.5 27.2 30.3 26.6 37.8 35.0 33.1 32.8 35.0 23.6 27.4 25.5 30.7 34.5 34.5 48.3 35.7 25.2 25.4 24.8 35.3 42.1 44.5 29.4 32.2 36.8 30.9 25.4 27.5 27.2 30.3 28.7 37.8 35.0 41.8 44.9 35.0 23.9 28.7 26.3 32.4 38.5 34.5 48.3 41.1 28.3 28.6 29.7 35.3 42.1 44.5 29.4 35.7 37.4 30.9 25.0 27.5 27.2 30.3 28.8 37.8 35.0 42.0 45.4 35.0 24.1 28.7 26.2 33.7 38.5 34.5 48.3 41.1 28.5 28.4 29.2 53.6 % 56.6 63.5 43.2 50.0 52.0 48.2 26.8 41.9 41.1 47.3 39.9 57.7 54.3 51.6 51.2 54.3 32.2 41.6 37.3 47.9 53.6 53.6 66.9 55.2 36.5 37.0 35.5 54.7 % 61.4 64.1 45.5 50.3 56.6 48.2 37.0 41.9 41.1 47.3 44.3 57.7 54.3 61.7 64.4 54.3 33.1 44.1 39.0 50.6 57.9 53.6 66.9 60.3 43.5 44.0 46.1 54.7 % 61.4 64.1 45.5 54.3 56.9 48.2 35.8 41.9 41.1 47.3 44.3 57.7 54.3 61.4 63.9 54.3 33.7 44.1 38.9 52.2 57.9 53.6 66.9 60.3 43.7 43.5 45.0 Sources: See Exhibit C, Column 8. Econ One 5/30/2014 Case 3:12-cv-01141-SMY-DGW Document 176-31 *SEALED* Filed 12/01/14 Page 1 of 85 Page ID #2889 Case: 16-3334 Document: 55-15 Filed: 02/08/2017 Pages: 85 (335 of 1511) Case 3:12-cv-01141-SMY-DGW Document 176-31 *SEALED* Filed 12/01/14 Page 2 of 85 Page ID #2890 Case: 16-3334 Document: 55-15 Filed: 02/08/2017 Pages: 85 (336 of 1511) Case 3:12-cv-01141-SMY-DGW Document 176-31 *SEALED* Filed 12/01/14 Page 3 of 85 Page ID #2891 Case: 16-3334 Document: 55-15 Filed: 02/08/2017 Pages: 85 (337 of 1511) Case 3:12-cv-01141-SMY-DGW Document 176-31 *SEALED* Filed 12/01/14 Page 4 of 85 Page ID #2892 Case: 16-3334 Document: 55-15 Filed: 02/08/2017 Pages: 85 (338 of 1511) Case 3:12-cv-01141-SMY-DGW Document 176-31 *SEALED* Filed 12/01/14 Page 5 of 85 Page ID #2893 Case: 16-3334 Document: 55-15 Filed: 02/08/2017 Pages: 85 (339 of 1511) Case 3:12-cv-01141-SMY-DGW Document 176-31 *SEALED* Filed 12/01/14 Page 6 of 85 Page ID #2894 Case: 16-3334 Document: 55-15 Filed: 02/08/2017 Pages: 85 (340 of 1511) Case 3:12-cv-01141-SMY-DGW Document 176-31 *SEALED* Filed 12/01/14 Page 7 of 85 Page ID #2895 Case: 16-3334 Document: 55-15 Filed: 02/08/2017 Pages: 85 (341 of 1511) Case 3:12-cv-01141-SMY-DGW Document 176-31 *SEALED* Filed 12/01/14 Page 8 of 85 Page ID #2896 Case: 16-3334 Document: 55-15 Filed: 02/08/2017 Pages: 85 (342 of 1511) Case 3:12-cv-01141-SMY-DGW Document 176-31 *SEALED* Filed 12/01/14 Page 9 of 85 Page ID #2897 Case: 16-3334 Document: 55-15 Filed: 02/08/2017 Pages: 85 (343 of 1511) Case 3:12-cv-01141-SMY-DGW Document 176-31 *SEALED* Filed 12/01/14 Page 10 of 85 Page ID #2898 Case: 16-3334 Document: 55-15 Filed: 02/08/2017 Pages: 85 (344 of 1511) Case 3:12-cv-01141-SMY-DGW Document 176-31 *SEALED* Filed 12/01/14 Page 11 of 85 Page ID #2899 Case: 16-3334 Document: 55-15 Filed: 02/08/2017 Pages: 85 (345 of 1511) Case 3:12-cv-01141-SMY-DGW Document 176-31 *SEALED* Filed 12/01/14 Page 12 of 85 Page ID #2900 Case: 16-3334 Document: 55-15 Filed: 02/08/2017 Pages: 85 (346 of 1511) Case 3:12-cv-01141-SMY-DGW Document 176-31 *SEALED* Filed 12/01/14 Page 13 of 85 Page ID #2901 Case: 16-3334 Document: 55-15 Filed: 02/08/2017 Pages: 85 (347 of 1511) Case 3:12-cv-01141-SMY-DGW Document 176-31 *SEALED* Filed 12/01/14 Page 14 of 85 Page ID #2902 Case: 16-3334 Document: 55-15 Filed: 02/08/2017 Pages: 85 (348 of 1511) Case 3:12-cv-01141-SMY-DGW Document 176-31 *SEALED* Filed 12/01/14 Page 15 of 85 Page ID #2903 Case: 16-3334 Document: 55-15 Filed: 02/08/2017 Pages: 85 (349 of 1511) Case 3:12-cv-01141-SMY-DGW Document 176-31 *SEALED* Filed 12/01/14 Page 16 of 85 Page ID #2904 Case: 16-3334 Document: 55-15 Filed: 02/08/2017 Pages: 85 (350 of 1511) Case 3:12-cv-01141-SMY-DGW Document 176-31 *SEALED* Filed 12/01/14 Page 17 of 85 Page ID #2905 Case: 16-3334 Document: 55-15 Filed: 02/08/2017 Pages: 85 (351 of 1511) Case 3:12-cv-01141-SMY-DGW Document 176-31 *SEALED* Filed 12/01/14 Page 18 of 85 Page ID #2906 Case: 16-3334 Document: 55-15 Filed: 02/08/2017 Pages: 85 (352 of 1511) Case 3:12-cv-01141-SMY-DGW Document 176-31 *SEALED* Filed 12/01/14 Page 19 of 85 Page ID #2907 Case: 16-3334 Document: 55-15 Filed: 02/08/2017 Pages: 85 (353 of 1511) Case 3:12-cv-01141-SMY-DGW Document 176-31 *SEALED* Filed 12/01/14 Page 20 of 85 Page ID #2908 Case: 16-3334 Document: 55-15 Filed: 02/08/2017 Pages: 85 (354 of 1511) Case 3:12-cv-01141-SMY-DGW Document 176-31 *SEALED* Filed 12/01/14 Page 21 of 85 Page ID #2909 Case: 16-3334 Document: 55-15 Filed: 02/08/2017 Pages: 85 (355 of 1511) Case 3:12-cv-01141-SMY-DGW Document 176-31 *SEALED* Filed 12/01/14 Page 22 of 85 Page ID #2910 Case: 16-3334 Document: 55-15 Filed: 02/08/2017 Pages: 85 (356 of 1511) Case 3:12-cv-01141-SMY-DGW Document 176-31 *SEALED* Filed 12/01/14 Page 23 of 85 Page ID #2911 Case: 16-3334 Document: 55-15 Filed: 02/08/2017 Pages: 85 (357 of 1511) Case 3:12-cv-01141-SMY-DGW Document 176-31 *SEALED* Filed 12/01/14 Page 24 of 85 Page ID #2912 Case: 16-3334 Document: 55-15 Filed: 02/08/2017 Pages: 85 (358 of 1511) Case 3:12-cv-01141-SMY-DGW Document 176-31 *SEALED* Filed 12/01/14 Page 25 of 85 Page ID #2913 Case: 16-3334 Document: 55-15 Filed: 02/08/2017 Pages: 85 (359 of 1511) Case 3:12-cv-01141-SMY-DGW Document 176-31 *SEALED* Filed 12/01/14 Page 26 of 85 Page ID #2914 Case: 16-3334 Document: 55-15 Filed: 02/08/2017 Pages: 85 (360 of 1511) Case 3:12-cv-01141-SMY-DGW Document 176-31 *SEALED* Filed 12/01/14 Page 27 of 85 Page ID #2915 Case: 16-3334 Document: 55-15 Filed: 02/08/2017 Pages: 85 (361 of 1511) Case 3:12-cv-01141-SMY-DGW Document 176-31 *SEALED* Filed 12/01/14 Page 28 of 85 Page ID #2916 Case: 16-3334 Document: 55-15 Filed: 02/08/2017 Pages: 85 (362 of 1511) Case 3:12-cv-01141-SMY-DGW Document 176-31 *SEALED* Filed 12/01/14 Page 29 of 85 Page ID #2917 Case: 16-3334 Document: 55-15 Filed: 02/08/2017 Pages: 85 (363 of 1511) Case 3:12-cv-01141-SMY-DGW Document 176-31 *SEALED* Filed 12/01/14 Page 30 of 85 Page ID #2918 Case: 16-3334 Document: 55-15 Filed: 02/08/2017 Pages: 85 (364 of 1511) Case 3:12-cv-01141-SMY-DGW Document 176-31 *SEALED* Filed 12/01/14 Page 31 of 85 Page ID #2919 Case: 16-3334 Document: 55-15 Filed: 02/08/2017 Pages: 85 (365 of 1511) Case 3:12-cv-01141-SMY-DGW Document 176-31 *SEALED* Filed 12/01/14 Page 32 of 85 Page ID #2920 Case: 16-3334 Document: 55-15 Filed: 02/08/2017 Pages: 85 (366 of 1511) Case 3:12-cv-01141-SMY-DGW Document 176-31 *SEALED* Filed 12/01/14 Page 33 of 85 Page ID #2921 Case: 16-3334 Document: 55-15 Filed: 02/08/2017 Pages: 85 (367 of 1511) Case 3:12-cv-01141-SMY-DGW Document 176-31 *SEALED* Filed 12/01/14 Page 34 of 85 Page ID #2922 Case: 16-3334 Document: 55-15 Filed: 02/08/2017 Pages: 85 (368 of 1511) Case 3:12-cv-01141-SMY-DGW Document 176-31 *SEALED* Filed 12/01/14 Page 35 of 85 Page ID #2923 Case: 16-3334 Document: 55-15 Filed: 02/08/2017 Pages: 85 (369 of 1511) Case 3:12-cv-01141-SMY-DGW Document 176-31 *SEALED* Filed 12/01/14 Page 36 of 85 Page ID #2924 Case: 16-3334 Document: 55-15 Filed: 02/08/2017 Pages: 85 (370 of 1511) Case 3:12-cv-01141-SMY-DGW Document 176-31 *SEALED* Filed 12/01/14 Page 37 of 85 Page ID #2925 Case: 16-3334 Document: 55-15 Filed: 02/08/2017 Pages: 85 (371 of 1511) Case 3:12-cv-01141-SMY-DGW Document 176-31 *SEALED* Filed 12/01/14 Page 38 of 85 Page ID #2926 Case: 16-3334 Document: 55-15 Filed: 02/08/2017 Pages: 85 (372 of 1511) Case 3:12-cv-01141-SMY-DGW Document 176-31 *SEALED* Filed 12/01/14 Page 39 of 85 Page ID #2927 Case: 16-3334 Document: 55-15 Filed: 02/08/2017 Pages: 85 (373 of 1511) Case 3:12-cv-01141-SMY-DGW Document 176-31 *SEALED* Filed 12/01/14 Page 40 of 85 Page ID #2928 Case: 16-3334 Document: 55-15 Filed: 02/08/2017 Pages: 85 (374 of 1511) Case 3:12-cv-01141-SMY-DGW Document 176-31 *SEALED* Filed 12/01/14 Page 41 of 85 Page ID #2929 Case: 16-3334 Document: 55-15 Filed: 02/08/2017 Pages: 85 (375 of 1511) Case 3:12-cv-01141-SMY-DGW Document 176-31 *SEALED* Filed 12/01/14 Page 42 of 85 Page ID #2930 Case: 16-3334 Document: 55-15 Filed: 02/08/2017 Pages: 85 (376 of 1511) Case 3:12-cv-01141-SMY-DGW Document 176-31 *SEALED* Filed 12/01/14 Page 43 of 85 Page ID #2931 Case: 16-3334 Document: 55-15 Filed: 02/08/2017 Pages: 85 (377 of 1511) Case 3:12-cv-01141-SMY-DGW Document 176-31 *SEALED* Filed 12/01/14 Page 44 of 85 Page ID #2932 Case: 16-3334 Document: 55-15 Filed: 02/08/2017 Pages: 85 (378 of 1511) Case 3:12-cv-01141-SMY-DGW Document 176-31 *SEALED* Filed 12/01/14 Page 45 of 85 Page ID #2933 Case: 16-3334 Document: 55-15 Filed: 02/08/2017 Pages: 85 (379 of 1511) Case 3:12-cv-01141-SMY-DGW Document 176-31 *SEALED* Filed 12/01/14 Page 46 of 85 Page ID #2934 Case: 16-3334 Document: 55-15 Filed: 02/08/2017 Pages: 85 (380 of 1511) Case 3:12-cv-01141-SMY-DGW Document 176-31 *SEALED* Filed 12/01/14 Page 47 of 85 Page ID #2935 Case: 16-3334 Document: 55-15 Filed: 02/08/2017 Pages: 85 (381 of 1511) Case 3:12-cv-01141-SMY-DGW Document 176-31 *SEALED* Filed 12/01/14 Page 48 of 85 Page ID #2936 Case: 16-3334 Document: 55-15 Filed: 02/08/2017 Pages: 85 (382 of 1511) Case 3:12-cv-01141-SMY-DGW Document 176-31 *SEALED* Filed 12/01/14 Page 49 of 85 Page ID #2937 Case: 16-3334 Document: 55-15 Filed: 02/08/2017 Pages: 85 (383 of 1511) Case 3:12-cv-01141-SMY-DGW Document 176-31 *SEALED* Filed 12/01/14 Page 50 of 85 Page ID #2938 Case: 16-3334 Document: 55-15 Filed: 02/08/2017 Pages: 85 (384 of 1511) Case 3:12-cv-01141-SMY-DGW Document 176-31 *SEALED* Filed 12/01/14 Page 51 of 85 Page ID #2939 Case: 16-3334 Document: 55-15 Filed: 02/08/2017 Pages: 85 (385 of 1511) Case 3:12-cv-01141-SMY-DGW Document 176-31 *SEALED* Filed 12/01/14 Page 52 of 85 Page ID #2940 Case: 16-3334 Document: 55-15 Filed: 02/08/2017 Pages: 85 (386 of 1511) Case 3:12-cv-01141-SMY-DGW Document 176-31 *SEALED* Filed 12/01/14 Page 53 of 85 Page ID #2941 Case: 16-3334 Document: 55-15 Filed: 02/08/2017 Pages: 85 (387 of 1511) Case 3:12-cv-01141-SMY-DGW Document 176-31 *SEALED* Filed 12/01/14 Page 54 of 85 Page ID #2942 Case: 16-3334 Document: 55-15 Filed: 02/08/2017 Pages: 85 (388 of 1511) Case 3:12-cv-01141-SMY-DGW Document 176-31 *SEALED* Filed 12/01/14 Page 55 of 85 Page ID #2943 Case: 16-3334 Document: 55-15 Filed: 02/08/2017 Pages: 85 (389 of 1511) Case 3:12-cv-01141-SMY-DGW Document 176-31 *SEALED* Filed 12/01/14 Page 56 of 85 Page ID #2944 Case: 16-3334 Document: 55-15 Filed: 02/08/2017 Pages: 85 (390 of 1511) Case 3:12-cv-01141-SMY-DGW Document 176-31 *SEALED* Filed 12/01/14 Page 57 of 85 Page ID #2945 Case: 16-3334 Document: 55-15 Filed: 02/08/2017 Pages: 85 (391 of 1511) Case 3:12-cv-01141-SMY-DGW Document 176-31 *SEALED* Filed 12/01/14 Page 58 of 85 Page ID #2946 Case: 16-3334 Document: 55-15 Filed: 02/08/2017 Pages: 85 (392 of 1511) Case 3:12-cv-01141-SMY-DGW Document 176-31 *SEALED* Filed 12/01/14 Page 59 of 85 Page ID #2947 Case: 16-3334 Document: 55-15 Filed: 02/08/2017 Pages: 85 (393 of 1511) Case 3:12-cv-01141-SMY-DGW Document 176-31 *SEALED* Filed 12/01/14 Page 60 of 85 Page ID #2948 Case: 16-3334 Document: 55-15 Filed: 02/08/2017 Pages: 85 (394 of 1511) Case 3:12-cv-01141-SMY-DGW Document 176-31 *SEALED* Filed 12/01/14 Page 61 of 85 Page ID #2949 Case: 16-3334 Document: 55-15 Filed: 02/08/2017 Pages: 85 (395 of 1511) Case 3:12-cv-01141-SMY-DGW Document 176-31 *SEALED* Filed 12/01/14 Page 62 of 85 Page ID #2950 Case: 16-3334 Document: 55-15 Filed: 02/08/2017 Pages: 85 (396 of 1511) Case 3:12-cv-01141-SMY-DGW Document 176-31 *SEALED* Filed 12/01/14 Page 63 of 85 Page ID #2951 Case: 16-3334 Document: 55-15 Filed: 02/08/2017 Pages: 85 (397 of 1511) Case 3:12-cv-01141-SMY-DGW Document 176-31 *SEALED* Filed 12/01/14 Page 64 of 85 Page ID #2952 Case: 16-3334 Document: 55-15 Filed: 02/08/2017 Pages: 85 (398 of 1511) Case 3:12-cv-01141-SMY-DGW Document 176-31 *SEALED* Filed 12/01/14 Page 65 of 85 Page ID #2953 Case: 16-3334 Document: 55-15 Filed: 02/08/2017 Pages: 85 (399 of 1511) Case 3:12-cv-01141-SMY-DGW Document 176-31 *SEALED* Filed 12/01/14 Page 66 of 85 Page ID #2954 Case: 16-3334 Document: 55-15 Filed: 02/08/2017 Pages: 85 (400 of 1511) Case 3:12-cv-01141-SMY-DGW Document 176-31 *SEALED* Filed 12/01/14 Page 67 of 85 Page ID #2955 Case: 16-3334 Document: 55-15 Filed: 02/08/2017 Pages: 85 (401 of 1511) Case 3:12-cv-01141-SMY-DGW Document 176-31 *SEALED* Filed 12/01/14 Page 68 of 85 Page ID #2956 Case: 16-3334 Document: 55-15 Filed: 02/08/2017 Pages: 85 (402 of 1511) Case 3:12-cv-01141-SMY-DGW Document 176-31 *SEALED* Filed 12/01/14 Page 69 of 85 Page ID #2957 Case: 16-3334 Document: 55-15 Filed: 02/08/2017 Pages: 85 (403 of 1511) Case 3:12-cv-01141-SMY-DGW Document 176-31 *SEALED* Filed 12/01/14 Page 70 of 85 Page ID #2958 Case: 16-3334 Document: 55-15 Filed: 02/08/2017 Pages: 85 (404 of 1511) Case 3:12-cv-01141-SMY-DGW Document 176-31 *SEALED* Filed 12/01/14 Page 71 of 85 Page ID #2959 Case: 16-3334 Document: 55-15 Filed: 02/08/2017 Pages: 85 (405 of 1511) Case 3:12-cv-01141-SMY-DGW Document 176-31 *SEALED* Filed 12/01/14 Page 72 of 85 Page ID #2960 Case: 16-3334 Document: 55-15 Filed: 02/08/2017 Pages: 85 (406 of 1511) Case 3:12-cv-01141-SMY-DGW Document 176-31 *SEALED* Filed 12/01/14 Page 73 of 85 Page ID #2961 Case: 16-3334 Document: 55-15 Filed: 02/08/2017 Pages: 85 (407 of 1511) Case 3:12-cv-01141-SMY-DGW Document 176-31 *SEALED* Filed 12/01/14 Page 74 of 85 Page ID #2962 Case: 16-3334 Document: 55-15 Filed: 02/08/2017 Pages: 85 (408 of 1511) Case 3:12-cv-01141-SMY-DGW Document 176-31 *SEALED* Filed 12/01/14 Page 75 of 85 Page ID #2963 Case: 16-3334 Document: 55-15 Filed: 02/08/2017 Pages: 85 (409 of 1511) Case 3:12-cv-01141-SMY-DGW Document 176-31 *SEALED* Filed 12/01/14 Page 76 of 85 Page ID #2964 Case: 16-3334 Document: 55-15 Filed: 02/08/2017 Pages: 85 (410 of 1511) Case 3:12-cv-01141-SMY-DGW Document 176-31 *SEALED* Filed 12/01/14 Page 77 of 85 Page ID #2965 Case: 16-3334 Document: 55-15 Filed: 02/08/2017 Pages: 85 (411 of 1511) Case 3:12-cv-01141-SMY-DGW Document 176-31 *SEALED* Filed 12/01/14 Page 78 of 85 Page ID #2966 Case: 16-3334 Document: 55-15 Filed: 02/08/2017 Pages: 85 (412 of 1511) Case 3:12-cv-01141-SMY-DGW Document 176-31 *SEALED* Filed 12/01/14 Page 79 of 85 Page ID #2967 Case: 16-3334 Document: 55-15 Filed: 02/08/2017 Pages: 85 (413 of 1511) Case 3:12-cv-01141-SMY-DGW Document 176-31 *SEALED* Filed 12/01/14 Page 80 of 85 Page ID #2968 Case: 16-3334 Document: 55-15 Filed: 02/08/2017 Pages: 85 (414 of 1511) Case 3:12-cv-01141-SMY-DGW Document 176-31 *SEALED* Filed 12/01/14 Page 81 of 85 Page ID #2969 Case: 16-3334 Document: 55-15 Filed: 02/08/2017 Pages: 85 (415 of 1511) Case 3:12-cv-01141-SMY-DGW Document 176-31 *SEALED* Filed 12/01/14 Page 82 of 85 Page ID #2970 Case: 16-3334 Document: 55-15 Filed: 02/08/2017 Pages: 85 (416 of 1511) Case 3:12-cv-01141-SMY-DGW Document 176-31 *SEALED* Filed 12/01/14 Page 83 of 85 Page ID #2971 Case: 16-3334 Document: 55-15 Filed: 02/08/2017 Pages: 85 (417 of 1511) Case 3:12-cv-01141-SMY-DGW Document 176-31 *SEALED* Filed 12/01/14 Page 84 of 85 Page ID #2972 Case: 16-3334 Document: 55-15 Filed: 02/08/2017 Pages: 85 (418 of 1511) Case 3:12-cv-01141-SMY-DGW Document 176-31 *SEALED* Filed 12/01/14 Page 85 of 85 Page ID #2973 Case: 16-3334 Document: 55-15 Filed: 02/08/2017 Pages: 85 (419 of 1511) Case 3:12-cv-01141-SMY-DGW Document 176-54 *SEALED* Filed 12/01/14 Page 1 of 116 Page ID #3496 Case: 16-3334 Document: 55-16 Filed: 02/08/2017 Pages: 116 (420 of 1511) Case 3:12-cv-01141-SMY-DGW Document 176-54 *SEALED* Filed 12/01/14 Page 2 of 116 Page ID #3497 Case: 16-3334 Document: 55-16 Filed: 02/08/2017 Pages: 116 (421 of 1511) Case 3:12-cv-01141-SMY-DGW Document 176-54 *SEALED* Filed 12/01/14 Page 3 of 116 Page ID #3498 Case: 16-3334 Document: 55-16 Filed: 02/08/2017 Pages: 116 (422 of 1511) Case 3:12-cv-01141-SMY-DGW Document 176-54 *SEALED* Filed 12/01/14 Page 4 of 116 Page ID #3499 Case: 16-3334 Document: 55-16 Filed: 02/08/2017 Pages: 116 (423 of 1511) Case 3:12-cv-01141-SMY-DGW Document 176-54 *SEALED* Filed 12/01/14 Page 5 of 116 Page ID #3500 Case: 16-3334 Document: 55-16 Filed: 02/08/2017 Pages: 116 (424 of 1511) Case 3:12-cv-01141-SMY-DGW Document 176-54 *SEALED* Filed 12/01/14 Page 6 of 116 Page ID #3501 Case: 16-3334 Document: 55-16 Filed: 02/08/2017 Pages: 116 (425 of 1511) Case 3:12-cv-01141-SMY-DGW Document 176-54 *SEALED* Filed 12/01/14 Page 7 of 116 Page ID #3502 Case: 16-3334 Document: 55-16 Filed: 02/08/2017 Pages: 116 (426 of 1511) Case 3:12-cv-01141-SMY-DGW Document 176-54 *SEALED* Filed 12/01/14 Page 8 of 116 Page ID #3503 Case: 16-3334 Document: 55-16 Filed: 02/08/2017 Pages: 116 (427 of 1511) Case 3:12-cv-01141-SMY-DGW Document 176-54 *SEALED* Filed 12/01/14 Page 9 of 116 Page ID #3504 Case: 16-3334 Document: 55-16 Filed: 02/08/2017 Pages: 116 (428 of 1511) Case 3:12-cv-01141-SMY-DGW Document 176-54 *SEALED* Filed 12/01/14 Page 10 of 116 Page ID #3505 Case: 16-3334 Document: 55-16 Filed: 02/08/2017 Pages: 116 (429 of 1511) Case 3:12-cv-01141-SMY-DGW Document 176-54 *SEALED* Filed 12/01/14 Page 11 of 116 Page ID #3506 Case: 16-3334 Document: 55-16 Filed: 02/08/2017 Pages: 116 (430 of 1511) Case 3:12-cv-01141-SMY-DGW Document 176-54 *SEALED* Filed 12/01/14 Page 12 of 116 Page ID #3507 Case: 16-3334 Document: 55-16 Filed: 02/08/2017 Pages: 116 (431 of 1511) Case 3:12-cv-01141-SMY-DGW Document 176-54 *SEALED* Filed 12/01/14 Page 13 of 116 Page ID #3508 Case: 16-3334 Document: 55-16 Filed: 02/08/2017 Pages: 116 (432 of 1511) Case 3:12-cv-01141-SMY-DGW Document 176-54 *SEALED* Filed 12/01/14 Page 14 of 116 Page ID #3509 Case: 16-3334 Document: 55-16 Filed: 02/08/2017 Pages: 116 (433 of 1511) Case 3:12-cv-01141-SMY-DGW Document 176-54 *SEALED* Filed 12/01/14 Page 15 of 116 Page ID #3510 Case: 16-3334 Document: 55-16 Filed: 02/08/2017 Pages: 116 (434 of 1511) Case 3:12-cv-01141-SMY-DGW Document 176-54 *SEALED* Filed 12/01/14 Page 16 of 116 Page ID #3511 Case: 16-3334 Document: 55-16 Filed: 02/08/2017 Pages: 116 (435 of 1511) Case 3:12-cv-01141-SMY-DGW Document 176-54 *SEALED* Filed 12/01/14 Page 17 of 116 Page ID #3512 Case: 16-3334 Document: 55-16 Filed: 02/08/2017 Pages: 116 (436 of 1511) Case 3:12-cv-01141-SMY-DGW Document 176-54 *SEALED* Filed 12/01/14 Page 18 of 116 Page ID #3513 Case: 16-3334 Document: 55-16 Filed: 02/08/2017 Pages: 116 (437 of 1511) Case 3:12-cv-01141-SMY-DGW Document 176-54 *SEALED* Filed 12/01/14 Page 19 of 116 Page ID #3514 Case: 16-3334 Document: 55-16 Filed: 02/08/2017 Pages: 116 (438 of 1511) Case 3:12-cv-01141-SMY-DGW Document 176-54 *SEALED* Filed 12/01/14 Page 20 of 116 Page ID #3515 Case: 16-3334 Document: 55-16 Filed: 02/08/2017 Pages: 116 (439 of 1511) Case 3:12-cv-01141-SMY-DGW Document 176-54 *SEALED* Filed 12/01/14 Page 21 of 116 Page ID #3516 Case: 16-3334 Document: 55-16 Filed: 02/08/2017 Pages: 116 (440 of 1511) Case 3:12-cv-01141-SMY-DGW Document 176-54 *SEALED* Filed 12/01/14 Page 22 of 116 Page ID #3517 Case: 16-3334 Document: 55-16 Filed: 02/08/2017 Pages: 116 (441 of 1511) Case 3:12-cv-01141-SMY-DGW Document 176-54 *SEALED* Filed 12/01/14 Page 23 of 116 Page ID #3518 Case: 16-3334 Document: 55-16 Filed: 02/08/2017 Pages: 116 (442 of 1511) Case 3:12-cv-01141-SMY-DGW Document 176-54 *SEALED* Filed 12/01/14 Page 24 of 116 Page ID #3519 Case: 16-3334 Document: 55-16 Filed: 02/08/2017 Pages: 116 (443 of 1511) Case 3:12-cv-01141-SMY-DGW Document 176-54 *SEALED* Filed 12/01/14 Page 25 of 116 Page ID #3520 Case: 16-3334 Document: 55-16 Filed: 02/08/2017 Pages: 116 (444 of 1511) Case 3:12-cv-01141-SMY-DGW Document 176-54 *SEALED* Filed 12/01/14 Page 26 of 116 Page ID #3521 Case: 16-3334 Document: 55-16 Filed: 02/08/2017 Pages: 116 (445 of 1511) Case 3:12-cv-01141-SMY-DGW Document 176-54 *SEALED* Filed 12/01/14 Page 27 of 116 Page ID #3522 Case: 16-3334 Document: 55-16 Filed: 02/08/2017 Pages: 116 (446 of 1511) Case 3:12-cv-01141-SMY-DGW Document 176-54 *SEALED* Filed 12/01/14 Page 28 of 116 Page ID #3523 Case: 16-3334 Document: 55-16 Filed: 02/08/2017 Pages: 116 (447 of 1511) Case 3:12-cv-01141-SMY-DGW Document 176-54 *SEALED* Filed 12/01/14 Page 29 of 116 Page ID #3524 Case: 16-3334 Document: 55-16 Filed: 02/08/2017 Pages: 116 (448 of 1511) Case 3:12-cv-01141-SMY-DGW Document 176-54 *SEALED* Filed 12/01/14 Page 30 of 116 Page ID #3525 Case: 16-3334 Document: 55-16 Filed: 02/08/2017 Pages: 116 (449 of 1511) Case 3:12-cv-01141-SMY-DGW Document 176-54 *SEALED* Filed 12/01/14 Page 31 of 116 Page ID #3526 Case: 16-3334 Document: 55-16 Filed: 02/08/2017 Pages: 116 (450 of 1511) Case 3:12-cv-01141-SMY-DGW Document 176-54 *SEALED* Filed 12/01/14 Page 32 of 116 Page ID #3527 Case: 16-3334 Document: 55-16 Filed: 02/08/2017 Pages: 116 (451 of 1511) Case 3:12-cv-01141-SMY-DGW Document 176-54 *SEALED* Filed 12/01/14 Page 33 of 116 Page ID #3528 Case: 16-3334 Document: 55-16 Filed: 02/08/2017 Pages: 116 (452 of 1511) Case 3:12-cv-01141-SMY-DGW Document 176-54 *SEALED* Filed 12/01/14 Page 34 of 116 Page ID #3529 Case: 16-3334 Document: 55-16 Filed: 02/08/2017 Pages: 116 (453 of 1511) Case 3:12-cv-01141-SMY-DGW Document 176-54 *SEALED* Filed 12/01/14 Page 35 of 116 Page ID #3530 Case: 16-3334 Document: 55-16 Filed: 02/08/2017 Pages: 116 (454 of 1511) Case 3:12-cv-01141-SMY-DGW Document 176-54 *SEALED* Filed 12/01/14 Page 36 of 116 Page ID #3531 Case: 16-3334 Document: 55-16 Filed: 02/08/2017 Pages: 116 (455 of 1511) Case 3:12-cv-01141-SMY-DGW Document 176-54 *SEALED* Filed 12/01/14 Page 37 of 116 Page ID #3532 Case: 16-3334 Document: 55-16 Filed: 02/08/2017 Pages: 116 (456 of 1511) Case 3:12-cv-01141-SMY-DGW Document 176-54 *SEALED* Filed 12/01/14 Page 38 of 116 Page ID #3533 Case: 16-3334 Document: 55-16 Filed: 02/08/2017 Pages: 116 (457 of 1511) Case 3:12-cv-01141-SMY-DGW Document 176-54 *SEALED* Filed 12/01/14 Page 39 of 116 Page ID #3534 Case: 16-3334 Document: 55-16 Filed: 02/08/2017 Pages: 116 (458 of 1511) Case 3:12-cv-01141-SMY-DGW Document 176-54 *SEALED* Filed 12/01/14 Page 40 of 116 Page ID #3535 Case: 16-3334 Document: 55-16 Filed: 02/08/2017 Pages: 116 (459 of 1511) Case 3:12-cv-01141-SMY-DGW Document 176-54 *SEALED* Filed 12/01/14 Page 41 of 116 Page ID #3536 Case: 16-3334 Document: 55-16 Filed: 02/08/2017 Pages: 116 (460 of 1511) Case 3:12-cv-01141-SMY-DGW Document 176-54 *SEALED* Filed 12/01/14 Page 42 of 116 Page ID #3537 Case: 16-3334 Document: 55-16 Filed: 02/08/2017 Pages: 116 (461 of 1511) Case 3:12-cv-01141-SMY-DGW Document 176-54 *SEALED* Filed 12/01/14 Page 43 of 116 Page ID #3538 Case: 16-3334 Document: 55-16 Filed: 02/08/2017 Pages: 116 (462 of 1511) Case 3:12-cv-01141-SMY-DGW Document 176-54 *SEALED* Filed 12/01/14 Page 44 of 116 Page ID #3539 Case: 16-3334 Document: 55-16 Filed: 02/08/2017 Pages: 116 (463 of 1511) Case 3:12-cv-01141-SMY-DGW Document 176-54 *SEALED* Filed 12/01/14 Page 45 of 116 Page ID #3540 Case: 16-3334 Document: 55-16 Filed: 02/08/2017 Pages: 116 (464 of 1511) Case 3:12-cv-01141-SMY-DGW Document 176-54 *SEALED* Filed 12/01/14 Page 46 of 116 Page ID #3541 Case: 16-3334 Document: 55-16 Filed: 02/08/2017 Pages: 116 (465 of 1511) Case 3:12-cv-01141-SMY-DGW Document 176-54 *SEALED* Filed 12/01/14 Page 47 of 116 Page ID #3542 Case: 16-3334 Document: 55-16 Filed: 02/08/2017 Pages: 116 (466 of 1511) Case 3:12-cv-01141-SMY-DGW Document 176-54 *SEALED* Filed 12/01/14 Page 48 of 116 Page ID #3543 Case: 16-3334 Document: 55-16 Filed: 02/08/2017 Pages: 116 (467 of 1511) Case 3:12-cv-01141-SMY-DGW Document 176-54 *SEALED* Filed 12/01/14 Page 49 of 116 Page ID #3544 Case: 16-3334 Document: 55-16 Filed: 02/08/2017 Pages: 116 (468 of 1511) Case 3:12-cv-01141-SMY-DGW Document 176-54 *SEALED* Filed 12/01/14 Page 50 of 116 Page ID #3545 Case: 16-3334 Document: 55-16 Filed: 02/08/2017 Pages: 116 (469 of 1511) Case 3:12-cv-01141-SMY-DGW Document 176-54 *SEALED* Filed 12/01/14 Page 51 of 116 Page ID #3546 Case: 16-3334 Document: 55-16 Filed: 02/08/2017 Pages: 116 (470 of 1511) Case 3:12-cv-01141-SMY-DGW Document 176-54 *SEALED* Filed 12/01/14 Page 52 of 116 Page ID #3547 Case: 16-3334 Document: 55-16 Filed: 02/08/2017 Pages: 116 (471 of 1511) Case 3:12-cv-01141-SMY-DGW Document 176-54 *SEALED* Filed 12/01/14 Page 53 of 116 Page ID #3548 Case: 16-3334 Document: 55-16 Filed: 02/08/2017 Pages: 116 (472 of 1511) Case 3:12-cv-01141-SMY-DGW Document 176-54 *SEALED* Filed 12/01/14 Page 54 of 116 Page ID #3549 Case: 16-3334 Document: 55-16 Filed: 02/08/2017 Pages: 116 (473 of 1511) Case 3:12-cv-01141-SMY-DGW Document 176-54 *SEALED* Filed 12/01/14 Page 55 of 116 Page ID #3550 Case: 16-3334 Document: 55-16 Filed: 02/08/2017 Pages: 116 (474 of 1511) Case 3:12-cv-01141-SMY-DGW Document 176-54 *SEALED* Filed 12/01/14 Page 56 of 116 Page ID #3551 Case: 16-3334 Document: 55-16 Filed: 02/08/2017 Pages: 116 (475 of 1511) Case 3:12-cv-01141-SMY-DGW Document 176-54 *SEALED* Filed 12/01/14 Page 57 of 116 Page ID #3552 Case: 16-3334 Document: 55-16 Filed: 02/08/2017 Pages: 116 (476 of 1511) Case 3:12-cv-01141-SMY-DGW Document 176-54 *SEALED* Filed 12/01/14 Page 58 of 116 Page ID #3553 Case: 16-3334 Document: 55-16 Filed: 02/08/2017 Pages: 116 (477 of 1511) Case 3:12-cv-01141-SMY-DGW Document 176-54 *SEALED* Filed 12/01/14 Page 59 of 116 Page ID #3554 Case: 16-3334 Document: 55-16 Filed: 02/08/2017 Pages: 116 (478 of 1511) Case 3:12-cv-01141-SMY-DGW Document 176-54 *SEALED* Filed 12/01/14 Page 60 of 116 Page ID #3555 Case: 16-3334 Document: 55-16 Filed: 02/08/2017 Pages: 116 (479 of 1511) Case 3:12-cv-01141-SMY-DGW Document 176-54 *SEALED* Filed 12/01/14 Page 61 of 116 Page ID #3556 Case: 16-3334 Document: 55-16 Filed: 02/08/2017 Pages: 116 (480 of 1511) Case 3:12-cv-01141-SMY-DGW Document 176-54 *SEALED* Filed 12/01/14 Page 62 of 116 Page ID #3557 Case: 16-3334 Document: 55-16 Filed: 02/08/2017 Pages: 116 (481 of 1511) Case 3:12-cv-01141-SMY-DGW Document 176-54 *SEALED* Filed 12/01/14 Page 63 of 116 Page ID #3558 Case: 16-3334 Document: 55-16 Filed: 02/08/2017 Pages: 116 (482 of 1511) Case 3:12-cv-01141-SMY-DGW Document 176-54 *SEALED* Filed 12/01/14 Page 64 of 116 Page ID #3559 Case: 16-3334 Document: 55-16 Filed: 02/08/2017 Pages: 116 (483 of 1511) Case 3:12-cv-01141-SMY-DGW Document 176-54 *SEALED* Filed 12/01/14 Page 65 of 116 Page ID #3560 Case: 16-3334 Document: 55-16 Filed: 02/08/2017 Pages: 116 (484 of 1511) Case 3:12-cv-01141-SMY-DGW Document 176-54 *SEALED* Filed 12/01/14 Page 66 of 116 Page ID #3561 Case: 16-3334 Document: 55-16 Filed: 02/08/2017 Pages: 116 (485 of 1511) Case 3:12-cv-01141-SMY-DGW Document 176-54 *SEALED* Filed 12/01/14 Page 67 of 116 Page ID #3562 Case: 16-3334 Document: 55-16 Filed: 02/08/2017 Pages: 116 (486 of 1511) Case 3:12-cv-01141-SMY-DGW Document 176-54 *SEALED* Filed 12/01/14 Page 68 of 116 Page ID #3563 Case: 16-3334 Document: 55-16 Filed: 02/08/2017 Pages: 116 (487 of 1511) Case 3:12-cv-01141-SMY-DGW Document 176-54 *SEALED* Filed 12/01/14 Page 69 of 116 Page ID #3564 Case: 16-3334 Document: 55-16 Filed: 02/08/2017 Pages: 116 (488 of 1511) Case 3:12-cv-01141-SMY-DGW Document 176-54 *SEALED* Filed 12/01/14 Page 70 of 116 Page ID #3565 Case: 16-3334 Document: 55-16 Filed: 02/08/2017 Pages: 116 (489 of 1511) Case 3:12-cv-01141-SMY-DGW Document 176-54 *SEALED* Filed 12/01/14 Page 71 of 116 Page ID #3566 Case: 16-3334 Document: 55-16 Filed: 02/08/2017 Pages: 116 (490 of 1511) Case 3:12-cv-01141-SMY-DGW Document 176-54 *SEALED* Filed 12/01/14 Page 72 of 116 Page ID #3567 Case: 16-3334 Document: 55-16 Filed: 02/08/2017 Pages: 116 (491 of 1511) Case 3:12-cv-01141-SMY-DGW Document 176-54 *SEALED* Filed 12/01/14 Page 73 of 116 Page ID #3568 Case: 16-3334 Document: 55-16 Filed: 02/08/2017 Pages: 116 (492 of 1511) Case 3:12-cv-01141-SMY-DGW Document 176-54 *SEALED* Filed 12/01/14 Page 74 of 116 Page ID #3569 Case: 16-3334 Document: 55-16 Filed: 02/08/2017 Pages: 116 (493 of 1511) Case 3:12-cv-01141-SMY-DGW Document 176-54 *SEALED* Filed 12/01/14 Page 75 of 116 Page ID #3570 Case: 16-3334 Document: 55-16 Filed: 02/08/2017 Pages: 116 (494 of 1511) Case 3:12-cv-01141-SMY-DGW Document 176-54 *SEALED* Filed 12/01/14 Page 76 of 116 Page ID #3571 Case: 16-3334 Document: 55-16 Filed: 02/08/2017 Pages: 116 (495 of 1511) Case 3:12-cv-01141-SMY-DGW Document 176-54 *SEALED* Filed 12/01/14 Page 77 of 116 Page ID #3572 Case: 16-3334 Document: 55-16 Filed: 02/08/2017 Pages: 116 (496 of 1511) Case 3:12-cv-01141-SMY-DGW Document 176-54 *SEALED* Filed 12/01/14 Page 78 of 116 Page ID #3573 Case: 16-3334 Document: 55-16 Filed: 02/08/2017 Pages: 116 (497 of 1511) Case 3:12-cv-01141-SMY-DGW Document 176-54 *SEALED* Filed 12/01/14 Page 79 of 116 Page ID #3574 Case: 16-3334 Document: 55-16 Filed: 02/08/2017 Pages: 116 (498 of 1511) Case 3:12-cv-01141-SMY-DGW Document 176-54 *SEALED* Filed 12/01/14 Page 80 of 116 Page ID #3575 Case: 16-3334 Document: 55-16 Filed: 02/08/2017 Pages: 116 (499 of 1511) Case 3:12-cv-01141-SMY-DGW Document 176-54 *SEALED* Filed 12/01/14 Page 81 of 116 Page ID #3576 Case: 16-3334 Document: 55-16 Filed: 02/08/2017 Pages: 116 (500 of 1511) Case 3:12-cv-01141-SMY-DGW Document 176-54 *SEALED* Filed 12/01/14 Page 82 of 116 Page ID #3577 Case: 16-3334 Document: 55-16 Filed: 02/08/2017 Pages: 116 (501 of 1511) Case 3:12-cv-01141-SMY-DGW Document 176-54 *SEALED* Filed 12/01/14 Page 83 of 116 Page ID #3578 Case: 16-3334 Document: 55-16 Filed: 02/08/2017 Pages: 116 (502 of 1511) Case 3:12-cv-01141-SMY-DGW Document 176-54 *SEALED* Filed 12/01/14 Page 84 of 116 Page ID #3579 Case: 16-3334 Document: 55-16 Filed: 02/08/2017 Pages: 116 (503 of 1511) Case 3:12-cv-01141-SMY-DGW Document 176-54 *SEALED* Filed 12/01/14 Page 85 of 116 Page ID #3580 Case: 16-3334 Document: 55-16 Filed: 02/08/2017 Pages: 116 (504 of 1511) Case 3:12-cv-01141-SMY-DGW Document 176-54 *SEALED* Filed 12/01/14 Page 86 of 116 Page ID #3581 Case: 16-3334 Document: 55-16 Filed: 02/08/2017 Pages: 116 (505 of 1511) Case 3:12-cv-01141-SMY-DGW Document 176-54 *SEALED* Filed 12/01/14 Page 87 of 116 Page ID #3582 Case: 16-3334 Document: 55-16 Filed: 02/08/2017 Pages: 116 (506 of 1511) Case 3:12-cv-01141-SMY-DGW Document 176-54 *SEALED* Filed 12/01/14 Page 88 of 116 Page ID #3583 Case: 16-3334 Document: 55-16 Filed: 02/08/2017 Pages: 116 (507 of 1511) Case 3:12-cv-01141-SMY-DGW Document 176-54 *SEALED* Filed 12/01/14 Page 89 of 116 Page ID #3584 Case: 16-3334 Document: 55-16 Filed: 02/08/2017 Pages: 116 (508 of 1511) Case 3:12-cv-01141-SMY-DGW Document 176-54 *SEALED* Filed 12/01/14 Page 90 of 116 Page ID #3585 Case: 16-3334 Document: 55-16 Filed: 02/08/2017 Pages: 116 (509 of 1511) Case 3:12-cv-01141-SMY-DGW Document 176-54 *SEALED* Filed 12/01/14 Page 91 of 116 Page ID #3586 Case: 16-3334 Document: 55-16 Filed: 02/08/2017 Pages: 116 (510 of 1511) Case 3:12-cv-01141-SMY-DGW Document 176-54 *SEALED* Filed 12/01/14 Page 92 of 116 Page ID #3587 Case: 16-3334 Document: 55-16 Filed: 02/08/2017 Pages: 116 (511 of 1511) Case 3:12-cv-01141-SMY-DGW Document 176-54 *SEALED* Filed 12/01/14 Page 93 of 116 Page ID #3588 Case: 16-3334 Document: 55-16 Filed: 02/08/2017 Pages: 116 (512 of 1511) Case 3:12-cv-01141-SMY-DGW Document 176-54 *SEALED* Filed 12/01/14 Page 94 of 116 Page ID #3589 Case: 16-3334 Document: 55-16 Filed: 02/08/2017 Pages: 116 (513 of 1511) Case 3:12-cv-01141-SMY-DGW Document 176-54 *SEALED* Filed 12/01/14 Page 95 of 116 Page ID #3590 Case: 16-3334 Document: 55-16 Filed: 02/08/2017 Pages: 116 (514 of 1511) Case 3:12-cv-01141-SMY-DGW Document 176-54 *SEALED* Filed 12/01/14 Page 96 of 116 Page ID #3591 Case: 16-3334 Document: 55-16 Filed: 02/08/2017 Pages: 116 (515 of 1511) Case 3:12-cv-01141-SMY-DGW Document 176-54 *SEALED* Filed 12/01/14 Page 97 of 116 Page ID #3592 Case: 16-3334 Document: 55-16 Filed: 02/08/2017 Pages: 116 (516 of 1511) Case 3:12-cv-01141-SMY-DGW Document 176-54 *SEALED* Filed 12/01/14 Page 98 of 116 Page ID #3593 Case: 16-3334 Document: 55-16 Filed: 02/08/2017 Pages: 116 (517 of 1511) Case 3:12-cv-01141-SMY-DGW Document 176-54 *SEALED* Filed 12/01/14 Page 99 of 116 Page ID #3594 Case: 16-3334 Document: 55-16 Filed: 02/08/2017 Pages: 116 (518 of 1511) Case 3:12-cv-01141-SMY-DGW Document 176-54 *SEALED* Filed 12/01/14 Page 100 of 116 Page ID #3595 Case: 16-3334 Document: 55-16 Filed: 02/08/2017 Pages: 116 (519 of 1511) Case 3:12-cv-01141-SMY-DGW Document 176-54 *SEALED* Filed 12/01/14 Page 101 of 116 Page ID #3596 Case: 16-3334 Document: 55-16 Filed: 02/08/2017 Pages: 116 (520 of 1511) Case 3:12-cv-01141-SMY-DGW Document 176-54 *SEALED* Filed 12/01/14 Page 102 of 116 Page ID #3597 Case: 16-3334 Document: 55-16 Filed: 02/08/2017 Pages: 116 (521 of 1511) Case 3:12-cv-01141-SMY-DGW Document 176-54 *SEALED* Filed 12/01/14 Page 103 of 116 Page ID #3598 Case: 16-3334 Document: 55-16 Filed: 02/08/2017 Pages: 116 (522 of 1511) Case 3:12-cv-01141-SMY-DGW Document 176-54 *SEALED* Filed 12/01/14 Page 104 of 116 Page ID #3599 Case: 16-3334 Document: 55-16 Filed: 02/08/2017 Pages: 116 (523 of 1511) Case 3:12-cv-01141-SMY-DGW Document 176-54 *SEALED* Filed 12/01/14 Page 105 of 116 Page ID #3600 Case: 16-3334 Document: 55-16 Filed: 02/08/2017 Pages: 116 (524 of 1511) Case 3:12-cv-01141-SMY-DGW Document 176-54 *SEALED* Filed 12/01/14 Page 106 of 116 Page ID #3601 Case: 16-3334 Document: 55-16 Filed: 02/08/2017 Pages: 116 (525 of 1511) Case 3:12-cv-01141-SMY-DGW Document 176-54 *SEALED* Filed 12/01/14 Page 107 of 116 Page ID #3602 Case: 16-3334 Document: 55-16 Filed: 02/08/2017 Pages: 116 (526 of 1511) Case 3:12-cv-01141-SMY-DGW Document 176-54 *SEALED* Filed 12/01/14 Page 108 of 116 Page ID #3603 Case: 16-3334 Document: 55-16 Filed: 02/08/2017 Pages: 116 (527 of 1511) Case 3:12-cv-01141-SMY-DGW Document 176-54 *SEALED* Filed 12/01/14 Page 109 of 116 Page ID #3604 Case: 16-3334 Document: 55-16 Filed: 02/08/2017 Pages: 116 (528 of 1511) Case 3:12-cv-01141-SMY-DGW Document 176-54 *SEALED* Filed 12/01/14 Page 110 of 116 Page ID #3605 Case: 16-3334 Document: 55-16 Filed: 02/08/2017 Pages: 116 (529 of 1511) Case 3:12-cv-01141-SMY-DGW Document 176-54 *SEALED* Filed 12/01/14 Page 111 of 116 Page ID #3606 Case: 16-3334 Document: 55-16 Filed: 02/08/2017 Pages: 116 (530 of 1511) Case 3:12-cv-01141-SMY-DGW Document 176-54 *SEALED* Filed 12/01/14 Page 112 of 116 Page ID #3607 Case: 16-3334 Document: 55-16 Filed: 02/08/2017 Pages: 116 (531 of 1511) Case 3:12-cv-01141-SMY-DGW Document 176-54 *SEALED* Filed 12/01/14 Page 113 of 116 Page ID #3608 Case: 16-3334 Document: 55-16 Filed: 02/08/2017 Pages: 116 (532 of 1511) Case 3:12-cv-01141-SMY-DGW Document 176-54 *SEALED* Filed 12/01/14 Page 114 of 116 Page ID #3609 Case: 16-3334 Document: 55-16 Filed: 02/08/2017 Pages: 116 (533 of 1511) Case 3:12-cv-01141-SMY-DGW Document 176-54 *SEALED* Filed 12/01/14 Page 115 of 116 Page ID #3610 Case: 16-3334 Document: 55-16 Filed: 02/08/2017 Pages: 116 (534 of 1511) Case 3:12-cv-01141-SMY-DGW Document 176-54 *SEALED* Filed 12/01/14 Page 116 of 116 Page ID #3611 Case: 16-3334 Document: 55-16 Filed: 02/08/2017 Pages: 116 (535 of 1511) Case 3:12-cv-01141-SMY-DGW Document 176-32 *SEALED* Filed 12/01/14 Page 1 of 40 Page ID #2974 Case: 16-3334 Document: 55-17 Filed: 02/08/2017 Pages: 40 (536 of 1511) EXPERT REPORT JANET B. ARROWSMITH, M.D., F.A.C.P., F.A.C.E I. QUALIFICATIONS 1. My name is Janet B. Arrowsmith. I am the sole proprietor of Arrowsmith Consulting, LLC, a drug, biologic, device, and epidemiologic consulting firm. 2. I earned a Bachelor of Arts degree in Zoology from Duke University in 1972 and a Doctor of Medicine degree from Tulane University Medical School in 1979. I completed an internship and residency in internal medicine through the University of Alabama at Birmingham in 1982. I am board certified in internal medicine and licensed to practice medicine in New Mexico. I am an elected Fellow of both the American College of Physicians and the American College of Epidemiology. I also am a member of the International Society of Pharmacoepidemiology, the Drug Information Association, the Reserve Officer Association, the American Medical Association, and the New Mexico Medical Society. 3. I served as an Epidemic Intelligence Service Officer at the National Centers for Disease Control and Prevention (CDC) from 1984 through 1986 and was assigned to the United States Food and Drug Administration (FDA). In this position, I participated in CDC and FDA epidemiologic investigations of reported adverse drug events and infectious disease problems of national and regional interest. 4. I worked in several capacities for FDA. I served as a staff epidemiologist in the Center for Drug Evaluation and Research (CDER) at FDA, monitoring and assessing postmarket safety of marketed drugs. I also was a medical review officer in the Division of Antiviral Drug Products in CDER, and in the Division of Blood and Blood Products in the FDA Center for Biologics Evaluation and Research (CBER). In these positions, I was responsible for reviewing Case 3:12-cv-01141-SMY-DGW Document 176-32 *SEALED* Filed 12/01/14 Page 2 of 40 Page ID #2975 Case: 16-3334 Document: 55-17 Filed: 02/08/2017 Pages: 40 (537 of 1511) Investigational New Drug (IND) or Biological Investigational New Drug (BIND) submissions and New Drug Applications (NDAs). I was selected to be Deputy Director of the Office of AIDS and Special Health Interests, now located administratively in the Office of the Commissioner of the FDA. Later, I was appointed as Acting Director of the Office of Surveillance and Biometrics in the Center for Devices and Radiologic Health. 5. During the time I was employed at FDA, and since leaving FDA, I have published a number of peer-reviewed medical articles and have written or co-authored several book chapters addressing FDA's regulations and practices, especially as they relate to the safety of pharmaceutical products marketed in the United States. 6. I have consulted with a number of pharmaceutical companies in products liability litigation and worked with plaintiffs in both medical device and pharmaceutical products liability litigation. I have participated in mock advisory committees for companies preparing to meet with FDA; conducted postmarket safety reviews and risk assessments for medical device companies; completed health hazard evaluations for medical device companies with potential safety problems related to marketed products; and assisted a pharmaceutical company in the review and assessment of a potential safety signal from the published medical literature as it may impact labeling. 7. My Curriculum Vitae, including a list of my publications, is attached as Exhibit A. A list of the other cases in which I have testified as an expert witness both in trial and at deposition during the last four years is attached as Exhibit B. II. MATERIALS REVIEWED 8. Attached as Exhibit C is a list of documents I have considered. In addition, I rely upon my education, training, and experience during my employment with FDA, as a consultant, and as a practicing physician. I hold the opinions summarized in this report to a reasonable 2 Case 3:12-cv-01141-SMY-DGW Document 176-32 *SEALED* Filed 12/01/14 Page 3 of 40 Page ID #2976 Case: 16-3334 Document: 55-17 Filed: 02/08/2017 Pages: 40 (538 of 1511) degree of scientific and professional certainty. I am being compensated at a rate of $750 per hour for my time spent directly on this matter, including deposition and trial testimony. III. SUMMARY OF OPINIONS 9. I was retained in this matter to provide a general overview of the regulatory framework within which pharmaceutical companies work in order to bring new drugs to market. This regulatory framework governs premarket and post-approval prescription drug development, including the development of prescription eye drops. It also governs changes to an approved NDA, which would be required in order to effect the changes in eye drop volume proposed by Plaintiffs for the medications listed in the Amended Complaint. It is my opinion based on the applicable regulations, FDA guidances, and examples provided in this report that reducing the drop volume and modifying the container closure systems for these medications as proposed by AWN lb. Plaintiffs would require, for each medication, a large, Phase III-type clinical trial to demonstrate equivalent safety and effectiveness of the medication with the new dosage and container closure system as compared to the currently approved dosage and container closure systems. 10. Prescription eye drops are approved as safe and effective based on the dose studied during the Phase III clinical trials as administered by the specific, approved dose delivery device, including the dropper tip, specified and described in the NDA. I also refer to the dose delivery device as the container closure system, which consists of the bottle, tip, and cap used with each ophthalmic product. 11. Dose is a function of the amount of the Active Pharmaceutical Ingredient (API)— the pharmacologically active chemical or drug in a solution or other liquid/semi-liquid formulation intended for administration into the eye—and the volume of the finished liquid/semi-liquid product administered as a drop. The approved and recommended total daily dose is the total number of drops of the finished drug product administered per day according to Case 3:12-cv-01141-SMY-DGW Document 176-32 *SEALED* Filed 12/01/14 Page 4 of 40 Page ID #2977 Case: 16-3334 Document: 55-17 Filed: 02/08/2017 Pages: 40 (539 of 1511) the FDA-approved, labeled instructions. As noted in various FDA pharmacology reviews of approved prescription eye drops, the daily dose may be described as the amount of API delivered to the eye in terms of the amount of API in each drop (e.g., moxifloxacin 0.25 mg/drop), or the concentration of API in the drug product (e.g., bimatoprost 0.01%), as well as the number of drops administered per day per eye. 12. Reducing the drop volume for the ophthalmic products at issue in this lawsuit to an estimated volume of 15 or 16 1.1,1 per drop, as Plaintiffs propose, would, under the governing FDA regulations, constitute a major change to the approved NDA for each individual medication. Such a reduction of volume of the drop would reduce by one-half, or more, depending on the medication, the amount of API administered in each dose. 13. Before allowing Defendants to market these medications with this reduced drop volume, FDA would require, for each medication, a supplemental new drug application (sNDA) based on an adequately powered, controlled, randomiied, double-blind clinical trial of adequate size and duration, to establish equivalence of the new dose to the previously approved dose. Study of the proposed new dose would involve evaluation of the new drop volume as dispensed by patients using the new container closure system for each medication. At a minimum, FDA would require one Phase III-type clinical study to demonstrate statistically and clinically that the reduction in volume of the administered drop with the concomitant reduction in amount of API delivered to the eye is equivalent in safety and effectiveness to the previously approved dose. 14. In addition to a full safety and effectiveness evaluation of the new drop volume for each medication, FDA would also require data showing that the new container closure system, including a tip that can reliably deliver to the eye the proposed reduced drop volume, is safe and effective for use as part of a new dosing regimen. As to safety, this review would 4 Case 3:12-cv-01141-SMY-DGW Document 176-32 *SEALED* Filed 12/01/14 Page 5 of 40 Page ID #2978 Case: 16-3334 Document: 55-17 Filed: 02/08/2017 Pages: 40 (540 of 1511) include assessment of the risk of ocular injury from a smaller dropper tip (such as the 16 investigational tip pictured in Dr. Robin's report), as well as the very real potential for contamination of the dispensing tip and an increased risk for infection of the eye associated with extending the use of each opened bottle of medication, as Plaintiffs propose. 15. The clinical studies Dr. Robin cites in his expert report are inadequate for purposes of establishing the clinically or statistically equivalent efficacy of smaller drop volumes for any of the glaucoma medications in the Amended Complaint. FDA has described its standard for determining clinical equivalence for medications intended to lower intraocular pressure (TOP). The studies referenced by Dr. Robin do not provide clinically or statistically meaningful data on which to base an assessment of the equivalent efficacy of smaller drop volumes to the currently approved drop volume under this standard. Similarly, the studies referenced by Dr. Robin do not provide clinically or statistically meaningful data on which to base an assessment of any of the other, non-glaucoma medications listed in the Amended Complaint. IV. FDA REGULATION OF PRESCRIPTION DRUGS — AN OVERVIEW 16. FDA is the federal regulatory agency charged with promoting and protecting the public health through regulation of: (1) pharmaceutical (drug) products; (2) medical devices and radiation-emitting devices; (3) biological products such as vaccines, allergenic extracts, blood, and blood products; (4) veterinary products; (5) foods and cosmetics, and (6) tobacco. Each of these areas requires specialized scientific expertise and training. Several thousand scientists, regulatory and management professionals, and support staff are engaged in this mission. 17. The drug evaluation section of FDA, the Center for Drug Evaluation and Research (referred to as CDER), is the largest drug regulatory body in the world. FDA regulates virtually every aspect of the manufacturing, distribution, evaluation, labeling, and post-market surveillance of drugs marketed and sold in the United States. The FDA regulatory framework 5 Case 3:12-cv-01141-SMY-DGW Document 176-32 *SEALED* Filed 12/01/14 Page 6 of 40 Page ID #2979 Case: 16-3334 Document: 55-17 Filed: 02/08/2017 Pages: 40 (541 of 1511) for the premarket development of new prescription drug products governs development of all prescription drug products, whether administered as an oral, parenteral (e.g., intravenous or intramuscular) or topical product. Liquid and semi-liquid preparations, including the prescription solutions, emulsions, gels, and suspensions administered as drops to the eye, are subject to FDA's regulatory authority in order to be legally marketed in the United States. 18. The drug regulatory center at FDA, CDER, comprises various Offices, Divisions, and Branches, within each of which are employed scientists with specialized expertise in their subject areas. For example, the Division of Transplant and Ophthalmology Products employs physicians, pharmacologists, chemists, and other scientists with experience and expertise in the development, review, and evaluation of medications used to treat health and medical conditions affecting the eye. 19. The FDA regulatory processes are rigorous and demanding of manufacturers. It takes up to 15 years of research and about $800 million to develop a single drug in the United States. (www.phrma.org/innovation). A. Investigational New Drugs 20. Under the provisions of Section 505 of the Federal Food, Drug and Cosmetic Act and 21 C.F.R. § 312, FDA requires that an Investigational New Drug (IND) exemption request be submitted to the agency for review prior to administration of any unapproved pharmaceutical product to any human being in the United States. The IND must contain extensive data addressing the pre-clinical (i.e., non-human) development process for the drug. The details of those data requirements are provided at 21 C.F.R. § 312.23(a)(9)(i) and (ii). 21. The initial human trials are conducted according to protocols submitted to FDA prior to enrolling patients. FDA physicians and other scientists review the clinical trial protocols 6 Case 3:12-cv-01141-SMY-DGW Document 176-32 *SEALED* Filed 12/01/14 Page 7 of 40 Page ID #2980 Case: 16-3334 Document: 55-17 Filed: 02/08/2017 Pages: 40 (542 of 1511) and provide recommendations for, or require revisions to, the clinical protocols to help assure the safety of the human subjects and to help ensure the success of the trials in developing reliable data concerning safety and effectiveness. As a medical review officer both in CDER and CBER, I was responsible for the review of initial clinical trials proposed in an IND or BIND and was responsible for ensuring that these trials were appropriately designed in accordance with good scientific principles and FDA regulatory requirements. 22. FDA has extensive oversight power and exercises considerable caution throughout all clinical phases of product development. Development during the IND stage generally proceeds through three well-defined stages identified as Phase I, Phase II, and Phase III. 23. In Phase I studies, single or limited dosing studies generally are conducted in healthy subjects to determine the human pharmacology of the drug, including information on the absorption, distribution, metabolism, and excretion of the drug. Information on human safety and a possible the range of side effects is developed through laboratory testing and monitoring as well as clinical evaluation of the human subjects. 24. Assuming the safety and tolerance data indicate reasonable assurance of patient safety, Phase II studies may be initiated. Phase II studies include use of the drug in larger populations, often including the types of patients in whom the drug is expected to be effective, if approved. Phase II studies include dose ranging studies intended to establish a candidate dose of the drug for further investigation and enroll several hundred patients overall. 25. Dose ranging studies are clinical studies in which patients are randomly assigned to several different doses of the API administered in a formulation likely to be used if approved. Evidence of safety and effectiveness is monitored to establish a dose that provides potential 7 Case 3:12-cv-01141-SMY-DGW Document 176-32 *SEALED* Filed 12/01/14 Page 8 of 40 Page ID #2981 Case: 16-3334 Document: 55-17 Filed: 02/08/2017 Pages: 40 (543 of 1511) benefits (efficacy) and demonstrates acceptable levels of side effects (safety) in treating the population and disease for which it is developed. For liquid or semi-liquid, gel or other formulations, the doses evaluated as candidates for the final phase of development (Phase III trials) are usually described as the amount of the API dissolved or otherwise contained in a specific volume of the liquid. The final drug product will contain the API and may also contain a preservative and ingredients or chemicals needed for solubility, stability, patient tolerability, and other necessary physical and chemical characteristics of the final formulation. The final dosage formulation is determined based on information developed in the previous clinical trials. How well a drug is tolerated is one measure of safety, while objective or subjective measurements of effectiveness indicate potential benefit. 26. The candidate dose selected for further development in Phase III trials must be a dose that is well tolerated and shows good evidence of effectiveness in treating the medical condition for which it has been developed. Establishing an appropriate and safe dose is an essential part of drug development. 27. Phase III clinical trials are considered pivotal to drug approval. It is in Phase III trials that the previously selected dose is used in the large "adequate and well-controlled" clinical studies, the results of which will be used to determine whether the drug can be approved for marketing in the United States. 21 C.F.R. § 312 and § 314; FDA Guidance for Industry: Providing Clinical Evidence for Effectiveness for Human Drugs and Biological Products (May 1998). Phase III trials typically enroll several hundred to several thousand patients with the disease of interest and are conducted according to detailed protocols administered by physician investigators in clinical centers around the country or internationally. These are multicenter, randomized, double-blind, placebo or active controlled clinical trials in which the safety and 8 Case 3:12-cv-01141-SMY-DGW Document 176-32 *SEALED* Filed 12/01/14 Page 9 of 40 Page ID #2982 Case: 16-3334 Document: 55-17 Filed: 02/08/2017 Pages: 40 (544 of 1511) effectiveness of the proposed new drug is carefully measured by clinical evaluations, laboratory tests, and by clinic visits. Because of their size and complexity, Phase III trials are expensive to sponsor and conduct. 28. The size, duration, outcome measurements, statistical methods for data analysis, and all other aspects of the Phase III clinical trials are carefully reviewed and discussed with FDA to make sure that data from those trials are likely to be reliable in determining whether the drug is safe and effective. These are the types of reviews and discussions in which I was frequently involved while serving as a medical review officer both in CDER and in CBER. In general, patients in these trials are randomly assigned either to the proposed new treatment or a comparative treatment (or placebo). Double blind means that neither the participants nor the clinical investigator know which patient is receiving which treatment, active or control. The differences observed in risks and benefits between the treatment groups then can be evaluated statistically to determine if the new medicine is as good as or better than the comparator. 29. While the specific outcomes used to determine safety and effectiveness vary according to the specific disease treated and the route of drug product administration, each drug's safety and effectiveness are always evaluated using a specified dose, frequency of dose administration, and duration of treatment. B. The New Drug Application (NDA) 30. Assuming that the sponsor (usually, the manufacturer) concludes that sufficient information has been compiled to demonstrate safety and effectiveness, it submits to FDA an NDA containing all of the clinical and preclinical information relevant to the indication sought. The regulatory requirements for an NDA are set out in 21 C.F.R. § 314. In general, the NDA must contain: (1) detailed reports on all relevant investigations (pre-clinical studies and clinical 9 Case 3:12-cv-01141-SMY-DGW Document 176-32 *SEALED* Filed 12/01/14 Page 10 of 40 Page ID #2983 Case: 16-3334 Document: 55-17 Filed: 02/08/2017 Pages: 40 (545 of 1511) trials) conducted by or for the sponsor, the results of those data analyses, and the actual data from those trials; (2) a summary of the safety and effectiveness data based on the clinical and preclinical investigations; (3) a description of the chemical composition of the drug; (4) detailed descriptions of the methods and facilities used in the manufacture of the drug; (5) drug product samples; (6) published and unpublished scientific literature relevant to the safety and effectiveness of the drug product; and (7) a draft of the proposed labeling. 21 C.F.R. § 314.50. C. NDA Review 31. The NDA is rigorously reviewed by FDA scientists to determine whether the information it contains is sufficient to establish that the drug meets FDA's demanding safety and efficacy requirements, as set forth in 21 C.F.R. § 314. The FDA scientists on the review teams are experts in relevant fields and conduct extensive and detailed reviews of the data and information comprising the NDA and prepare detailed reports on their findings. FDA's approval of a medication for marketing means FDA scientists and regulators have determined that the specific dose that was studied and administered in the Phase III clinical trials according to the agreed-upon protocol and as reflected in the approved label has been found to be safe and effective in treating patients with the disease or medical condition in which it was studied. D. FDA Advisory Committees 32. At times, FDA may convene a panel of outside experts to assist the agency in assessing important scientific or regulatory issues. An advisory committee includes physicians, statisticians, industry representatives and consumer representatives with expertise and experience in the area of science or medicine that is the subject of the advisory committee meeting. While FDA usually accepts the advice of its advisory committees, it is not obligated to do so. In February 2012, FDA convened the Dermatologic and Ophthalmic Drugs Advisory Committee to 10 Case 3:12-cv-01141-SMY-DGW Document 176-32 *SEALED* Filed 12/01/14 Page 11 of 40 Page ID #2984 Case: 16-3334 Document: 55-17 Filed: 02/08/2017 Pages: 40 (546 of 1511) obtain the committee members' advice on the potential risks of bacterial contamination and eye infection associated with the use of a single, larger fill-volume bottle of anti-inflammatory eye medication intended for the treatment of pain and inflammation associated with cataract surgery. In that meeting, FDA presented data indicating that use of a single bottle in treating both eyes post-operatively could increase the risk of eye infection. After consideration of the data and discussions from the Advisory Committee, FDA declined to approve a bottle containing sufficient medication to treat both eyes following successive cataract surgeries, citing concerns about bacterial contamination. V. A CHANGE TO DROP VOLUME IS A CHANGE TO DOSAGE THAT WOULD REQUIRE SUBMISSION AND PRIOR FDA APPROVAL OF A SUPPLEMENTAL NEW DRUG APPLICATION FOR EACH MEDICATION BEFORE MARKETING 33. My understanding is that Plaintiffs are seeking to require Defendants to change the dosing and administration for all of the medications listed in the Amended Complaint such that each medication will be dispensed by the patient as drops that are, on average, no larger than 15 or 16 IA Based on my experience at FDA and my knowledge of the regulations, it is my opinion that before Defendants could implement these changes FDA would require them to submit clinical trial and other data supporting the safety and effectiveness of each medication with the new dosage and redesigned container closure systems. 34. FDA requires manufacturers to submit a supplemental new drug application, or sNDA, and obtain prior approval before instituting any change "in the drug substance, drug product, production process, quality controls, equipment, or facilities that has a substantial potential to have an adverse effect on the identity, strength, quality, purity, or potency of the drug product as these factors may relate to the safety or effectiveness of the drug product." 21 C.F.R § 314.70(b)(1). A change in drop volume from the current range of 30, 40 or 50 [t1 per drop to a 11 Case 3:12-cv-01141-SMY-DGW Document 176-32 *SEALED* Filed 12/01/14 Page 12 of 40 Page ID #2985 Case: 16-3334 Document: 55-17 Filed: 02/08/2017 Pages: 40 (547 of 1511) drop volume of 15 or 16 tl per drop, as proposed by Plaintiffs' expert, Dr. Alan Robin, would reduce by approximately one-half to two-thirds the amount of API in each dose administered to the eye. Changing the amount of API in each administered dose would have "a substantial potential to have an adverse effect on the identity, strength, quality, purity, or potency of the drug product as these factors may relate to the safety or effectiveness of the drug product." Though the changes may or may not have an actual adverse effect on these characteristics of the eye medications, the proposed changes need only have a "substantial potential" to do so. Based on my experience, there is no doubt that FDA would require a reassessment of both the safety and the effectiveness of the new dose for each medication as delivered by each redesigned container and tip. 35. In 21 C.F.R. § 314.70(b)(2), FDA provides a non-exhaustive list of the changes that constitute "major changes" to a drug product and therefore require agency review and approval prior to distribution of the medication with the changes. While it is self-evident that changing the dose of a medication would have a "substantial potential" to affect the safety or effectiveness of the medication by adversely affecting its "identity, strength, quality, purity, or potency," § 314.70(b)(2)(ii) addresses this circumstance by requiring prior approval for "[c]hanges requiring completion of studies in accordance with part 320 of this chapter to demonstrate the equivalence of the drug product to the drug product as manufactured without the change . . . ." 36. Plaintiffs' proposed dosage reduction would fall under 21 C.F.R. § 320, which includes supplemental applications for a "change in the manufacturing process, including a change in product formulation or dosage strength, beyond the variations provided for in the approved application." 21 C.F.R § 320.21(c)(1). Any change in the dose or dosing regimen 12 Case 3:12-cv-01141-SMY-DGW Document 176-32 *SEALED* Filed 12/01/14 Page 13 of 40 Page ID #2986 Case: 16-3334 Document: 55-17 Filed: 02/08/2017 Pages: 40 (548 of 1511) "beyond the variations provided for in the approved application" requires one or more clinical trials to establish the comparability of the new dose or dosing regimen to the previously approved dose or dosing regimen. These types of trials typically are referred to as "equivalence" trials. Generally, the proposed new dose would be compared to the previously approved dose in patients with the disease of interest to determine if the effects of the new dose are comparable in safety and effectiveness to the approved dose. 37. In April 2004, FDA issued a final Guidance for the pharmaceutical industry regarding changes to approved NDAs and abbreviated new drug applications (ANDA). In this Guidance, FDA provides examples of changes considered to have "a substantial potential to have an adverse effect on the identity, strength, quality, purity, or potency of a drug product as these factors may relate to the safety or effectiveness of the drug product." (FDA Guidance for Industry, Changes to an Approved NDA or ANDA, p. 12 (April 2004)). Among these examples are "[Ohanges that may affect the controlled (or modified) release, metering or other characteristics (e.g., particle size) of the dose delivered to the patient . . . ." Ibid. The changes Plaintiffs are proposing would change "the dose delivered to the patient." 38. As discussed above, with respect to prescription eye drops, dose is generally described as the amount of API contained in each drop, or the concentration of API in the drug product. Dose also refers to the number of drops to be administered into each eye per day. For example, this is illustrated in the following excerpt from an FDA pharmacology review for the prescription drug, Azopt®. The FDA pharmacology review states: DOSAGE AND ADMINISTRATION: The recommended starting dose is 1 drop - 0.5 mg (10 mg brinzolamide/mL) per day in the affected eyes. Dosage can be increased to 1 drop tid (1.5 mg/day) if no response is seen after four weeks. (FDA CDER, NDA 20-816, Pharmacology/Toxicology Review, p.1 (May 31, 1997)). 13 Case 3:12-cv-01141-SMY-DGW Document 176-32 *SEALED* Filed 12/01/14 Page 14 of 40 Page ID #2987 Case: 16-3334 Document: 55-17 Filed: 02/08/2017 Pages: 40 (549 of 1511) 39. The daily dose of Azopt® is described here as one drop, which contains approximately 0.5 mg of brinzolamide. Brinzolamide is the API in Azopt®. The formulation or concentration of brinzolamide in Azopt® is 10 mg per ml. If the patient does not respond to treatment in the first four weeks, the dosage of Azopt® may be increased to one drop three times per day (TID), which would result in a daily dose of 1.5 mg of brinzolamide per day. 40. A similar quantification of dose is described in FDA's pharmacology review for Alrexe: RECOMMENDED DOSAGE: According to the proposed package labeling, 1 drop should be instilled into the affected eye(s) 4 times daily. Assuming a drop size of 50 uL and both eyes being affected, each patient will instill 400 uL of loteprednol etabonate 0.2% each day. A dose of 400 uL/day will contain 0.8 mg/day or 0.016 mg/kg/day (16 ug/kg/day) based on a 50 kg body weight. (FDA CDER, NDA 20-803, Review of Pharmacology and Toxicology Data, p. 2 (April 18, 1997)). 41. The FDA Summary Review for Moxeza®, an ocular antibiotic indicated for the treatment of bacterial conjunctivitis, describes the dose as 0.25 mg of the API, moxifloxacin, per drop of ophthalmic solution in the Clinical Microbiological Review discussing the drug product's likely effectiveness for treating the bacteria that may cause conjunctivitis: These organisms, as well as others listed in the proposed label, should be susceptible to moxifloxacin at the concentration that is available per drop of solution (0.25 mg/drop). (FDA CDER, NDA 22-428, Division Director Review, p. 7 (November 19, 2010)). 42. For the prescription anti-inflammatory medication, Bromday®, the current approved label identifies the amount of the API, bromfenac, contained in each drop: 12.3 Pharmacokinetics The plasma concentration of bromfenac following ocular administration of 0.09% Bromday (bromfenac ophthalmic solution) in humans is unknown. Based on the maximum proposed dose of one drop to the eye (0.045 mg) and PK 14 Case 3:12-cv-01141-SMY-DGW Document 176-32 *SEALED* Filed 12/01/14 Page 15 of 40 Page ID #2988 Case: 16-3334 Document: 55-17 Filed: 02/08/2017 Pages: 40 (550 of 1511) information from other routes of administration, the systemic concentration of bromfenac is estimated to be below the limit of quantification (50 ng/mL) at steady-state in humans. (Bromday® Prescribing Information, p. 2 (October 2012)). 43. The approved label for the prostaglandin glaucoma medication, Xalatan® (www.xalatan.com), describes the drug product as containing approximately 1.5 [tg [micrograms] of the API, latanoprost, per drop. 44. Reducing the dosage of medications that identify the amount of the API in each drop in the product labeling, such as Bromday® and Xalatan®, among others, would require prior FDA approval for the additional reason that FDA must pre-approve substantive labeling changes (with a few limited exceptions), including changes in the strength of each dose. 21 C.F.R. § 314.70(b)(2)(v). ....,. 45. For the changes Plaintiffs propose, each sNDA would need to describe the scientific basis for the change and would have to include clinical trial data to support the safety and effectiveness of the new dose resulting from the proposed change in treating the disease and the population for which the initial approval was granted. Defendants would be required to submit an sNDA for each medication. 46. The types of trials required to demonstrate equivalence generally are large, multi- center, double blind, controlled clinical trials very similar to the Phase III clinical trials required for the original approval of each drug product. The equivalence trials must be of sufficient size and duration to establish that the results from the new clinical studies can be compared to the previous results in statistically valid ways. The size, duration, and other specific requirements for each clinical trial would vary from drug to drug. 47. To establish the equivalence of 15-16 p.1 drops to the drop volume for a currently 15 Case 3:12-cv-01141-SMY-DGW Document 176-32 *SEALED* Filed 12/01/14 Page 16 of 40 Page ID #2989 Case: 16-3334 Document: 55-17 Filed: 02/08/2017 Pages: 40 (551 of 1511) marketed ophthalmic product used to treat glaucoma, FDA would require a clinical study involving at least a three-month efficacy evaluation, likely an extended safety evaluation of as much as twelve months, and with a sufficient number of subjects per study arm, including a study arm with the new drug volume compared to the existing approved drug product or possibly other comparator arms. For example, approximately 1,000 patients were enrolled in an equivalency trial involving the approved glaucoma drug, Lumigan®. In July 2007, Allergan submitted an sNDA for approval to market a new concentration of Lumigan®. In this sNDA, Allergan proposed to market Lumigan® with a lower concentration of the API, bimatoprost. The original Lumigan® NDA was approved with an API concentration of 0.03%; the new formulation used a 0.01% concentration of bimatoprost. The Acting Director of the responsible review division, then called the Division of Anti-Infective and Ophthalmology Drugs, described the requirements for establishing clinical equivalence in his Summary Review. (FDA CDER, NDA 22-184, Division Director Review, pp. 6-10 (July 13, 2010)). 48. To establish the therapeutic equivalence of the new concentration to the original concentration, Allergan was required to conduct two dose ranging studies enrolling a total of 437 patients, and a single Phase III study with 561 patients, for a total patient enrollment of nearly 1,000 persons. The first dose ranging study enrolled 188 patients randomly assigned to various combinations of dosing frequency (twice a day versus once a day) and concentrations of API (0.01%, .015%, 0.02% or 0.025%), compared to the original formulation or a standard antiglaucoma drug, Timolol®, and followed them for one month. The second dose ranging study enrolled 249 patients, randomly assigned subjects to one of five treatment groups and followed them for five days. A third, Phase III clinical trial was required in which subjects were enrolled in a twelve-month study with a three-month efficacy assessment. There were between 186 and 16 Case 3:12-cv-01141-SMY-DGW Document 176-32 *SEALED* Filed 12/01/14 Page 17 of 40 Page ID #2990 Case: 16-3334 Document: 55-17 Filed: 02/08/2017 Pages: 40 (552 of 1511) 188 patients enrolled in each of the three study arms, for a total of 561 subjects. Subjects were randomly assigned to the original Lumigan® formulation or one of two test concentrations (0.01% or 0.0125%), all of which were administered once a day. 49. In all three studies, intraocular pressures (IOP) were measured according to the protocols and the differences in IOP in each treatment group were used to determine the comparative efficacy of each dose and dosing frequency. The FDA described its standard for establishing clinical equivalence of 'OP-lowering medications in this same review: The Ophthalmology group uses a relatively strict definition for clinical equivalence. The definition of equivalence in IOP reduction is that the difference must be within a 95% confidence interval of 1.5 mmHg for all timepoints and with a 95% confidence interval of 1 mmHg for the majority of timepoints. This definition for the largest clinically acceptable difference between test drug and control is a matter of clinical judgment. (FDA CDER, NDA 22-184, Division Director Review, p. 9 (July 13, 2010)). Thus, FDA has AIN 11., established clinically relevant, statistically defined criteria for determining equivalence when comparing the efficacy of two or more treatments for glaucoma. 50. The results of this Lumigan® Phase III study were used to determine the relative efficacy of the 0.01% concentration as compared to the approved 0.03% concentration, and to the approved drug, Timolol®. While the clinical trials described above did demonstrate the efficacy of the lower concentration in treating the increased ocular pressure of glaucoma, the large Phase HI study did not meet the Division's standard for equivalence and thus the labeling for Lumigan® 0.01% product reflects this finding. 51. The Lumigan® experience is an excellent road map for the types of clinical trials of glaucoma medications that would be required to demonstrate equivalent efficacy of a smaller drop and dropper tip to the drop volume and tip initially approved. 52. A reasonable example of the type of information FDA would require in the case 17 Case 3:12-cv-01141-SMY-DGW Document 176-32 *SEALED* Filed 12/01/14 Page 18 of 40 Page ID #2991 Case: 16-3334 Document: 55-17 Filed: 02/08/2017 Pages: 40 (553 of 1511) of an anti-infective medication is provided in the NDA for Besivance®, a topical antibiotic eye medication approved by FDA in 2009. In order to demonstrate safety and effectiveness of a novel ocular antibiotic medication, an equivalence trial comparing the new medicine, besifloxacin, to an approved topical ocular antibiotic, Vigamox®, required enrollment of a total of 1,130 patients with clinical evidence of bacterial conjunctivitis; 566 in the Besivance® arm and 564 in the Vigamox® arm. The Medical Officer review indicated that more than 80 clinical investigators enrolled these patients and conducted clinical evaluations of each patient three times over eight days. (FDA CDER, NDA 22-308, Clinical Review (February 5, 2009)). This means that there were 3,390 separate clinic visits involved in developing the data submitted in this single ocular antibiotic equivalence trial. As the Lumigan® and Besivance® examples illustrate, the size and duration of the clinical trials required to demonstrate equivalence varies from drug to drug, depending on the disease being treated, but clearly would involve enrollment of hundreds to a thousand or more patients. 53. If the data from an equivalence trial indicated that the currently approved formulation of a drug product in a smaller drop volume was not equivalent in effectiveness to the original formulation in the currently approved drop volume, the manufacturer would be required to entirely reformulate the product. Such reformulation could include developing a higher concentration of API per drop so that an equivalent amount of the API would be delivered in the smaller drop volume, increasing the number of drops per dose, or developing some other currently unspecified and undefined means of delivering the drug to the eye. If these efforts were unsuccessful, reformulation might have to be abandoned entirely. The technical issues in reformulation of the drug or developing a novel delivery system are far more complex than the issue of establishing the therapeutic equivalence of a smaller drop to a larger drop and would 18 Case 3:12-cv-01141-SMY-DGW Document 176-32 *SEALED* Filed 12/01/14 Page 19 of 40 Page ID #2992 Case: 16-3334 Document: 55-17 Filed: 02/08/2017 Pages: 40 (554 of 1511) require even more in-depth study and investigation and subsequent review by FDA. Reformulation may or may not be possible depending upon the solubility of the API, its stability in a higher concentration, the tolerability of a higher concentration of API per volume, the ability of a dropper to dispense a formulation containing a higher concentration of API, and other physical, chemical, pharmacokinetic, and clinical issues. VI. CHANGES IN DROP VOLUME WOULD ALSO INVOLVE CHANGES TO THE CONTAINER CLOSURE SYSTEMS, WHICH FDA WOULD HAVE TO PREAPPROVE FOLLOWING SUBMISSION OF A SUPPLEMENTAL NEW DRUG APPLICATION FOR EACH MEDICATION 54. An important part of FDA's risk-benefit assessment is examining the safety and efficacy of the drug using a defined dose, dosing regimen, and dose delivery system. As an FDA Guidance explains: CDER and CBER approve a container closure system to be used in the packaging of a human drug or biologic as part of the application (NDA, ANDA or BLA) for the drug or biologic. A packaging system found acceptable for one drug product is not automatically assumed to be appropriate for another. Each application should contain enough information to show that each proposed container closure system and its components are suitable for its intended use. (FDA Guidance for Industry: Container Closure Systems for Packaging Human Drugs and Biologics, p. 5 (May 1999)). 55. This FDA Guidance discusses the requirements FDA imposes on containers and container closure systems intended to be used with sterile solutions, specifically addressing ophthalmic solutions, the safety of which is dependent on maintaining its sterility, at least until the applicator is opened for use. In addition, information must be submitted to FDA demonstrating that the container closure systems for ophthalmic solutions can properly deliver the medication to the eye as described in the product label. (Ibid. at 23-27.) 56. Based on my knowledge of and experience with FDA's regulations and regulatory authority, I am confident that Plaintiffs' proposed changes to these container closure systems to 19 Case 3:12-cv-01141-SMY-DGW Document 176-32 *SEALED* Filed 12/01/14 Page 20 of 40 Page ID #2993 Case: 16-3334 Document: 55-17 Filed: 02/08/2017 Pages: 40 (555 of 1511) effect a reduction in drop volume also would require submission of clinical data to demonstrate equivalent safety and efficacy of the new container closure system as compared to the currently approved container closure system for each drug product. For example, a new container closure system designed to produce a smaller drop may have greater risks for eye injury from direct contact with the surface of the eye with the smaller, possibly more pointed dispensing tip (similar to the photograph of the 16 ul investigational tip in Dr. Robin's report). FDA would consider such information independently of the clinical data required to establish equivalent effectiveness of a smaller drop volume. 57. As I understand it, Plaintiffs expect that the redesigned medication bottles dispensing smaller drop volumes will provide patients with a significantly longer duration of treatment than possible with the currently approved bottles, due to the smaller drop volume. Based on FDA's February 2012 Dermatologic and Ophthalmic Drugs Advisory Committee, it is clear that FDA has concerns about extended use of eye drop medications and container closure systems due to an increased risk of bacterial contamination (from touching the dropper tip to the eye, the eyelid, or the fingers) with increasing duration of use and the corresponding increased risk of eye infection. FDA's concern about container closure and medication contamination in considering ISTA' s proposal to increase the fill volume of the anti-inflammatory eye medication, Bromday®, leads me to believe that the agency would have similar concerns about possible infection and contamination regarding Plaintiffs' proposed "benefit" of extending the use of eye drop bottles by reducing drop volume. 58. In 2011, FDA rejected ISTA Pharmaceutical's request to increase the fill volume for Bromday®, one of ISTA's eye medications used to treat postoperative pain and inflammation, due to concerns about microbial contamination and the risk of eye infection post- 20 Case 3:12-cv-01141-SMY-DGW Document 176-32 *SEALED* Filed 12/01/14 Page 21 of 40 Page ID #2994 Case: 16-3334 Document: 55-17 Filed: 02/08/2017 Pages: 40 (556 of 1511) operatively. ISTA had asked FDA to approve an increased fill volume for Bromday® so that patients could use one bottle to treat both eyes following surgery, instead of patients having to purchase one bottle of medication for each eye. FDA rejected that proposal for extended use of a single bottle, responding in part that "CDER believes that use of a single bottle of Bromday to treat two eyes unacceptably and unnecessarily increases the risk of microbial infection." 76 Fed. Reg. 46,821 (Aug. 3, 2011). FDA further advised that "[m]icrobial infection is a significant concern for ophthalmic products with postoperative indications, because an eye whose surface is compromised by a surgical procedure is more prone to infection than an eye with an intact cornea." Ibid. FDA expressed concern that patients might contaminate the product by, for example, touching one eye with the dropper tip, then transmitting the bacteria to the other eye. Ibid. at 46,822. 59. FDA convened an advisory committee meeting in February 2012 to explore the contamination issue, among others. During the meeting, FDA discussed the incidence of microbial contamination of ophthalmic products reported in the published literature as well as the difficulty patients have administering eye drops without touching the dropper tip to their eye, eyelid, fingers, etc. FDA referenced two video studies by Hennessy, which Dr. Robin coauthored, one of which found that low-vision glaucoma and retina patients over the age of 70 touched their eye with the dropper tip 72% of the time when administering eye drops, while patients under age 70 touched their eye 53% of the time. FDA also discussed published cases of clinical infections resulting from contaminated eyedroppers and eye medications. (FDA Slide Presentation, Dermatologic and Ophthalmic Drugs Advisory Committee Meeting (February 27, 2012)). 60. It is evident that a proposal to extend the use of eye medications through smaller 21 Case 3:12-cv-01141-SMY-DGW Document 176-32 *SEALED* Filed 12/01/14 Page 22 of 40 Page ID #2995 Case: 16-3334 Document: 55-17 Filed: 02/08/2017 Pages: 40 (557 of 1511) drop volumes would raise concerns about contamination and possible infection similar to those FDA investigated in the case of Bromday®. While it is not possible to predict whether FDA would convene an advisory committee to discuss the issue of smaller drops and any corresponding change in fill volume, the Bromday® Advisory Committee provides important insight into the agency's concerns. Plaintiffs are proposing fundamental changes to the way prescription eye medications have been dosed, delivered, and packaged for many decades. The changes proposed by Plaintiffs would impact most multi-dose eye drop products, across many drug classes. With or without advisory committee input, I can say without hesitation that FDA would require Defendants to investigate these safety issues for each of the medications before approving the changes proposed by Plaintiffs. 61. Furthermore, there is no practical reason to believe that FDA would allow the fill volume for all of these medications to remain at the current fill levels, in light of the increased risk of contamination associated with extending the use of the bottles through smaller drop volumes. As part of its background materials for the February 2012 Advisory Committee meeting, FDA provided a chart indicating the fill volume, number of drops per bottle, and expected number of drops required to complete a prescribed course of post-operative pain and inflammation treatment for each of the medications potentially impacted by the increased fill volume requested by ISTA. This chart clearly indicates that FDA considers the relationship between fill volume, the number of drops delivered by that volume, and the recommended treatment period for each of the eye medicines discussed. There is no reason to believe that FDA would permit a medication that is expected to deliver two weeks of therapy to be filled with sufficient volume for a four or six-week course of treatment. 62. Considering the concerns of FDA and the medical community regarding 22 Case 3:12-cv-01141-SMY-DGW Document 176-32 *SEALED* Filed 12/01/14 Page 23 of 40 Page ID #2996 Case: 16-3334 Document: 55-17 Filed: 02/08/2017 Pages: 40 (558 of 1511) contamination and possible infection, it is my opinion that FDA would require a reduction in the fill volumes commensurate with the amount of drug product needed to produce the same number of drops as each of the current containers. This would almost certainly be the case with antiinfective medicines like Mozexa® or Besivance®, which are prescribed for a specific short-term course of treatment and not intended to be used longer than that specific length of time; medicines to treat pain and inflammation following cataract or other eye surgeries, which are also intended to be used for a specific length of time following eye surgeries; and glaucoma medications, which are used chronically by elderly patients who may be more likely to contaminate the dropper tip, as noted in one of the Hennessy studies co-authored by Dr. Robin, and referenced by FDA at the February 2012 Advisory Committee meeting. 63. In my view, Plaintiffs' claimed economic advantage of smaller drops, based on the assumption that the fill volumes of the containers with new dispensing tips would remain unchanged and thus extending the potential lifespan of each individual container, is not a valid assumption. VII. THE STUDIES RELIED ON BY DR. ROBIN DO NOT MEET FDA STANDARDS FOR EQUIVALENCE AND WOULD NOT SUPPORT FDA APPROVAL OF A SMALLER DROP VOLUME FOR ANY OF THE MEDICATIONS AT ISSUE 64. While Plaintiffs' expert Dr. Robin references several studies in his expert report for the proposition that smaller drop volumes are just as efficacious as larger drop volumes, he testified at his deposition that he had not analyzed the confidence intervals in the data for two of the studies and acknowledged that the studies do not satisfy the FDA standard for clinical equivalence of glaucoma medications. He also stated at his deposition that he has no experience with or knowledge of the requirements FDA might impose on a manufacturer to lawfully market an ophthalmic product with a smaller drop volume and dose delivery system that were not the subject of the original Phase III studies and FDA approval. 23 Case 3:12-cv-01141-SMY-DGW Document 176-32 *SEALED* Filed 12/01/14 Page 24 of 40 Page ID #2997 Case: 16-3334 Document: 55-17 Filed: 02/08/2017 Pages: 40 (559 of 1511) 65. Data from the studies Dr. Robin relies upon are inadequate to establish clinically equivalent efficacy and safety for any ofthe glaucoma medications in this lawsuit. Dr. Robin relies on several published clinical studies evaluating various combinations of smaller eye drops, novel drug delivery technologies, and novel formulations of eye medications conducted in healthy volunteers and in patients with glaucoma either as short, single, or multi-dose studies. For a number of reasons, including small sample size, use of unapproved drug formulations (adding methylcellulose to an existing formulation creates a new unapproved drug), shorter duration of treatment, lack of well-defined safety and effectiveness measurements, and incomplete presentation of data analysis, none of these studies is of the quality that would meet the FDA standards for "adequate and well-controlled" studies. 66. My knowledge of IDA regulations governing the review and approval of prescription drug products, my experience at FDA, and my experience as a consultant to pharmaceutical manufacturers whose drug products are dependent on such delivery systems for appropriate dosing allows me to conclude that Plaintiffs are mistaken in their assumption that additional Phase III-type clinical trial requirements would not be imposed on the Defendants in this case. It is absolutely certain that new safety and effectiveness data would be required for a manufacturer to implement the types of changes suggested by Plaintiffs, and that the cost and complexity of such clinical trials would be quite significant. Date: Vh)/02 0 01 ant :. Arrowsmith, M.D., F.A.C.P., F.A.C.E. 24 Case 3:12-cv-01141-SMY-DGW Document 176-32 *SEALED* Filed 12/01/14 Page 25 of 40 Page ID #2998 Case: 16-3334 Document: 55-17 Filed: 02/08/2017 Pages: 40 (560 of 1511) Exhibit A Case 3:12-cv-01141-SMY-DGW Document 176-32 *SEALED* Filed 12/01/14 Page 26 of 40 Page ID #2999 Case: 16-3334 Document: 55-17 Filed: 02/08/2017 Pages: 40 (561 of 1511) CURRICULUM VITAE JANET B. ARROWSMITH, M.D., F.A.C.P, F.A.C.E. September 2014 Office: Arrowsmith Consulting, LLC Cell 575-937-3161 81B N. Shining Sun office 505-455-9875 Santa Fe NM 87506-8837 Fax 505-455-9875 Jarrowsmith@arrowsmithconsultinglIc.com Education: Bachelor of Arts Doctor of Medicine Internship and Residency: Internal Medicine Additional Training: Epidemic Intelligence Service Duke University Tulane University 1972 1979 University of Alabama at Birmingham 1979 through 1982 National Centers for Disease Control and Prevention, 1984 through 1986 Licensure: Federal Licensing Exam New Mexico June 1979 November 1996 Specialty Board Certification: American Board of Internal Medicine September 1986 Professional Associations: Member, American College of Physicians Fellow, American College of Physicians Member, American College of Epidemiology Fellow, American College of Epidemiology American Medical Association International Society of Pharmacoepidemiology Drug Information Association Reserve Officers Association Lincoln County Medical Society Elected 1987 Elected April 1994 Elected April 2002 Elected October 2008 Professional Experience: August 2014 to present NDA Partners LLP Premier Expert Consultant for a product development and regulatory strategy firm providing advice to medical products industries and associated service industries. 2008 to present Arrowsmith Consulting, LLC *President and sole proprietor of medical, epidemiological, and regulatory consulting firm Santa Fe, New Mexico *Special Emphasis Panel MAID, NIH November 2009 Case 3:12-cv-01141-SMY-DGW Document 176-32 *SEALED* Filed 12/01/14 Page 27 of 40 Page ID #3000 Case: 16-3334 Document: 55-17 Filed: 02/08/2017 Pages: 40 (562 of 1511) Janet Arrowsmith, M.D., F.A.C.P., F.A.C.E. Curriculum vitae Page 2 of 8 Professional Experience, continued: 1999 to 2008 Arrowsmith-Lowe Consulting, Inc, * President of drug, biologic, and device consulting firm * Consultant, NIDA Division of Research and Development, National Institutes of Health; * Member, Special Emphasis Panel, National Institute of Allergy and Infectious Diseases, NIH 1999 to 2009 * Primary Care provider, Family Practice Associates of Ruidoso, NM 1998 to 1999 Internal Medicine Associates, Ruidoso, NM *Full time internal medicine practice with ICU privileges *Member, Critical Care / Cardiorespiratory Committee *Physician member, Infection Control Committee *Physician Board member, Headstart of Lincoln County *Ryan White provider, University of New Mexico Health Sciences Center 1996-1998: Clinical Specialty Consultant, Mescalero PHS Indian Health Service Hospital, Mescalero, NM * Full time clinician in a family practice inpatient and outpatient setting * Consultant on Internal Medicine specialty problems * Member of the Quality Assurance special team * Co-chair of the Hospital Infection Control Committee * Mescalero Service Unit member of the Albuquerque Area Diabetes Team *Acting Clinical Director, June 1997 — November 1997 1995-1996: Medical Review Officer, Division of Blood Applications, Office of Blood Research and Review, Center for Biologics Evaluation and Research, U.S. Food and Drug Administration, Rockville, MD * Internal medicine clinical specialist with expertise in clinical trial design and xenograft transplantation * Primary care provider for HIV-infected persons, Whitman-Walker Clinic, Washington, DC 1993 - 1995 Acting Director, Office of Surveillance and Biometrics, Center for Devices and Radiological Health. U.S. Food and Drug Administration, Rockville, MD * Supervised staff of 113 professional and support personnel with an annual budget of $2.5 million * Responsible for monitoring safety and effectiveness of all medical devices marketed in the U.S. * Primary care provider for HIV-infected persons, Whitman-Walker Clinic, Washington, DC 1991-1993: Medical Review Officer, Division of Antiviral Drug Products, Center for Drug Evaluation and Research, U.S. Food and Drug Administration, Rockville, MD * Reviewer for initial clinical trials of new drugs developed to treat HIV, Herpes, Varicella-Zoster and other human viral pathogens Case 3:12-cv-01141-SMY-DGW Document 176-32 *SEALED* Filed 12/01/14 Page 28 of 40 Page ID #3001 Case: 16-3334 Document: 55-17 Filed: 02/08/2017 Pages: 40 (563 of 1511) Janet Arrowsmith, M.D. F.A.C.P., F.A.C.E. Curriculum vitae Page 3 of 8 Professional Experience, continued * Clinical consultant to the Division's laboratory for pre- and post-exposure prophylaxis to reduce risk for Hepatitis B and HIV infections * Field reviewer for CDC's community-based programs in HIV prevention * Primary care provider for HIV-infected persons, Whitman-Walker Clinic, Washington, DC 1990-1991: Senior Medical Officer (HIV), Office of the Forum on Quality in Health Care, Agency for Health Care Policy and Research, Rockville, MD * Senior Agency clinical consultant HIV-related policies * Established and convened panel of clinical and community experts for the development of clinical care and treatment guidelines for I-11V infection, published in 1993. * Primary care provider for HIV-infected persons, Whitman-Walker Clinic, Washington, DC 1988-1990 Deputy Director, Office of AIDS and Special Health Concerns, Office of the Commissioner, U.S. Food and Drug Administration, Rockville, MD *Directed the FDA activities for the AIDS Clinical Trials Information Service, a publicly accessible database of all clinical trials to treat HIV infection *National and international representative for FDA policies on regulation of HIV-related products for diagnosis and treatment * Primary care provider for HIV-infected persons, Whitman-Walker Clinic, Washington, DC 1986 to 1996 Clinical Instructor Department of Medicine Georgetown University Medical Center Washington, DC 1986-1988 Staff Epidemiologist, Office of Epidemiology and Biostatistics, Center for Drug Evaluation and Research, U.S. Food and Drug Administration * Monitored postmarket safety and effectiveness of marketed drugs * Consultant to Centers for Drug and Biologics Evaluation and Research on epidemiologic issues and problems * Special consultant to the U.S. Department of Justice * Primary care, Department of Medicine, Georgetown University Medical Center, Washington, DC. 1984-1986 Epidemic Intelligence Service Officer, National Centers for Disease Control and Prevention, Atlanta, GA * First EIS officer assigned to the FDA * Participated in CDC and FDA epidemiologic investigations of problems of national and regional interest, see bibliography and abstract listings * Assigned as editor pro temp ore Morbidity and Mortality Weekly Report, Case 3:12-cv-01141-SMY-DGW Document 176-32 *SEALED* Filed 12/01/14 Page 29 of 40 Page ID #3002 Case: 16-3334 Document: 55-17 Filed: 02/08/2017 Pages: 40 (564 of 1511) Janet Arrowsmith, M.D., F.A.C.P., F.A.C.E. Curriculum vitae Page 4 of 8 Professional Experience, continued 1982-1984 Staff Physician, Cooper Green Hospital, Birmingham AL * Internal Medicine attending physician with student, resident and intern teaching responsibilities * Quality Assurance review responsibilities and Chair, medical-nursing quality assurance program Other Professional Activities • Peer Reviewer, Annals of Epidemiology 2014 • Abstract reviewer, American College of Epidemiology 2013, 2014 • Consultant, Special Emphasis Panel, MAID, NTH November 2009 • Chair, Membership Committee, American College of Epidemiology, 2008-2009 • Medical specialist, Managed Health Care Bureau, N M Public Regulation Commission 2007 • Vice Chair, Membership Committee American College of Epidemiology 2006 - 2008 • Reviewer, 2006 Congress of Epidemiology abstracts • Lincoln County Councilor, New Mexico Medical Society Council of Governors, 2005 -2007 • Editorial Consultant, ACP's PIER program 2005 - 2006 • Reviewer, American College of Physicians' (ACP)'s Physician Information and Education Resource (PIER) modules 2004-2006 • President, Lincoln County Medical Society, 2004-2005 • Hoofbeats Therapeutic Riding Program Board of Directors, Alto NM, 2004 to 2006 • Membership Committee, American College of Epidemiology, 2002 • Volunteer physician, Bishop Stoney Camp, Episcopal Dioceses of the Rio Grande, 2004, 2005 • Reviewer, Scientific Program Committee, International Society for Pharmacoepidemiology, 2004, 2005, 2007, 2008, 2012 • Secretary/treasurer, Lincoln County Medical Society, elected December 2003-2004 • Medical Director, Ruidoso Home Care, September 2000 to 2013 • Professional Advisory Group, Ruidoso Home Care and Hospice, September 2000 to present • Medical Advisor, Hoofbeats Therapeutic Riding Program, Alto, NM 2001 to 2006 • Representative, NM Council of the American College of Physicians, 1998 - 2000 • Moderator, Pharmacoepidemiology session, Annual EIS Conference, CDC, Atlanta, GA; 4/97 • Physician Representative DC Branch of the Commissioned Officers' Association 7/95-4/96. • Member, PHS Medical Review Board July 1991 to 1998 • Member, PHS Co-Step Board Panel January 1991 to 1998. • FDA Representative, PHS working Group on management of occupational exposure to HIV, 2/89. • FDA Representative, AIDS Information Service Panel, US PHS Executive Task Force on AIDS; September 1989 - September 1990. • Editorial Board, Journal of Pharmacoepidemiology, April 1988. • Reviewer, Annals of Internal Medicine, 1988 to present Uniformed Services • US PHS 1984 —1998: Highest rank achieved Captain (0-6); Honorable discharge, February, 1998 at Commander (0-5) grade. Case 3:12-cv-01141-SMY-DGW Document 176-32 *SEALED* Filed 12/01/14 Page 30 of 40 Page ID #3003 Case: 16-3334 Document: 55-17 Filed: 02/08/2017 Pages: 40 (565 of 1511) Janet Arrowsmith, M.D., F.A.C.P., F.A.C.E. Curriculum vitae Page 5 of 8 Bibliography • Silverman BG, Brown SL, Kaczmarek RG, Arrowsmith-Lowe JB, Kessler DA. Reported complications of silicone breast implants: An epidemiologic review. Ann Int Med 1995; 124:74456. • Ulatowski TA and Arrowsmith-Lowe J. "Antiviral Claims for Medical Devices" . In: Proceeding from the First Workshop on Antiviral Claims for topical Antiseptics, May 31-June 1, 1994. U.S.GPO;1995-386-982:43728 ; pp 19-23. • Arrowsmith-Lowe J. Medical Device Regulations and the Postmarket Surveillance Studies Section of SMDA 1980. Jap J Medical Instrumentation 1995; 65:158-9. • Arrowsmith JB, Gerstman BB, Fleischer DE, Benjamin SB. Results from the ASGE/FDA collaborative study on complication rates and drug use during gastrointestinal endoscopy. Gastrointestinal Endoscopy 1991; 37: 421-7. • Arrowsmith JB. FDA contributing author. PHS Statement on management of occupational exposure to human immunodeficiency virus. MMWR 1990; 39 RR-1: 1-14. • Arrowsmith JB. AIDS therapy and the detection of adverse drug reactions in dental practice. J Am Dent Assoc 1989; 119: 46S-48S. • Arrowsmith JB, Faich GA, Tomita DL, et al. Morbidity and mortality among low birthweight infants exposed to an intravenous vitamin E product, Eferol. Pediatrics 1989; 83: 244-9. • Hine LK, Arrowsmith JB, Gallo-Torres H. Monooctanoin-associated pulmonary edema. Am J Gastroenterol 1988; 1128-31. • Spengler RF, Arrowsmith JB, Kilarski DJ, et al. Severe soft tissue injury following intravenous phenytoin: Patient and drug administration risk factors. Arch Med 1988; 148: 1329-33. • Arrowsmith JB, Creamer JI, Bosco L. Severe dermatologic reactions reported after treatment with tocainide. Ann Int Med 1987; 107: 693-6. • Arrowsmith JB, Kennedy DL, Kuritsky JN, Anello C, Faich GA. Trends in aspirin use and Reye syndrome reporting, United States, 1979-1985. Pediatrics; 79: 858-63. • Nelson WL, Fraunfelder FT, Sills JM, Arrowsmith JB, Kuritsky JN. Adverse respiratory and cardiovascular events attributed to timolol ophthalmic solution, 1978-1985. Am J Ophthal 1986; 102: 606-11. • Hoffman R. Zakonen S, Yang RH, Bruno E, LoBuglio AF, Arrowsmith JB, Prchal JT. An antibody cytotoxic to megakaryocyte progenitor cells in a patient with immune thrombocytopenic purpura, N Eng J Med 1985; 312: 1170-4. Abstracts • • • • • • Arrowsmith-Lowe, Janet. How Do Drugs Get onto the US Market and What Happens Next? Annual Meeting NM Chapter American College of Physicians November 3 — 5, 2005 Albuquerque, NM (poster presentation, second prize in presentation) Arrowsmith-Lowe J, Gogel HK, Lynn R, et al. Serendipitous overdose of octreotide acetate used for variceal hemorrhage. Annual meeting NM Chapter ACP-ACIM, Albuquerque NM, 1999. Arrowsmith JB and Kennedy DL. National patterns of aspirin use and Reye syndrome reporting APHA Annual Meeting; New Orleans, LA. 1987 Arrowsmith JB. Guillian-Barre Syndrome following Streptokinase Exposure : A case study in Pharmacoepidemiology, APHA Annual Meeting Washington DC 1986. Arrowsmith JB, Kuritsky JN, Faich GA, Hsu JP. Morbidity and mortality associated with the use of an intravenous vitamin E preparation, Eferol. EIS Conference, CDC Atlanta, GA 1986. Arrowsmith JB, Kuritsky JN, Faich GA, Kennedy DL, Anello C. Changing patterns of aspirin use, 1980-1983. EIS Conference, CDC, Atlanta GA, 1985. Case 3:12-cv-01141-SMY-DGW Document 176-32 *SEALED* Filed 12/01/14 Page 31 of 40 Page ID #3004 Case: 16-3334 Document: 55-17 Filed: 02/08/2017 Pages: 40 (566 of 1511) Janet Arrowsmith, M.D., F.A.C.P., F.A.C.E. Curriculum vitae Page 6 of 8 Letters • Arrowsmith-Lowe, JB Drug safety reporting. ACP Observer 2005;25:2. • Tanner LA, Arrowsmith JB. Histamine type-2 receptor blockers and bradyarrythmias. Ann Int Med 1988; 109:434-5. • Arrowsmith JB, Dreis M. Thrombocytopenia after treatment with danazol. N Engl J Med 1986; 315:302 • Arrowsmith JB, Kuritsky JN, Milstein J13, Murano G. Streptokinase and the Guillian-Barre syndrome. Ann Int Med 1985; 103: 302. • Arrowsmith JB, Gams R. Dystonia with Droperidol therapy. N Engl J Med 1981; 305: 227. Book Chapters • • • Seligman P, Braun M, Gross T, Arrowsmith J "Postmarket Surveillance of Medical Products in the United States" In: Principles and Practices of Public Health Surveillance. 3"1 edition Teutsch SM, St.Louis M, et al eds. Oxford University Press, 2010. Arrowsmith-Lowe J "Post-Market Safety Surveillance for Pharmaceuticals" In: Principles and Practice of Public Health Surveillance, 2nd edition Teutsch SM and Churchill RE, eds. Oxford University Press, 2000. Arrowsmith JB, Anello C. Postmarketing Surveillance: A view from a regulatory agency. In: Phartnacoepidemiology Strom BL, ed. Churchill Livingstone, New York, 1989; revised 1994. Other Publications • Arrowsmith-Lowe J. Summertime and the "stomach flu". Apache Scout; Mescalero NM, August 1996. • Arrowsmith-Lowe J and Simmons D "Recognizing Sexual Abuse in Children" Apache Scout, Mescalero, NM, September 1997. • Arrowsmith J and de laHoussaye MK. Flow of Federal Health Funds, State of Louisiana. Prepared for the Office of the Commissioner, Division of Administration, State of Louisiana, Baton Rouge LA, 1975. Representative Presentations: • • • • • • • • • • "Human Trafficking" 2014 National Women's Heritage Month Event, Celebrating Women of Character, Courage and Commitment" USDA Forest Service, Albuquerque NM March 26, 2014. "How FDA Works: Drugs and Medical Devices" Staff and Fellow Grand Rounds, Department of Gastroenterology, University of New Mexico, Albuquerque, NM January 10, 2013. "Dealing With Menopause" Mescalero Apache Women's Wellness Conference, Inn of the Mountain Gods. Mescalero, NM May 15, 2012 "Cardiovascular Safety of Prescription Drugs" John L. Wilson Cardiology lectureship, Presbyterian Healthcare Services, Albuquerque, NM October 1, 2010. "How drugs get to market in the US" Sacramento Mountain Village, Ruidoso NM May 2008 "How FDA Works" Lincoln County Medical Society, Ruidoso NM March 13, 2008 "Medication Errors in Children" Pediatric Research Roundtable, Consumer Healthcare Products Association, Washington DC, June 28, 2007 Arrowsmith-Lowe J, Gogel HK, Lynn R, et al. "Serendipitous overdose of octreotide acetate used for variceal hemorrhage". Annual meeting NM Chapter ACP-ACIM, Albuquerque NM, 1999. Medical Issues for Women Living with HIV. Positive Women's Retreat, sponsored by Camino de Vida of New Mexico. Las Cruces NM, May 12, 2000 Sexually Transmitted Diseases: Prevention and treatment. Camp Sierra Blanca Juvenile Detention Center, Capitan, NM December, 1999. Case 3:12-cv-01141-SMY-DGW Document 176-32 *SEALED* Filed 12/01/14 Page 32 of 40 Page ID #3005 Case: 16-3334 Document: 55-17 Filed: 02/08/2017 Pages: 40 (567 of 1511) Janet Arrowsmith, M.D.., F.A.C.P, F.A.C.E Curriculum vitae Page 7 of 8 Representative Presentations, continued • • • • • • • Awards • • • • • • • • • • • • • • • • • • • • • • Antibiotic Resistance and Misuse of Antibiotics, Artesia, NM and Portales NM March, 1998 Moderator, Postmarketing Surveillance Panel, Annual EIS Convention, CDC, April 1997. "Recognizing sexual abuse in a child" Mescalero Headstart Program continuing education series. September, 1996; Mescalero, NM. "Menopause" Federal Women's Association monthly meeting, Mescalero NM; August 1996. "CDRH Executive Roundtable" at the Regulatory Affairs Professional Society Annual Meeting Washington, DC; September 1994. "Medical Device Reporting " Medical Devices Update 1994, The Food and Drug Law Institute, Washington, DC; June 1994. "Epidemiology of Blood Borne Pathogens, Including HIV" University of Texas Universit y of Health Sciences School of Dentistry, October 1993. PHS Citation- 1987 epidemiology of aspirin and Reye syndrome and of the E-Ferol syndrome . American Medical Association's Physicians Recognition Award, July 1985 through June 1988, July 1988 through June 1991, July 1991 through June 1994, July 1994 through June 1997, July 1998 through June 2001, June 2001 through June 2003, June 2003 through June 2006. PHS Citation-1989 for outstanding effort in coordination of AIDS activities for the Food and Drug Administration. PHS Unit Commendation-1990 for extraordinary achievements in developing a toll-free accessible AIDS clinical trials database. PHS Unit Commendation-1991 for exemplary service in clinical guideline development. Whitman-Walker Clinic volunteer of the month, April 1992. PHS Outstanding Unit Commendation -1992 for contributions to the review and approval of ddl. Center for Devices and Radiological Health Certificate of Appreciation-1995 for outstandi ng leadership and exceptional achievement. US Food and Drug Administration Certificate of Appreciation-1995 for support and contributi on of the FDA MedWatch Program. PHS Unit Commendation -1995 as a member of the corporate wide injunctions group. PHS Unit Commendation -1995 as a member of the Ad Hoc Committee on Total Parentera l Nutrition Issues. PHS Unit commendation -1995 as a member of the MedWatch Coordinating Council. PHS Unit Commendation -1995 as a member of the Cables and Leads Working Group. DHHS Secretary's Award and PHS Unit Commendation -1996 for outstanding performa nce addressing the problems of electrodes and patient cables and leads Letters of appreciation,1996, David A. Kessler, Commissioner, U.S. Food and Drug Administration; and Mary Pendergast, Deputy Commissioner, US FDA Certificate of Appreciation for eight years of volunteer service, presented March 1996, WhitmanWalker Medical Center, Washington, DC. PHS Isolated Hardship Ribbon, 1996. Outstanding Alumna, Louise McGhee School, New Orleans, LA March 1997. "Angel of Adoption" Congressional Coalition on Adoption, September, 2001 Letter of recognition for "exceptionally fine quality" peer reviews, Annals of Internal Medicine , 2011 Community Service Award, 2012, New Mexico Medical Society Honored as "A Woman of Character, Courage and Commitment" 2014 National Women's Heritage Month 2014, Washington Office Civil Rights Office, USFS, USDA March 26, 2014. Case 3:12-cv-01141-SMY-DGW Document 176-32 *SEALED* Filed 12/01/14 Page 33 of 40 Page ID #3006 Case: 16-3334 Document: 55-17 Filed: 02/08/2017 Pages: 40 (568 of 1511) Janet Arrowsmith, M.D., F.A.C.P, F.A.C.E Curriculum vitae Page 8 of 8 Other Activities and Associations • • • Community Outreach council Episcopal Church in Lincoln County, NM September 2012 Host family, Up With People advance team , January - February 2012 President, Board of Directors, NM Organized Against Trafficking Humans (NM OATH), 2010 to 2012. • Volunteer, Spay and Neuter Clinic, Humane Society of Lincoln County, 2010 to 2012 • Lector, Episcopal Church in Lincoln County, NM 2008 • Hoofbeats Therapeutic Riding Program Board of Directors, 2004 - 2006 • Vice President, PAC, White Mountain Elementary School, 2002-2003 • Parent Advisory Council (PAC) Representative, SW 2001-2002 • Participant, Volunteer in Public Schools Program, Ruidoso Municipal Schools, 1998,1999,2000,2001,2002, 2003, 2004, 2005, 2006 • Homeroom Parent and Parents' Council member, Nob Hill Early Childhood Center, Ruidoso, NM, 1999-2000 • Physician Consultant, Headstart Program of Lincoln County, NM, 1998-1999 • Lector, St. Thomas' Episcopal Parish, Washington DC 1992 -1996. • Alumnae Advisor, Duke University Students' Career Counseling Program, 1992 to present. • Member, Education Committee, St. Thomas' Episcopal Parish, Washington DC 1990 to 1993. • Member, Latin American Parents' Association, Washington Metropolitan Area, 1989 to 1996. Continuing Medical Education Activities • Poster Presentation, Annual Meeting American College of Physicians, NM Chapter, November 3, 4, 5, 2005 • Massachusetts Medical Society's Journal Watch Program, 50 credit hours per year, 1997, 1998, 1999, 2000, 2001, 2002, 2003, 2004, 2005, 2006, 2007, 2008, 2009, 2010, 2011, 2012, 2013 • Drug Information Association Annual Meeting, 2003, 2004, 2006, 2008, 2010 • American College of Epidemiology Annual meeting 2002, 2006, 2008 • American College of Physicians Annual Meetings 1985, 1987, 1995, 1999, 2001 • ACP Regional Meeting, Albuquerque, NM1996, 1998, 1999, 2004, 2005 • IHS Course on Gynecology, Prenatal and Obstetrical Care, September 1996, Denver CO • Basic CPR Lincoln County Medical Center, 1996, 1997, 1998, 2000, 2002, 2003, 2004, 2005, 2006 • Advanced Cardiac Life Support, Lincoln County Medical Center 1996, 1998, 2000, 2002 • Medical Response to Public Health Emergencies, Albuquerque NM, May 2005 Case 3:12-cv-01141-SMY-DGW Document 176-32 *SEALED* Filed 12/01/14 Page 34 of 40 Page ID #3007 Case: 16-3334 Document: 55-17 Filed: 02/08/2017 Pages: 40 (569 of 1511) Exhibit B Case 3:12-cv-01141-SMY-DGW Document 176-32 *SEALED* Filed 12/01/14 Page 35 of 40 Page ID #3008 Case: 16-3334 Document: 55-17 Filed: 02/08/2017 Pages: 40 (570 of 1511) Cases in Which Dr. Janet Arrowsmith has Testified as an Expert at Trial or by Deposition September 2010 to September 2014 The State of Texas ex rel. Allen Jones v. Janssen L.P. et al. Cause D-1-GV-04-001288 250th Judicial District Travis County Texas, Santa Fe NM 18 February 2011. Larkan v. Baxter, et al. case 10L 7320 Circuit Court of Cook County, Illinois County Department — Law Division, Chicago IL April 13th, 2011. Gary L. Pierce vs. Lemuel 0. Granada and Janssen Pharmaceutica et al Cause No: D0950-cv-02003-00174 Ninth Judicial District Court, Count of Curry, State of New Mexico Albuquerque, NM May 24, 2011. Yasmin and Yaz (Drosperinone) Marketing, Sales Practices and Relevant Products Liability Litigation MDL No. 2100; Yaz/Yasmin/Ocella Product Liability, Court of Common Pleas, Philadelphia County and Superior Court of New Jersey, Bergen County. Albuquerque NM 14 October 2011 Sharon Brodie, Surviving spouse and executor of the Estate of John Brodie, Deceased v. Novartis Pharmaceuticals Corporation Eastern District of Missouri Case N.: 4:10-CV00138(HEA). St Louis MO 31 January 2012. In Re: Risperdal Litigation Philadelphia County Court of Common Pleas, Trial Division, State of Pennsylvania March Term 2010, No: 296, Santa Fe NM- August 3, 2012 Natasha Kyle Mahaney v. Novartis Pharmaceuticals Corporation (W.D. Ky. Case No. 1:06-CV-35) Western District of Kentucky. January 16, 2012. Christine L. Winter, Individually and as an Executor of the Estate of Ruth Baldwin, Deceased v. Novartis Pharmaceuticals Corporation (W.D. Mo. Case No. 2:06-CV-4049) Western District of Missouri. April 2, 2012. Barbara Davids v. Novartis Pharmaceuticals Corporation (E.D.N.Y. Case No. CV-060431) October 24, 2012. J. Hunter Chiles, III and Dianna Chiles v. Novartis Pharmaceuticals Corporation (M.D. Fla. Case No. 3:06-cv-96) Jacksonville FL February 21, 2013. Ariel Esterbrook and Donald and Adria Esterbrook v. Hoffman-La Roche, Inc; Roche Laboratories, Inc.; and Cascade Eye and Skin Centers P.C. Superior Court of Washington for the County of Pierce Case No. 11-2-08254-2. Denver CO April 23, 2013 Sheena Elmore individually and as next friend of A.E., a minor v. Janssen Pharmaceuticals et al. County Court of Nueces County, Texas, Cause no. 2012-CCV61916-1. Los Angeles CA July 25, 2013. 1 Case 3:12-cv-01141-SMY-DGW Document 176-32 *SEALED* Filed 12/01/14 Page 36 of 40 Page ID #3009 Case: 16-3334 Document: 55-17 Filed: 02/08/2017 Pages: 40 (571 of 1511) John C. Swallow, Attorney General of the State of Utah, ex rel. The State of Utah, Plaintiff vs, Janssen Ortho LLC, et al NO:2:10-CV-00519A-B SJ and Montana First Judicial District Court, Lewis and Clark County Timothy Fox Attorn ey General of the State of Montana vs Janssen Ortho LLC NO: CDV-2008-164. Santa Fe NM August 22, 2013. Louise Taylor vs. Johnson & Johnson, Inc.; Janssen Pharmaceuti ca, Inc.; et al. Cause No. 2002-0389. Circuit Court of Copiah County MS. Los Angeles CA. October 10, 2013. Lay v. DePuy Orthopaedics Inc No. 3:11cv3590-K and Paoli v.DeP uy Orthopaedics Inc.No. 3:12cv4975-K. In re: DePuy Orthopaedic s Pinnacle Hip Implant Products Liability Litigation. MDL Docket No.3:11-md2244-K. Santa Fe NM May 20, 2014. Catalino Carino and Cecilia Carino v. Alireza Katouzian, Bristo l-Myers Squibb Company, et al. San Francisco County Superior Court Case No. CGC-11-516590. Los Angeles CA July 18, 2014. 2 Case 3:12-cv-01141-SMY-DGW Document 176-32 *SEALED* Filed 12/01/14 Page 37 of 40 Page ID #3010 Case: 16-3334 Document: 55-17 Filed: 02/08/2017 Pages: 40 (572 of 1511) Exhibit C Case 3:12-cv-01141-SMY-DGW Document 176-32 *SEALED* Filed 12/01/14 Page 38 of 40 Page ID #3011 Case: 16-3334 Document: 55-17 Filed: 02/08/2017 Pages: 40 (573 of 1511) List of Materials Considered First Amended Class Action Complaint for Damages, Punitive Damages, and Injunctive Relief Expert Report of Alan Robin, MD and cited materials (5/30/14) Supplemental Expert Report of Alan Robin, MD (6/09/14) Deposition of Alan Robin, MD w/exhibits (8/6/14) Deposition of Gary Charbonneau (3/05/14) Deposition of Scott Grossman (2/19/14) Deposition of Diana Rocco w/exhibits (3/13/14) Deposition of Gregory Seitz w/exhibits (3/12/14) Deposition of Brad Wooldridge w/exhibits (3/28/14) FDA CDER, NDA 20-816, Pharmacology/Toxicology Review (May 31, 1997) FDA CDER, NDA 22-184, Division Director Review (July 13, 2010) FDA CDER, NDA 20-803, Review of Pharmacology and Toxicology Data (April 18, 1997) FDA CDER, NDA 22-428, Division Director Review (November 19, 2010) FDA CDER, NDA 22-308, Clinical Review (February 5, 2009) FDA CDER NDA 21-009, Review and Evaluation of Pharmacology/Toxicology Data (August 24, 1999) Lumigan® Full Prescribing Information Xalatan® Full Prescribing Information Bromday® Full Prescribing Information FDA Guidance for Industry: Providing Clinical Evidence for Effectiveness for Human Drugs and Biological Products (May 1998) FDA Guidance for Industry: Changes to an Approved NDA or ANDA (April 2004) Case 3:12-cv-01141-SMY-DGW Document 176-32 *SEALED* Filed 12/01/14 Page 39 of 40 Page ID #3012 Case: 16-3334 Document: 55-17 Filed: 02/08/2017 Pages: 40 (574 of 1511) FDA Guidance for Industry: Container Closure Systems for Packaging Human Drugs and Biologics (May 1999) FDA Guidance for Industry: Container Closure Systems for Packaging Human Drugs and Biologics Q&A (May 2002) FDA Guidance for Industry: Changes to an Approved NDA or ANDA Q&A (January 2001) FDA Dermatologic and Ophthalmic Drugs Advisory Committee Meeting, Briefing Document, NDA 22-308 (December 5, 2008) FDA Dermatologic and Ophthalmic Drugs Advisory Committee Meeting, Briefing Document, NDA 22-212 (May 29, 2008). FDA Dermatologic and Ophthalmic Drugs Advisory Committee Meeting, Briefing Package (February 27, 2012) FDA Dermatologic and Ophthalmic Drugs Advisory Committee Meeting, Slide Presentation (February 27, 2012) FDA Dermatologic and Ophthalmic Drugs Advisory Committee Meeting, Summary Minutes (February 27, 2012) FDA Division of Anti-Infective and Ophthalmology Products Advisory Committee Meeting, Briefing Package for Besifloxacin Hydrochloride Ophthalmic Suspension FDA Draft Guidance on Brinzolamide (April 2014) FDA Draft Guidance on Brimonidine (February 2014) 21 C.F.R. §§ 312, 314, 320 76 Fed. Reg. 46,821 (August 3, 2011) Vocci MJ, Robin AL, Wahl JC, et al. Reformulation and drop size of apraclonidine hydrochloride. Am J Ophthalmol 1992;113:154-60. Charap AD, Shin DH, Petursson G, et al. Effect of varying drop size on the efficacy and safety of a topical beta blocker. Ann Ophthalmol 1989;21:351-7. Clinical Study Report: A multicenter, double-masked, randomized, parallel, vehicle-controlled, two week study of the safety, tolerability, and efficacy of once-daily bimatoprost 0.03% ophthalmic solution administered in microdrop volumes of 5 RL, 10 15 RL, and 20 RL compared with the marketed volume (30 IlL) in patients with glaucoma or glaucoma suspects. 2 Case 3:12-cv-01141-SMY-DGW Document 176-32 *SEALED* Filed 12/01/14 Page 40 of 40 Page ID #3013 Case: 16-3334 Document: 55-17 Filed: 02/08/2017 Pages: 40 (575 of 1511) Clinical Study Report: A comparison of the safety and efficacy of brimonidine 0.5% in two drop sizes. November 1994. Hennessy AL, Katz J, Covert D, Protzko C, Robin AL. Videotaped evaluation of eyedrop instillation in glaucoma patients with visual impairment or moderate to severe visual field loss. Ophthalmology 2010;117:2345-52. Hennessy AL, Katz J, Covert D, et al. A video study of drop instillation in both glaucoma and retina patients with visual impairment. Am J Ophthalmol 2011;152:982-8. Stone JL, Robin AL, Novack GD, Covert DW, Cagle GD. An objective evaluation of eyedrop instillation in patients with glaucoma. Arch Ophthalmol 2009;127:732-6. Kelly JA, Molyneux PD, Smith SA, Smith SE. Relative bioavailability of pilocarpine from a novel ophthalmic delivery system and conventional eyedrop formulations. Br J Ophthalmol 1989;73:360-2. Petursson G, Cole R, Hanna C. Treatment of Glaucoma Using Minidrops of Clonidine, Arch Ophthalmology. 1984; 102: 1180-1181. Lynch MG, Brown RH, Goode SM, Schoenwald RD, Chien DS. Reduction of Phenylephrine Drop Size in Infants Achieves Equal Dilation with Decreased Systemic Absorption. Arch Ophthalmology. 1987; 105: 1364-1365. Geyer 0, Bottone EJ, Podos SM, Schumer RA, Asbell PA. Microbial contamination of medications used to treat glaucoma. Br J Ophthalmol 1995;79:376-9. 3 . -· 9, Case 3:12-cv-01141-SMY-DGW Document 176-7 *SEALED* Filed 12/01/14 Page 1 of 59 Page ID #2319 Case: 16-3334 Document: 55-18 Filed: 02/08/2017 Pages: 59 (576 of 1511) 8500 Hidden River Parkway Tampa FL 33637 www.bausch.com To: ValidationMemo to File # V51-U-00 Cc: Susanne Martz, Ph.D. From: Don Herber Process Technic· Date: 17 March 2002 Subject: Doc. # V51 -U-00 BAUSCH & LOMB r >' Drop Size Technical AssessmentReport for Approved ANDA / NDA OphthahnicDrug Products Introduction This technical report is limited to the analysis of the drop size delivery associated with ophthalmic dmg products manufactured commerciallyby Bausch and Lomb, Tampa. This report includes twenty five (25) ANDA or NDA drug products that are fitted with polyethylenetips specificallydesigned to dispense ophthalmicdrug product in a controlledmanner. The approved tips used are supplied through qualified manufacturer Wheaton plastic products, Millville, N.J. Wheaton plastics is a common supplier of stock ophthalmic delivery tips to the pharmaceutical industry. The selection process of a specific tip for a drug product occurs during the research and developmentstage. During the research and development stage, numerousvariables, characteristics and attributes are carefully consideredand scrutinized prior to the selection of.a specific tip for dispensing of drug product. These variables will be highlighted as part of the discussionof this report. Furthermore, this report will also summarize the library field data for the drop studies previouslyperformed by Bausch and Lomb. Dropper Tip SelectionProcess During the research and development stage of a drug productthe following attributes are considered prior to the selection of a specific dropper tip. These variables include the following when deemed appropriatefor the developmentof an ophthalmic ANDA or NDA drug product: O O O O O Approvedresin / colorant for use with dmgs Approved / qualified manufacturer of tips Compatabilityof resin / design with drug product Compatabilityof resin with sterilizationprocess Compatabilityof tip with bottle to prevent leakage Compatabilityof the tip with cap to prevent deformity Compatabilityof the tip with aseptic filling machinery Ease of dispensing and safe (no sharp edges) Deliversproper quantity per drop when required Delivers a consistentdrop size Generally, the drop size is considered during the development of products which are consideredto be chronic (i.e.Anti-Glaucoma).The drop size is studied for this classification of drugs to afford the days therapy listed drug (when to the regards reference consumer a similar amount of of with applicable).For all other classifications of drugs such as anti-infective, anti-inflammatory and diagnostics the dropper tips deliver drops which exceed that of which the physiology of the eye can retain. Ophthalmic Drug Productswith Dropper Tips Bausch and Lomb currently commercializes twenty five (25) drug products with dropper tips, the following table highlights these approved products,classificationsand approved tips. I:\WIN\WINPROJ\Dropsizememo1.doc Page 1 of3 Confjdeggygg EXHIBIT MA W J /// /14 alliancecourtreporting.net CONFIDENTIAL SUBJECT TO PROTECTIVE ORDER PRODUCED BY BAUSCH & LOMB INCORPORATEDIN CASE NO. 3:12-CV-01141-DRH-DGW(S.D: ILL.) - BHLB_BRIM_0001076 Case 3:12-cv-01141-SMY-DGW Document 176-7 *SEALED* Filed 12/01/14 Page 2 of 59 Page ID #2320 Case: 16-3334 Document: 55-18 Filed: 02/08/2017 Pages: 59 (577 of 1511) Doc. # V51 -U-00 / ANDA NDA Drug Products with Dropper Tips (in order of approval date) Redacted Other Product GrandfatherAnti-Glaucoma Drug Products Redacted Other Product * Calculation based on average drop weight of 0.044 grams andproduct specificgravity COPY I:\WINNWINPROJ\Dropsizememo1.doc CONFIDENTIAL SUBJECT TO PROTECTIVE ORDER PRODUCEDBY BAUSCH & LOMB INCORPORATEDIN CASE NO. 3:12-CV-01141-DRH-DGW(S.D. ILL.) Page2 of3 Confidential - BHLB_BRIM_0001077 Case 3:12-cv-01141-SMY-DGW Document 176-7 *SEALED* Filed 12/01/14 Page 3 of 59 Page ID #2321 Case: 16-3334 Document: 55-18 Filed: 02/08/2017 Pages: 59 (578 of 1511) Doc. # V51 -U-00 Dropper Tip Delivery Performance The reference drop studies performed for the highlighted products are included as attachments to dimensionally identical; tips (XD30696, this report. All other Cores highlighted in the .table utilize Redacted Other using the same standard stock wheaton molds and tooling and only vary in colorant. These dimensionally identical tips are pierced with a 0.20" needle and are designed to deliver 23 drops +/- 3 drops per 1 cc of product. Each drop weighs approximately .038 to (ReferenceAttachment 9). The general toleranceof the piercing is +/tips used .050 grams .003". All are inspected per specificationprior to release to production. Productj Conclusion Based on a review of the associated data it is determinedthat the dropper tips associated with the approved ANDA or NDA or grandfatherdrug products are proper for their intended function. Further, it is determined that the tips are specifically designed to administerthe proper ophthalmicdosage in a controlled manner. The approved tips do not compromise the quality, purity, strength or therapeutic effectiveness when used to dispense these drug products. . htachments Redacted Other Product Attachment 6 Tip specification XD30696 15 mm White Redacted Other Product Attachment 9 Wheaton Memo "Extended ControlledDropper Tips Dispensing Characteristics" Redacted ÖtherProduct ©©py InWIN\WINPROJ\Dropsizememo1.doc CONFIDENTIAL SUBJECT TO PROTECTIVE ORDER PRODUCEDBY BAUSCH & LOMB INCORPORATED IN CASE NO. 3:12-CV-01141-DRH-DGW(S.D. ILL.) Page 3 of3 Confidential - BHLB_BRIM_0001078 Case 3:12-cv-01141-SMY-DGW Document 176-7 *SEALED* Filed 12/01/14 Page 4 of 59 Page ID #2322 Case: 16-3334 Document: 55-18 Filed: 02/08/2017 Pages: 59 (579 of 1511) Redacted Other Product ©© PY CONFIDENTIAL SUBJECT TO PROTECTIVE ORDER PRODUCED BY BAUSCH & LOMB INCORPORATEDIN CASE NO. 3:12-CV-01141-DRH-DGW(S.D. ILL.) - BHLB_BRIM_0001079 Case 3:12-cv-01141-SMY-DGW Document 176-7 *SEALED* Filed 12/01/14 Page 5 of 59 Page ID #2323 Case: 16-3334 Document: 55-18 Filed: 02/08/2017 Pages: 59 (580 of 1511) Redacted Other Product if l/ CONFIDENTIAL SUBJECT TO PROTECTIVE ORDER PRODUCED BY BAUSCH & LOMB INCORPORATED IN CASE NO. 3:12-CV-01141-DRH-DGW (S.D. ILL.) - BHLB_BRIM_0001080 Case 3:12-cv-01141-SMY-DGW Document 176-7 *SEALED* Filed 12/01/14 Page 6 of 59 Page ID #2324 Case: 16-3334 Document: 55-18 Filed: 02/08/2017 Pages: 59 (581 of 1511) r . 1 ( JTF1Q, s 8 , Redacted Other Product L CONFIDENTIAL SUBJECT TO PROTECTIVEORDER PRODUCED BY BAUSCH & LOMB INCORPORATEDIN CASE NO. 3:12-CV-01141-DRH-DGW (S.D. ILL.) BHLB_BRIM_0001081 Case 3:12-cv-01141-SMY-DGW Document 176-7 *SEALED* Filed 12/01/14 Page 7 of 59 Page ID #2325 Case: 16-3334 Document: 55-18 Filed: 02/08/2017 Pages: 59 (582 of 1511) I- Redacted Other Product CONFIDENTIAL SUBJECT TO PROTECTIVE ORDER PRODUCED BY BAUSCH & LOMB INCORPORATED IN CASE NO. 3:12-CV-01141-DRH-DGW (S.D. ILL.) - BHLB_BRIM_0001082 Case 3:12-cv-01141-SMY-DGW Document 176-7 *SEALED* Filed 12/01/14 Page 8 of 59 Page ID #2326 Case: 16-3334 Document: 55-18 Filed: 02/08/2017 Pages: 59 (583 of 1511) Redacted Other Product CONFIDENTIAL SUBJECT TO PROTECTIVE ORDER PRODUCEDBY BAUSCH & LOMB INCORPORATED IN CASE NO. 3:12-CV-01141-DRH-DGW (S.D. ILL.) - - BHLB_BRIM_0001083 Case 3:12-cv-01141-SMY-DGW Document 176-7 *SEALED* Filed 12/01/14 Page 9 of 59 Page ID #2327 Case: 16-3334 Document: 55-18 Filed: 02/08/2017 Pages: 59 (584 of 1511) Redacted Other Product CONFIDENTIAL SUBJECT TO PROTECTIVE ORDER PRODUCEDBY BAUSCH & LOMB INCORPORATEDIN CASE NO. 3:12-CV-01141-DRH-DGW(S.D. ILL.) - BHLB_BRIM_0001084 Case 3:12-cv-01141-SMY-DGW Document 176-7 *SEALED* Filed 12/01/14 Page 10 of 59 Page ID #2328 Case: 16-3334 Document: 55-18 Filed: 02/08/2017 Pages: 59 (585 of 1511) Redacted Other Product CONFIDENTIAL -- SUBJECT TO PROTECTIVE ORDER PRODUCED BY BAUSCH & LOMB INCORPORATED IN CASE NO. 3:12-CV-01141-DRH-DGW(S.D. ILL.) BHLB_BRIM_0001085 Case 3:12-cv-01141-SMY-DGW Document 176-7 *SEALED* Filed 12/01/14 Page 11 of 59 Page ID #2329 Case: 16-3334 Document: 55-18 Filed: 02/08/2017 Pages: 59 (586 of 1511) Redacted Other Product . , CONFIDENTIAL SUBJECT TO PROTECTIVE ORDER PRODUCEDBY BAUSCH & LOMB INCORPORATED IN CASE NO. 3:12-CV-01141-DRH-DGW (S.D. ILL.) \ l \ l - BHLB_BRIM_0001086 Case 3:12-cv-01141-SMY-DGW Document 176-7 *SEALED* Filed 12/01/14 Page 12 of 59 Page ID #2330 Case: 16-3334 Document: 55-18 Filed: 02/08/2017 Pages: 59 (587 of 1511) Redacted Other Product CONFIDENTIAL SUBJECT TO PROTECTIVE ORDER PRODUCED BY BAUSCH & LOMB INCORPORATEDIN CASE NO. 3:12-CV-01141-DRH-DGW (S.D. ILL.) - BHLB_BRIM_0001087 Case 3:12-cv-01141-SMY-DGW Document 176-7 *SEALED* Filed 12/01/14 Page 13 of 59 Page ID #2331 Case: 16-3334 Document: 55-18 Filed: 02/08/2017 Pages: 59 (588 of 1511) Redacted Other Product CONFIDENTIAL SUBJECT TO PROTECTIVEORDER PRODUCED BY BAUSCH & LOMB INCORPORATEDIN CASE NO. 3:12-CV-01141-DRH-DGW(S.D. ILL.) - BHLB BRIM_0001088 Case 3:12-cv-01141-SMY-DGW Document 176-7 *SEALED* Filed 12/01/14 Page 14 of 59 Page ID #2332 Case: 16-3334 Document: 55-18 Filed: 02/08/2017 Pages: 59 (589 of 1511) Redacted Other Product CONFIDENTIAL SUBJECT TO PROTECTIVE ORDER PRODUCED BY BAUSCH & LOMB INCORPORATED IN CASE NO. 3:12-CV-01141-DRH-DGW (S.D. ILL.) - BHLB_BRIM_0001089 Case 3:12-cv-01141-SMY-DGW Document 176-7 *SEALED* Filed 12/01/14 Page 15 of 59 Page ID #2333 Case: 16-3334 Document: 55-18 Filed: 02/08/2017 Pages: 59 (590 of 1511) Redacted Other Product CONFIDENTIAL SUBJECT TO PROTECTIVEORDER PRODUCED BY BAUSCH & LOMB INCORPORATED IN CASE NO. 3:12-CV-01141-DRH-DGW(S.D. ILL.) - BHLB BRIM 0001090 Case 3:12-cv-01141-SMY-DGW Document 176-7 *SEALED* Filed 12/01/14 Page 16 of 59 Page ID #2334 Case: 16-3334 Document: 55-18 Filed: 02/08/2017 Pages: 59 (591 of 1511) Redacted Other Product CONFIDENTIAL SUBJECT TO PROTECTIVE ORDER PRODUCED BY BAUSCH & LOMB INCORPORATEDIN CASE NO. 3:12-CV-01141-DRH-DGW(S.D. ILL.) - BHLB_BRIM_0001091 Case 3:12-cv-01141-SMY-DGW Document 176-7 *SEALED* Filed 12/01/14 Page 17 of 59 Page ID #2335 Case: 16-3334 Document: 55-18 Filed: 02/08/2017 Pages: 59 (592 of 1511) / RedaCted Other ProduCt CONFIDENTIAL SUBJECT TO PROTECTIVE ORDER PRODUCED BY BAUSCH & LOMB INCORPORATED IN CASE NO. 3:12-CV-01141-DRH-DGW(S.D. ILL.) - BHLB_BRIM_0001092 Case 3:12-cv-01141-SMY-DGW Document 176-7 *SEALED* Filed 12/01/14 Page 18 of 59 Page ID #2336 Case: 16-3334 Document: 55-18 Filed: 02/08/2017 Pages: 59 (593 of 1511) Redacted Other Product CONFIDENTIAL SUBJECT TO PROTECTIVE ORDER PRODUCED BY BAUSCH & LOMB INCORPORATED IN CASE NO. 3:12-CV-01141-DRH-DGW (S.D. ILL.) - BHLB BRIM 0001093 Case 3:12-cv-01141-SMY-DGW Document 176-7 *SEALED* Filed 12/01/14 Page 19 of 59 Page ID #2337 Case: 16-3334 Document: 55-18 Filed: 02/08/2017 Pages: 59 (594 of 1511) Redacted Other Product CONFIDENTIAL SUBJECT TO PROTECTIVEORDER PRODUCED BY BAUSCH & LOMB INCORPORATEDIN CASE NO. 3:12-CV-01141-DRH-DGW (S.D. ILL.) - BHLB_BRIM_0001094 Case 3:12-cv-01141-SMY-DGW Document 176-7 *SEALED* Filed 12/01/14 Page 20 of 59 Page ID #2338 Case: 16-3334 Document: 55-18 Filed: 02/08/2017 Pages: 59 (595 of 1511) Redacted Other Product CONFIDENTIAL SUBJECT TO PROTECTIVEORDER PRODUCED BY BAUSCH & LOMB INCORPORATED IN CASE NO. 3:12-CV-01141-DRH-DGW(S.D. ILL.) - BHLB BRIM 0001095 Case 3:12-cv-01141-SMY-DGW Document 176-7 *SEALED* Filed 12/01/14 Page 21 of 59 Page ID #2339 Case: 16-3334 Document: 55-18 Filed: 02/08/2017 Pages: 59 (596 of 1511) Redacted Other Product ©©PY CONFIDENTIAL SUBJECT TO PROTECTIVE ORDER PRODUCEDBY BAUSCH & LOMB INCORPORATED IN CASE NO. 3:12-CV-01141-DRH-DGW(S.D. ILL.) - BHLB_BRIM_0001096 Case 3:12-cv-01141-SMY-DGW Document 176-7 *SEALED* Filed 12/01/14 Page 22 of 59 Page ID #2340 Case: 16-3334 Document: 55-18 Filed: 02/08/2017 Pages: 59 (597 of 1511) Redacted Other Product CONFIDENTIAL SUBJECT TO PROTECTIVE ORDER PRODUCED BY BAUSCH & LOMB INCORPORATEDIN CASE NO, 3:12-CV-01141-DRH-DGW (S.D. ILL.) - BHLB_BRIM 0001097 Case 3:12-cv-01141-SMY-DGW Document 176-7 *SEALED* Filed 12/01/14 Page 23 of 59 Page ID #2341 Case: 16-3334 Document: 55-18 Filed: 02/08/2017 Pages: 59 (598 of 1511) Redacted Other Product p 2 CONFIDENTIAL SUBJECT TO PROTECTIVE ORDER PRODUCED BY BAUSCH & LOMB INCORPORATEDIN CASE NO. 3:12-CV-01141-DRH-DGW(S.D. ILL.) - BHLB BRIM 0001098 Case 3:12-cv-01141-SMY-DGW Document 176-7 *SEALED* Filed 12/01/14 Page 24 of 59 Page ID #2342 Case: 16-3334 Document: 55-18 Filed: 02/08/2017 Pages: 59 (599 of 1511) Redacted Other Product CONFIDENTIAL-- SUBJECT TO PROTECTIVE ORDER PRODUCED BY BAUSCH & LOMB INCORPORATEDIN CASE NO. 3:12-CV-01141-DRH-DGW(S.D. ILL.) BHLB BRIM 0001099 Case 3:12-cv-01141-SMY-DGW Document 176-7 *SEALED* Filed 12/01/14 Page 25 of 59 Page ID #2343 Case: 16-3334 Document: 55-18 Filed: 02/08/2017 Pages: 59 (600 of 1511) Redacted Other Product \ l 4 CONFIDENTIAL SUBJECT TO PROTECTIVEORDER PRODUCEDBY BAUSCH & LOMB INCORPORATEDIN CASE NO. 3:12-CV-01141-DRH-DGW(S.D. ILL.) - BHLB BRIM_0001100 Case 3:12-cv-01141-SMY-DGW Document 176-7 *SEALED* Filed 12/01/14 Page 26 of 59 Page ID #2344 Case: 16-3334 Document: 55-18 Filed: 02/08/2017 Pages: 59 (601 of 1511) Redacted Other Product CONFIDENTIAL SUBJECT TO PROTECTIVE ORDER PRODUCEDBY BAUSCH & LOMB INCORPORATEDIN CASE NO. 3:12-CV-01141-DRH-DGW(S.D. ILL.) - BHLB_BRIM_0001101 Case 3:12-cv-01141-SMY-DGW Document 176-7 *SEALED* Filed 12/01/14 Page 27 of 59 Page ID #2345 Case: 16-3334 Document: 55-18 Filed: 02/08/2017 Pages: 59 (602 of 1511) L Redacted Other Product CONFIDENTIAL SUBJECT TO PROTECTIVEORDER PRODUCED BY BAUSCH & LOMB INCORPORATEDIN CASE NO. 3:12-CV-01141-DRH-DGW(S.D. ILL.) - BHLB BRIM 0001102 Case 3:12-cv-01141-SMY-DGW Document 176-7 *SEALED* Filed 12/01/14 Page 28 of 59 Page ID #2346 Case: 16-3334 Document: 55-18 Filed: 02/08/2017 Pages: 59 (603 of 1511) Redacted Other Product CONFIDENTIAL SUBJECT TO PROTECTIVE ORDER PRODUCED BY BAUSCH & LOMB INCORPORATEDIN CASE NO. 3:12-CV-01141-DRH-DGW(S.D. ILL.) - BHLB_BRIM_0001103 Case 3:12-cv-01141-SMY-DGW Document 176-7 *SEALED* Filed 12/01/14 Page 29 of 59 Page ID #2347 Case: 16-3334 Document: 55-18 Filed: 02/08/2017 Pages: 59 (604 of 1511) Redacted Other Product CONFIDENTIAL SUBJECT TO PROTECTIVE ORDER PRODUCED BY BAUSCH & LOMB INCORPORATEDIN CASE NO. 3:12-CV-01141-DRH-DGW(S.D. ILL.) - BHLB_BRIM_0001104 Case 3:12-cv-01141-SMY-DGW Document 176-7 *SEALED* Filed 12/01/14 Page 30 of 59 Page ID #2348 Case: 16-3334 Document: 55-18 Filed: 02/08/2017 Pages: 59 (605 of 1511) Redacted Other Product L - - ,- - - - _. - - -. - - - _. - - - . -- . ,- . - . - - - - - . - - ,- - - -- - CONFIDENTIAL SUBJECT- TO PROTECTIVEORDER PRODUCED BY BAUSCH & LOMB INCORPORATED IN CASE NO. 3:12-CV-01141-DRH-DGW (S.D. ILL.) .... - - .- . _. - . - . - - - . _ . _ . ... . _ . _ .. _. ... - - - . ___. _. . . -- --- - - - - - . - . - - - - - - - - - . - - - . _. ..- - -. - . - -..- -- -- - - - - - - . _ . - . . _.. _.. _. _ . _ . _ . _. _ . _ . _ . _ . _ . _ . _. . _ . _ . _ . _ . _ ._. _ . _ . _. - BHLB BRIM_0001105 Case 3:12-cv-01141-SMY-DGW Document 176-7 *SEALED* Filed 12/01/14 Page 31 of 59 Page ID #2349 Case: 16-3334 Document: 55-18 Filed: 02/08/2017 Pages: 59 (606 of 1511) Redacted Other Product / CONFIDENTIAL SUBJECT TO PROTECTIVE ORDER PRODUCEDBY BAUSCH & LOMB INCORPORATEDIN CASE NO. 3:12-CV-01141-DRH-DGW (S.D. ILL.) - BHLB_BRIM_0001106 Case 3:12-cv-01141-SMY-DGW Document 176-7 *SEALED* Filed 12/01/14 Page 32 of 59 Page ID #2350 Case: 16-3334 Document: 55-18 Filed: 02/08/2017 Pages: 59 (607 of 1511) I B Redacted Other Product CONFIDENTIAL SUBJECT TO PROTECTIVE ORDER PRODUCEDBY BAUSCH & LOMB INCORPORATED IN CASE NO. 3:12-CV-01141-DRH-DGW(S.D. ILL.) - BHLB_BRIM_0001107 Case 3:12-cv-01141-SMY-DGW Document 176-7 *SEALED* Filed 12/01/14 Page 33 of 59 Page ID #2351 Case: 16-3334 Document: 55-18 Filed: 02/08/2017 Pages: 59 (608 of 1511) / Redacted Other Product 9 CONFIDENTIAL SUBJECT TO PROTECTIVE ORDER PRODUCED BY BAUSCH & LOMB INCORPORATED IN CASE NO. 3:12-CV-01141-DRH-DGW(S.D. ILL.) - BHLB BRIM 0001108 Case 3:12-cv-01141-SMY-DGW Document 176-7 *SEALED* Filed 12/01/14 Page 34 of 59 Page ID #2352 Case: 16-3334 Document: 55-18 Filed: 02/08/2017 Pages: 59 (609 of 1511) Redacted Other Product CONFIDENTIAL SUBJECT TO PROTECTIVE ORDER PRODUCED BY BAUSCH & LOMB INCORPORATED IN CASE NO. 3:12-CV-01141-DRH-DGW(S.D. ILL.) - BHLB_BRIM_0001109 Case 3:12-cv-01141-SMY-DGW Document 176-7 *SEALED* Filed 12/01/14 Page 35 of 59 Page ID #2353 Case: 16-3334 Document: 55-18 Filed: 02/08/2017 Pages: 59 (610 of 1511) Redacted Other Product CONFIDENTIAL SUBJECT TO PROTECTIVE ORDER PRODUCED BY BAUSCH & LOMB INCORPORATEDIN CASE NO. 3:12-CV-01141-DRH-DGW(S.D. ILL.) - BHLB BRIM 0001110 Case 3:12-cv-01141-SMY-DGW Document 176-7 *SEALED* Filed 12/01/14 Page 36 of 59 Page ID #2354 Case: 16-3334 Document: 55-18 Filed: 02/08/2017 Pages: 59 (611 of 1511) Redacted Other Product CONFIDENTIAL SUBJECT TO PROTECTIVE ORDER PRODUCED BY BAUSCH & LOMB INCORPORATEDIN CASE NO. 3:12-CV-01141-DRH-DGW (S.D. ILL.) - BHLB_BRIM_0001111 Case 3:12-cv-01141-SMY-DGW Document 176-7 *SEALED* Filed 12/01/14 Page 37 of 59 Page ID #2355 Case: 16-3334 Document: 55-18 Filed: 02/08/2017 Pages: 59 (612 of 1511) Redacted Other Product CONFIDENTIAL SUBJECT TO PROTECTIVE ORDER PRODUCEDBY BAUSCH & LOMB INCORPORATEDIN CASE NO. 3:12-CV-01141-DRH-DGW(S.D. ILL.) - BHLB_BRIM_0001112 Case 3:12-cv-01141-SMY-DGW Document 176-7 *SEALED* Filed 12/01/14 Page 38 of 59 Page ID #2356 Case: 16-3334 Document: 55-18 Filed: 02/08/2017 Pages: 59 (613 of 1511) Redacted Other Product CONFIDENTIAL SUBJECTTO PROTECTIVE ORDER PRODUCED BY BAUSCH & LOMB INCORPORATED IN CASE NO. 3:12-CV-01141-DRH-DGW(S.D. ILL.) - BHLB_BRIM_0001113 Case 3:12-cv-01141-SMY-DGW Document 176-7 *SEALED* Filed 12/01/14 Page 39 of 59 Page ID #2357 Case: 16-3334 Document: 55-18 Filed: 02/08/2017 Pages: 59 (614 of 1511) Redacted Other Product CONFIDENTIAL SUBJECT TO PROTECTIVE ORDER PRODUCED BY BAUSCH & LOMB INCORPORATEDIN CASE NO. 3:12-CV-01141-DRH-DGW(S.D. ILL.) - BHLB_BRIM 0001114 Case 3:12-cv-01141-SMY-DGW Document 176-7 *SEALED* Filed 12/01/14 Page 40 of 59 Page ID #2358 Case: 16-3334 Document: 55-18 Filed: 02/08/2017 Pages: 59 (615 of 1511) Redacted Other Product CONFIDENTIAL SUBJECT TO PROTECTIVEORDER PRODUCED BY BAUSCH & LOMB INCORPORATEDIN CASE NO. 3:12-CV-01141-DRH-DGW(S.D. ILL.) - BHLB BRIM 0001115 Case 3:12-cv-01141-SMY-DGW Document 176-7 *SEALED* Filed 12/01/14 Page 41 of 59 Page ID #2359 Case: 16-3334 Document: 55-18 Filed: 02/08/2017 Pages: 59 (616 of 1511) Redacted Other Product CONFIDENTIAL SUBJECT TO PROTECTIVE ORDER PRODUCEDBY BAUSCH & LOMB INCORPORATEDIN CASE NO. 3:12-CV-01141-DRH-DGW(S.D. ILL.) - BHLB_BRIM_0001116 Case 3:12-cv-01141-SMY-DGW Document 176-7 *SEALED* Filed 12/01/14 Page 42 of 59 Page ID #2360 Case: 16-3334 Document: 55-18 Filed: 02/08/2017 Pages: 59 (617 of 1511) Redacted Other Product CONFIDENTIAL SUBJECT TO PROTECTIVE ORDER PRODUCED BY BAUSCH & LOMB INCORPORATED IN CASE NO. 3:12-CV-01141-DRH-DGW(S.D. ILL.) - . BHLB_BRIM 0001117 Case 3:12-cv-01141-SMY-DGW Document 176-7 *SEALED* Filed 12/01/14 Page 43 of 59 Page ID #2361 Case: 16-3334 Document: 55-18 Filed: 02/08/2017 Pages: 59 (618 of 1511) Redacted Other ProduCt I / CONFIDENTIAL SUBJECT TO PROTECTIVEORDER PRODUCEDBY BAUSCH & LOMB INCORPORATEDIN CASE NO. 3:12-CV-01141-DRH-DGW(S.D. ILL.) - BHLB_BRIM_0001118 Case 3:12-cv-01141-SMY-DGW Document 176-7 *SEALED* Filed 12/01/14 Page 44 of 59 Page ID #2362 Case: 16-3334 Document: 55-18 Filed: 02/08/2017 Pages: 59 (619 of 1511) Attachment 6 CONFIDENTIAL SUBJECT TO PROTECTIVE ORDER PRODUCEDBY BAUSCH & LOMB INCORPORATEDIN CASE NO. 3:12-CV-01141-DRH-DGW (S.D. ILL.) - . BHLB BRIM 0001119 Case 3:12-cv-01141-SMY-DGW Document 176-7 *SEALED* Filed 12/01/14 Page 45 of 59 Page ID #2363 Case: 16-3334 Document: 55-18 Filed: 02/08/2017 Pages: 59 (620 of 1511) N IDÈNTIAL THIS IS PROPRIETARY INFORMATION Bausch & Tip, Sterilized, Mat . Mgmt . Date: 3-244'l Supersedes: XD30696-08 Component Specification: XD30696-09 Lomb Pharmaceuticals, Inc. 15 mm, L.L.D.P.E., White, Extended Control Dropper Tip 2 // O : Production : Eff. Packaging Engi . Reg . (1°?7 , r /e 3..,jVf Af f airs : Q A. : . Purchasing : Per Policy P-37 XD30697 (Packed Distribution: References: for Sterilization Specification), M-012 (Visual Inspection), S-021 (Sterilization at Smyrna) '; ' General Requirements ' L.L.D.P.E. - Dow Chemical's Dowlex 2517 ICOO82-White, produced by Marval Industries, Inc. (#MCC3258C) RESIN: - COLORANT: PIERCED: Needle .020 CONTAINER: 7000 ± 2% QUANTITY PER BAUSCH & LOMB PART #: XD30696 PACKAGING: Double polybag, ring & filter assembly in an appropriate corrugated shipping case sealed with reinforced paper tape (H-pattern) top and bottom. in accordance with Tips are to be of sterilized Components Procedure #S-021. Bausch & Lomb's Sterili?ation Shipping Requirement Containers are to be clean and free of damage. In addition to the manufacturer's/supplier's labelling, the vendor must include the following information: sterilization STERILIEED Date Sterilization Vacugas Number Internal Note: &Containers are to be labelled as NON-STERILE prior to shipping to Bausch Lomb's designated sterilization vendor. shall be marked to instruct the carrier to "deliver goods as Bill of Lading " B&L tendered. ? ©©py Page 1 .... .. . CONFIDENTIAL SUBJECT TO PROTECTIVEORDER PRODUCEDBY BAUSCH & LOMB INCORPORATEDIN CASE NO. 3:12-CV-01141-DRH-DGW(S.D. ILL.) of 3 OFFICIAL COPY - BHLB BRIM 0001120 Case 3:12-cv-01141-SMY-DGW Document 176-7 *SEALED* Filed 12/01/14 Page 46 of 59 Page ID #2364 Case: 16-3334 Document: 55-18 Filed: 02/08/2017 Pages: 59 (621 of 1511) c18ÞIDÈNTIAL THfS IS PROPRIETARY INFORMATION Bausch Component Specification: XD30696-09 & Lomb iPhapnaceuticals, Inc. Tip, Sterilized, 15 mm, Eff. Date: 3Ö4J Supersedes: XD30696-08 L.L.D.P.E., White, Extended Control Dropper Tip '' Pai let Lug Requirement s Pallets are to be 4-Way Entry Type, 40" x 48", wood or plastic. height, with pallet, is 70". Pallet is to be stretch wrapped. - - Ápproved Manufacturers Lawson Mardon Wheaton - Drawing #B11953, Rev. C, Dated 12-05-94 . . . Maximum . Comments is required for each Certificate of Compliance Bausch & Lomb. A packing delivered to product manufacturer's lot of list from the supplier is required with the delivery. If any change is contemplated in the raw materials or processing method, Bausch & Lomb Pharmaceuticals, Inc. must be notified in writing prior to such change with adequate notice for evaluation. Samples for evaluating may be required. Shipment to Bausch & Lomb of product produced under the aforementioned changes are prohibited until prior written approval is obtained from Quality Bausch & Lomb Pharmaceuticals, Assurance A manufacturer's Inc.. of Reason e . for Revision DCO #96-10 -040 : Change company name . DCO #96-08-104: Remove DCO #97-03-005: Wheaton, Inc. was purchased by Alusuisse-Lonza and name was changed to Lawson Mardon Wheaton. Name change only. No change in manufacturing location, process, inaterials, equipment or personnel; Allowable variance added to aid shading. Manufacturing in reconciling quantity variances experienced during production runs. Page 2 of 3 OFFICIAL COPY CONFIDENTIAL SUBJECT TO PROTECTIVE ORDER PRODUCEDBY BAUSCH & LOMB INCORPORATEDIN CASE NO. 3:12-CV-01141-DRH-DGW (S.D. ILL.) - BHLB_BRIM_0001121 Case 3:12-cv-01141-SMY-DGW Document 176-7 *SEALED* Filed 12/01/14 Page 47 of 59 Page ID #2365 Case: 16-3334 Document: 55-18 Filed: 02/08/2017 Pages: 59 (622 of 1511) THIS IS PROPRIETARY INFORMATION XD30696-09 8 m COPY ? Page 3 CONFIDENTIAL SUBJECT TO PROTECTIVEORDER PRODUCEDBY BAUSCH & LOMB INCORPORATEDIN CASE NO. 3:12-CV-01141-DRH-DGW(S.D. ILL.) of 3 OFFICIAL COPY - BHLB_BRIM 0001122 Case 3:12-cv-01141-SMY-DGW Document 176-7 *SEALED* Filed 12/01/14 Page 48 of 59 Page ID #2366 Case: 16-3334 Document: 55-18 Filed: 02/08/2017 Pages: 59 (623 of 1511) I \ Redacted Other Product CONFIDENTIAL SUBJECT TO PROTECTIVE ORDER PRODUCEDBY BAUSCH & LOMB INCORPORATEDIN CASE NO. 3:12-CV-01141-DRH-DGW (S.D. ILL.) - BHLB_BRIM_0001123 Case 3:12-cv-01141-SMY-DGW Document 176-7 *SEALED* Filed 12/01/14 Page 49 of 59 Page ID #2367 Case: 16-3334 Document: 55-18 Filed: 02/08/2017 Pages: 59 (624 of 1511) Redacted Other Product CONFIDENTIAL SUBJECT TO PROTECTIVE ORDER PRODUCED BY BAUSCH & LOMB INCORPORATED IN CASE NO. 3:12-CV-01141-DRH-DGW (S.D. ILL.) - BHLB_BRIM_0001124 Case 3:12-cv-01141-SMY-DGW Document 176-7 *SEALED* Filed 12/01/14 Page 50 of 59 Page ID #2368 Case: 16-3334 Document: 55-18 Filed: 02/08/2017 Pages: 59 (625 of 1511) Redacted Other Product CONFIDENTIAL SUBJECT TO PROTECTIVEORDER PRODUCED BY BAUSCH & LOMB INCORPORATED IN (S.D. ILL.) CASE NO. 3:12-CV-01141-DRH-DGW - BHLB_BRIM_0001125 Case 3:12-cv-01141-SMY-DGW Document 176-7 *SEALED* Filed 12/01/14 Page 51 of 59 Page ID #2369 Case: 16-3334 Document: 55-18 Filed: 02/08/2017 Pages: 59 (626 of 1511) I Redacted Other Product CONFIDENTIAL SUBJECT TO PROTECTIVE ORDER PRODUCED BY BAUSCH & LOMB INCORPORATEDIN CASE NO. 3:12-CV-01141-DRH-DGW(S.D. ILL.) - BHLB_BRIM_0001126 Case 3:12-cv-01141-SMY-DGW Document 176-7 *SEALED* Filed 12/01/14 Page 52 of 59 Page ID #2370 Case: 16-3334 Document: 55-18 Filed: 02/08/2017 Pages: 59 (627 of 1511) Redacted Other Product I CONFIDENTIAL SUBJECT TO PROTECTIVEORDER PRODUCED BY BAUSCH & LOMB INCORPORATEDIN CASE NO. 3:12-CV-01141-DRH-DGW (S.D. ILL.) - . BHLB_BRIM_0001127 Case 3:12-cv-01141-SMY-DGW Document 176-7 *SEALED* Filed 12/01/14 Page 53 of 59 Page ID #2371 Case: 16-3334 Document: 55-18 Filed: 02/08/2017 Pages: 59 (628 of 1511) Redacted Ot er Product CONFIDENTIAL SUBJECT TO PROTECTIVE ORDER PRODUCEDBY BAUSCH & LOMB INCORPORATED IN CASE NO. 3:12-CV-01141-DRH-DGW(S.D. ILL.) - BHLB_BRIM 0001128 Case 3:12-cv-01141-SMY-DGW Document 176-7 *SEALED* Filed 12/01/14 Page 54 of 59 Page ID #2372 Case: 16-3334 Document: 55-18 Filed: 02/08/2017 Pages: 59 (629 of 1511) Redacted Other Product CONFIDENTIAL SUBJECT TO PROTECTIVE ORDER PRODUCED BY BAUSCH & LOMB INCORPORATEDIN CASE NO. 3:12-CV-01141-DRH-DGW (S.D. ILL.) 1 - BHLB_BRIM 0001129 Case 3:12-cv-01141-SMY-DGW Document 176-7 *SEALED* Filed 12/01/14 Page 55 of 59 Page ID #2373 Case: 16-3334 Document: 55-18 Filed: 02/08/2017 Pages: 59 (630 of 1511) Redacted Other Product CONFIDENTIAL SUBJECT TO PROTECTIVE ORDER PRODUCED BY BAUSCH & LOMB INCORPORATEDIN CASE NO. 3:12-CV-01141-DRH-DGW(S.D. ILL.) - BHLB_BRIM_0001130 Case 3:12-cv-01141-SMY-DGW Document 176-7 *SEALED* Filed 12/01/14 Page 56 of 59 Page ID #2374 Case: 16-3334 Document: 55-18 Filed: 02/08/2017 Pages: 59 (631 of 1511) Attachment 9 e opy CONFIDENTIAL SUBJECT TO PROTECTIVE ORDER PRODUCEDBY BAUSCH & LOMB INCORPORATED IN CASE NO. 3:12-CV-01141-DRH-DGW (S.D. ILL.) - BHLB_BRIM_0001131 Case 3:12-cv-01141-SMY-DGW Document 176-7 *SEALED* Filed 12/01/14 Page 57 of 59 Page ID #2375 Case: 16-3334 Document: 55-18 Filed: 02/08/2017 Pages: 59 (632 of 1511) Dropper Tips (Extended) PARTS/ CAT.# PIC DE50UP110N SEE MATL CTN. 11225 13MM Round1/64(.016) 3-13-1 LDPE 10000 11122 13MM Round1ß2 (.031) 3-13-1 LDPE 10000 10998 13MM Round3/32(.094) 3-13-1 LDPE 10000 12080 15MM Squarelß2 (.031) 1-15-1 LDPE 14000 11947 15MM Round122 (.031) 1-15-1 LDPE 9000 11948 15MM Round1/16(.062) 1-15-1 LDPE 9000 11949 15MM Round 1/64(.016) 1-15-1 LDPE 9000 Square122 (.031) 1-15-1 LDPE 10000 Square3/64(.047) 1-15-1 LDPE 10000 10315 15MM 10323 15MM 11913 18MM Round1/64(.016) 1-16-1 LDPE 6500 11909 18MM Round1/32(.031) 1-18.1 LDPE 6500 11910 18MM Round1/16(.062) 1-18-1 LDPE 6500 10952 18MM Round382(.094) 1-18-1 LDPE 11915 20MM Round1164(.016) 1-20-1 LDPE ? ? 6500 . 4500 11917 20MM Round1ß2(.031) 1-20.1 LDPE 4500 11918 20MM Round1/16(.062) 1-20-1 LDPE 4500 10969 20MM Round382 (.094) 1-20.1 LDPE 4500 . Extended Controlled Dropper Tips DispensingCharacteristics DropperTips (Extended Controlled) SEE CAT.# DESOUPTION Pic MATL PARTS/ CfN. LDPE 20000 120B6 BMM EXTROUND TIP 3-08-1 12198 8MM EXTROUNDTIPMO 3.08-1 LDPE 20000 12208 BMM EXTROUNDTlP 348-1 1.DPE 20000 10270 8MM EXTROUNDTIP 3-08-1 LDPE 20000 11987 13MM EXTROUNDTIP 3-13-1 LDPE 10000 12214 13MM EXTROUNDTIPMO 3-13-1 LDPE 10000 11215 13MM EXTSQUARE TIP 3-13-1 LDPE 10000 · 12209 15MM EXTROUNDTIPMO 1-15-1 LDPE 9000 11953 15MM EXTROUNDTIP 1-15-1 LDPE 9000 11954 15MM EXTSQUARE TIP 1-15-1 LDPE 8500 11911 18MM EXTROUND TIP 1-18-1 LDPE 6000 . 10593 18MM EXTSQUARE TIP 1-18-1 LDPE 6000 11914 20MM EXTROUND TIP 1-20-1 LLPE 5000 11877 20MM EXT5QUARETIP 1-20-1 LDPE 4500 10886 20MM EXTVACGNE TIP 1-20-1 LDPE 6500 uo uoldef orifice. Beloware the results of testing conductedusing distilled wateras the dispensedproduct. 1.There is no variation in volume dispensed when changing the diameter of the pin used to pierce the tip (i.e. a part piercedwith a .018" needle will dispense the same volume as one pierced with a .037" needle).The purpose of piercing with a larger needle is to ease dispensing when a more viscous product is being used. 2, All round tip plugs (8mm - 20mm) are designed to deliver 23 drops ± 3 drops per 1 cc of products except 12086, 8mm, designed at 55 drops ±3 drops. 3.All square tip plugs (13mm - 20mm) are designed to deliver 16 drops ± 2 drops per 1 cc of product. 4.The gÄneral tolerance for the hole size in pierced part is ± .003". ! a 5..Fofa round tip, each drop weighs approximately 12086, which .038 to .050 grams, except is designed to deliver drops weighing approximately .017 to .019 grams. 6.For a square tip, each drop weighs approximately .055 to .070 grams. 7. Molded orifice available in 8MM, 13MM, and 15MM ext. round tip. ©OPY CONFIDENTIAL SUBJECTTO PROTECTIVE ORDER PRODUCEDBY BAUSCH & LOMB INCORPORATEDIN CASE NO. 3:12-CV-01141-DRH-DGW(S.D. ILL.) These statements aæ to be used as gamelines on . and shouldnot be - BHLB BRIM 0001132 Case 3:12-cv-01141-SMY-DGW Document 176-7 *SEALED* Filed 12/01/14 Page 58 of 59 Page ID #2376 Case: 16-3334 Document: 55-18 Filed: 02/08/2017 Pages: 59 (633 of 1511) Redacted Other Product CONFIDENTIAL SUBJECT TO PROTECTIVE ORDER PRODUCED BY BAUSCH & LOMB INCORPORATED IN CASE NO. 3:12-CV-01141-DRH-DGW(S.D. ILL.) - BHLB_BRIM_0001133 Case 3:12-cv-01141-SMY-DGW Document 176-7 *SEALED* Filed 12/01/14 Page 59 of 59 Page ID #2377 Case: 16-3334 Document: 55-18 Filed: 02/08/2017 Pages: 59 (634 of 1511) Redacted Other Product CONF DENTIAL SUBJECTTO PROTECTIVEORDER PRODUCED BY BAUSCH & LOMB INCORPORATED IN CASE NO. 3:12-CV-01141-DRH-DGW(S.D. ILL.) - BHLB BRIM 0001134 Case 3:12-cv-01141-SMY-DGW Document 176-33 *SEALED* Filed 12/01/14 Page 1 of 126 Page ID #3014 Case: 16-3334 Document: 55-19 Filed: 02/08/2017 Pages: 126 (635 of 1511) Expert Report of Jimmy D. Bartlett, O.D., D.O.S., D.Sc. Introduction and Oualifications I have been asked to offer my opinions 1. in Eike, et al v Allergan, et al. I received , Tennessee in thern College of Optometry in Memphis my Doctor of Optometry degree from Sou ometry Service at the Tampa Veterans 1974. After serving as Chief of the Opt Affairs Medical ity of South artment of Ophthalmology at the Univers Dep the in r esso prof t stan assi as and Center try, University a faculty position at the School of Optome pted acce I e, icin Med of lege Col ida Flor served as 7. I rose through the academic ranks and of Alabama at Birmingham (UAB) in 197 essor and ctor of Residency Programs, and as prof Director of Continuing Education, Dire gram. I also try and Director of the Professional Pro chairman of the Department of Optome icology at the the Department of Pharmacology and Tox in gy colo rma pha of r esso prof as ed serv e. University of Alabama School of Medicin ometry — Journal of the American I have served as Editor-in-Chief of Opt 2. edition; and Ocular Pharmacology, now in its fifth ical Clin of r dito ; co-e tion ocia Ass tric Optome l of Ocular for Ophthalmic Drug Facts and Journa I served on the editorial advisory board Alabama at ng a 34-year career at' the University of Pharmacology and Therapeutics. Followi y serve as ment of Professor Emeritus and currentl oint app the with ored hon was I am, Birmingh ceutical isory service to the ophthalmic pharma adv an up, Gro ON AK RM PHA of t presiden industry. 3. literature and ic and abstracts in the clinical and scientif I have published more than 240 papers lectures throughout the world to both have delivered more than 1,200 invited clinical and research audiences. I am the recipient of two honorary degrees and in 2000 was tury. t influential optometrists of the 20th Cen selected by Review of Optometry as one of the mos 4. My optometry education was completed re at Southern College of Optometry, whe orary honored by my alma mater with the hon was I 6 198 In 4. 197 in n oria dict vale as I graduated ical ocular for my contributions to the field of clin .S.) (D.O nce Scie lar Ocu of tor Doc ree deg become one of textbook by the same name that was to pharmacology. I had published a major Case 3:12-cv-01141-SMY-DGW Document 176-33 *SEALED* Filed 12/01/14 Page 2 of 126 Page ID #3015 Case: 16-3334 Document: 55-19 Filed: 02/08/2017 Pages: 126 (636 of 1511) the standard textbooks in the field. Clinical Ocular Pharmacology 2002 I was honored by State Univer sity of New York (SUNY), which gra Doctor of Science (D.Sc.) degree for public service in the area of pharma 5. is now in its fifth edition. In nted the honorary my longstanding contributions in teac hing, research, and cologic education and scholarly wor k. Over the past four decades I have held clinical appointments and positions. a number of important academic and These include director of the ocular electrodiagnostic laboratory at All Children's Hospita l in St. Petersburg, Florida. I have also served as director of the Low Vision Service in the Departm ent of Ophthalmology at the Univer sity of South Florida. I was a consultant to the Atlanta Are a Services for the Blind in Atlanta, Geo rgia, and served as consultant to the Florida Department of Professional Regulation. Among my many commitments to the University of Alabama at Birmin gham I was a member of the Gradua te Faculty in the Department of Vision Sciences, whe re I served on the admissions commit tee and on the graduate committee of numerous students see king the PhD degree in vision science . 6. I have held numerous professional soc iety memberships and affiliations, incl uding leadership positions in the American Academy of Optometry, the Americ an Optometric Association, Association for Researc h in Vision and Ophthalmology, Ass ociation for Ocular Pharmacology and Therapeutics, Opt ometric Glaucoma Society, and the Association of Optometric Educators. Leadership com mitments have included chairing the Section on Disease of the American Academy of Optom etry, chairing the research committee of Optometric Glaucoma Society and serving on its executive committee, and serving as Editor-in-Chief of Optometry — Journal of the American Optometric Association, the largest eyecare journal (by circulation) indexed in MEDLINE (Pu bMed). 7. Over the past four decades I have serv both the University of South Florida ed on innumerable academic commit tees at and the University of Alabama at Bir mingham. These assignments include chairing the sub committee on basic health sciences at UA B, serving as chair of the Clinical Research Advisory Com mittee, director of the Residency and Advisory Committee, a member of the Fellowship Program Curriculum Committee, and a member of the Association 2 Case 3:12-cv-01141-SMY-DGW Document 176-33 *SEALED* Filed 12/01/14 Page 3 of 126 Page ID #3016 Case: 16-3334 Document: 55-19 Filed: 02/08/2017 Pages: 126 (637 of 1511) of Schools and Colleges of Optometry Ad hoc lum Committee for the Development of a Curricu lar Disease. Model in Treatment and Management of Ocu awards, and distinctions. These I have been the recipient of numerous honors, 8. 2012, by SECO International, Atlanta, Georgia) in include Optometrist of the South (awarded ) in 2011. I arded by Alabama Optometric Association (Aw r Yea the of trist ome Opt ama Alab and in the Colorado Optometric Glaucoma Society received the Distinguished Service Award from ting organizing committee for several biennial 2008. I have served as Trustee and on the mee only Ocular Pharmacology and Therapeutics, the international meetings of the Association for in focused solely on basic and clinical research interdisciplinary society in the United States Top cted for inclusion in the "Guide to America's ophthalmic pharmacology. In 2007 I was sele cted earch Council of America. In 2004 I was indu Optometrists," published by Consumers Res onal followed in 2005 by induction into the Nati into the National Optometry Hall of Fame, ical p of healthcare providers representing all med Academies of Practice, a distinguished grou disciplines and subspecialty groups. of optometry's representative to the Since 1995 I have served as the profession policies on's standards-setting organization that sets United States Pharmacopeia (USP), the nati the purity, and production of pharmaceuticals in and criteria for the manufacturing, content, ege of time Achievement Award by Southern Coll United States. In 2005 I was awarded the Life and substantial contributions to the fields of Optometry for my longstanding, consistent, for served on the Clinical Expert Review Panel optometry and ocular pharmacology. I also a, Care of Patients with Open-Angle Glaucom Optometric Clinical Practice Guidelines on rnational ociation. In my role as a member of the Inte published by the American Optometric Ass ip in organizing several meetings of the Scientific Advisory Board, I provided leadersh in cology and Pharmaceutics for meetings held International Symposium on Ocular Pharma tzerland; and Munich, Germany. Seville, Spain; Lisbon, Portugal; Geneva, Swi erous ophthalmic pharmaceutical I have served on the advisory boards for num 10. & Lomb, Vistakon, Pfizer, Ciba Vision companies including Alcon, Allergan, Bausch 9. 3 Case 3:12-cv-01141-SMY-DGW Document 176-33 *SEALED* Filed 12/01/14 Page 4 of 126 Page ID #3017 Case: 16-3334 Document: 55-19 Filed: 02/08/2017 Pages: 126 (638 of 1511) Ophthalmics, Novartis, Pharmacia, Insp ire, ISTA, Merck, and Shire, among othe rs. In addition, I have served as a referee for papers subm itted for potential publication to journals such as Journal of the American Pharmaceutical Asso ciation, Biodrugs, Investigative Ophthalmol and Visual Science, Current Eye Researc h, Experimental Eye Research, Journal of ogy Ocular Pharmacology and Therapeutics, and Oph thalmic Research. In the late 1980s I was asked to serve as principal investigator for the initi al Phase II clinical trials of several new inve stigational drugs, including loteprednol, a novel ocu lar steroid, and lodoxamide, a mast cell stab ilizer for ocular allergy. My work on loteprednol con tribu ted substantially to our knowledge of how corticosteroid affects intraocular pressure 11. compared to other commonly used ocular this steroids. I have a passion for clinical ocular pharma cology and have broad interests in the field, especially drug delivery and medicat ions affecting the anterior segment of the glaucoma. I have published papers on nov eye and el drug delivery systems such as ophthal diagnostic agents to improve the detectio n and ophthalmic steroids, and publications on mic sprays, diagnosis of ocular disease, ocular allergy, ocular hypotensive agents used to treat pati ocular hypertension and glaucoma (see CV, ents with Appendix A, for complete list). Twenty provided leadership on a UAB team to inve years ago I stigate potential systemic delivery of high weight proteins and drugs following topi molecular cal ocular administration. This work capi systemic absorption of medications applied human studies to document the feasibility talizes on the topically to the eye. We performed both of treating diabetes with insulin eyedrops animal and applied topically to the eye. By our having establis hed the basic principle of such a novel app roach, other investigators have expanded this wor k, which led to the recent FDA approval June 27, 2014. Afrezza is a form of insu of Afrezza on lin that is inhaled by the patient at mealtim e to control blood sugar in persons with diabetes. 12. My interest in ocular pharmacology and pharmaceutical education led to my editorship of two major texts. Clinical Ocular Pha rmacology is in its fifth edit comprehensive ocular pharmacology text has become a major reference source for ion and is the only currently in print in the United States. This textbook students, residents, and practitioners in opto metry and 4 Case 3:12-cv-01141-SMY-DGW Document 176-33 *SEALED* Filed 12/01/14 Page 5 of 126 Page ID #3018 Case: 16-3334 Document: 55-19 Filed: 02/08/2017 Pages: 126 (639 of 1511) thalmic Drug ual editions of Oph ann 25 of hief in-C torEdi as ed serv ophthalmology. I have also products, both prescription and ensive compendium of ophthalmic drug preh com t mos the ts, Fac and is used ses on commercially available products over-the-counter. This publication focu eyecare fields. ents, residents, and practitioners in the widely by pharmacists as well as by stud rs of patient care and scholarly work, I have 37 yea c emi acad my to ition add In 13. onally instilled more than 35,000 patients, and have pers seen e hav I that e mat esti I . nce experie to 2011, either as I saw patients continuously from 1974 eyedrops in more than 15,000 patients. ida, I saw patients in the setting of private practice. In Flor part of my teaching responsibilities or in the faculty l in Tampa, Florida, and private patients at the James A. Haley Veterans' Hospita a, I th Florida College of Medicine. In Alabam Sou of ity vers Uni the with d liate affi practice practice, facilities as well as in the faculty private continued to see patients in our teaching bama at tice is affiliated with the University of Ala University Optometric Group. This prac y adults, I sisted of patients of all ages, but primaril con tice prac al vidu indi My am. ingh Birm but also active care (glasses and contact lenses), treated patients who not only required refr etic eye infections, macular degeneration, diab patients with diseases such as glaucoma, and ditions, and injuries. I also provided precon y ator amm infl , eye dry s, rgie alle retinopathy, surgery. Many racts and for those undergoing refractive cata with ents pati for care e rativ tope pos including those who were legally blind. of my patients were visually impaired, ncipal lecturer and administrator) for the For 32 years I served as coursemaster (pri 14. of Alabama at Pharmacology offered at the University lar Ocu in rse cou c emi acad al form only covers the entire spectrum of ophthalmic Birmingham. This 40 clock-hour course ulations, cokinetics and drug delivery, drug form pharmacology, including ocular pharma ses of drugs basic and clinical pharmacology of all clas pharmaceutical and regulatory aspects, used in ophthalmic care, and toxicology. 15. ) is attached as Appendix A. Curriculum Vitae. My curriculum vitae (CV rt are listed in preparing this repo Materials Reviewed. The materials I reviewed report and in Appendix B. in the References section at the end of the 16. 5 Case 3:12-cv-01141-SMY-DGW Document 176-33 *SEALED* Filed 12/01/14 Page 6 of 126 Page ID #3019 Case: 16-3334 Document: 55-19 Filed: 02/08/2017 Pages: 126 (640 of 1511) 17. four years. 18. Prior Testimony. I have not given a deposition or testified in court in the past Fees. My fee for consultation in this case, incl uding depo sition and trial testimony, is $650 per hour. Summary of Opinions 19. I understand that Plaintiffs in this lawsuit eye drop products should dispense drops of are contending that each of Defendants' no greater than 16 microliters (µ1.), on the understanding that any volume in excess of 16 µI, goes to waste.FN1 It is my opin ion that, for many reasons, this proposal is flawed. A rede sign of dropper tips for all of Defendants' to ensure an across-the-board reduction of drop volume to no greater than 16 microlit impact each of these medications different ly, differently. It would require detailed studies medication would have the same efficacy products ers would and would also affect individual patients of each drug product to determine whether the with such a significant reduction in drop volu me, and such a reduction in volume may actually resu lt in patients being harmed. 20. The eyedrop medications at issue in this laws uit fall into several different classes and have different pharmacologic and pha rrnacokinetic properties. Clinical and othe r scientific studies would be necessary for each individu al solution, suspension, or gel to determin e whether it could be consistently delivered in a 15-1 6 IAL "micro" drop volume, and if so, whe reduced drop volume would be efficacious ther this and safe in treating the respective patient pop ulations for which these medications are indicated. 21. The human conjunctival sac/tear volume is the classic works in the field used small sam exceptionally difficult to measure, and ple sizes and had some methodological diffi These factors make stated tear volumes less than culties. definitive. The eyes of many patients, rxi In their Complaint, Plaintiffs take the position that eyedrops should be no larger than 15 µL. However, Plaintiffs' expert, Dr. Alan Rob in, offers that drops should be an "average " of 16 µL. Accordingly, I refer to both of these "micro" drop volumes in this report. 6 Case 3:12-cv-01141-SMY-DGW Document 176-33 *SEALED* Filed 12/01/14 Page 7 of 126 Page ID #3020 Case: 16-3334 Document: 55-19 Filed: 02/08/2017 Pages: 126 (641 of 1511) , can often accommodate commercial eyedrops including older adults and patients with dry eyes up to 30 µL. n, especially the elderly and Patients are notoriously poor at eyedrop instillatio ng glaucoma or retinal disease. Many patients those with dexterity problems or vision-impairi y ering only a partial drop into the eye. Just as man miss the eye entirely or are successful in deliv 22. one drop into the eye. others have to use multiple drops before getting ase the risk of underdosing The use of 15-16 [1,1_, "micro" drops would incre 23. n culty accurately instilling these tiny drops whe because many patients would have greater diffi This would be challenging not only for patients compared to the larger conventional eyedrops. for the pediatric population, who often struggle, who are less adept at drop instillation, but also only part of the "micro" drop were to reach the cry, or otherwise resist eyedrop instillation. If dose necessary for effective treatment. eye, the patient may not receive the minimum "micro" drop volumes potentially Bottles of a given size manufactured to deliver 24. ication, with a correspondingly greater would extend the duration of each bottle of med on bottle or product deterioration until the medicati opportunity for bacterial contamination of the e the patient at risk for a vision-threatening eye is depleted. Bacterial contamination could plac that many patients touch the dropper tip to their infection. Contributing to this problem is the fact eye during instillation. p and pointed, as demonstrated by "Micro" tips, by their very nature, are more shar that patients routinely touch their eye with the the 16 [Li, tip used in Dr. Robin's study. Given substantially increase the risk of eye injury, dropper tip, use of these rather sharp tips would 25. including corneal abrasion and possible resulting 26. infection. s may have comparable efficacy to While certain studies suggest that smaller drop ort reducing the drop volumes of the products larger drops, these studies are inadequate to supp d for several reasons. These studies: (1) evaluate identified in Plaintiffs' Complaint to 15-16 [IL tions and thus were insufficiently powered for only a small number of patients for shorter dura efficacy; (2) in many instances, used healthy purposes of establishing statistically equivalent 7 Case 3:12-cv-01141-SMY-DGW Document 176-33 *SEALED* Filed 12/01/14 Page 8 of 126 Page ID #3021 Case: 16-3334 Document: 55-19 Filed: 02/08/2017 Pages: 126 (642 of 1511) volunteers instead of actual patients; (3) often used study personnel to instill the drops; and (4) involved only a few of the many medicati ons at issue in this lawsuit. 27. Most of the research on small eyedrop volumes medications in carefully controlled laboratory or has been done with glaucoma clinical environments using investigator- instilled eyedrops, and often in normal voluntee rs. To validate the potential efficacy and safe ty of 15-16 µL "micro" drops in patients with glau coma or any other disease, large-scale multicenter clinical trials of each medication would have to be completed with patients usin g the proposed new dropper bottles. To date, there has been no attempt to study the efficacy and safety of "micro" drop volumes for topical ocul ar steroids, antibiotics, allergy drugs, or othe r prescription medications used for ophthalmic ther apy. 28. Studies of several drugs in smaller drop volu mes have not shown any improved safety or tolerability when compared to conv entional eyedrops. These studies also demonst rate that adequate and well-controlled studies wou ld have to be conducted for each drug at issu e in this lawsuit to determine whether reducing the the medication for the indicated use as well as 29. drop volume would in fact ensure effectiveness of decrease the incidence of certain side effects. Reasonable alternatives to topical eyedrop ther apy exist for patients with glaucoma, ocular infections, inflammatory dise ases, allergies, ocular pain, and other condition These include oral medications, ointments, and, s. for glaucoma patients, laser treatment and surgery. Deciding whether any of these med ications or other alternatives would be an appropriate treatment for a particular patient would require knowledge of the patient's med condition and history, and the choices would vary from patient to patient. ical Overview of Prescription Evedrop Medicat ions at Issue 30. Prescription eyedrops, also known as "topical used by millions of Americans to treat various available only through a prescription from a ophthalmic pharmaceuticals," are conditions. These FDA-approved medications licensed healthcare provider. The Complaint allegations as to nearly 60 prescription eyedrop are raises medications. These medications can be 8 Case 3:12-cv-01141-SMY-DGW Document 176-33 *SEALED* Filed 12/01/14 Page 9 of 126 Page ID #3022 Case: 16-3334 Document: 55-19 Filed: 02/08/2017 Pages: 126 (643 of 1511) different classes: classified pharmacologically into five (1) ocular hypotensive (for glaucoma); ; (4) anti-bacterial; and (5) anti-viral. (2) anti-allergy; (3) anti-inflammatory drops Differences Among the Subject Eye Pharmacologic and Pharmacokinetic rmacologically diverse of eyedrop medications at issue are pha ses clas five se The 31. etics" refers to the ic properties. The term "pharmacokin and have vastly different pharmacokinet e drugs. The , and elimination characteristics of thes administration, distribution, metabolism ability to ely from one class to the next, and the wid er diff on acti of s ism han mec gic pharmacolo anticlass. Indeed, some agents, such as the to s clas from ers diff also nea cor the penetrate e their target not designed to penetrate the cornea sinc are nts, age y erg -all anti and es ctiv infe high intraocular Other medications, however, require tissues are on the surface of the eye. glaucoma efit. Examples of this group include penetration to provide therapeutic ben using for ions to dilate the pupil and inhibit foc icat med and s, oid ster lar ocu s, ion medicat such as uveitis. treatment of intraocular inflammation, with "micro" class differences, efficacy outcomes ant ific sign e thes of e aus Bec 32. ses. For t among the various pharmacologic clas eren diff ly inct dist be ld wou es um drop vol high doses to be ful anti-inflammatory drugs) require wer (po s oid ster lar ocu ical top le, mp exa benefit. Similarly, hes the eye, the greater is the clinical effective. The more steroid that reac local drug h and sufficient dosage to permit the hig in en giv be st mu tics bio anti lar topical ocu ion (MIC) for the than the minimum inhibitory concentrat her hig ly tial stan sub be to ion trat cen con rease the ucing drop size to 15-16 gL would dec bacterial infection being treated. Red 1,2 hout improving systemic safety. One wit ses, clas ion icat med e thes of h effectiveness of bot ly. This s usually "water," sometimes profuse eye cted infe or d ame infl that is this reason for ing the medication any instilled ocular medication, render out h was or te dilu idly rap l wil ing tear s suffering from with inflamed and infected eyes, eye partially or completely ineffective. As . itis, often water, in addition to itching ctiv jun con rgic alle as h suc s, rgie alle seasonal or perennial rgy or immediately wash out a "micro" alle te dilu l wel y ver may ing tear the , For many patients improve nasal owing systemic absorption, can actually foll ps, dro eye rgy alle e som , ther Fur drop. 9 Case 3:12-cv-01141-SMY-DGW Document 176-33 *SEALED* Filed 12/01/14 Page 10 of 126 Page ID #3023 Case: 16-3334 Document: 55-19 Filed: 02/08/2017 Pages: 126 (644 of 1511) congestion and runny nose associ ated with seasonal allergies. 3 A "micro" drop would necessarily have less systemic abs orption, reducing or eliminating this "Larger" drops have a greater like lihood of staying in contact with the eye, especially if the drug is formulated in a newer vehicle wit h higher ocular retention time, as report. 33. beneficial effect. discussed later in this There are pharmacologic difference s even within the same drug class. glaucoma medications are a good example. The five main classes of intraocular pressure (IOP), each of adrenergic agonists; (3) carbonic which is at issue here, are: (1) bet a blockers; (2) alpha- (5) prostaglandin analogs. Beta blo ckers, alpha-adrenergic agonists, inhibitors reduce 10P by decreasin from the eye. Each of these five drugs used to reduce anhydrase inhibitors; (4) cholinergic the eye). Cholinergic agonists and The agonists; and and carbonic anhydrase g the formation of aqueous humor (the fluid inside the front of prostaglandin analogs increase the outflow of aqueous humor classes acts in a distinct way to red uce IOP. The beta blockers act on various beta-adrenergic rec eptors in the ciliary processes to red uce aqueous production. Latanoprost, a prostaglandin analog , binds to and activates receptors in the ciliary body and improves aqueous outflow. The alp ha-adrenergic agonists, such as apr aclonidine and brimonidine, suppress aqueous pro duction, and brimonidine also low ers aqueous outflow. On the other han IOP by increasing d, the carbonic anhydrase inhibit ciliary epithelium, subsequently target the ciliary body inside the ors inhibit an enzyme in the decreasing the synthesis of aqueou s humor. All of these drugs eye, but their physicochemical pro the cornea, receptor binding inside perties, ability to penetrate the eye, and ocular tolerability are unique to each drug and/or drug class. 34. Dr. Robin does not address the diff of action of the drugs at issue in the which he confines his opinions). erent pharmacologic properties or lawsuit, including the glaucoma dru gs (the class of drug to He appears to be recommending uL for all the glaucoma medicatio mechanisms an "average" drop size of 16 ns identified in Plaintiffs' Complain very limited data, and only for a few t. Yet, he provides only glaucoma drugs (apraclonidine, lev obunolol, bimatoprost, 10 Case 3:12-cv-01141-SMY-DGW Document 176-33 *SEALED* Filed 12/01/14 Page 11 of 126 Page ID #3024 Case: 16-3334 Document: 55-19 Filed: 02/08/2017 Pages: 126 (645 of 1511) sufficiently smaller studies of shorter duration and not lved ent efficacy. Moreover, some of them invo powered to establish statistically equival y one from instilling their own medication. Onl ents pati ng ludi prec s, drop d tille -ins ator investig as 16 p,L, lved self-administration of drops as small invo even s usse disc in Rob Dr. ies stud the of il later in this ents. (I discuss these studies in more deta and that study did not involve actual pati icient size and adequate and well-controlled studies of suff been had e thes if n Eve FN2 rt.) repo other drug results to all glaucoma drugs, much less duration, one cannot broadly apply their pilocarpine, and brimonidine). These are classes. 35. tions, suspensions, and gels, and the Pharmacokinetic differences among solu powered drug classes necessitate that appropriately distinct mechanisms of action among the volume for rate the safety and efficacy of reduced drop clinical studies be performed to demonst ide and tions of these agents. Consider dorzolam bina com d fixe and s clas drug and drug each mercially anhydrase inhibitors. Dorzolamide is com brinzolamide, both classified as carbonic s, the active mide is prepared in suspension. In solution formulated in solution, whereas brinzola h that delivers the medication to the eye. Wit drug is effectively dissolved in the vehicle ing is but not dissolved, in the vehicle, and shak suspensions, the active drug is dispersed, thicker and ike solutions or suspensions, gels are even required before the drop is instilled. Unl when used ensure effective diurnal lowering of IOP are designed to stay on the eye longer. To e, in be instilled three-times daily.4'5 Brinzolamid t mus ide olam dorz y), erap noth (mo e alon oubtedly attributed to its unique vehicle.6 contrast, can be used only twice daily, und xolol and timolol. Betaxolol is The same is true of the beta blockers beta 36. gel-forming le timolol is prepared in either solution or whi on ensi susp and tion solu in ed ulat form less solution vehicles, betaxolol is consistently in d -hea d-to hea d pare com en Wh . icle veh ked by each of owing to the different receptor sites bloc effective in reducing IOP than is timolol studies using "micro" drops only for one To my knowledge, there are published IOP agonist available, one commercial alpha-adrenergic are that five ng amo ker bloc beta cial commer lable. linergic agonist among three that are avai among two that are available, and one cho 11 FN2 Case 3:12-cv-01141-SMY-DGW Document 176-33 *SEALED* Filed 12/01/14 Page 12 of 126 Page ID #3025 Case: 16-3334 Document: 55-19 Filed: 02/08/2017 Pages: 126 (646 of 1511) the drugs. One cannot assume that a 15- 16 tL drop of betaxolol suspension (ass uming a volume this small could even be dispensed from a "micro" dropper tip) would provide lowering as the current drop. Indeed, for each "micro" drop volumes would provide 37. of these medications, determining whe ther equivalent 'OP-lowering efficacy and would require adequate and well-contro lled duration of action studies. Further, due to their differing physical on each medication at issue to determi the same IOP properties, testing would need to be don e ne which of them could even be delivere volume of 15-16 pi. Surface tension and d as a drop viscosity differ from one medication to another. Medications with a higher surface tens ion or higher viscosity may require a larg er dropper tip. For example, ocular products formulat ed in newer vehicles such as gels (e.g., the steroid loteprednol) (Lotemax), emulsions (e.g ., the steroid difluprednate) (Durezol), viscous mucoadhesive vehicles (e.g., the antibiot ic besifloxacin) (Besivance), and susp ensions (e.g., the nonsteroidal anti-inflammatory drug nep afenac (Nevanac), the glaucoma drug brinzolamide (Azopt), and most ocular steroids) all have higher viscosity and/or high surf ace tension. Among glaucoma medications, products at issu e such as timolol in gel-forming solution (Timoptic GFS) and betaxolol in its unique resin suspens ion (Betoptic S) have increased viscosit y to prolong ocular contact time following instillat ion. These drugs would be extremely difficult to deliver in a "micro" drop and for a number of them , there simply is no evidence that it wou ld even be feasible. 38. Similarly, reducing the drop volume to 15- 16 µL might require changes to the formulation or concentration of certain med ications, based on their respective pha properties. Individual sterility and stab ility would be necessary to make these dete rmacologic studies of each drug, as well as clinical evaluation, rminations. These studies typically requ 18 months to meet FDA requirements ire at least 12 to . 12 Case 3:12-cv-01141-SMY-DGW Document 176-33 *SEALED* Filed 12/01/14 Page 13 of 126 Page ID #3026 Case: 16-3334 Document: 55-19 Filed: 02/08/2017 Pages: 126 (647 of 1511) llation Requires Consideration Determining Correct Eyedrop Dosing and Insti Factors for Each Medication of Numerous Separate Biologic and Behavioral requires high local The pharmacologic treatment of any disease generally 39. tment of ocular surface infections or concentrations of drug at the relevant tissue site. Trea to the eyelids, conjunctiva, or cornea. In inflammations necessitates effective drug delivery involves delivering therapeutic drug levels contrast, treatment of uveitis, glaucoma, and retinitis ough many systems have been developed to appropriate target sites deep within the eye. Alth , including eyedrops, suffer from lack of specifically for drug delivery to the eye, most of them with intraocular drug delivery can lead to precision. Moreover, delivery systems associated route of administration for ophthalmic drugs. toxicity. Eyedrop application is the most common cost effective since patients can selfThis method is convenient, simple, noninvasive, and administer the medication at home. administered, distributed, Pharmacokinetic parameters, such as amount of drug y determined in the human eye. To make and eliminated from the target tissues, cannot be easil y of the eyes of various animal models, matters more problematic, the anatomy and physiolog to estimate pharmacokinetic parameters of such as rabbits, are not similar enough to human eyes s applied topically to the eye are importance.7 The rate and extent of absorption of drug eover, tear secretion promotes the dilution of extremely difficult to measure experimentally. Mor removal. The largest factor is the drainage any instilled drug dose, and blinking facilitates its rapid than the absorption rate. Because of rate, which, for solutions, is about 100 times more that topical solutions reside in the these precorneal factors, it is not surprising to find 7 wing application, and only a very small conjunctival sac for only about 3 to 5 minutes follo es the cornea into the eye. Larger drops portion (1-7%) of the instilled drug actually cross effective dose of drug. maximize the opportunity to deliver the minimally unt increases its activity. Generally speaking, increasing a drug's dosage amo 41. amount of drug to produce the desired This "dose-response" curve will reveal the maximum , its vehicle, preservative, and other inactive response. When taking into account the active drug 40. 13 Case 3:12-cv-01141-SMY-DGW Document 176-33 *SEALED* Filed 12/01/14 Page 14 of 126 Page ID #3027 Case: 16-3334 Document: 55-19 Filed: 02/08/2017 Pages: 126 (648 of 1511) ingredients, pharmaceutical manufacturers seek to formulate a product to achieve the optimal therapeutic effect while minimizing undesirab le side effects. In the case of eyedrops, even unde r optimal circumstances, only a small fraction of the instilled dose actually penetrates the cornea for activity inside the eye, such as for treatmen t of glaucoma or uveitis. 42. This situation is analogous to the structure and medications, where the amount of active drug formulation of systemic after oral administration, expressed as a percentage of the administered dose, may be very small. The binding of a drug to plasma proteins in systemic circulation effectively restr icts a portion of the administered dose, and the protein-bound portion of the dose is not available protein-binding of aspirin, atorvastatin (Lipitor, to exert a therapeutic effect. For example, for high cholesterol), loratadine (Claritin, for allergies), and ibuprofen (Advil, for inflammation and pain) is 49%, >98%, 97%, and >99%, respectively.8 Thus, the amount of active drug avai lable to exert a therapeutic effect may be less than 1-2%. In short, whether it is eyedrops or an oral medication, the amount of medicine that ultimately reaches the target location in the hum an body and is bioavailable to provide a therapeutic benefit routinely is much less than Determining the correct dosage must take into affecting the amount of medicine that reaches the amount of medicine in the dose administered . account all of the factors, biologic and behavior al, the target tissue. FDA accounts for these issue s when approving dosages based on adequate and well-controlled Phase III trials demonstrating clinical efficacy and safety at the dosage studied. I discuss behavioral considerations (i.e., patients' poor proficiency in instilling drop s) later in this report. The Amount of Ophthalmic Solution the Hum an Eye Can Hold Without Overflow or Drainage Through the Nasolac rimal System Varies Among Patients 43. When a patient instills an eyedrop properly, the the lower eyelid retracted, and the drop placed head should be tilted backwards, in the "pouch" created by the eyelid retraction. This pouch is known as the cul-de-sac, or conj unctival sac. The potential spaces between the eyelid and ocular surface, age of the patient, and ocular surface, make it difficult to measure the extent and quality of the tear film coating the amount of tears coating the eye surface. Equally 14 Case 3:12-cv-01141-SMY-DGW Document 176-33 *SEALED* Filed 12/01/14 Page 15 of 126 Page ID #3028 Case: 16-3334 Document: 55-19 Filed: 02/08/2017 Pages: 126 (649 of 1511) tially be placed on the eye without difficult to assess is the volume of eyedrop that could poten n as the nasolacrimal drainage system. overflow or loss to the drainage system for tears, know 44. While it is true that the cul-de-sac can hold only a finite precise amount is uncertain and differs from person to quantity of fluid, the person. Biological systems vary from one not always have the same weight, person to the next. So-called "average" individuals will — or conjunctival sac size. There are height, shoe size, waist size, heart rate, blood pressure nt when one considers the volume of known individual differences that must be taken into accou low. medication that can be held in the human eye without overf to instill topical ocular Fraunfelder9 provided the seminal work on how 45. with the cul-de-sac that are known for medication, and he expounded on the variables associated was that the eyelids of older individuals their wide range of normal values. Among his findings le of holding more fluid without (over age 50 years) are often "looser" and therefore capab instilled eyedrops in more than 15,000 spillage. This has been my personal observation. I have ularly older patients, are able to hold patients and have observed that numerous patients, partic eyelids or cheek. In fact, this has been commercial eyedrops with little or no overflow onto the tigating the quality of eyedrop documented in a study by Dr. Robin and colleaguesl° inves oma or ocular hypertension. Only oneinstillation technique in patients with open-angle glauc following eyedrop instillation. The third of the patients had overflow of tears immediately nts did not have overflow at all. corollary to this, of course, is that two-thirds of the patie s to attempt to measure the In 1964, Zintz and Schilling" were the first researcher 46. involving dye dilution methods, they fluid volume in the conjunctival sac. Using technology 1966, a classic paper was published by reported tear volumes ranging from 10 RL to 60 pi. In in major reviews of this subject.13-15 Mishima and coworkers,12 which is still widely quoted today and Schilling, but also added This research used similar methods to the studies by Zintz group encountered some difficulties additional methodology to refine the results. Mishima's ems in the published paper. There was with their methods and readily acknowledged the probl e due to the constant secretion of tears procedural uncertainty in the determination of tear volum 15 Case 3:12-cv-01141-SMY-DGW Document 176-33 *SEALED* Filed 12/01/14 Page 16 of 126 Page ID #3029 Case: 16-3334 Document: 55-19 Filed: 02/08/2017 Pages: 126 (650 of 1511) and rapid tear drainage. The tear dilution meth od using fluorescein dye to determine tear volu also was conducted in only 13 people, an exce edingly small sample size that, in comparison today's scientific standards, would be deemed me to inadequate. The average tear volume was 16 µL, but with a wide range from 5.3 to 66 µL. Measure ments obtained for a single individual also varied considerably, by as much as 9 to 66 µL. 47. Using a second calculation method, tear volume 21 women to be 7.0±2.0 µL, with a range from emphasize the latter figures in their results but was deteimined for 16 men and 4.0 to 13 µL. The investigators decided to noted, "It should be stressed, however, that a small scattering of the data in this method does not guarantee that it gives the tear volume accurately." They go on to say, "One cannot be certain that the fluorescein is well mixed with the tears under the palpebral conjunctiva and in the fornices. Nonuniform mixing produces unpredictable errors — a most undesirable situa tion in any quantitative determination." So, to evaluate the experimentally determined quantity, the probable (emphasis added) tear volume was estimated from anatomical considerations. Aga in, a small sample size of only 30 eyes of norm al men and women were photographed, and the dista nce between the upper and lower eyelids was assumed to have a single horizontal curvature, neglecting the curvature in the vertical plane. To estimate the tear volume between the eyelids and a small mirror into the anterior chamber (behind ocular surface, the researchers actually inserted the cornea) of rabbit eyes to observe the surface of the eyelid from behind. Human eyes were not "no large tear reservoirs were observed, and the used for this purpose. The researchers noted, tear layer seemed to have a thickness close to that of the precorneal tear film, although one cann ot be certain of its exact dimension." The investigators concluded, "The above calculation of the probable tear volume involved some uncertainties." 48. Thus, the results of this 48-year-old research (con sidered "definitive" by many who have not actually read the report) are subj ect to a degree of uncertainty, which is readily acknowledged by the authors. Nevertheless, Mish ima and coworkers concluded that the cul-de- sac could hold an additional (emphasis added) amount of fluid of about 25 µL, and other auth ors 16 Case 3:12-cv-01141-SMY-DGW Document 176-33 *SEALED* Filed 12/01/14 Page 17 of 126 Page ID #3030 Case: 16-3334 Document: 55-19 Filed: 02/08/2017 Pages: 126 (651 of 1511) t beyond 15 or 16 µL is suggest an amount as much as 30 RL. Plaintiffs' claim that any amoun ts to measure tear volume necessarily wasted runs contrary to these findings. More recent attemp for their methodological using contemporary technology also have been called into question shortcomings. 49. ing the Aside from the differing physical dimensions of the eye itself, includ bute to the varying amounts of conjunctival sac, medical conditions such as "dry eye" also contri fluid the conjunctival sac can hold. Patients with a low tear flow rate, atrophy of the lacrimal ducts and glands, are usually considered to often due to aging or have "dry eye." This s, individuals with rheumatoid condition is extremely common and includes many elderly person are exposed to dry climates arthritis, many peri- and postmenopausal women, and persons who or dusty work environments. Most persons with primary open-angle glaucoma are older adults ma begins. Moreover, and are often found to have dry eye even before treatment of the glauco can cause changes in the numerous studies have shown that long-term glaucoma medications both prevalent in older ocular surface that lead to dry eye. Thus, dry eye and glaucoma are recent study, 52% of patients adults and are common comorbidities in the same patient. In one eye.16 The total tear volume treated with preserved glaucoma eyedrops showed symptoms of dry of medication is not diluted in patients with dry eye is less than normal, which means that a drop tion across the cornea or into as much with the tears and will be more readily available for absorp space in the conjunctival sac the conjunctival tissues. Having a reduced tear volume leaves more size can be and ocular surface for the ophthalmic medication. Thus, a larger drop accommodated, and ocular absorption increased.'7 ps would be The eyes of some glaucoma patients with dry eye using topical eyedro ma patient who does not have able to accommodate a larger drop than would the eyes of a glauco kers,1° who reported in a dry eyes.FN3 This is consistent with the findings of Dr. Robin and cowor 50. actually demonstrate tearing or F"sA confounding variable is that some patients with dry eye can condition is caused by epiphora, which is the overflow of tears from the ocular surface. This with significant epiphora reflex tearing due to irritation from the dry ocular surface. Patients eye. might have difficulty retaining any size of eyedrop applied to the 17 Case 3:12-cv-01141-SMY-DGW Document 176-33 *SEALED* Filed 12/01/14 Page 18 of 126 Page ID #3031 Case: 16-3334 Document: 55-19 Filed: 02/08/2017 Pages: 126 (652 of 1511) formal assessment of eyedrop instillation technique that only one-third of patients with glaucoma or ocular hypertension had any tear overflow just after personal observation. I have witnessed that many eyedrop instillation — and my own of my patients (including those with glaucoma) have little or no overflow, indicating that their eyes were able to accommodate eyedrop sizes up to 30 p,L. In my 37 years of clini cal practice, I have never had a patient complain of wasted eyedrops or problems with eyed rop overflow. 51. Individual factors affecting the extent of eyedrop abso rption include other variable characteristics of the eye. The length of time a drop remains in contact with the external surface of the eye depends on several factors, inclu ding the amount of tearing and blinking, intactness of the corneal surface, and the medicatio n's viscosity, which varies from drug to drug. In addition, the medication may remain in contact with the eye longer if the patient has an alteration of the lipid barrier of the tear film, such as dry eyes. The corneal penetration effects of surface defects would be seen with some eyedrop medications, but not others. 52. Reflex blinking may occur with any foreign object, physical impact of the drops, as well as the reflex tearing including "micro" drops. The induced by the drop, will reduce the efficacy of any applied medication. Such loss of effic acy would be even more significant with small drug volumes delivered with "micro" tips. 53. Many patients, including three of the four Plaintiffs, use more than one eyedrop medication, which also affects the amount of medi cine absorbed by the eye. In my practice, 40 to 50% of my glaucoma patients were on multiple eyedrop medications. When a patient instills a second drop of medication closely after the first drop absorption of the first drop, a significant portion of without allowing adequate time for the first drop is washed out, which reduces the medication's effect. If an eyedrop were only 15 or16 this would be of significant concern from an efficacy standpoint. A "microdro p" instilled before a "conventional" drop would likely be diluted or washed out, rendering it completely ineffective. In general, it is important for the patient to wait approximately five minutes or more between medications to avoid the washout effect. Plaintiffs Fisher and Eike both use multiple eye medications. Plaintiff 18 Case 3:12-cv-01141-SMY-DGW Document 176-33 *SEALED* Filed 12/01/14 Page 19 of 126 Page ID #3032 Case: 16-3334 Document: 55-19 Filed: 02/08/2017 Pages: 126 (653 of 1511) n drops. In contrast, Fisher testified that she waits an average of only 35 to 45 seconds betwee Plaintiff Eike stated that she waits 15 minutes. Patient Difficulties With Evedrop Administration 54. Patients have difficulty instilling eyedrops. Any clinician (or layperson for inherently inaccurate matter) who has observed a patient instill eyedrop medication knows how and imprecise topical dosing to the eye can be.PN4 It is obvious that that if a patient misses the eye matic for when applying the drops, medicine will be wasted. This is especially proble of glaucoma, ocular medications that are used over long periods of time, such as in the treatment hypertension, dry eye, or chronic uveitis. If a patient is properly instructed eyedrops, or has a caregiver to help administer them, wasted medication on how to use the can be reduced. It has t a patient on how to been my personal experience, however, that even when I carefully instruc The improper selfproperly instill eyedrops, many patients still have difficulty months later. ng by Dr. Robin administration of topical ocular medication has been well documented, includi 75) ophthalmology and colleagues.18-22 This problem is especially common in elderly (over age lty with the application patients. In one study,23 the majority of patients experienced some difficu their own treatment of their eyedrops, and it was estimated that half of those who usually applied were unlikely to succeed in instilling a drop into the conjunctival sac. 55. vely Numerous studies have been conducted with glaucoma patients to objecti ented the difficulty evaluate the quality of eyedrop administration. These studies have docum have used glaucoma patients have in instilling their eyedrops, even for experienced patients who medications for many years. Dr. Robin and colleagues20 found that less than one-third of le and imprecise. One 'There are two major reasons why topical dosing to the eye can be variab self-instills the is the variable size of the eyedrop that is formed at the bottle tip as the patient the eyedrop to be medication. The angle at which the bottle is held by the patient can cause vertically, held is larger or smaller by as much as 50%, depending on whether the bottle tion. Bottle and horizontally, or somewhere between. This variability differs for each medica a role in drop size. solution temperature as well as viscosity and surface tension can also play drop emitted from the the of tion The second major factor influencing topical dosing is the propor bottle that actually reaches the eye. This ranges from 0 to 100%. 19 Case 3:12-cv-01141-SMY-DGW Document 176-33 *SEALED* Filed 12/01/14 Page 20 of 126 Page ID #3033 Case: 16-3334 Document: 55-19 Filed: 02/08/2017 Pages: 126 (654 of 1511) observed instillations could be performed successfully in patients with glaucoma or ocular hypertension who had used one or more medications for at least six months and who instilled their own eyedrops. Of equal importance is the fact that patient percep tions and self-reporting about their eyedrop instillation skills do not correlate with actual instilla tion performance.18,20,21 Dr. Robin and coworkers21 showed in another study of glauco ma and retina patients with visual impairment that, of patients claiming not to miss the eye, nearly one-th ird actually missed. Approximately one-third could not even get a single drop onto the eye. It is clear that many patients waste drops and have inaccurate perceptions of their eyedro p instillation abilities. For example, in this same study, though fewer than 30% of patients were able to instill a drop onto the eye, nearly 80% of patients stated that they had no trouble instill ing eye drops. For those with a history of conditions such as arthritis, stroke, or hand tremo r, accurate instillation can be even more difficult. Awkward instillation technique can also lead to bacterial contamination of the bottle tip. This is a significant concern, especially in the long-t erm application of eyedrops, as in glaucoma. This may place the patient at risk of a serious, vision -threatening infection, especially for those who have had prior glaucoma filtration proced ures or cataract surgery.24,25 The Risk of Underdosing with "Micro" Drops 56. The currently marketed medications provide a margin of safety for patients who are less adept at instilling eyedrops. If a drop does not therapeutic benefit. It has been my observation and that of Dr. Robin the many reach the eye, it will have no and colleagues,18,20,21 that many patients either miss their eye entirely or may get only a "partia l" eyedrop into the eye after the drop hits the edge of the eyelid or inner or outer corner of the eye. This partial eyedrop, with the currently marketed drops, might have a volume of perhaps 10 to 20 µL, which in the case of some glaucoma medications, may be adequate to reduce TOP. With a "micro" drop, however, patients would have virtually no margin of error during instillation. If only part of the "micro" drop reached the eye, the patient might be underdosed, resulting in inadequate treatment. Underdosing would be of particular concern for glaucoma patients because the disease in its 20 Case 3:12-cv-01141-SMY-DGW Document 176-33 *SEALED* Filed 12/01/14 Page 21 of 126 Page ID #3034 Case: 16-3334 Document: 55-19 Filed: 02/08/2017 Pages: 126 (655 of 1511) early stages often is asymptomatic and could progress unnoticed until the patient is seen by his or her physician. 57. Many patients would have greater difficulty accurately instilling "micro" drops compared to the larger conventional eyedrops. Consider the analogy of attempting to hit a bull's-eye target using either a shotgun or BB gun. It is easier to hit the bull's-eye using the shotgun than using a small BB. Likewise, a patient is expected to be more successful in hitting the target conjunctival sac using a larger drop than a smaller one, even if only a portion of the drop reaches its target. The greater precision needed to accurately instill "micro" drops would be challenging for many patients, especially the elderly, who may have physical limitations relating to vision, dexterity, and hand-to-eye coordination. 58. There have been no clinical studies documenting that "micro" drops, compared to conventional drop volumes, will improve the accuracy or precision of drop instillation and minimize wastage. The lone study to evaluate self-administration of 16 uL eye drops, with which Dr. Robin was involved, did not formally assess dosing accuracy, let alone in actual glaucoma patients. Dr. Robin and colleagues10 have further observed that patients are less likely to properly administer their eyedrops as glaucoma progresses because the disease causes vision loss. My interpretation of their data and response is, "Why would we want to give these patients a smaller 'micro' drop that might be even more difficult to accurately instill?" 59. The use of "micro" drops also would be a serious disadvantage in the pediatric population, including those with glaucoma. All of the medications included in Plaintiffs' Complaint are regularly used in children. Any doctor, nurse, ophthalmic technician, or parent who has ever attempted to put an eyedrop in a child's eye knows how difficult this can be. Depending on the age of the child, the child may struggle, cry, or otherwise resist eyedrop instillation. The current commercial eyedrop volumes are ideal in these situations because they maximize the opportunity to reach and stay in the target conjunctival sac. Eyedrop instillation may be aided by having the child close their eyes so that the drop can be placed on the lashes, and when the child opens the eye and begins to blink, a portion of the drop reaches the cul-de21 Case 3:12-cv-01141-SMY-DGW Document 176-33 *SEALED* Filed 12/01/14 Page 22 of 126 1 Page ID #3035 Case: 16-3334 Document: 55-19 Filed: 02/08/2017 Pages: 126 (656 of 1511) sac. I have done studies26'27 to show that administerin g commercial drop volumes to the closed eyelids in children can be as effective as instilling medication to the open eye in the conventional way. A "micro" drop is less likely to be effective under this metho d of administration, because there would be less medication on the lashes to reach the cul-de -sac when the child opens the eye and begins to blink. Moreover, as mentioned previously, topica l ocular antibiotics, steroids, and allergy medications should be applied in their maximum volum es to overcome eye "watering" and to achieve the desired therapeutic benefit. The Risk of Corneal Abrasion and Bacterial Contamination 60. with "Micro" Drops Small eyedropper tips, such as those that would deliver the 15-16 4 drops Plaintiffs are proposing, also have greater potential for inadvertent eye injury by patients who are not proficient in eyedrop instillation. Dr. Robin and colleagues18,20,21 evaluated the performance of patients in three separate studies in which patients were video taped administering their own eyedrops. The vast majority of the patients were experienced in the instillation of eyedrops. In the first study, 47% of glaucoma patients touched their eye or adjace nt tissue with the bottle tip. In the second study, as noted by Dr. Robin in his expert report, 32% of glaucoma patients touched the bottle tip to the surface of the eye. Finally, in the third study, which involved retina and glaucoma patients, the percentage of patients touching their eye with the bottle tip in each group was 47% and 33%, respectively. Of the 290 patients who denied touching the bottle tip to the eye in the third study, 41% of retina patients and 24% of glauco ma patients did touch the bottle to the eye on review of the videos. 61. It is my personal experience in treating patients for nearly four patients often touch the eye with the dropper tip. One reason for decades that this is to increase tactile sensation since they may not feel the eyedrop itself. In an unpub lished study28 of small drops of bimatoprost, approximately 44% of patients could not feel instill ation of a 15 td., drop (instilled by micropipette). It is obvious that larger drops have a greater likelihood of being felt than "micro" drops. Many individuals are simply unskilled in the techn ique of instilling eyedrops. As the above studies show, a significant number of experienced patients touch their eye with the 22 4....pie Case 3:12-cv-01141-SMY-DGW Document 176-33 *SEALED* Filed 12/01/14 Page 23 of 126 Page ID #3036 Case: 16-3334 Document: 55-19 Filed: 02/08/2017 Pages: 126 (657 of 1511) ps for the first dropper tip. Even higher numbers would be expected with patients using eyedro time. Cataract surgery patients, for example, are often first-time users who must instill antibiotic, steroid, and nonsteroidal anti-inflammatory eyedrops daily for several weeks following surgery. As Dr. Robin and colleagues reported, patients with a history of arthritis, stroke, or hand tremor, also may have added difficulty. Regardless of the reasons patients touch the ocular surface with the dropper tip, this can lead to injury. 62. The dropper tips used with most commercial eyedrop medications are slightly is minimized if rounded, and they have a large enough surface area that the risk of corneal injury Dr. Robin is the tip contacts the eye. In contrast, "micro" tips, such as the investigational tip ly touch their proposing, are narrow and pointed (see Figs. 1 and 2). Given that patients routine substantially eye with the dropper tip, use of these rather sharp "micro" dropper tips would s loss of increase the risk of eye injury, including corneal abrasion. Corneal abrasion involve ed to have tissue, potentially leading to serious eye infection. Eye injury is well-document ted individuals. occurred with small, sharp tips of artificial tear dispensers, even in normally-sigh Dr. Lon Spada, a scientist at Allergan, has testified that Allergan developed some investigational "micro" dropper tips many years ago but rejected them for this very reason. supplied by Alcon for use Fig. 1. Commercial 30 µL dropper tip (left) and investigational 16 [tL, dropper tip (right) of version this same photo appears in the Vocci study, as described in Dr. Robin's report. A significantly enlarged size of the dropper tips. actual the on page 8 of Dr. Robin's report. The above photo, however, approximates injury. eye causing Investigational tip on right is more capable of 23 Case 3:12-cv-01141-SMY-DGW Document 176-33 *SEALED* Filed 12/01/14 Page 24 of 126 Page ID #3037 Case: 16-3334 Document: 55-19 Filed: 02/08/2017 Pages: 126 (658 of 1511) Fig. 2. Commercial 30 ttL dropper tip for Allergan's Lumigan (left) and pointed "micro" tip (right) that delivers 17194 drops (using distilled water). Tip on right, if supplied for self-administratio n by patients, is more capable of causing eye injury. (Left tip courtesy of Allergan; right tip courtesy of Amcor [http://www.amcor.com]). 63. Touching the eye with the dropper tip creates another problem: possible bacteri al contamination. Most ophthalmic solutions designed for nonsurgical, multiple use after opening must contain antimicrobial preservatives. These additives ensure sterility of the product throughout the stated shelf life. However, it is quite common for patients to touch eyedropper bottle to the eyelids or ocular surface, thus contaminating the bottle the tip of the with bacteria from the eye. 64. Several researchers24'25 have documented the problem of microbial contamination of eye medications, including those used to treat glaucoma. Geyer, et al.25 found bacterial contamination of 28% of the medications used by glaucoma patients, and 91% of the bacteria were gram positive. The frequency of contamination increased with increasing duration of use. The researchers found a statistically significant difference in the rate of contam ination in drops used eight weeks or less when compared to those used more than eight weeks (19% vs. 40%), and recommended that opened containers of glaucoma eyedrops be replaced regular ly. 65. In a study to investigate the quality of eyedrop instillation technique in patient s diagnosed as having open-angle glaucoma or ocular hypertension, Dr. Robin and coworkersl° found that almost 20% of the patients contaminated their eyedrop bottle by allowin g the tip to touch the eye. Dr. Robin and colleagues18 have stated that "[cjontamination of the bottle tip is a significant concern, especially in the chronic application of eyedrops as in glaucom a, because this may place the patient at risk, especially those who have prior filtration or catarac t surgery, for vision-threatening infection." I share this concern. I also agree with the authors ' comment 24 Case 3:12-cv-01141-SMY-DGW Document 176-33 *SEALED* Filed 12/01/14 Page 25 of 126 Page ID #3038 Case: 16-3334 Document: 55-19 Filed: 02/08/2017 Pages: 126 (659 of 1511) that "[Oven that the most common population that has glaucoma is elderly, and that many also have ocular surface disease that could possibly predispose to infection, this is potentially a serious issue." Reducing the drop volume of eyedropper bottles to 15 or 16 !AL to extend the use of each bottle, as Plaintiffs propose, would create an even greater opportunity for bottle contamination than exists with the current commercial products. Without a corresponding to three reduction in the amount of medicine per bottle, patients likely would use each bottle two of times longer. In addition, once a sealed bottle is opened, the contents are subject to the risk excessive oxidation and deterioration from the long-term exposure to heat or light!' Large-Scale Clinical Trials for Each Medication Would Be Necessary to Determine the Safety and Efficacy of "Micro" Drops 66. To validate the potential efficacy and safety of 16 uL "microdrops" in patients ion with glaucoma or any other disease, large-scale multicenter clinical trials of each medicat would have to be completed with patients using the proposed new dropper bottles. To my ix knowledge, this has not been done for any of the drugs at issue. I have summarized in Append C the principal pilot "microdrop" studies of glaucoma medications and reasons why each study is inadequate to demonstrate equivalence with conventional eyedrop volumes. 67. Considering the haphazard and often unpredictable eyedrop instillation methods used by patients, as noted above, it is not surprising that most of the research on reduced volumes has been done in carefully controlled laboratory or clinical environments using eyedrop rs, investigator-instilled eyedrops. These studies have often been done using healthy voluntee rather than actual patients with disease. As an example, Kelly and coworkers29 tested a small rather group of eight normal, young volunteers using the glaucoma drug pilocarpine. Pupil size, . In a than IOP, was assessed, and the investigational delivery system was never commercialized study Dr. Robin discusses at length in his expert report, he and colleagues3° evaluated the of potential viability of a 16 tL drop of apraclonidine in a short-term study of a small group healthy volunteers. To ensure accurate dosing, the researchers "carefully placed only a single d drop of study medication in both eyes of each subject." Though the patients were then instructe 25 Case 3:12-cv-01141-SMY-DGW Document 176-33 *SEALED* Filed 12/01/14 Page 26 of 126 Page ID #3039 Case: 16-3334 Document: 55-19 Filed: 02/08/2017 Pages: 126 (660 of 1511) to self-administer drops using the investigational 16 µI, dropper bottles, these bottles were used for a total of less than three weeks (one week for each formulation) and only by healthy volunteers, none of whom was older than age 55 (mean age: 33). The results showed that apraclonidine formulated in a 0.5% solution with a 16 pi, drop volume was both effectiv e and well tolerated but not tolerated better than the 30 !IL drop volume. In another study patients (not involving "micro" drops), Dr. Robin and associates21 reported with actual that younger patients instilled drops more accurately than older patients and noted the potential impact of attributes such as tremor or arthritis, which affect manual dexterity. My older patients have often indicated concerns with proper eyedrop instillation due to their physical limitations. 68. Research using investigator-instilled "micro" drops has been done primarily to explore the safety profile of medications that reduce IOP or to reduce systemic side effects agents used to dilate the pupil. In some pharmacokinetic studies investigating the basic of ocular drug delivery, drop volumes as small as 2 to 5 vL have been employed using from science specially designed micropipettes and other technologies. These techniques are used strictly for investigational purposes as they allow instillation of drugs without greatly affecting size of the tear reservoir, and tell us nothing about real world use of eyedrops in the expected patient populations. Studies of Smaller Drops Have Not Documented Improved Systemic 69. Safety Plaintiffs reference published literature in their Complaint hypothesizing that "micro" drop volumes might reduce systemic side effects (Complaint at g[ 57). While hypothesis is reasonable, studies of several drugs in smaller drop volumes have not this shown an improved safety or tolerability profile. 70. Following topical administration of solutions to the eye, most of the eyedrop dose leaves the conjunctival sac through the lacrimal drainage system, and in some cases, some of the excess also spills onto the eyelid or cheek. The portion of the drop that drains through the nasolacrimal system may be absorbed into the systemic circulation via the nasal mucosa . For the vast majority of ophthalmic drug classes, this systemic absorption is of no consequ ence. In the 26 Case 3:12-cv-01141-SMY-DGW Document 176-33 *SEALED* Filed 12/01/14 Page 27 of 126 Page ID #3040 Case: 16-3334 Document: 55-19 Filed: 02/08/2017 Pages: 126 (661 of 1511) early 1980s, however, it was recognized that topical ocular timolol and other beta blockers might have potentially serious systemic side effects. This stimulated interest in reducing the systemic load of this class of glaucoma medication by reducing drop size or by reformulating the agents in vehicles and delivery systems that would increase ocular retention and reduce systemic absorption. The interest in reducing eyedrop size was initially driven solely by the concern for systemic complications associated with beta blockers. It was suggested that reducing the drop size of existing medications might reduce systemic absorption without sacrificing effectiveness in reducing IOP. Charap and colleagues31 were among the first to test this hypothesis in the late 1980s but, disappointingly, found no significant differences over three months in overall mean heart rate or blood pressure with drop volumes of 20, 35, and 50 µL of levobunolol 0.5%. 71. In the 1990s, researchers also sought to reduce some unwanted side effects associated with the alpha-adrenergic agonists apraclonidine and brimonidine. Dr. Robin and coworkers3° compared three different formulations of apraclonidine in both the conventional 30 µL drop size and an investigational 16 µL size. Unfortunately, the researchers recruited only 29 healthy volunteers whose mean age was 33 (no patient older than age 55), not representative of persons with glaucoma. Nevertheless, the results of the study failed to demonstrate any differences between the 16 µL and 30 p,L drop sizes in symptoms of dry mouth, drowsiness, or tiredness. 72. Allergan similarly found that reducing the drop size of brimonidine did not reduce the incidence of side effects. As part of its effort to determine the proper formulation and dose for brimonidine in the 1990s, Allergan conducted a study32 comparing the safety and efficacy of brimonidine 0.5% in two drop sizes: approximately 35 ± 9 µL and approximately 26 ± 5 µL. The authors of this seven-day study found no differences with regard to safety between the two drop volumes FNS Given the lack of any reduction in side effects with the smaller drop size, Allergan apparently adopted a strategy to reduce the active drug concentration and to reformulate brimonidine using a rapidly-disappearing preservative. Allergan submitted to the FDA New Drug Applications ("NDA") for 0.2% and 0.5% brimonidine (Alphagan), which were approved on September 6, FNS 27 Case 3:12-cv-01141-SMY-DGW Document 176-33 *SEALED* Filed 12/01/14 Page 28 of 126 Page ID #3041 Case: 16-3334 Document: 55-19 Filed: 02/08/2017 Pages: 126 (662 of 1511) 73. In late 2002 and early 2003, Allergan also studied its prostaglandin analog, bimatoprost (brand name Lumigan) to determine if reducing the drop size might lower the incidence of hyperemia (eye redness) previously seen during the Phase III clinical trials. 28 Researchers dispensed bimatoprost to patients using micropipettes in microdrop volumes of 5 pi, 10 p,L, 15 µL, 20 tiL, and 30 4. The 30 pi dose was intended to approximate the markete d dose of Lumigan (approximately 28 [J,L). Allergan had hoped that the smaller "micro" drop volumes would reduce hyperemia, but maintain efficacy. The results of this study were similar to the above studies of levobunolol, apraclonidine, and brimonidine, in that the microdrop volumes did not reduce the incidence of hyperemia.FN6 74. The above studies showed that reducing the drop size of several glaucoma medications did not reduce side effects, contrary to the hypotheses suggested by some researchers in the published literature. Further, these results demonstrate that adequate and well- controlled studies would have to be conducted for each drug at issue in this lawsuit to determin e 1996 and March 13, 1997, respectively. The 0.5% product was never commercialized, presumably because of its unfavorable side effect profile. As clinical experience was gained with the 0.2% formulation, doctors recognized that many patients incurred ocular allergy, red eye reactions, dry mouth, and the CNS side effects noted above. Allergan responded by reformulating brimonidine using a rapidly-disappearing preservative and lower active drug concentration. This new formulation (Alphagan P) was tested in Phase III clinical trials and approved by FDA in a 0.15% concentration shown to be as effective as the 0.2% solution . Further research demonstrated that an even lower concentration (0.1%) offered the same I0Plowering efficacy while further reducing both ocular and systemic side effects. This formula tion was FDA approved on August 19, 2005 and is in wide use today. With "micro" drop use not resulting in reduced hyperemia, bimatoprost similarly underwe nt reformulation to reduce its concentration from 0.03% to 0.01%. The 0.03% concentration was FDA approved on March 16, 2001, and it was quickly recognized that this medication often induced unwanted conjunctival hyperemia (eye redness). A large-scale randomized controll ed trial was developed to evaluate the efficacy and safety of several lower-concentration formulations, including 0.01%. This 12-month study demonstrated that bimatoprost 0.01% was comparable to bimatoprost 0.03% in lowering IOP and also showed improved tolerability, including less frequent and severe conjunctival hyperemia. This new formulation was FDA approved on August 31, 2010, and Allergan has since discontinued the 0.03% product. F1N6 28 Case 3:12-cv-01141-SMY-DGW Document 176-33 *SEALED* Filed 12/01/14 Page 29 of 126 Page ID #3042 Case: 16-3334 Document: 55-19 Filed: 02/08/2017 Pages: 126 (663 of 1511) whether reducing the drop size would in fact decrease certain side effects for a particular medication. 75. As the pharmacologic treatment of glaucoma has evolved over the past several decades, newer medication classes, such as the prostaglandin analogs, have been developed, further increasing the efficacy and safety of glaucoma treatment. Currently, the prostaglandin analogs (latanoprost, travoprost, bimatoprost, and tafluprost) are considered the first line medical treatment for ocular hypertension and open-angle glaucoma. The prostaglandin analogs have excellent ocular and systemic safety profiles and have I0P-reducing efficacy greater than that of any other single medication class. The IOP-lowering efficacy and safety of these medications, used either alone as monotherapy or in combination with other drugs, have lessened the interest in reformulating older medication classes, such as beta blockers, in smaller eyedrops. 76. In addition to new formulations of medications, simple mechanical maneuvers may be used by patients to decrease systemic absorption following eyedrop administration. One such technique is known as nasolacrimal occlusion, and it is now commonly recommended by eye doctors for patients using chronic medications such as glaucoma eyedrops. Immediately following drop instillation, the patient places gentle pressure with the fingertips over the inside corners of the eyes with the eyelids closed for 1 to 2 minutes. This simple maneuver has been demonstrated to increase the efficacy of several glaucoma medications while decreasing their systemic effects. Further, when patients use more than one eyedrop medication, they should wait about five minutes between drops and perform nasolacrimal occlusion after each instillation. This method maximizes the amount of medication reaching the target tissues and minimizes medication overflow and systemic absorption. Had Plaintiffs voiced their concerns about overflow of eyedrop solution to their doctors (which none did), the doctors could have watched them instill drops and instructed them on the proper technique in order to minimize this occurrence. 29 Case 3:12-cv-01141-SMY-DGW Document 176-33 *SEALED* Filed 12/01/14 Page 30 of 126 Page ID #3043 Case: 16-3334 Document: 55-19 Filed: 02/08/2017 Pages: 126 (664 of 1511) Reasonable Alternatives to Evedroc. Therapy 77. I disagree with Plaintiffs' contention in the Complaint that no reasonable alternatives to these prescription eyedrops are available. Systemic medications are often used for ocular conditions. As alternatives to topically applied eyedrops, or sometimes favored over eyedrops, these medications include oral antimicrobial agents such as doxycycline, cephalexin, and amoxicillin/clavulanate acid. Oral antiviral agents are often used along with, or in lieu of, topical antivirals. For example, I had a patient with Down syndrome who had a significant viral infection of the cornea but who could not tolerate eyedrop instillation. I changed him to oral acyclovir, and he had a very successful outcome. Other examples of systemic alternatives to topical eyedrops include oral antihistamines for ocular allergy and oral anti-inflammatory agents such as the steroid prednisone that can be used for treatment of scleritis or uveitis. For glaucoma patients, there are oral alternatives to eyedrops that include the carbonic anhydrase inhibitors acetazolamide and methazolamide. These agents, however, are almost always reserved for patients who cannot tolerate topical therapy, have exhausted all eyedrop choices, or who have acute elevations of IOP. For such patients, or those who either do not want or cannot tolerate eye drops, laser treatment and surgery are alternatives. Topical nonsteroidal anti-inflammatory drugs such as ketorolac can be used for treatment of ocular surface pain associated with trauma or refractive surgery, and oral analgesics, such as acetaminophen, ibuprofen, or narcotic agents, can serve as useful alternatives. Some topical antibiotics and steroids are available as ointments; these medications can be used in lieu of topical eyedrops for various conditions. Deciding whether any of these medications or other alternatives would be an appropriate treatment for a particular patient would require knowledge of the patient's medical condition and history, and the choices would vary from patient to patient. 30 Case 3:12-cv-01141-SMY-DGW Document 176-33 *SEALED* Filed 12/01/14 Page 31 of 126 Page ID #3044 Case: 16-3334 Document: 55-19 Filed: 02/08/2017 Pages: 126 (665 of 1511) Jimmy D. Bartlett. O.D D.O.S., D.Sc. References 9. 11 12. Clin Leibowitz 11M, Kupferman A. Antiinflammatory medications. Int Ophthalmol 1980;20:117-34. Spanu T, Santangelo R, Andreotti F, Cascio GL, Velardi G. Fadda G. Antibiotic therapy for severe bacterial infections: correlation between the inhibitory quotient and outcome. Jut J Antimicrob Agents 2004:23:120-8. Torkildsen GL. Williams JI. Gow JA, Gornes PJ, Abelson MB, McNamara TR. Bepotastine besilate ophthalmic solution for the relief of nonocular symptoms provoked by conjunctival allergen challenge. Ann Allergy Asthma Immunol 2010;105:57-64. Lippa EA. Carlson LE, Ehinger B, et al. Dose response and duration of action of dorzolamide, a topical carbonic anhydrase inhibitor. Arch Ophthalmol 1992;110:495-9. Wilkerson NI, Cyrlin M, Lippa EAi* et al. Four-week safety and efficacy- study of dorzolamide, a novel, active topical carbonic anhydrase inhibitor. Arch Ophthalmol 1993;111:1343-50. March WF, Ochsner KI. The long-term safety and efficacy of brinzolamide 1.0% (azont) in patients with primary open-angle glaucoma or ocular hypertension. The Brinzolarnide Long-Term Therapy Study Group. Am J Ophthalmol 2000;129:136-43. Schoenwald R. Ocular pharmacokinetics. In: Zimmerman T, ed. Textbook of ocular pharmacology. Philadelphia: Lippincott-Raven; 1997:119-38. Thummel KE, Shen DD, lsoherranen N. Design and optimization of dosage regimens: Pharmacokinetic data. In: Bruton LL, Chabner BA, ICnollmann BC, eds. Goodman & Gilman's The pharmacological basis of therapeutics. 12th ed. New York: McGraw Hill 2011:1891-990. Fraunfelder FT. Extraocular fluid dynamics: how best to apply topical ocular medication. Trans Am Ophthalmol Soc 1976;74:457-87.. Aptel F. Masser H, Burillon C, Robin A, Denis P. The influence of disease severity on quality of eye-drop administration in patients with glaucoma OT ocular hypertension. 'kJ Ophthalmol 2009;93:700-1. Zintz R. Schilling T. [a Colorimetric Method for Measuring the Fluid Volume in the Conjunctival Sac]. Klin Monbi Atigenheilkd 1964;144:393-413. Mishima S, Gasset A, Klyce SD, Jr., Baum JL. Determination of tear volume and tear flow. Invest Ophthalmol 1966;5:264-76. 31 Case 3:12-cv-01141-SMY-DGW Document 176-33 *SEALED* Filed 12/01/14 Page 32 of 126 Page ID #3045 Case: 16-3334 Document: 55-19 Filed: 02/08/2017 Pages: 126 (666 of 1511) 13. Ghate D, Edelhauser HF. Barriers to glaucoma drug delivery. J Glaucoma 2008;17:14756. 14. Gaudana R, Ananthula HK, Parenky A, Mitra AK. Ocular drug delivery. Aaps J 2010;12:348-60. 15. Van Santvliet L, Ludwig A. Determinants of eye drop size. Sury Ophthalmol 2004;49:197-213. 16. Valente C, Iester M, Corsi E, Rolando M. Symptoms and signs of tear film dysfunction in glaucomatous patients. J Ocul Pharmacol Ther 2011;27:281-5. 17. Fiscella R. Ophthalmic drug formulations. In: Bartlett J, Jaanus S, eds. Clinical ocular pharmacology. 5th ed. St. Louis: Elsevier; 2008:17-37. 18. Hennessy AL, Katz J, Covert D, Protzko C, Robin AL. Videotaped evaluation of eyedrop instillation in glaucoma patients with visual impairment or moderate to severe visual field loss. Ophthalmology 2010;117:2345-52. 19. Brown MM, Brown GC, Spaeth GL. Improper topical self-administration of ocular medication among patients with glaucoma. Can J Ophthalmol 1984;19:2-5. 20. Stone JL, Robin AL, Novack GD, Covert DW, Cagle GD. An objective evaluation of eyedrop instillation in patients with glaucoma. Arch Ophthalmol 2009;127:732-6. 21. Hennessy AL, Katz J, Covert D, et al. A video study of drop instillation in both glaucoma and retina patients with visual impairment. Am J Ophthalmol 2011;152:982-8. 22. Schwartz GF, Hollander DA, Williams JM. Evaluation of eye drop administration technique in patients with glaucoma or ocular hypertension. Curr Med Res Opin 2013;29:1515-22. 23. Burns E, Mulley GP. Practical problems with eye-drops among elderly ophthalmology outpatients. Age Ageing 1992;21:168-70. 24. Schein OD, Hibberd PL, Starck T, Baker AS, Kenyon KR. Microbial contamination of in-use ocular medications. Arch Ophthalmol 1992;110:82-5. 25. Geyer 0, Bottone EJ, Podos SM, Schumer RA, Asbell PA. Microbial contamination of medications used to treat glaucoma. Br J Ophthalmol 1995;79:376-9. 26. Bartlett JD, Wesson MD, Swiatocha J, Woolley T. Efficacy of a pediatric cycloplegic administered as a spray. J Am Optom Assoc 1993;64:617-21. 27. Wesson MD, Bartlett JD, Swiatocha J, Woolley T. Mydriatic efficacy of a cycloplegic spray in the pediatric population. J Am Optom Assoc 1993;64:637-40. 28. Unpublished Clinical Study Report: A multicenter, double-masked, randomized, parallel, vehicle-controlled, two week study of the safety, tolerability, and efficacy of once-daily bimatoprost 0.03% ophthalmic solution administered in microdrop volumes of 5 RL, 10 111., 15 4, and 20 v1_, compared with the marketed volume (301.1L) in patients with glaucoma or glaucoma suspects. In: Allergan; 2003. Kelly JA, Molyneux PD, Smith SA, Smith SE. Relative bioavailability of pilocarpine from a novel ophthalmic delivery system and conventional eyedrop formulations. Br J Ophthalmol 1989;73:360-2. 29. 32 Case 3:12-cv-01141-SMY-DGW Document 176-33 *SEALED* Filed 12/01/14 Page 33 of 126 Page ID #3046 Case: 16-3334 Document: 55-19 Filed: 02/08/2017 Pages: 126 (667 of 1511) 30. 31. 32. size of apraclonidine Vocci MJ, Robin AL, Wahl JC, et al. Reformulation and drop hydrochloride. Am J Ophthalmol 1992;113:154-60. size on the efficacy and Charap AD, Shin DH, Petursson G, et al. Effect of varying drop safety of a topical beta blocker. Ann Ophthalmol 1989;21:351-7. 8042. A comparison of Unpublished Clinical Study Report: Allergan Report A342-1161994. the safety and efficacy of brimonidine 0.5% in two drop sizes. 33 Case 3:12-cv-01141-SMY-DGW Document 176-33 *SEALED* Filed 12/01/14 Page 34 of 126 Page ID #3047 Case: 16-3334 Document: 55-19 Filed: 02/08/2017 Pages: 126 (668 of 1511) APPENDIX A Case 3:12-cv-01141-SMY-DGW Document 176-33 *SEALED* Filed 12/01/14 Page 35 of 126 Page ID #3048 Case: 16-3334 Document: 55-19 Filed: 02/08/2017 Pages: 126 (669 of 1511) CURRICULUM VITAE JIMMY D. BARTLETT BIRTHDATE: December 19, 1949 BIRTHPLACE: Fort Smith, Arkansas MARITAL STATUS: (Cynthia Lynn Lundberg) Married Children: Andrew Horton Bartlett (D.O.B. 3/27/85) Kenton Woodard Bartlett (D.O.B. 4/8/88) Harrison Logan Bartlett (D.O.B. 11/21/91) CURRENT POSITION: Professor Emeritus, School of Optometry, University of Alabama at Birmingham (2013 to present) President PHARMAKON Group 2328 Country Ridge Drive Birmingham, Alabama 35243 Telephone: (205) 907-6764 Fax: (205) 969-2551 RECENT APPOINTMENTS 2005-2011 Chairman, Department of Optometry, School of Optometry, University of Alabama at Birmingham 1993-2011 Professor, Department of Optometry, School of Optometry, University of Alabama at Birmingham 1994-2011 Professor, Division of Clinical Pharmacology, Department of Pharmacology and Toxicology, University of Alabama School of Medicine 1993-2011 Member, Graduate Faculty, Department of Vision Sciences, School of Optometry, University of Alabama at Birmingham 1984-2011 Adjunct Professor of Optometry, Southern California College of Optometry, Fullerton Case 3:12-cv-01141-SMY-DGW Document 176-33 *SEALED* Filed 12/01/14 Page 36 of 126 Page ID #3049 Case: 16-3334 Document: 55-19 Filed: 02/08/2017 Pages: 126 (670 of 1511) Curriculum Vitae Jimmy D. Bartlett 2 Consultant Veterans Administration Medical Center, Birmingham Medical Information Service (via) Telephone (MIST), University of Alabama at Birmingham PREVIOUS APPOINTMENTS 2000-2005 Interim Chairman, Department of Optometry, School of Optometry, University of Alabama at Birmingham 1994-2000 Director, Residency Programs and Fellowships, UAB School of Optometry, University of Alabama at Birmingham 1980-1993 Associate Professor, Department of Optometry, School of Optometry, University of Alabama at Birmingham 1983-1989 Chief, Family Practice Optometry Clinic, School of Optometry, University of Alabama at Birmingham 1988 Consultant, Florida Department of Professional Regulation 1980-1987 Consultant, Family Medical Services, Birmingham 1981-1984 Director of Continuing Education, School of Optometry, University of Alabama at Birmingham 1977-1980 Assistant Professor, Department of Optometry, School of Optometry, University of Alabama at Birmingham 1979-1980 Acting Director, Residency Programs, School of Optometry, University of Alabama at Birmingham 1977 Consultant, Atlanta Area Services for the Blind, Atlanta, Georgia 1974-1977 Chief, Optometry Section, VA Hospital, Tampa, Florida 1976-1977 Assistant Professor, Department of Ophthalmology, College of Medicine, University of South Florida, Tampa, Florida 1974-1977 Director, Low Vision Service, Department of Ophthalmology, University of South Florida Teaching Hospitals, Tampa, Florida 1976-1977 Director, Ocular Electrodiagnostic Laboratory, All Children's Hospital, St. Petersburg, Florida Case 3:12-cv-01141-SMY-DGW Document 176-33 *SEALED* Filed 12/01/14 Page 37 of 126 Page ID #3050 Case: 16-3334 Document: 55-19 Filed: 02/08/2017 Pages: 126 (671 of 1511) Curriculum Vitae Jimmy D. Bartlett 3 1974-1976 Instructor, Department of Ophthalmology, College of Medicine, University of South Florida, Tampa, Florida EDUCATION AND DEGREES Arkansas Tech University, Russellville, Arkansas 1967-1970 University of Memphis, Memphis, Tennessee 1971 Southern College of Optometry, Memphis, Tennessee 1972, B.S. Southern College of Optometry, Memphis, Tennessee 1974, O.D. Southern College of Optometry, Memphis, Tennessee 1986, D.O.S. 2002, Sc.D. (Honoris causa) State University of New York Terry College of Business, University of Georgia 2013 Executive Program in Financial Planning PROFESSIONAL SOCIETY AFFILIATIONS American Academy of Optometry Chairman, Section on Disease, 1979-1980 Member, Low Vision Section Member, Executive Committee, Low Vision Diplomate Program, 1979-1982 Chairman, Ocular Disease Sub-Committee, Low Vision Diplomate Examination Committee, 1979-1980 Chairman, Case Reports Sub-Committee, Low Vision Diplomate Examination Committee, 1981 Member, Ad Hoc Committee on Classification of Visual Impairment (1976) American Optometric Association Association for Research in Vision and Ophthalmology Association for Ocular Pharmacology and Therapeutics Optometric Glaucoma Society American Optometric Foundation Alabama Optometric Association Association of Optometric Educators Prentice Society Southern Council of Optometrists Florida Optometric Association (1974-1977) Case 3:12-cv-01141-SMY-DGW Document 176-33 *SEALED* Filed 12/01/14 Page 38 of 126 Page ID #3051 Case: 16-3334 Document: 55-19 Filed: 02/08/2017 Pages: 126 (672 of 1511) Curriculum Vitae Jimmy D. Bartlett 4 Member, Ad Hoc Committee on Pharmacology, 1975 Hillsborough (Florida) Society of Optometrists (1974-1977) UAB Circle of Omicron Delta Kappa COMMUNITY SERVICE ACTIVIIIES Chairman, Board of Trustees, Vestavia Hills Library in the Forest, 2013 Treasurer, Victoria Square Condominium Association, Inc., 2009-2012 Editor and Publisher, Vestavia Hills High School Band Newsletter, 1999-2003, 2006 Member, Planning and Public Relations Committee, Vestavia Hills Ford Festival, 2000 Secretary-Treasurer, Country Ridge Homeowners Association, Inc. 1998-2001 Member, Fall Carnival Planning Committee, Vestavia Hills Elementary East, 2000 Editor and Publisher, Pizitz Middle School Band Newsletter (1997-1999) Tampa (Florida) Lighthouse for the Blind Member, Board of Directors (1976-1977) Florida Society for the Prevention of Blindness Member, Board of Directors, West Coast Branch (1974-1977) Chairman, Public Relations Committee, West Coast Branch (1975) State Chairman, Personnel Committee, 1975-1976 Secretary-Treasurer, Hillsborough County Advisory Council (1977) UNIVERSITY COMMITTEE ASSIGNMENTS Chair, Subcommittee on Basic Health Sciences, Curriculum Committee Member, UAB Focus Group for Strategic Planning Member, Clinical Research Advisory Committee Member, Continuing Education Advisory Committee Member, Clinic Council Member, Research Advisory Committee Member, Residency and Fellowship Program Advisory Committee Member, Executive Committee Member, Curriculum Committee Case 3:12-cv-01141-SMY-DGW Document 176-33 *SEALED* Filed 12/01/14 Page 39 of 126 Page ID #3052 Case: 16-3334 Document: 55-19 Filed: 02/08/2017 Pages: 126 (673 of 1511) Curriculum Vitae Jimmy D. Bartlett 5 Member, Combined Degree Programs Committee Member, Externship and Placement Advisory Committee Co-Chair, Strategic Planning Committee Member, Student-Faculty Liaison Committee Member, Vision Science Graduate Program Admission/Advisory Committee Vision Science Graduate Program Admission/Advisory Committee (Member) Research Advisory Committee (Member) Clinical Research Advisory Committee (Member) University Optometric Group Advisory Committee (Member) Ad Hoc Task Force Group on Definition of a Model for Optimal Clinical Teaching (Chair) Residency and Fellowship Program Advisory Committee Member, Quality Assessment and Improvement Committee, UAB School of Optometry, 1991 — Present Continuing Education Advisory Committee Chairman, AIDS Policy Committee, UAB School of Optometry, 1987-1988 t Member, ASCO ad hoc committee for development of curriculum model in treatmen and management of ocular disease, 1985-1988 Member, Executive Committee, University Optometric Group, UAB School of Optometry, 1987 85 Member, Student Affairs Advisory Committee, UAB School of Optometry, 1984-19 Member, Promotions Committee, UAB School of Optometry, 1980-82 Member, University Faculty Grievance Panel, UAB, 1984-present Member, Executive Committee, UAB School of Optometry, 1979-1984 Member, Professional Standards Review Committee, University Optometric Group, Case 3:12-cv-01141-SMY-DGW Document 176-33 *SEALED* Filed 12/01/14 Page 40 of 126 Page ID #3053 Case: 16-3334 Document: 55-19 Filed: 02/08/2017 Pages: 126 (674 of 1511) Curriculum Vitae Jimmy D. Bartlett 6 UAB School of Optometry, 1984-1986 Member, Optometry Faculty Advisory Committee, Department of Optometry, UAB School of Optometry, 1980-1983, 1994-present Member, Residency and Fellowship Program Advisory Committee, UAB School of Optometry, January 1978-present, Chairman, 1979-1980, 1995-present Member, Clinic Council, UAB School of Optometry, 1981-1994 Chairman, Intramural Practice Committee, UAB School of Optometry, 1977-1980 Chairman, Continuing Education Advisory Committee, UAB School of Optometry, 1981-1984; member, 1981-present Visual Impairment Service Team, Tampa V.A. Hospital (1974-1977) Admissions and Examinations Committee, Southern College of Optometry, 1972-1974, Secretary, 1972-1973 President's Council, Arkansas Tech University, 1969-1970 Improvement of Instruction Committee, Arkansas Tech University, 1969-1970 PROFESSIONAL HONORS, AWARDS, AND SERVICE ACTIVII1ES Optometrist of the South, SECO International, Atlanta, Georgia, 2012 Optometrist of the Year, Alabama Optometric Association, 2011 Member, Organizing Committee, Biennial Meeting of Association for Ocular Pharmacology and Therapeutics, Fort Worth, Texas, 2011 Visiting Lecturer, New England College of Optometry, Boston, 2008, 2009, 2010 Selected for inclusion in Biltmore 2009 Honors Edition of Who's Who Among Executives and Professionals Distinguished Service Award, Colorado Optometric Glaucoma Society, Denver, 2008 Chair, Pharmacology Section, Optometry Times Member of Search Committee for UAB Associate Provost for Faculty Development and Faculty Affairs, 2008 Case 3:12-cv-01141-SMY-DGW Document 176-33 *SEALED* Filed 12/01/14 Page 41 of 126 Page ID #3054 Case: 16-3334 Document: 55-19 Filed: 02/08/2017 Pages: 126 (675 of 1511) Curriculum Vitae Jimmy D. Bartlett 7 Member, Organizing Committee, Biennial Meeting of Association for Ocular Pharmacology and Therapeutics, Salzburg, Austria 2009 Selected for inclusion in "Guide to America's Top Optometrists", 2007 edition, published by Consumers' Research Council of America Inducted into National Academies of Practice, 2005 Member, United States Pharmacopeia (representing the profession of optometry) Member, Ph.D. Graduate Committee for Ferial Zeried Lifetime Achievement Award, Southern College of Optometry, 2005 Consultant, Infant and Children's Coalition, Drug Reference Guide, American Optometric Association Member, Pfizer Ophthalmics Advisory Board, 2002 - present Member, Executive Committee, Optometric Glaucoma Society Member, Alcon Laboratories Glaucoma Advisory Panel Speaker, VSP National Education Plan Member, Inspire Pharmaceuticals Distinguished Speakers Bureau, 2007- present Member, Alabama Prescription Drug Monitoring Advisory Committee, 2004 - present Member, Organizing Committee, Biennial Meeting of Association for Ocular Pharmacology and Therapeutics, Catania, Sicily, 2005 Member, Organizing Committee, Biennial Meeting of Association for Ocular Pharmacology and Therapeutics, San Diego, CA, 2007 Member, Honorary Editorial Board, Therapeutics and Clinical Risk Management Consultant, Virginia Optometric Association Consultant, Louisiana Optometric Association Consultant, Board of Examiners in Optometry, British Columbia Inductee, National Optometry Hall of Fame, 2004 Consultant, Oklahoma Board of Optometry Case 3:12-cv-01141-SMY-DGW Document 176-33 *SEALED* Filed 12/01/14 Page 42 of 126 Page ID #3055 Case: 16-3334 Document: 55-19 Filed: 02/08/2017 Pages: 126 (676 of 1511) Curriculum Vitae Jimmy D. Bartlett 8 Consultant, Novartis Ophthalmics Member, Promotions/Tenure Committee for Sarah Hosking, O.D., Ph.D., Aston University, United Kingdom Member, Program Committee, Optometric Glaucoma Society Member, Bausch and Lomb Advisory Panel Member, Pharmacia Advisory Board Speaker, VSP National Education Plan Trustee, Association for Ocular Pharmacology and Therapeutics Member, Organizing Committee, Biennial Meeting of Association for Ocular Pharmacology and Therapeutics, Kona, Hawaii Moderator, Clinical Studies Section, Annual Meeting, Association for Ocular Pharmacology and Therapeutics, Kona, Hawaii Member, Clinical Expert Review Panel, Optometric Clinical Practice Guidelines on Care of Patients with Open-Angle Glaucoma, 2nd edition, American Optometric Association Member, Ph.D. Graduate Committee for John Arnold Member, Promotions/Tenure Committee for Cynthia Green, O.D., Ohio State University Member, Prescription Drug Marketing Project Team, American Optometric Association, 2000-2002 Member, Clinical Expert Review Panel, Optometric Clinical Practice Guidelines on Care of Patients with Open-Angle Glaucoma, 2nd edition, American Optometric Association Member, International Scientific Advisory Board, Fourth International Symposium on Ocular Pharmacology and Pharmaceutics, Seville, Spain, February 2002. Elected Trustee to Association for Ocular Pharmacology and Therapeutics 2002-2003 Member, Fight for Sight Grant Review Section 2002-2005 Member, Allergan Pharmaceuticals Advisory Board Case 3:12-cv-01141-SMY-DGW Document 176-33 *SEALED* Filed 12/01/14 Page 43 of 126 Page ID #3056 Case: 16-3334 Document: 55-19 Filed: 02/08/2017 Pages: 126 (677 of 1511) Curriculum Vitae Jimmy D. Bartlett 9 Member, Editorial Advisory Board, optometryonline.net (web server in United Kingdom) Member, Scientific Advisory Committee, 5th Annual Meeting of the Association for Ocular Pharmacology and Therapeutics, Birmingham, Alabama, November 2000 Selected by Review of Optometry as one of the most influential optometrists of the twentieth century Member, Alcon Laboratories Allergy Advisory Panel Member, Alcon Laboratories Glaucoma Advisory Panel Chair, Organizing Committee, Association for Ocular Pharmacology and Therapeutics Annual Meeting 2000 Moderated Clinical Research Session, Association for Ocular Pharmacology and Therapeutics Annual Meeting 2000 Moderated Optometry Glaucoma Research Consortium, ARVO meeting, May 2000 Received American Optometric Student Association (AOSA) Teaching Award for Clinical Science (2000) Chair, Toxicology Section, International Ocular Pharmacology and Pharmaceutics Symposium, Lisbon, Portugal, February 2000 Chair, Organizing Committee, Association for Ocular Pharmacology and Therapeutics, Birmingham, October 2000 Member, International Scientific Advisory Board, Third International Symposium on Ocular Pharmacology and Pharmaceutics, Lisbon, Portugal, February 2000 Distinguished Visiting Professor, New England College of Optometry, Boston, 1999 Clinical Practice Guidelines Consensus Panel, "Care of the Patient with Open-Angle -Glaucoma", American Optometric Association (Member) Chair, Toxicology Section, Second International Symposium on Experimental and Clinical Ocular Pharmacology and Pharmaceutics, Munich, Germany (Chair) Referee for Ophthalmic Research Referee for Experimental Eye Research Case 3:12-cv-01141-SMY-DGW Document 176-33 *SEALED* Filed 12/01/14 Page 44 of 126 Page ID #3057 Case: 16-3334 Document: 55-19 Filed: 02/08/2017 Pages: 126 (678 of 1511) Curriculum Vitae Jimmy D. Bartlett 10 Referee for Current Eye Research Referee for Investigative Ophthalmology and Visual Science Referee for Biodrugs (Adis International) Referee for Handbook of Nonprescription Drugs, American Pharmaceutical Association Referee for Journal of the American Pharmaceutical Association Member, Editorial Board, Foresight (Glaucoma newsletter) Pharmacology Editor, Optometric Management, 1997-2002 Member, Optometric Advisory Board, Akorn, Inc. Member, Promotion Committee for Alfred Rosenbloom, O.D., University of Illinois at Chicago Consultant to Prescription - to - OTC Project, College of Pharmacy, University of Tennessee, Memphis Member, Promotion Committee, John Nishimoto, O.D., Southern California College of Optometry Member, Promotion Committee, Jerome Feldman, Ph.D., State University of New York College of Optometry AOSA Clinical Science Teaching Award, 1996 Chair, Residency and Fellowship Program Advisory Committee, UAB School of Optometry, 1995-present Coordinator, American Academy of Optometry Symposium on New Ophthalmic Medications Chair, Ocular Toxicology Section, International Symposium on Experimental and Clinical Ocular Pharmacology and Pharmaceutics, Geneva, Switzerland, 1995 "The New Alabama TPA Law - What does it mean for students?" Lecture to Phi Epsilon Chi, November 1995 Member, Promotion Committee for Anastasia F. Pass, O.D., University of Houston College of Optometry Case 3:12-cv-01141-SMY-DGW Document 176-33 *SEALED* Filed 12/01/14 Page 45 of 126 Page ID #3058 Case: 16-3334 Document: 55-19 Filed: 02/08/2017 Pages: 126 (679 of 1511) Curriculum Vitae Jimmy D. Bartlett 11 Chair, Promotion Committee for Robert P. Rutstein, O.D., School of Optometry, University of Alabama at Birmingham Member, Promotion Committee for John Nishimoto, O.D., Southern California College of Optometry Member, Promotion Committee for Karan P. Singh, Ph.D., Department of Biostatistics, School of Public Health, University of Alabama at Birmingham Member, Scientific Advisory Board, Second International Symposium on Experimental and Clinical Ocular Pharmacology and Pharmaceutics, Munich, Germany, 1997 Invited member (representing American Optometric Association), United States Pharmacopeia Invited member, Vision Science Research Center, University of Alabama at Birmingham AOSA Clinical Science Teaching Award, 1994 Member, Editorial Advisory Board, Eye Care Technology, 1994-1996 Member, Medical Advisory Board, Ciba Vision Ophthalmics Member, Editorial Board, Journal of Ocular Pharmacology and Therapeutics Member, Scientific Advisory Board, International Symposium on Experimental and Clinical Ocular Pharmacology and Pharmaceutics, Geneva, Switzerland, 1995 Member, Planning Committee, Henry B. Peters Invitational Lectureship Series, 1995 Member, Goals and Objectives Self-Study Committee for COE Accreditation, 1994 Chair, Organization and Evaluation Self-Study Committee for COE Accreditation, 1994 Member, Ad Hoc Pharmacology Curriculum Committee, UAB Schools of Optometry and Dentistry, 1995 Member, Promotion Committee for Richard G. Fiscella, Pharm. D., University of Illinois School of Pharmacy, 1995 Member, Clinical Research Advisory Committee, UAB School of Optometry Member, By-laws Subcommittee, Association for Ocular Pharmacology and Therapeutics Member, Clinical Expert Review Panel for Clinical Practice Guideline on Open-angle Glaucoma, American Optometric Association, 1994 Case 3:12-cv-01141-SMY-DGW Document 176-33 *SEALED* Filed 12/01/14 Page 46 of 126 Page ID #3059 Case: 16-3334 Document: 55-19 Filed: 02/08/2017 Pages: 126 (680 of 1511) Curriculum Vitae Jimmy D. Bartlett 12 Visiting Professor, State College of Optometry, State University of New York, May, 1992 Participant, 1992 Summer Invitational Clinical Research Institute, Pacific University, Forest Grove, Oregon Bartlett JD. Giant papillary conjunctivitis therapeutic drug trials in optometry. American Academy of Optometry, Orlando Florida, December 1992. (paper presentation) Bartlett JD. Pharmacology as a specific research issue. In Conference on Optometric Research, Summit on Optometric Education, Birmingham, Alabama, April 1993. (paper presentation) Consultant, New Technologies Committee, American Optometric Association, 1993 President's Award for Excellence in Teaching, UAB School of Optometry, 1992 Member, Editorial Panel, Optometry--Current Literature in Perspective, 1990-1996 Member, Advisory Committee, Omega Eye Care Center, 1991-1996 Member, Geriatric Committee, American Optometric Association, 1991-1992 Consultant, Center for Vision Care Policy, State University of New York, 1991-1992 Reviewer, Handbook of Nonprescription Drugs, 10th edition, 1993 Vision Service Award, Heart of America Contact Lens Society, 1992 Visiting Associate Professor of Ophthalmology and Visual Sciences, Department of Ophthalmology, University of Louisville School of Medicine, Louisville, KY (sabbatical 1990) Commissioned Kentucky Colonel, October 10, 1990 by Kentucky Governor Wilkinson Member, Contributing Review Panel, Drug Facts and Comparisons, J.B. Lippincott, 1990present Contributor to Cline D, Griffin J, Hofstetter H, eds. Dictionary of Visual Science, 4th edition, Chilton, 1989 Consultant, Primary Care Committee, American Optometric Association, 1989-Present Member, Review Panel, Handbook of Nonprescription Drugs, 9th edition, 1991, American Pharmaceutical Association Case 3:12-cv-01141-SMY-DGW Document 176-33 *SEALED* Filed 12/01/14 Page 47 of 126 Page ID #3060 Case: 16-3334 Document: 55-19 Filed: 02/08/2017 Pages: 126 (681 of 1511) AMU Curriculum Vitae Jimmy D. Bartlett 13 Consultant, School of Optometry, University of Missouri-St. Louis, 1990 Consultant to Statutory Definition Committee, American Optometric Association, 1988 Participant in panel discussion, "The Future of Optometry/Ophthalmology Relations", House of Delegates, American Optometric Association, Chicago, June 1988 Moderator of Optometric Orientation Conference, American Optometric Association, Birmingham, November 1988 Participant in panel discussion, "TPA Law Components", State Legislation Conference, American Optometric Association, Birmingham, November 1988 Participant in panel discussion, "Clinical Education", State Legislation Conference, American Optometric Association, Birmingham, November 1988 Member, Optometric Advisory Board, Akorn, Inc. Member, Editorial Panel, Ophthalmic Drug Facts, J. B. Lippincott Chairman, The International Style Guide Committee for Uniform Submissions to Optometric Journals, 1987 Special Government Relations Task Force, American Optometric Association, 1987 Optometric Editor's Association Award: Most Improved Publication, National (Honorable Mention), Journal of American Optometric Association, Jimmy D. Bartlett,O.D., Editor, 1986 Optometric Editor's Association Award: Best Technical Article, National (Honorable Mention), Potter J. Bartlett JD, Alexander LJ, et al. Oral Fluorography. J Am Optom Assoc 1985; 56:784-92 Principal Commencement Speaker, Southern College of Optometry, June 1986: "Your Involvement in Optometry - the Primary Eye and Vision Care Profession" Board of Advisors, Pacific University College of Optometry, 1986-present Editor-in-Chief, Journal of the American Optometric Association, 1985-1990 Statutory Definition Subcommittee, State Legislative Affairs Advisory Committee, American Optometric Association, 1986 1984 Spurgeon Eure Award, American Optometric Foundation Case 3:12-cv-01141-SMY-DGW Document 176-33 *SEALED* Filed 12/01/14 Page 48 of 126 Page ID #3061 Case: 16-3334 Document: 55-19 Filed: 02/08/2017 Pages: 126 (682 of 1511) Curriculum Vitae Jimmy D. Bartlett 14 Listed in The International Authors and Writers Who's Who, 1 1 th edition, International Biographical Centre, Cambridge, England, 1988 Listed in Community Leaders of America, 12th edition Listed in Who's Who in the South and Southwest, 18th edition, 1982-83 Listed in American Men and Women of Science Listed in The International Blue Book, 1982-1983 edition Listed in 1981 Personalities of the South, Eleventh ed., American Biographical Institute Listed in Men of Achievement 1981 Listed in Outstanding Young Men of America 1980 Listed in Outstanding Young Men of America 1979 Council on Clinical Competency (State of Alabama), 1981 Ad hoc Committee for Continuing Education (Southern Council of Optometrists), 1982 Abstracts Editor, Journal of the American Optometric Association, 1982-1985 Long Range Planning Committee for Continuing Education (University of Alabama at Birmingham), 1981-1983 Division Editor, Section on Ocular Disease, National Board of Examiners in Optometry, 1980 Fellow, American Academy of Optometry Chairman, Section on Disease, American Academy of Optometry, 1979-1980 Diplomate, Low Vision Section, American Academy of Optometry Member, Low Vision Diplomate Executive Committee, American Academy of Optometry, 1979-1981 Member, Editorial Board, Optometry Times, 1984-1985 Referee, Optometry and Vision Science Referee, Journal of the American Optometric Association Case 3:12-cv-01141-SMY-DGW Document 176-33 *SEALED* Filed 12/01/14 Page 49 of 126 Page ID #3062 Case: 16-3334 Document: 55-19 Filed: 02/08/2017 Pages: 126 (683 of 1511) Curriculum Vitae Jimmy D. Bartlett 15 Clinical Investigator, Bausch and Lomb Soflens Division (Rochester, NY), 1976-1977 Valedictorian Appointment, Southern College of Optometry, 1974 Beta Sigma Kappa Silver Medal Award, Southern College of Optometry, 1974 Sigma Alpha Sigma Outstanding Senior Award, Southern College of Optometry, 1974 Distinguished Service Award, presented by Interprofessional Development Committee, American Optometric Student Association, 1974 Co-founder, Memphis Student Coalition of Health Professions, Memphis, Tennessee Who's Who Among Students in American Universities and Colleges, Southern College of Optometry, 1973-1974 National Associate Editor, American Optometric Student Review 1971-1972 Who' Who Among Students in American Universities and Colleges, Arkansas Polytechnic University, 1969-1970 OPTOMETRIC LICENSURE Tennessee 1974-2001 Florida 1974-present National Board of Examiners in Optometry (Part I, 1972; Part II, 1974) Alabama 1977-present PRIVATE PRACTICE EXPERIENCE University Optometric Group, (intramural practice affiliated with the University of Alabama at Birmingham School of Optometry), August 1977-present University Medical Service Association, Inc., Tampa, Florida (multidisciplinary intramural practice affiliated with the University of South Florida College of Medicine), September 1974 to June 1977 INVITED CLINICAL AND SCIEN I 'P IC PRESENTATIONS 1. "The Utilization of Electroretinography in Optometric Practice," Southern College of Optometry, March 1973. 2. "Retinal Fluorescein Angiography - an Aid to Ocular Diagnosis," Southern College of Optometry, February 1974. Case 3:12-cv-01141-SMY-DGW Document 176-33 *SEALED* Filed 12/01/14 Page 50 of 126 Page ID #3063 Case: 16-3334 Document: 55-19 Filed: 02/08/2017 Pages: 126 (684 of 1511) Curriculum Vitae Jimmy D. Bartlett 16 3. "Clinical Optometric Pharmacology and Diagnostic Techniques," Manasota Optometric Association (Florida), February 1976. 4. "The Interdisciplinary Approach to Low Vision Rehabilitation," American Academy of Optometry, Florida Chapter, Leesburg, Florida, March 1976. 5. "Visual Rehabilitation of the Partially-sighted Adult," Community Workshop on Aging and Blindness, Tampa Lighthouse for the Blind, Tampa, Florida, May 1976. 6. "Rehabilitation of the Congenitally Blind Child," Symposium on Ocular Developmental Anomalies, University of South Florida, November 1976. 7. "Low Vision Rehabilitation," Sunshine State Association for the Blind, Lake Wales, Florida, November 1976. 8. "Effective Utilization of Mydriatic Agents in Office Practice," School of Optometry, University of Alabama at Birmingham, February 1977. 9. "Clinical Diagnostic Procedures Utilizing Mydriatic Agents," Lake Region Optometric Association (Florida), February 1977. 10. "Current Concepts in Management of the Patient with Low Vision," Southern Educational Congress of Optometry, Atlanta, Georgia, February 1977. 11. "Current Concepts in Management of the Patient with Low Vision," Tampa Lighthouse for the Blind," Tampa, Florida, June 1977. 12. "Slit Lamp Biomicroscopy," (clinical laboratory) UAB, August 1977. 13. "Low Vision Rehabilitation," UAB, September 1977. 14. "Administration of and Adverse Reactions to Cycloplegic Agents, Symposium on Cycloplegic Refraction, American Academy of Optometry, Birmingham, Alabama, December 1977. 15. "Congenital Cone Dysfunction," Section on Disease, American Academy of Optometry, Birmingham, Alabama, December 1977. 16. "Effective Utilization of Mydriatics," Zone I Optometric Society, Montgomery, Alabama, February 1978. 17. "Genetic Considerations in Low Vision Practice," Southern Congress of Optometry, Atlanta, Georgia, February 1978. 18. "Low Vision Rehabilitation in General Optometric Practice," Southern Congress of Optometry, Atlanta, Georgia, February 1978. 19. "General Principles of Ocular Disease," (lecture and clinical laboratory) UAB, April 1978. 20. "The Dilated Pupil - Effective Utilization of Mydriatic Agents in Office Practice," Mountain West Council of Optometrists, Salt Lake City, Utah, April 1978. 21. "Fundus Biomicroscopy," (clinical laboratory) UAB, August 1978. 85. "Goldmann Perimetry," (clinical laboratory), UAB, July 1978. 22. "Diseases of the Posterior Pole," (lecture and clinical laboratory) UAB, September 1978. 23. "Headache - The Most Common Symptom," Alabama Optometric Association, Birmingham, October 1978. 24. "Highlights of Anterior Segment Disease," UAB Faculty Institute Day, November 1978. Case 3:12-cv-01141-SMY-DGW Document 176-33 *SEALED* Filed 12/01/14 Page 51 of 126 Page ID #3064 Case: 16-3334 Document: 55-19 Filed: 02/08/2017 Pages: 126 (685 of 1511) Curriculum Vitae Jimmy D. Bartlett 17 25. "The Pharmacological Diagnosis of Pupillary Abnormalities," American Academy of Optometry, Boston, December 1978. 26. "Analysis of Low Vision Services in a Veterans Administration Hospital," American Academy of Optometry, Boston, December 1978. 27. "Bacterial Conjunctivitis - Diagnosis and Management," American Academy of Optometry, Boston, December 1978. Rehabilitation Process for the Low Vision Patient," American Academy of "The 28. Optometry, Boston, December 1978. 29. "Anterior Segment Disease," Alabama Association of Optometrists, Birmingham, January 1979. 30. "Technique of Perimetry," in Visual Fields Symposium, Atlanta, January 1979. 31. "Psychogenic Vision Loss," in Visual Fields Symposium, Atlanta, January 1979. 32. "Post-Chiasmal Lesions," in Visual Fields Symposium, Atlanta, January 1979. 33. "Toxic Amblyopia," in Visual Fields Symposium, Atlanta, January 1979. 34. "New Developments in Functional Aids for the Blind," in Low Vision Symposium, UAB, February 1979. Considerations in Low Vision Practice," in Low Vision Symposium, "Genetic 35. UAB, February 1979. 36. "The Low Vision Examination," in Low Vision Symposium, UAB, February 1979. 37. "Low Vision Rehabilitation in General Optometric Practice," Mountain West Council of Optometrists, Salt Lake City, March 1979. 38. "The Therapeutic Use of Pharmaceutical Agents," Kentucky Optometric Association, Louisville, April 1979. 39. "Effective Utilization of Mydriatic Agents in Office Practice," Tennessee Optometric Association, Nashville, May 1979. 40. "Diagnosis and Management of Bacterial Conjunctivitis," Tennessee Optometric Association, Nashville, May 1979. 41. "Diagnostic Laboratory Procedures in External Infectious Disease," North Carolina Optometric Association, Pinehurst, June 1979. 42. "The Clinical Management of Aphakia," North Carolina Optometric Association, Pinehurst, June 1979. 43. "Diagnosis and Management of Anisocoria," Jefferson Health Foundation, Birmingham, August 1979. 44. "Thyroid Eye Disease," University of Alabama in Birmingham, August 1979. 45. "Ocular Manifestations of Pituitary Disease," University of Alabama at Birmingham, August 1979. 46. "Diagnosis and Management of Diseases of the Posterior Pole," Alabama Optometric Association, Birmingham, October 1979. 47. "A Clinical Approach to Pharmacological Therapeutics," Florida Optometric Association, Miami Beach, November 1979. 48. "A Clinical Approach to Pharmacological Diagnosis," Florida Optometric Association, Miami Beach, November 1979. 49. "Thyroid Eye Disease," Endocrine Conference, Diabetes Hospital, UAB, November 1979. Case 3:12-cv-01141-SMY-DGW Document 176-33 *SEALED* Filed 12/01/14 Page 52 of 126 Page ID #3065 Case: 16-3334 Document: 55-19 Filed: 02/08/2017 Pages: 126 (686 of 1511) Curriculum Vitae Jimmy D. Bartlett 18 50. "Effective Utilization of Mydriatic Drugs," American Academy of Optometry, Anaheim, December 1979. 51. Moderated Symposium on Diagnosis and Management of Infectious External Disease, American Academy of Optometry, Anaheim, December 1979. 52. Participant in Panel Discussion, "Optometry's Role in Health Counseling and Patient Education," American Academy of Optometry, Anaheim, December 1979. 53. "Tamoxifen Ocular Toxicity - A Case Report," American Academy of Optometry, Anaheim, December 1979. 54. "Low Vision Management," in Symposium on Diagnosis and Management of Hereditary Dystrophies of the Posterior Pole, American Academy of Optometry, Anaheim, December 1979. 55. "Bacterial Disease," in Symposium on Diagnosis and Management of Infectious External Disease, American Academy of Optometry, Anaheim, December 1979. 56. "Effective Utilization of Mydriatic Agents," Alabama Association of Optometrists, Birmingham, January 1980. 57. "Viral Conjunctivitis," in Symposium on Diagnosis and Management of Anterior Segment Disease, UAB, January 1980. 58. "Bacterial Conjunctivitis," in Symposium on Diagnosis and Management of Anterior Segment Disease, UAB, January 1980. 59. "Diagnostic Laboratory Procedures," in Symposium on Diagnosis and Management of Anterior Segment Disease, UAB, January 1980. 60. "General Principles of Drug Usage," in Symposium on Diagnosis and Management of Anterior Segment Disease, UAB, January 1980. 61. "Low Vision Rehabilitation in General Optometric Practice," Southern Educational Congress of Optometry, Atlanta, February 1980. 62. "Vision-Impairing Diseases and Disorders of the Posterior Pole," Southern Educational Congress of Optometry, Atlanta, February 1980. 63. Participant in Symposium on Anterior Segment Disease, Southern Educational Congress of Optometry, Atlanta, February 1980. 64. "Effective Utilization of Mydriatic Drugs," Illinois Optometric Association, Chicago, March 1980. 65. "Diagnostic Laboratory Procedures," in Symposium on Diagnosis and Management of Anterior Segment Disease, Northwestern State University, Natchitoches, Louisiana, March 1980. 66. Diagnosis and Management of Diseases of the Lids," in Symposium on Diagnosis and Management of Anterior Segment Disease, Northwestern State University, Natchitoches, Louisiana, March 1980. 67. "Diagnosis and Management of Viral Disease," in Symposium on Diagnosis and Management of Anterior Segment Disease, Northwestern State University, Natchitoches, Louisiana, March 1980. 68. "Diagnosis and Management of Bacterial Disease," in Symposium on Diagnosis and Management of Anterior Segment Disease, Northwestern State University, Natchitoches, Louisiana, March 1980. Case 3:12-cv-01141-SMY-DGW Document 176-33 *SEALED* Filed 12/01/14 Page 53 of 126 Page ID #3066 Case: 16-3334 Document: 55-19 Filed: 02/08/2017 Pages: 126 (687 of 1511) Curriculum Vitae Jimmy D. Bartlett 19 69. "General Principles of Drug Usage," in Symposium on Diagnosis and Management of Anterior Segment Disease, Northwestern State University, Natchitoches, Louisiana, March 1980. 70. "Effective Utilization of Mydriatic Drugs," Illinois Optometric Association, Springfield, Illinois, April 1980. 71. "Goldmann Perimetry", in Symposium on Visual Fields, University of Alabama at Birmingham, May 1980. 72. "Post-Chiasmal Lesions", in Symposium on Visual Fields, University of Alabama at Birmingham, May 1980. a", in Symposium on Visual Fields, University of Alabama at "Glaucom 73. Birmingham, May 1980. 74. "The Paraoptometric's Role in Office Emergencies", Alabama Optometric Association, Eufaula, June 1980. 75. "Hand Magnification, Stand Magnification, and Non-optical Aids", in Low Vision Symposium, University of Alabama at Birmingham, July 1980. 76. "Genetic Considerations in Low Vision Practice", in Low Vision Symposium, University of Alabama at Birmingham, July 1980. 77. "The Low Vision Examination", in Low Vision Symposium, University of Alabama at Birmingham, July 1980. 78. "Ocular Toxicology", in Symposium on the Clinical Utilization of Drugs for Diagnostic Purposes/Ocular Toxicology, University of Alabama at Birmingham, August 1980. 79. "Cycloplegic Refraction", in Symposium on the Clinical Utilization of Drugs for Diagnostic Purposes/Ocular Toxicology, University of Alabama at Birmingham, August 1980. 80. "Clinical Utilization of Mydriatic/Miotic Drugs", in Symposium on the Clinical Utilization of Drugs for Diagnostic Purposes/Ocular Toxicology, University of Alabama at Birmingham, August 1980. 81. "Basic Pharmacology of Ophthalmic Drugs Utilized for Diagnostic Purposes", in Symposium on the Clinical Utilization of Drugs for Diagnostic Purposes/Ocular Toxicology, University of Alabama at Birmingham, August 1980. 82. "Goldmann Visual Fields", lecture and clinical laboratory, University of Alabama at Birmingham, September 1980. 83. "Electrophysiology", lecture and clinical laboratory, University of Alabama at Birmingham, September 1980. 84. "Diseases of the Posterior Pole", Iowa Optometric Association, Iowa City, October 1980. 85. "Binocular, Refractive, and Other Vision Function Problems Associated with Aging", North Carolina State Optometric Society, Winston-Salem, November 1980. 86. "Therapeutics Review", North Carolina State Optometric Society, Winston-Salem, November 1980. 87. "Mydriatic Effectiveness of Hydroxyamphetamine", American Academy of Optometry, Chicago, December 1980. Case 3:12-cv-01141-SMY-DGW Document 176-33 *SEALED* Filed 12/01/14 Page 54 of 126 Page ID #3067 Case: 16-3334 Document: 55-19 Filed: 02/08/2017 Pages: 126 (688 of 1511) Curriculum Vitae Jimmy D. Bartlett 20 88. "Presumed Ocular Giardiasis", American Academy of Optometry, Chicago, December 1980. 89. "Morning Glory Syndrome", American Academy of Optometry, Chicago, December 1980. 90. "Clinical Characteristics of Senile Macular Disease, in Symposium on the Diagnosis and Management of Senile Macular Disease, American Academy of Optometry, Chicago, December 1980. 91. "Effective Utilization of Mydriatic Drugs", American Academy of Optometry, Chicago, December 1980. 92. "Visual Rehabilitation of the Visually-Impaired Glaucoma Patient", in Symposium on the Glaucomas, University of Alabama at Birmingham, February 1981. 93. "Diagnosis and Management of Primary Open Angle Glaucoma", in Symposium on the Glaucomas, University of Alabama at Birmingham, February 1981. 94. "Visual Field Changes Associated with Glaucoma", Symposium on the Glaucomas, University of Alabama at Birmingham, February 1981. 95. "Low Vision Rehabilitation in Family Practice Optometry", Southern Educational Congress of Optometry, Atlanta, February 1981. 96. "Effective Utilization of Mydriatic Drugs", Southern Educational Congress of Optometry, Atlanta, February 1981. 97. Participant in Symposium on Gonioscopy and Goldmann Tonometry, Southern Educational Congress of Optometry, Atlanta, February, 1981. 98. Participant in Symposium on Binocular Indirect Ophthalmoscopy, Southern Educational Congress of Optometry, Atlanta, February 1981. 99. "Low Vision Management of Diseases of the Posterior Pole", in Symposium on the Differential Diagnosis and Management of Diseases of the Posterior Pole, Northwestern State University, Natchitoches, Louisiana, March 1981. 100. "Differential Diagnosis and Management of Hereditary and Acquired Macular Disease", in Symposium on the Differential Diagnosis and Management of Diseases of the Posterior Pole, Northwestern State University, Natchitoches, Louisiana, March 1981. 101. "Clinical Genetics and Electrodiagnosis", in Symposium on the Differential Diagnosis and Management of Diseases of the Posterior Pole, Northwestern State University, Natchitoches, Louisiana, March 1981. 102. The Clinical Application of Mydriatic Drugs", in Symposium on the Differential Diagnosis and Management of Diseases of the Posterior Pole, Northwestern State University, Natchitoches, Louisiana, March 1981. 103. "Cycloplegic Refraction", in Symposium on New Techniques in Refraction, University of Alabama at Birmingham, April 1981. 104. "Ocular Pharmacology and Therapeutics Update", Florida Optometric Association, Tampa, May 1981. 105. "Ocular Drug-Induced Systemic Emergencies," University of Alabama at Birmingham, July 1981. 106."Diagnosis and Management of Primary Open Angle Glaucoma", Southwest Florida Educational Retreat, Captiva Island, Florida, August 15-16, 1981. Case 3:12-cv-01141-SMY-DGW Document 176-33 *SEALED* Filed 12/01/14 Page 55 of 126 Page ID #3068 Case: 16-3334 Document: 55-19 Filed: 02/08/2017 Pages: 126 (689 of 1511) Curriculum Vitae Jimmy D. Bartlett 21 107. "Diagnosis and Management of Diseases of the Posterior Pole", Southwest Florida Educational Retreat, Captiva Island, Florida, August 15-16, 1981. 108. "Ocular Pharmacology and Therapeutics Update", Southwest Florida Educational Retreat, Captiva Island, Florida, August 15-16, 1981. 109. "Thyroid Eye Disease - Grand Rounds", University of Alabama at Birmingham, August 1981. 110. "Corticosteroid - Induced Cataract - Grand Rounds", University of Alabama at Birmingham, August 1981. 111. "Diagnosis and Management of Anterior Segment Disease", Alabama Optometric Association, Birmingham, October 1981. 112. "Clinical Ocular Pharmacology and Therapeutics Update", American Academy of Optometry, Orlando, Florida, December 1981. 113. "Diagnosis and Management of Primary Open Angle Glaucoma", American Academy of Optometry, Orlando, Florida, December 1981. Pharmacology and Therapeutics Update", Alabama Association of "Ocular 114. Optometrists, Birmingham, January 1982. 115. "Diagnosis of Cataract - Laboratory", University of Alabama at Birmingham, February 1982. 116. "Workshop on Diagnosis and Management of Primary Open Angle Glaucoma", Southern Educational Congress of Optometry, Atlanta, Georgia, February 1982. 117. "Workshop on Comprehensive Diagnostic Procedures and Techniques for Internal Ocular Examination", Southern Educational Congress of Optometry, Atlanta, Georgia, February 1982. 118. "Ocular Pharmacology and Therapeutics Update", Southwest Council of Optometry, Dallas, Texas, March 1982. 119. "Effective Utilization of Mydriatic Drugs", Southwest Council of Optometry, Dallas, Texas, March 1982. 120. "Clinical Ocular Pharmacology", Oregon Optometric Association, Portland, Oregon, March 1982. 121. "Clinical Ocular Pharmacology", Alaska Optometric Association, Anchorage, Alaska, March 1982. 122. "Components of a Curriculum Essential for Utilization of Therapeutic Pharmaceutical Agents", Southern California College of Optometry 1982 Faculty and Board of Trustees Retreat, California State Polytechnic University, Pomona, California, April 1982. 123. "Aniseikonia", University of Alabama at Birmingham, May 1982. 124. "Pharmacology Update", Georgia Optometric Association, Savannah, Georgia, June 1982. 125. "Diagnostic Laboratory Procedures", in Symposium on Anterior Segment Disease, University of Alabama at Birmingham, July 1982. 126. Clinical Laboratory in Diagnostic Laboratory Procedures, in Symposium on Anterior Segment Disease, University of Alabama at Birmingham, July 1982. 127. Participant in Panel Discussion, in Symposium on Anterior Segment Disease, University of Alabama at Birmingham, July 1982. Case 3:12-cv-01141-SMY-DGW Document 176-33 *SEALED* Filed 12/01/14 Page 56 of 126 Page ID #3069 Case: 16-3334 Document: 55-19 Filed: 02/08/2017 Pages: 126 (690 of 1511) Curriculum Vitae Jimmy D. Bartlett 22 128. "Clinical Use of Mydriatic Drugs", Missouri Optometric Association, Kansas City, September 1982. 129. "Cycloplegic Refraction", Missouri Optometric Association, Kansas City, September 1982. 130. "Clinical Aspects and Uses of Ocular Drugs", University of Alabama at Birmingham, October 1982. 131. "Review of Glaucoma", Fall Educational Seminar, Alabama Optometric Association, November 1982. 132. "Drug Therapy of Glaucoma", North Carolina State Optometric Society, Charlotte, November 1982. 133. "Ocular Pharmacology Update", North Carolina State Optometric Society, Charlotte, November 1982. 134. "Low Vision Rehabilitation", Mississippi Optometric Association, Oxford, December 1982. 135. "Ocular Side Effects of Systemic Drug Therapy", American Academy of Optometry, Philadelphia, December 1982. 136. "Ocular Pharmacology and Therapeutic Update", American Academy of Optometry, Philadelphia, December 1982. 137. "Medical Management of Glaucoma", University of Alabama at Birmingham, February 1983. 138. "Diagnosis and Management of the Contact Lens-Related Red Eye, Heart of America Contact Lens Congress, Kansas City, February 1983. 139. "Prefitting Ocular Health Requirements for Maximum Fitting Success", Heart of America Contact Lens Congress, Kansas City, February 1983. 140. "Topical and Systemic Drug Therapy and Contact Lens Wear", Heart of America Contact Lens Congress, Kansas City, February 1983. 141. "Medical Management of Primary Open-Angle Glaucoma, Southern Educational Congress of Optometry, Atlanta, February 1983. 142. "Clinical Ocular Pharmacology", in Symposium on Ophthalmic Pharmaceutical Sciences, University of Alabama at Birmingham, February 1983. 143. "Ocular Adrenergic Agonists and Antagonists", University of Alabama at Birmingham, April 1983. 144. "Ocular Cholinergic Agonists and Antagonists", University of Alabama at Birmingham, April 1983. 145. "Local Ocular Anesthetics", University of Alabama at Birmingham, April 1983. 146. "Clinical Administration of Ocular Drugs", University of Alabama at Birmingham, April 1983. "Diagnosis and Management of Anterior Segment Diseases", Montana 147. Optometric Association, Butte, April 1983. 148. "Cycloplegic Refraction", Montana Optometric Association, Butte, April 1983. 149. "Clinical Uses of Mydriatic Drugs", Montana Optometric Association, Butte, April 1983. "Pupillary Dilation", University of Alabama at Birmingham, May 1983. 150. 151. "Ocular Decongestants and Antihistamines", University of Alabama at Birmingham, May 1983. Case 3:12-cv-01141-SMY-DGW Document 176-33 *SEALED* Filed 12/01/14 Page 57 of 126 Page ID #3070 Case: 16-3334 Document: 55-19 Filed: 02/08/2017 Pages: 126 (691 of 1511) Curriculum Vitae Jimmy D. Bartlett 23 152. "Ocular anti-inflammatory Agents", University of Alabama at Birmingham, May 1983 153. "Ocular Antibacterial Agents", University of Alabama at Birmingham, May 1983. 154. "Ocular Pharmacology and Therapeutics Update", Optometric Institute of Toronto, Toronto, Ontario, Canada, May 1983. "Ocular Side Effects of Systemic Drug Therapy", Optometric Institute of 155. Toronto, Toronto, Ontario, Canada, May 1983. 156."Diagnostic Drugs - The Last Chapter", American Optometric Association, Washington, D.C., June 1983. "Ocular Pharmacology and Therapeutics Update", American Optometric 157. Association, Washington, D.C., June 1983. 158. "Ocular Side Effects of Systemic Drug Therapy", American Optometric Association, Washington, D.C., June 1983. "Pharmacologic Diagnosis of Pupil Abnormalities", University of Alabama at 159. Birmingham, July 1983. 160. "Clinical Ocular Pharmacology", University of Alabama at Birmingham, August 1983. 161. "Medical Therapy of Glaucoma", Southwest Florida Optometric Association, Captiva Island, August 1983. "Thyroid Eye Disease", Southwest Florida Optometric Association, Captiva 162. Island, August 1983. 163. "Pharmacologic Diagnosis of Pupil Abnormalities", Southwest Florida Optometric Association, Captiva Island, August 1983 "Ocular Side Effects of Systemic Drug Therapy", Southwest Florida Optometric 164. Association, Captiva Island, August 1983. 165. "Management of Anterior Segment Ocular Disease", Washington Optometric Association, Seattle, August 1983. 166. "Effective Use of Cycloplegic and Mydriatic Drugs", Washington Optometric Association, Seattle, August 1983. 167."Clinical Ocular Pharmacology and Therapeutics Update", Tennessee Optometric Association, Nashville, September 1983. 168. "Topical and Systemic Medications and Contact Lens Wear", Wisconsin optometric Association, Appleton, October 1983. "Prefitting Ocular Health Evaluation", Wisconsin Optometric Association, 169. Appleton, October 1983. 170. "The Contact Lens - Related Red Eye", Wisconsin Optometric Association, Appleton, October 1983. 171. "Ocular Steroids - How to Use and Abuse Them", Florida Optometric Association, Orlando, October 1983. 172. "Systemic Side Effects of Ocular Drug Therapy -Recognition, Diagnosis and Management", Florida Optometric Association, Orlando, October 1983. "The Pharmacologic Management of Glaucoma", Florida Optometric 173. Association, Orlando, October 1983. 174. "A Practical Approach to Eyelid Disease", Florida Optometric Association, Orlando, October 1983. Case 3:12-cv-01141-SMY-DGW Document 176-33 *SEALED* Filed 12/01/14 Page 58 of 126 Page ID #3071 Case: 16-3334 Document: 55-19 Filed: 02/08/2017 Pages: 126 (692 of 1511) Curriculum Vitae Jimmy D. Bartlett 24 175. "Ocular Side Effects of Systemic Drugs", Northeast Florida Optometric Society, Jacksonville, November 1983. 176. "Common Anterior Segment Disease", Northeast Florida Optometric Society, Jacksonville, November 1983. 177. "Pharmacologic Management of Glaucoma", Northeast Florida Optometric Society, Jacksonville, November 1983. 178. "Pharmacology Update", Mississippi Optometric Association, Oxford, December 1983. 179. "Low Vision and Aphakia", Mississippi Optometric Association, Oxford, December 1983. 180."Clinical Ocular Pharmacology and Therapeutics Update", American Academy of Optometry, Houston, December 1983. 181. "Ocular Side Effects of Systemic Drug Therapy", American Academy of Optometry, Houston, December 1983. 182. "Diagnosis and Management of Anterior Segment Ocular Disease", Pacific University International Vision Conference, Weilea, Maui, Hawaii, January 1984. 183. "Effective Office Use of Mydriatics, Miotics, and Cycloplegics", Pacific University International Vision Conference, Weilea, Maui, Hawaii, January 1984. 184. "Oral Fluorescein Techniques", Southern Congress of Optometry, Atlanta, February 1984. 185."Diagnosis and Management of Primary Open-Angle Glaucoma", Southern Congress of Optometry, Atlanta, February 1984. 186. "Clinical Ocular Pharmacology Update", University of Alabama at Birmingham, March 1984. 187. "Maximizing the Clinical Effectiveness of Diagnostic Drugs", Opti Fair East, New York City, March 1984. 188. "Ocular Side Effects of Systemic Drug Therapy", Opti Fair East, New York City, March 1984. 189. "Diseases of the Lacrimal System", University of Alabama at Birmingham, May 1984. 190. "Controversies in Anterior Segment Disease-Panel Discussion", University of Alabama at Birmingham, May 1984. 191. "Practical Aspects of Diagnostic Drug Use in Office Practice", Optometric Educational Cruise (Freeport, Nausau), May 1984. 192. "Cycloplegic Refraction", Optometric Educational Cruise (Freeport, Nausau), May 1984. 193. "Management of the Wet and Dry Eye", Optometric Educational Cruise (Freeport, Nausau), May 1984. 194. "Diagnosis and Management of Common Anterior Segment Disorders", Optometric Educational Cruise (Freeport, Nausau), May 1984. 195. "Diagnosis and Management of Open-Angle Glaucoma", Mississippi Optometric Association, Jackson, May 1984. 196. "Maximizing the Clinical Effectiveness of Diagnostic Drugs", Opti Fair Midwest, Chicago, May 1984. Case 3:12-cv-01141-SMY-DGW Document 176-33 *SEALED* Filed 12/01/14 Page 59 of 126 Page ID #3072 Case: 16-3334 Document: 55-19 Filed: 02/08/2017 Pages: 126 (693 of 1511) Curriculum Vitae Jimmy D. Bartlett 25 197. "Ocular Side Effects of Systemic Drug Therapy", Opti Fair Midwest, Chicago, June 1984. 198. "Pharmacology of Ocular Anti-infective Drugs", Seventh MEDCOM Medical Services, Heidelberg, Germany, June 1984. 199. "Pharmacology of Ocular Corticosteroids", Seventh MEDCOM Medical Services, Heidelberg, Germany, June 1984. of Antihistaminic Drugs", Seventh MEDCOM Medical Services, "Pharmacology 200. Heidelberg, Germany, June 1984. 201. "Diseases of the Lacrimal System", Seventh MEDCOM Medical Services, Heidelberg, Germany, June 1984. 202. "Optometric Approach to Anisocoria", in symposium on Neuro- Optometry for the Clinician, UAB, July 1984. 203. "Eye Examination in Family Medicine", Department of Family Medicine, UAB, July 1984. 204. "Ocular Pharmacology and Therapeutics Update", Oklahoma Academy of Optometry, Oklahoma City, August 1984. 205. "Medical Management of Glaucoma", Oklahoma Academy of Optometry, Oklahoma City, August 1984. 206. "Current Topics in Anterior Segment Disease", Oklahoma Academy of Optometry, Oklahoma City, August 1984. 207. "Guidelines for Drug Therapy of Ocular Allergy", UAB, September 1984. 208. "Maximizing the Clinical Effectiveness of Diagnostic Drugs", Opti Fair West, San Francisco, September 1984. 209. "Ocular Side Effects of Systemic Drug Therapy", Opti Fair West, San Francisco, September 1984. 210. "Guidelines for the Clinical Administration of Ocular Drugs", Oklahoma Optometric Association, Tulsa, October 1984. 211. "Drugs Used in the Management of Anterior Segment Disease", Oklahoma Optometric Association, Tulsa, October 1984. 212. "Diagnosis and Management of Diseases of the Eyelids", Oklahoma Optometric Association, Tulsa, October 1984. 213. "New Concepts and Controversies in Ocular Therapy", panel discussion with Louis J. Catania, O.D. and Siret D. Jaanus, Ph.D., Florida Optometric Association, Orlando, October 1984. 214. "Ocular Side Effects of Systemic Medications", Florida Optometric Association, Orlando, October 1984. 215. "Diagnostic Drug Use in Optometric Practice", Optometric Educational Cruise (Freeport, Nausau), October 1984. 216. "Practical Aspects of Cycloplegic Refraction", Optometric Educational Cruise (Freeport, Nausau), October 1984. 217. "Anterior Segment Ocular Disease", Optometric Educational Cruise (Freeport, Nausau), October 1984. 218. "How to Work Up and Manage Wet and Dry Eye Complaints", Optometric Educational Cruise (Freeport, Nausau), October 1984. 219. "Practical Applications of Ocular Pharmaceutical Agents", New England College of Optometry, Boston, October 1984. Case 3:12-cv-01141-SMY-DGW Document 176-33 *SEALED* Filed 12/01/14 Page 60 of 126 Page ID #3073 Case: 16-3334 Document: 55-19 Filed: 02/08/2017 Pages: 126 (694 of 1511) Curriculum Vitae Jimmy D. Bartlett 26 220. "Therapeutic Protocols in Ocular Therapy", New England College of Optometry, Boston, October 1984. 221. "Current Developments in Ocular Pharmacology", New England College of Optometry, Boston, October 1984. 222. "Ocular Signs and Symptoms of Pituitary Disease", UAB, November 1984. 223. "Thyroid Eye Disease", UAB, November 1984. 224. "Diseases of the Macula and Posterior Pole", Northeast Florida Optometric Society, Jacksonville, November 1984. 225. "Diagnosis and Management of the Wet and Dry Eye", Northeast Florida Optometric Society, Jacksonville, November 1984. 226. "How to Work Up and Manage Funny Pupils", Northeast Florida Optometric Society, Jacksonville, November 1984. 227. "Clinical Ocular Pharmacology and Therapeutics Update", American Academy of Optometry, St. Louis, December 1984. 228. "Low Vision in Ocular Disease", American Academy of Optometry, St. Louis, December 1984. 229. "Ocular Side Effects of Systemic Drugs", American Academy of Optometry, St. Louis, December 1984. 230. "Diagnosis and Management of Ocular Disease in Optometric Practice", Iowa Optometric Association, Desmoines, December 1984. 231. "Ocular Side Effects of Systemic Medications", North Central States Optometric Conference, Minneapolis, January 1985. 232. "Maximizing the Clinical Effectiveness of Diagnostic Drugs", North Central States Optometric Conference, Minneapolis, January 1985. 233. "Workshop on the Diagnosis and Management of Open-Angle Glaucoma", Southern Educational Congress of Optometry, Atlanta, February 1985. 234. "Ocular Side Effects of Systemic Medications", Southern Educational Congress of Optometry, Atlanta, February 1985. 235. "Drugs Used in the Treatment of Anterior Segment Eye Disease", Washington Optometric Association, Wenatchee, May 1985. 236. "Diseases of the Eyelids", Washington Optometric Association, Wenatchee, May 1985. 237. "Diseases of the Cornea and Conjunctiva", Washington Optometric Association, Wenatchee, May 1985. 238. "Clinical Uses of Drugs for Diagnostic Purposes", Texas Optometric Association, Odessa, May 1985. 239. "What's New in Ocular Pharmacology?", Louisiana Optometric Association, Baton Rouge, June 1985. 240. "Management of Glaucoma in Optometric Practice", Louisiana Optometric Association, Baton Rouge, June 1985. 241. "Diseases of the Eyelids", Louisiana Optometric Association, Baton Rouge, June 1985. 242. "Glaucoma Treatment Protocols", in Glaucoma Symposium, American Optometric Association, Las Vegas, Nevada, June 1985. 243. Moderator, Symposium on Radial Keratotomy, American Optometric Association, Las Vegas, Nevada, June 1985. Case 3:12-cv-01141-SMY-DGW Document 176-33 *SEALED* Filed 12/01/14 Page 61 of 126 Page ID #3074 Case: 16-3334 Document: 55-19 Filed: 02/08/2017 Pages: 126 (695 of 1511) Curriculum Vitae Jimmy D. Bartlett 27 244. Optic Nerve Head Clinic, American Optometric Association, Las Vegas, Nevada, June 1985. 245. Gonioscopy Clinic, American Optometric Association, Lns Vegas, Nevada, June 1985. g the Glaucoma Patient", American Optometric Association, Las "Followin 246. Vegas, Nevada, June 1985. 247. "Standing Orders", in Symposium on Innovations in Optometric Specialty Care, American Optometric Association, Las Vegas, Nevada, June 1985. 248. "New Ocular Drugs", University of Alabama at Birmingham, September 1985. 249. "Controversies in Ocular Therapy - Panel Discussion", University of Alabama at Birmingham, September 1985. 250. "New Concepts and Controversies in Ocular Therapy", Florida Optometric Association, Orlando, October 1985. Applications of Diagnostic Ocular Drugs", Arkansas Optometric "Practical 251. Association, Fayetteville, November 1985. 252. "Drugs Used in the Treatment of Anterior Segment Ocular Disease", Arkansas Optometric Association, Fayetteville, November 1985. 253. "Diagnosis and Treatment of Common Anterior Segment Ocular Disorders", Arkansas Optometric Association, Fayetteville, November 1985. 254. "Ocular Side Effects of Systemic Drug Therapy", American Academy of Optometry, Atlanta, December 1985. Ocular Pharmacology and Therapeutics Update - 1985", American "Clinical 255. Academy of Optometry, Atlanta, December 1985. 256. "The Didactic Therapeutics Curriculum - The Broader Issues", American Academy of Optometry, Atlanta, December 1985. 257. "The Didactic Residency Curriculum Design", American Academy of Optometry, Atlanta, December 1985. 258. "Pharmacology Update", Primary Care Symposium, Pacific University, Maui, Hawaii, January 1986. 259. "Case Presentations in Primary Eye Care", Primary Care Symposium, Pacific University, Maui, Hawaii, January 1986. 260. "Age-Related Maculopathy: Diagnosis, Prognosis, and Management", University of Alabama at Birmingham, February 1986. 261. "Cromolyn Sodium - A New Treatment for GPC", Heart of America Contact Lens Society, Kansas City, February 1986. 262. "Current Diagnosis and Management of the Dry Eye", Heart of America Contact Lens Society, Kansas City, February 1986. 263. "Current Diagnosis and Management of Blepharitis and Related Lid Disorders", Heart of America Contact Lens Society, Kansas City, February 1986. 264. "Adverse Anterior Segment Effects of Systemic Drugs", Heart of America Contact Lens Society, Kansas City, February 1986. 265. "Current Diagnosis and Management of Common Pupil Problems", Heart of America Contact Lens Society, Kansas City, February 1986. 266. "Viewing the Fundus", in Binocular Indirect Ophthalmoscopy Workshop, Southern Congress of Optometry, Atlanta, February 1986. Case 3:12-cv-01141-SMY-DGW Document 176-33 *SEALED* Filed 12/01/14 Page 62 of 126 Page ID #3075 Case: 16-3334 Document: 55-19 Filed: 02/08/2017 Pages: 126 (696 of 1511) Curriculum Vitae Jimmy D. Bartlett 28 267. "Controversies in Ocular Therapy", Southern Congress of Optometry, Atlanta, February 1986. 268. "Pupillary Abnormalities", 7th Medcom, Heidelberg, West Germany, April 1986. 269. "Thyroid Eye Disease", 7th Medcom, Heidelberg, West Germany, April 1986. 270. "Ocular Pharmacology Update", 7th Medcom, Heidelberg, West Germany, April 1986. 271. "Ocular Steroids", 7th Medcom, Heidelberg, West Germany, April 1986. 272. "Ocular Therapeutics", 7th Medcom, Heidelberg, West Germany, April 1986. 273. "What's New in Ocular Pharmacology?" Mountain States Congress of Optometry/Colorado Optometric Association, August 1986. 274. "Diagnosis of Common Anterior Segment Eye Disease", Mountain States Congress of Optometry/Colorado Optometric Association, August 1986. 275. "Current Controversies in Ocular Therapy", Southwest Florida Optometric Association, Captiva Island, August 1986. 276. "Diagnosis and Management of Pituitary Disease", Southwest Florida Optometric Association, Captiva Island, August 1986. 277. "Clinical Pharmacology in Primary Eye Care", Oklahoma Area Health Education Center, Eufaula, August 1986. 278. "Diagnosis and Management of Common Pupillary Abnormalities", Oklahoma Area Health Education Center, Eufaula, August 1986. 279. "Ocular Toxicology", Oklahoma Area Health Education Center, Eufaula, August 1986. 280. "Ocular Pharmacology and Therapeutics Update", International Vision Expo and Conference, New York, New York, September 1986. 281. Uses and Misuses of Ocular Steroids", International Vision Expo and Conference, New York, New York, September 1986. 282. "Diagnosis and Management of Common Pupil Problems", International Vision Expo and Conference, New York, New York, September 1986. 283. "The Elements of Therapeutic Drug Legislation", Primary Care Symposium, American Optometric Association, Atlanta, September 1986. 284. "New Ocular Drugs and Procedures-1986", University of Alabama at Birmingham, October 1986. 285. "Ocular Effects of Systemic Drugs", University of Alabama at Birmingham, October 1986. 286. "Controversies in Ocular Therapy-Panel Discussion", University of Alabama at Birmingham, October 1986. 287. "Pharmacology Update-Panel Discussion", Florida Optometric Association, Orlando, October 1986. "Pharmacology Update-1986", Alabama Optometric Association, Birmingham, 288. November 1986. 289. "Optometric Referrals-Panel Discussion", Alabama Optometric Association, Birmingham, November 1986. 290. "Diagnosis and Management of Anterior Segment Disease", Hudson Valley Optometric Society, West Point, New York, November 1986. Case 3:12-cv-01141-SMY-DGW Document 176-33 *SEALED* Filed 12/01/14 Page 63 of 126 Page ID #3076 Case: 16-3334 Document: 55-19 Filed: 02/08/2017 Pages: 126 (697 of 1511) Curriculum Vitae Jimmy D. Bartlett 29 291. "Diagnosis and Management of Common Disorders of the Posterior Pole", Hudson Valley Optometric Society, West Point, New York, November 1986. 292. "Clinical Ocular Pharmacology and Therapeutics", American Academy of Optometry, Toronto, Canada, December 1986. 293. "Ocular Side Effects of Systemic Drug Therapy", American Academy of Optometry, Toronto, Canada, December 1986. 294. "Optometry in the Year 2000", National Association of VA Optometrists, Toronto, Canada, December 1986. Pharmacological Basis of Ocular Therapeutics", Palm Beach Optometric "The 295. Society, West Palm Beach, Florida, January 1987. 296. "New Development in Ocular Pharmacology", California Optometric Association, Monterey, February 1987. 297. "Cycloplegic Refraction", California Optometric Association, Monterey, February 1987. 298. "Ocular Disease Grand Rounds", Southern Congress of Optometry, Atlanta, February 1987. 299. "Advanced Binocular Indirect Ophthalmoscopy Workshop", Southern Congress of Optometry, Atlanta, February 1987. 300. "Medical Conditions and Related Drugs", Southern Congress of Optometry, Atlanta, February 1987. 301. "Glaucoma Drugs", in Symposium on Pharmaceuticals in Optometric Practice, Southern Congress of Optometry, Atlanta, February 1987. 302. "Ocular Disease Grand Rounds", Southwest Council of Optometrists, Dallas, March 1987. 303. "New Developments in Ocular Therapeutics", Southwest Council of Optometrists, Dallas, March 1987. 304. "Common Diseases and Disorders of the Anterior Segment", Southwest Council of Optometrists, Dallas, March 1987. 305. "Medical Conditions and Related Drugs of Interest to the Primary Care Practitioner", University of Alabama at Birmingham, March 1987. 306. "Pharmacology Update", Utah Optometric Association, Park City, June 1987. 307. "Ocular Disease Grand Rounds", Utah Optometric Association, Park City, June 1987. 308. "Ocular Disease Grand Rounds", Northern Rockies Optometric Conference, Jackson Hole, Wyoming, August 1987. 309. "Thyroid Eye Disease", Northern Rockies Optometric Conference, Jackson Hole, Wyoming, August 1987. 310. "Diagnosis and Management of Disorders of the Pupil", Northern Rockies Optometric Conference, Jackson Hole, Wyoming, August 1987. 311. 'New Drugs in Optometric Practice", Northern Rockies Optometric Conference, Jackson Hole, Wyoming, August 1987. 312. "Therapeutics Review", Tennessee Optometric Association, Nashville, October 1987. 313. "Ocular Implications of New Systemic Drugs", University of Alabama at Birmingham, November 1987. Case 3:12-cv-01141-SMY-DGW Document 176-33 *SEALED* Filed 12/01/14 Page 64 of 126 Page ID #3077 Case: 16-3334 Document: 55-19 Filed: 02/08/2017 Pages: 126 (698 of 1511) Curriculum Vitae Jimmy D. Bartlett 30 314. "Practical Management of Open-Angle Glaucoma", University of Alabama at Birmingham, November 1987. 315. "Pharmacology Update 1987", Oregon Optometric Association, Eugene, November 1987. 316. "Ocular Effects of Systemic Medications", Oregon Optometric Association, Eugene, November 1987. 317. "Advanced Diagnostic Procedures", Oregon Optometric Association, Eugene, November 1987. 318. "Case Challenges in Ocular Therapeutics", Oregon Optometric Association, Eugene, November 1987. 319. "Ocular Effects of Systemic Drugs", North Carolina Optometric Society, Winston-Salem, November 1987. 320. "New Drugs with Ocular Implications", North Carolina Optometric Society, Winston-Salem, November 1987. 321. "Thyroid Eye Disease", North Carolina Optometric Society, Winston-Salem, November 1987. 322. "Case Challenges in Ocular Therapeutics", North Carolina Optometric Society, Winston-Salem, November 1987. 323. "New Drugs with Ocular Implications", American Academy of Optometry, Denver, December 1987. 324. "Management of Open-Angle Glaucomas", American Academy of Optometry, Denver, December 1987. 325. "New Anti-inflammatory Agents for the Treatment of Uveitis", Section of Ocular Disease, American Academy of Optometry, Denver, December 1987. 326. "Drugs that Cause Low Vision and Blindness", Section on Low Vision, American Academy of Optometry, Denver, December 1987. 327. Moderator, Symposium on Impact of Drugs Laws on the Practice of Low Vision, American Academy of Optometry, Denver, December 1987. 328. "New Drugs of Optometric Interest", Primary Care Symposium, Pacific University, Maui, Hawaii, January 1988. 329. "Case Challenges in Ocular Diagnosis and Treatment", Primary Care Symposium, Pacific University, Maui, Hawaii, January 1988. 330. Current Issues and Controversies in Ocular Therapy Panel Discussion, Pacific University, Maui, Hawaii, January 1988. 331. Developing a Therapeutics Curriculum in Optometry ____. Faculty Development Seminar, School of Optometry, InterAmerican University of Puerto Rico, San Juan, February 1988. 332. Legislative Strategies in Optometric Therapeutics, School of Optometry, InterAmerican University of Puerto Rico, San Juan, February 1988. 333. Angle-Closure Glaucoma, Southern Congress of Optometry, Atlanta, February 1988. 334. Clinical Decision-Making in Open-Angle Glaucoma (Workshop), Southern Congress of Optometry, Atlanta, February 1988. 335. Ocular Disease Grand Rounds, Southern Congress of Optometry, Atlanta, February 1988. Case 3:12-cv-01141-SMY-DGW Document 176-33 *SEALED* Filed 12/01/14 Page 65 of 126 Page ID #3078 Case: 16-3334 Document: 55-19 Filed: 02/08/2017 Pages: 126 (699 of 1511) ....., AMIN, Curriculum Vitae Jimmy D. Bartlett 31 336. Current Concepts and Controversies in Ocular Disease, Southern Congress of Optometry, Atlanta, February 1988. 337. How to Start Using Diagnostic Pharmaceutical Agents, Southwest Council of Optometry, Dallas, March 1988. 338. Hereditary Dystrophies of the Retina, Southwest Council of Optometry, Dallas, March 1988. 339. Current Concepts and Controversies in Ocular Therapy, Southwest Council of Optometry, Dallas, March 1988. 340. "Guidelines for the Clinical Administration of Ocular Drugs". Georgia Optometric Association, Sea Island, June 1988 341. "Systemic Side Effects of Ocular Drugs". Georgia Optometric Association, Sea Island, June 1988 Considerations". American Optometric Association, Chicago, June "Therapeutic 342. 1988 343. "New Drugs of Optometric Interest". American Optometric Association, Chicago, June 1988 344. "Therapeutic Drug Review". Georgia Optometric Foundation, Atlanta, August 1988 345. "Anterior Segment Pharmacology". Baptist Eye Institute, Knoxville, September 1988 346. "New Ocular Drugs". University of Alabama at Birmingham, September 1988 347. "New Ocular Drugs". Maine Optometric Association, Rockport, October 1988 348. "Glaucoma Management in Optometric Practice". Maine Optometric Association, Rockport, October 1988 349. "Ocular Urgencies and Emergencies". Maine Optometric Association, Rockport, October 1988 350. "Diseases of the Eyelids". Maine Optometric Association, Rockport, October 1988 351. "Diseases of the Conjunctiva". California Optometric Association, San Diego, November 1988 352. "Ocular Urgencies and Emergencies". California Optometric Association, San Diego, November 1988 353. "New Medications in Optometry". Heart of America Contact Lens and Primary Care Congress, Kansas City, February 1989 354. "Oral Medications in Optometry". Heart of America Contact Lens and Primary Care Congress, Kansas City, February 1989 355. "Glaucoma Patient Compliance". Heart of America Contact Lens and Primary Care Congress, Kansas City, February 1989 356. "Thyroid Eye Disease". Heart of America Contact Lens and Primary Care Congress, Kansas City, February 1989 357. "Medical Management of Open-Angle Glaucoma". Southern Congress of Optometry, Atlanta, February 1989 358. "Workshop on Decision Making in Open-Angle Glaucoma". Southern Congress of Optometry, Atlanta, February 1989 359. "Therapeutics Overview". Southern Congress of Optometry, Atlanta, February 1989 Case 3:12-cv-01141-SMY-DGW Document 176-33 *SEALED* Filed 12/01/14 Page 66 of 126 Page ID #3079 Case: 16-3334 Document: 55-19 Filed: 02/08/2017 Pages: 126 (700 of 1511) Curriculum Vitae Jimmy D. Bartlett 32 360. "Clinical Update on Diagnostic Drugs". Vision Expo, Anaheim, April 1989 361. "Clinical Update on Therapeutic Drugs". Vision Expo, Anaheim, April 1989 362. "Panel Discussion on Challenges in Primary Eye Care". Vision Expo, Anaheim, April 1989 363. "Management of Open-Angle Glaucoma". Vision Expo, Anaheim, April 1989 364. "Panel Discussion on Therapeutic Update". Optometric Institute, University of Missouri-St. Louis, May 1989 365. "Pharmacology of Allergic Eye Disease". Optometric Institute, University of Missouri-St. Louis, May 1989 366. "Practical Considerations in Ocular Therapeutics". American Optometric Association, New York, June 1989 367. "Glaucoma Management". American Optometric Association, New York, June 1989 368. "Drugs Affecting Contact Lens Wear". American Optometric Association, New York, June 1989 369. "Ocular Pharmacology". Maryland Optometric Association, Baltimore, July 1989 370. "New and Investigational Drugs for Ocular Allergy". In symposium on Ocular Allergy Update, Fisons Corp., Hilton Head, South Carolina, May 1989 371. "New Drugs and Treatment Procedures", Southwest Florida Optometric Association, Captiva Island, August 1989 372. "Oral Medications in Optometry", Southwest Florida Optometric Association, Captiva Island, August 1989 373. "How to Improve Patient Compliance", Southwest Florida Optometric Association, Cativa Island, August 1989 374. "Case Challenges in Ocular Disease Management", Southwest Florida Optometric Association, Captiva Island, August 1989 375. "Pharmacology Update", Vision America, Nashville, Tennessee, August 1989 376. "New Drugs and Treatment Procedures", Georgia Optometric Foundation, Atlanta, August 1989 "Clinical Utilization of Oral Medications", Georgia Optometric Foundation, 377. Atlanta, August 1989 378. "Case Challenges in Ocular Disease Management", Georgia Optometric Foundation, Atlanta, August 1989 379. "New Drugs and Treatment Procedures", Baptist Eye Institute, Knoxville, Tennessee, September 1989 380. "Oral Medications in Optometry", Baptist Eye Institute, Knoxville, Tennessee, September 1989 381. "Ocular Disease Grand Rounds", Baptist Eye Institute, Knoxville, Tennessee, September 1989 382. "Treatment Pearls in Ocular Therapeutics", Southern College of Optometry, Memphis, Tennessee, September 1989 383. "Selection and Clinical Use of Oral Antihistamines", Southern College of Optometry, Memphis, Tennessee, September 1989 384. "Management of Open-Angle Glaucoma", Southern College of Optometry, Memphis, Tennessee, September 1989 Case 3:12-cv-01141-SMY-DGW Document 176-33 *SEALED* Filed 12/01/14 Page 67 of 126 Page ID #3080 Case: 16-3334 Document: 55-19 Filed: 02/08/2017 Pages: 126 (701 of 1511) Curriculum Vitae Jimmy D. Bartlett 33 385. "Ocular Pharmacology Update", in Ocular Disease Update 1989, Primary Eye Care Institute, Philadelphia, October 1989 Drugs and Procedures", Mississippi Optometric Association, Jackson, "New 386. November 1989 387. "Oral Medications Intended for Treatment of the Eye", Mississippi Optometric Association, Jackson, November 1989 Interactions in Optometry", Mississippi Optometric Association, Jackson, "Drug 388. November 1989 389. "Anterior Uveitis", Mississippi Optometric Association, Jackson, November 1989 390. "New Medications -- The Facts", American Academy of Optometry, New Orleans, December 1989 391. "Thyroid Dysfunction", In Symposium on Pathological Causes of Binocular Vision Disorders, American Academy of Optometry, New Orleans, December 1989 392. "Optometric Use of Anti-Infective Agents Following Cataract Surgery", in Primary Care Symposium, Pacific University, Maui, Hawaii, January 1990 393. "Optometric Use of Anti-Inflammatory Agents Following Cataract Surgery", in Primary Care Symposium, Pacific University, Maui, Hawaii, January 1990 394. "Oral Medications in Optometry", in Primary Care Symposium, Pacific University, Maui, Hawaii, January 1990 395. "Oral Analgesics", in Symposium on Ocular Therapeutics, Southern Educational Congress of Optometry, Atlanta, Georgia, February, 1990 396. "New Medications--The Facts", Southern Educational Congress of Optometry, Atlanta, Georgia, February 1990 397. "Medical Management of Primary Open-Angle Glaucoma", Southern Educational Congress of Optometry, Atlanta, Georgia, February 1990 398. "Ocular Autonomics", in Symposium on Ocular Pharmacology, Southern Educational Congress of Optometry, Atlanta, Georgia, February 1990 399. "Pharmacology of Allergic Eye Disease", in Symposium on Allergic Eye Disease, New England Council of Optometrists, Boston, March 1990 400. "New Ocular Drugs and Procedures", New England Council of Optometrists, Boston, March 1990 401. "Clinical Pharmacology of Drugs Used to Treat Glaucoma", Massachusetts Society of Optometrists, Boston, March 1990 402. "New Drugs for the 1990s", Iowa Optometric Association, Des Moines, April 1990 403. "Oral Medications in Optometry", Iowa Optometric Association, Des Moines, April 1990 404. "Visual Rehabilitation of the Adult Low Vision Patient", Iowa Optometric Association, Des Moines, April 1990 405. "Recent Advances in Viral Eye Disease", Iowa Optometric Association, Des Moines, April 1990 406. "Clinical Pharmacology of Drugs Used to Treat Allergic Eye Disease", in Update on Ocular Allergy and Contact Lenses, Fisons Pharmaceutical Corporation, Amelia Island, Florida, April 1990 Case 3:12-cv-01141-SMY-DGW Document 176-33 *SEALED* Filed 12/01/14 Page 68 of 126 Page ID #3081 Case: 16-3334 Document: 55-19 Filed: 02/08/2017 Pages: 126 (702 of 1511) Curriculum Vitae Jimmy D. Bartlett 34 407. Participant in panel discussion, "Writing for Publication by the Contact Lens Educator", Association of Optometric Contact Lens Educators, University of Alabama at Birmingham, June 1990 408. "New Glaucoma Drugs for the 1990's", American Optometric Association, Honolulu, Hawaii, June 1990 409. "Glaucoma-the Disease, the Diagnosis, the Management", American Optometric Association, Honolulu, Hawaii, June 1990 410. Moderator, Symposium on Ocular Allergy, American Optometric Association, Honolulu, Hawaii, June 1990 411. "Pharmacology of Allergic Eye Disease", American Optometric Association, Honolulu, Hawaii, June 1990 412. "Point/Counterpoint - Current Controversies in Primary Eye Care", panel discussion with L. Catania and L. Ferguson, American Optometric Association, Kauai, Hawaii, June 1990 413. "New Drugs for the 1990's", Eastern Oklahoma Area Health Education Center, Checotah, OK, August 1990 414. "Recent Advances in Viral Eye Disease", Eastern Oklahoma Area Health Education Center, Checotah, OK, August 1990 415. "Oral Medications in Optometry", Eastern Oklahoma Area Health Education Center, Checotah, OK, August 1990 416. "Optometric Drugs for the 1990's", Vision Expo West, Anaheim, CA, September 1990 417. "Controversies in Ocular Therapy", panel discussion with L. Catania, Vision Expo West, Anaheim, CA, September 1990 418. "Oral Medications in Optometry", Vision Expo West, Anaheim, CA, September 1990 419. "Diagnosis and Management of the Secondary Open-Angle Glaucomas", Tennessee Optometric Association, Gatlinburg, TN, September 1990 420. "Management of Thyroid Eye Disease", Tennessee Optometric Association, Gatlinburg, TN, September 1990 421. "Ocular Effects of Systemic Drugs", Tennessee Optometric Association, Gatlinburg, TN, September 1990 422. "New Ocular Drugs", University of Alabama at Birmingham, September 1990 423. "Diagnosis and Management of the Secondary Open-Angle Glaucomas", University of Alabama at Birmingham, September 1990 424. "Ocular Effects of Systemic Drugs", University of Alabama at Birmingham, September 1990 425. "Diagnosis and Management of Anisocoria", Kentucky Optometric Association, Lexington, KY, October 1990 426. "Anterior Segment Effects of Systemic Drugs", Kentucky Optometric Association, Lexington, KY, October 1990 427. "Ocular Drug Update", Kentucky Optometric Association, Lexington, KY, October 1990 428. "Drug Update", California Optometric Association, Newport Beach, CA, November 1990 Case 3:12-cv-01141-SMY-DGW Document 176-33 *SEALED* Filed 12/01/14 Page 69 of 126 Page ID #3082 Case: 16-3334 Document: 55-19 Filed: 02/08/2017 Pages: 126 (703 of 1511) Curriculum Vitae Jimmy D. Bartlett 35 429. "Pharmaceutical Agents for the 1990's", panel discussion with S. Jaanus, California Optometric Association, Newport Beach, CA, November 1990 430. "Diagnosis and Management of the Secondary Open Angle Glaucomas", Baptist Eye Institute, Jacksonville, FL, November 1990 431. "Thyroid Eye Disease", Baptist Eye Institute, Jacksonville, FL, November 1990 432. "Pharmacologic Diagnosis of Anisocoria", Baptist Eye Institute, Jacksonville, FL, November 1990 433. "Ocular and Visual Effects of Systemic Drugs", Baptist Eye Institute, Jacksonville, FL, November 1990 434. "New Anti-Inflammatory Considerations", Ocular Disease Update 1990, Philadelphia, PA, November 1990 435. "Diagnostic Considerations in Glaucoma", South Carolina Optometric Association, Hilton Head Island, November 1990 436. Management of Primary Open Angle Glaucoma and the Secondary Glaucomas", South Carolina Optometric Association, Hilton Head Island, November 1990 437. "Management of Angle Closure Glaucoma", South Carolina Optometric Association, Hilton Head Island, November 1990 438. "Oral Medications in Optometry", American Academy of Optometry, Nashville, TN, December 1990 439. "Preparing and Submitting Case Reports", American Academy of Optometry, Nashville, TN, December 1990 440. "Drugs Affecting the Cornea and Contact Lens", Sarver Lecture Series, University of California, Berkeley, January 1991 441. "Pharmacologic Management of Ocular Allergy Including New Drugs for GPC", Sarver Lecture Series, University of California, Berkeley, January 1991 442. "Advanced Technology in Optometry", Keynote address, North Central States Council of Optometrists, Minneapolis, MN, February 1991 443. "New Medications in Optometry", North Central States Council of Optometrists, Minneapolis, MN, February 1991 444. "New Drugs for External Disease", Southern Educational Congress of Optometry, Atlanta, GA, February 1991 445. "Management of Open-Angle Glaucoma", Southern Educational Congress of Optometry, Atlanta, GA, February 1991 446. "Lacrimal Dilation and Irrigation, In Workshop on Anterior Segment Procedures, Southern Educational Congress of Optometry, Atlanta, GA, February 1991 447. "Current Management of Open-Angle Glaucoma", Southwest Council of Optometry, Dallas, TX, March 1991 448. "New FDA-Approved Ophthalmic Drugs", Southwest Council of Optometry, Dallas, TX, March 1991 449. "Practical Issues in Ocular Pharmacology and Therapeutics", Southwest Council of Optometry, Dallas, TX, March 1991 450. "New Drugs for Optometric Use", McKinley Eye Institute, Winston Salem, NC, April 1991 451. "Infections and Inflammations of the Eyelids", McKinley Eye Institute, Winston Salem, NC, April 1991 Case 3:12-cv-01141-SMY-DGW Document 176-33 *SEALED* Filed 12/01/14 Page 70 of 126 Page ID #3083 Case: 16-3334 Document: 55-19 Filed: 02/08/2017 Pages: 126 (704 of 1511) Curriculum Vitae Jimmy D. Bartlett 36 452. "Oral Analgesics in Optometry", McKinley Eye Institute, Winston Salem, NC, April 1991 453. "Secondary Open-Angle Glaucoma", McKinley Eye Institute, Winston Salem, NC, April 1991 454. "Management of Ocular Allergy", Wisconsin Optometric Association, Eau Claire, WI, April 1991 455. "Inflammation of the Eyelid: Diagnosis and Management", Wisconsin Optometric Association, Eau Claire, WI, April 1991 456. "New Ocular Medications for External Disease and Glaucoma", Wisconsin Optometric Association, Eau Claire, WI, April 1991 457. "Systemic Medications Affecting Contact Lens Wear", Wisconsin Optometric Association, Eau Claire, WI, April 1991 458. "Systemic Management of Ocular Disease", Georgia Optometric Association, Sandestin, FL, June 1991 459. "Glaucoma", American Optometric Association, Dallas, TX, June 1991 460. Participant in "Defining Primary Care: A Panel Discussion", American Optometric Association, Dallas, TX, June 1991 461. "Practical Aspects of Anterior Segment Therapeutics", Canadian Association of Optometrists, Winnipeg, Manitoba, Canada, August 1991 462. "Oral Medications in Optometric Practice", Oklahoma Chapter, American Academy of Optometry, Oklahoma City, Oklahoma, August 1991 463. "Anterior Segment Laser Therapy", Oklahoma Chapter, American Academy of Optometry, Oklahoma City, OK, August 1991 464. "New FDA-Approved Ophthalmic Drugs", Oklahoma Chapter, American Academy of Optometry, Oklahoma City, OK, August 1991 465. "Oral Medications in Optometry", Vision Expo West, Anaheim, CA, September 1991 466. "New Ocular Drugs", Vision Expo West, Anaheim, CA, September 1991 467. "Systemic Medications Affecting Contact Lens Wear", Vision Expo West, Anaheim, CA, September 1991 468. "Practical Issues in Glaucoma Diagnosis and Management", Arkansas Optometric Association, Fort Smith, October 1991 469. "Practical Issues in Ocular Pharmacology and Therapeutics", Arkansas Optometric Association, Fort Smith, October 1991 470. "Lasers in the Management of Glaucoma", University of Alabama at Birmingham, October 1991 471. "New Ocular Drugs Including Glaucoma Medications", University of Alabama at Birmingham, October 1991 472. "Systemic Pharmacologic Management of Ocular Disease", University of Alabama at Birmingham, October 1991 473. "Diagnosis and Management of the Glaucomas", McKinley Eye Institute, Winston-Salem, NC, October 1991 474. "New Ophthalmic Medications", Indiana Optometric Association, Indianapolis, November 1991 475. "Selected Topics in Inflammatory Diseases of the Eyelids", Indiana Optometric Association, Indianapolis, November 1991 Case 3:12-cv-01141-SMY-DGW Document 176-33 *SEALED* Filed 12/01/14 Page 71 of 126 Page ID #3084 Case: 16-3334 Document: 55-19 Filed: 02/08/2017 Pages: 126 (705 of 1511) Curriculum Vitae Jimmy D. Bartlett 37 476. "Ocular Therapeutics Review Course", Texas Association of Optometrists, Dallas and Houston, November 1991 "New Ocular Drugs", North Carolina Optometric Society, Charlotte, November 477. 1991 478. "Systemic Management of Anterior Segment Disease", North Carolina Optometric Society, Charlotte, November 1991 479. "New Ocular Medications", Heart of America Primary Care and Contact Lens Congress, Kansas City, February 1992 "Systemic Medications Affecting Contact Lens Wear", Heart of America 480. Primary Care and Contact Lens Congress, Kansas City, February 1992 481. "Oral Medications in Optometry", Heart of America Primary Care and Contact Lens Congress, Kansas City, February 1992 "Practical Issues in Glaucoma Management", Heart of America Primary Care 482. and Contact Lens Congress, Kansas City, February 1992 483. "New Drugs for External Disease and Glaucoma", Southern Educational Congress of Optometry, Atlanta, February 1992 484. "Oral Medications in Optometry", Southern Educational Congress of Optometry, Atlanta, February 1992 485. "Workshop on Anterior Segment Procedures", Southern Educational Congress of Optometry, Atlanta, February 1992 486. "Ocular Drug Delivery Systems", Texas Association of Optometrists, Dallas, March 1992 "Drugs Affecting the Cholinergic Nervous System", Texas Association of 487. Optometrists, Dallas, March 1992 488. "Drugs Affecting the Adrenergic Nervous System", Texas Association of Optometrists, Dallas, March 1992 489. "Local Ocular Anesthetics", Texas Association of Optometrists, Dallas, March 1992 490. "Dilation of the Pupil", Texas Association of Optometrists, Dallas, March 1992 491. "Differential Diagnosis of Anisocoria", Texas Association of Optometrists, Dallas, March 1992 492. "Ocular Anti-Infective Agents", Texas Association of Optometrists, Dallas, March 1992 493. "Ocular Anti-Inflammatory Agents", Texas Association of Optometrists, Dallas, March 1992 494. "Diagnosis and Management of Diseases of the Eyelids", Texas Association of Optometrists, Dallas, March 1992 495. "Diagnosis and Management of Diseases of the Conjunctiva", Texas Association of Optometrists, Dallas, March 1992 496. "Diagnosis and Management of Diseases of the Cornea", Texas Association of Optometrists, Dallas, March 1992 497. "Classification, Etiology, Epidemiology, and Pathogenesis of Glaucoma", Texas Association of Optometrists, Dallas, March 1992 498. "Management of Open-Angle Glaucoma", Texas Association of Optometrists, Dallas, March 1992 Case 3:12-cv-01141-SMY-DGW Document 176-33 *SEALED* Filed 12/01/14 Page 72 of 126 Page ID #3085 Case: 16-3334 Document: 55-19 Filed: 02/08/2017 Pages: 126 (706 of 1511) Curriculum Vitae Jimmy D. Bartlett 38 499. "Diagnosis and Management of Angle-Closure Glaucoma", Texas Association of Optometrists, Dallas, March 1992 500. "Glaucoma Grand Rounds", Texas Association of Optometrists, Dallas March 1992 501. "New Glaucoma Drugs", Southwest Council of Optometry, Dallas, March 1992 502. "Oral Medications in Optometry", Southwest Council of Optometry, Dallas, March 1992 503. "Effective Clinical Use of Mydriatics and Mydriatic Antagonists", Washington Optometric Association, Seattle, March 1992 504. "Therapeutics Review Course", Texas Association of Optometrists, Dallas, Houston, April 1992 505. "New Topical and Oral Ophthalmic Medications for Optometric Practice", Mountain States Council of Optometrists, Las Vegas, Nevada, May 1992 506. "Oculodermatologic Disease", UAB Department of Dermatology, May 1992 507. "New Technology in Optometry", South African Optometric Association, Sun City, Bophuthatswana, South Africa, June 1992 508. "Diagnosis and Treatment of Glaucoma", South African Optometric Association, Sun City, Bophuthatswana, South Africa, June 1992 509. "Ocular Allergy", South African Optometric Association, Sun City, Bophuthatswana, South Africa, June 1992 510. "New Medications for Optometric Practice", South African Optometric Association, Sun City, Bophuthatswana, South Africa, June 1992 511. "Infections of the Eyelids", South African Optometric Association, Sun City, Bophuthatswana, South Africa, June 1992 512. "Systemic Medications Affecting Contact Lens Wear", South African Optometric Association, Sun City, Bophuthatswana, South Africa, June 1992 513. "The Aging Eye", American Optometric Association, Montreal, Canada, June 1992 514. "Introduction to Ocular Pharmacotherapy", Tennessee Optometric Association, Nashville, Tennessee, June 1992 515. "Ophthalmic Drug Delivery Systems", Tennessee Optometric Association, Nashville, Tennessee, June 1992 516. "Drugs Affecting the Autonomic Nervous System", Tennessee Optometric Association, Nashville, Tennessee, June 1992 517. "Local Anesthetics", Tennessee Optometric Association, Nashville, Tennessee, June 1992 518. "Dilation of the Pupil", Tennessee Optometric Association, Nashville, Tennessee, June 1992 519. "Differential Diagnosis and Management of Anisocoria", Tennessee Optometric Association, Nashville, Tennessee, June 1992 520. "Anti-Infective Drugs", Tennessee Optometric Association, Nashville, Tennessee, June 1992 521. "Anti-Inflammatory Drugs", Tennessee Optometric Association, Nashville, Tennessee, June 1992 Case 3:12-cv-01141-SMY-DGW Document 176-33 *SEALED* Filed 12/01/14 Page 73 of 126 Page ID #3086 Case: 16-3334 Document: 55-19 Filed: 02/08/2017 Pages: 126 (707 of 1511) ....., Curriculum Vitae Jimmy D. Bartlett 39 522. "Medical Management of the Glaucomas", Tennessee Optometric Association, Nashville, Tennessee, July 1992 523. "Diagnosis and Management of Diseases of the Eyelids", Tennessee Optometric Association, Nashville, Tennessee, July 1992 and Management of Diseases of the Conjunctiva", Tennessee "Diagnosis 524. Optometric Association, Nashville, Tennessee, July 1992 525. "Diagnosis and Management of Diseases of the Cornea", Tennessee Optometric Association, Nashville, Tennessee, July 1992 526. "Ophthalmic Drug Update", University of Alabama at Birmingham, September 1992 527. "Glaucoma Grand Rounds", Wisconsin Optometric Association, Milwaukee, September 1992 528. "Diagnosis and Management of Unequal Pupils", Wisconsin Optometric Association, Milwaukee, September 1992 529. "Thyroid Eye Disease", Wisconsin Optometric Association, Milwaukee, September 1992 530. "The Watery, White Eye", Wisconsin Optometric Association, Milwaukee, September 1992 531. "The Infected Eyelid", Optometry Alumni Association, University of California, Berkeley, October 1992 532. "New Ocular Medications for Diagnosis and Treatment", Optometry Alumni Association, University of California, Berkeley, October 1992 533. "New Ocular Medications--1992", Ocular Disease Symposium, California Optometric Association, Palm Springs, October 1992 534. "Systemic Treatment of Primary Ocular Disease", Ocular Disease Symposium, California Optometric Association, Palm Springs, October 1992 535. "Systemic Treatment of Primary Eye Disease", Pennsylvania Optometric Association, Lancaster, November 1992 536. "Investigational New Drugs for Ophthalmic Practice", Storz Ophthalmics, Phoenix, Arizona, December 1992 537. "New Ocular Medications", American Academy of Optometry, Orlando, Florida, December 1992 538. "Systemic Medications Affecting Contact Lens Wear", American Academy of Optometry, Orlando, Florida, December 1992 539. "Ocular Pharmacokinetics and Pharmacotherapy of Eye Disease: Diagnostic Pharmaceutical Agent Course, University of Alabama at Birmingham, December 1992 540. "Differential Diagnosis and Management of Anisocoria", University of Alabama at Birmingham, December 1992 541. "Diagnosis of the Glaucomas", University of Alabama at Birmingham, December 1992 542. "Overview of Anterior Segment Disease Diagnosis", University of Alabama at Birmingham, December 1992 543. "New Anti-Infective Drugs", Ohio Optometric Association, Columbus, January 1993 Case 3:12-cv-01141-SMY-DGW Document 176-33 *SEALED* Filed 12/01/14 Page 74 of 126 Page ID #3087 Case: 16-3334 Document: 55-19 Filed: 02/08/2017 Pages: 126 (708 of 1511) Curriculum Vitae Jimmy D. Bartlett 40 544. "New Anti-Glaucoma Drugs", Ohio Optometric Association, Columbus, January 1993 545. "Systemic Management of Eyelid Infections", Ohio Optometric Association, Columbus, January 1993 546. "Current Pharmacological Treatment of Giant Papillary Conjunctivitis (GPC)", Ohio Optometric Association, Columbus, January 1993 547. "Pharmaceutical Myths and Realities--Panel Discussion", Ohio Optometric Association, Columbus, January 1993 548. "Anti-Glaucoma Drugs", National Glaucoma Clinical Update, Iowa Optometric Association, Cedar Rapids, March 1993 549. "latrogenic (Steroid) Glaucoma", National Glaucoma Clinical Update, Iowa Optometric Association, Cedar Rapids, March 1993 550. "Oral Analgesics, Antihistamines, Anti-Infective Agents and Carbonic Anhydrase Inhibitors in Optometric Practice", Georgia Optometric Association, Atlanta, March 1993 551. "Practical Aspects of Glaucoma", Gilbert Cataract Center, Ponte Vedra Beach, Florida, May 1993 552. "Grand Rounds in Glaucoma Management", Gilbert Cataract Center, Ponte Vedra Beach, Florida, May 1993 553. "New Ophthalmic Medications", Gilbert Cataract Center, Ponte Vedra Beach, Florida, May 1993 554. "Pharmacologic Management of Ocular Allergy", Gilbert Cataract Center, Ponte Vedra Beach, Florida, May 1993 555. "Diseases of the Eyelids", South Carolina Optometric Association, Columbia, June 1993 556. "Diseases of the Conjunctiva and Cornea", South Carolina Optometric Association, Columbia, June 1993 557. "Anterior Segment Grand Rounds", South Carolina Optometric Association, Columbia, June 1993 558. "Diagnosis and Treatment of the Glaucomas", South Carolina Optometric Association, Columbia, June 1993 559. "New Ophthalmic Medications", South Carolina Optometric Association, Columbia, June 1993 560. "Ocular Toxicology", South Carolina Optometric Association, Columbia, June 1993 561. "Oral Anti-Infectives, Antihistamines, Analgesics, and Carbonic Anhydrase Inhibitors", South Carolina Optometric Association, Columbia, June 1993 562. "Prescription Writing and Regulatory Affairs", South Carolina Optometric Association, Columbia, June 1993 563. "Glaucoma Grand Rounds", South Carolina Optometric Association, Columbia, June 1993 564. "Clinical Issues in Aging: A Primary Care Challenge", American Optometric Association, Anaheim, June 1993 565. "Pharmacology Update", American Optometric Association, Anaheim, June 1993 Case 3:12-cv-01141-SMY-DGW Document 176-33 *SEALED* Filed 12/01/14 Page 75 of 126 Page ID #3088 Case: 16-3334 Document: 55-19 Filed: 02/08/2017 Pages: 126 (709 of 1511) Curriculum Vitae Jimmy D. Bartlett 41 566. "Systemic Treatment of Primary Ocular Disease", Southwest Florida Optometric Society, Captiva Island, August 1993 567. "New Ocular Medications, 1992-1993", Southwest Florida Optometric Society, Captiva Island, August 1993 568. "Oral Analgesics in Primary Eye Care", Southwest Florida Optometric Society, Captiva Island, August 1993 Decisions in Glaucoma Management", Southwest Florida Optometric "Difficult 569. Society, Captiva Island, August 1993 570. "New Drugs for External Disease and Glaucoma", University of Alabama at Birmingham, September 1993 571. "Diagnosis of Glaucoma", Bay Point Anterior Segment Symposium, Panama City Beach, Florida, September 1993 572. "Systemic Drugs and Anterior Segment Ocular Effects", Bay Point Anterior Segment Symposium, Panama City Beach, Florida, September 1993 573. "Review of Fundamental Concepts in Ocular Pharmacotherapy", Mississippi Optometric Association, Jackson, October/November 1993 574. "Ophthalmic Drug Delivery Systems", Mississippi Optometric Association, Jackson, October/November 1993 575. "Drugs Affecting the Autonomic Nervous System", Mississippi Optometric Association, Jackson, October/November 1993 576. "Local Anesthetics", Mississippi Optometric Association, Jackson, October/November 1993 577. "Differential Diagnosis and Management of Anisocoria", Mississippi Optometric Association, Jackson, October/November 1993 578. "Topical and Oral Anti-Infective Drugs" Mississippi Optometric Association, Jackson, October/November 1993 579. "Anti-Inflammatory Drugs", Mississippi Optometric Association, Jackson, October/November 1993 580. "New Concepts in Oral Analgesics", Mississippi Optometric Association, Jackson, October/November 1993 581. "Carbonic Anhydrase Inhibitors and Oral Hyperosmotics", Mississippi Optometric Association, Jackson, October/November 1993 582. "Medical Treatment of the Glaucomas", Mississippi Optometric Association, Jackson, October/November 1993 583. "New Strategies for Treatment of Diseases of the Eyelids", Mississippi Optometric Association, Jackson, October/November 1993 584. "New Strategies for Treatment of Diseases of the Cornea and Conjunctiva", Mississippi Optometric Association, Jackson, October/November 1993 585. "Episcleritis and Scleritis", Mississippi Optometric Association, Jackson, October/November 1993 586. "Prescription Writing and Regulatory Issues", Mississippi Optometric Association, Jackson, October/November 1993 587. "New Drugs for Optometric Practice", Kansas Optometric Association, Wichita, October 1994 588. "Systemic Pharmacotherapy of Primary Eye Disease", Kansas Optometric Association, Wichita, October 1994 Case 3:12-cv-01141-SMY-DGW Document 176-33 *SEALED* Filed 12/01/14 Page 76 of 126 Page ID #3089 Case: 16-3334 Document: 55-19 Filed: 02/08/2017 Pages: 126 (710 of 1511) Curriculum Vitae Jimmy D. Bartlett 42 589. "Clinical Ocular Pharmacology", Denver, Colorado, November 1993 590. "Drugs Affecting the Autonomic Nervous System", Denver, Colorado, November 1993 591. "Cycloplegic Refraction", Denver, Colorado, November 1993 592. "Diagnosis and Management of Anisocoria", Denver, Colorado, November 1993 593. "Ocular Effects of Systemic Drugs", Denver, Colorado, November 1993 594. "Systemic Treatment of Primary Ocular Disease", Maryland Optometric Association, Baltimore, December 1993 595. "Prescription Writing and Regulatory Issues", Maryland Optometric Association, Baltimore, December 1993 596. "Clinical Ocular Pharmacology", University of Alabama at Birmingham, December 1993 597. "Practical Diagnostic Ocular Applications", University of Alabama at Birmingham, December 1993 598. "Differential Diagnosis of Anisocoria", University of Alabama at Birmingham, December 1993 599. "Diagnosis of the Glaucomas", University of Alabama at Birmingham, December 1993 600. "Anterior Segment Disease", University of Alabama at Birmingham, December 1993 601. "Difficult Decisions in Glaucoma Management", Gold Coast Educational Retreat, Broward County Optometric Association, Ft. Lauderdale, Florida, January 1994 602. "New Ophthalmic Medications", Gold Coast Educational Retreat, Broward County Optometric Association, Ft. Lauderdale, Florida, January 1994 603. "Ocular Allergy", Gold Coast Educational Retreat, Broward County Optometric Association, Ft. Lauderdale, Florida, January 1994 604. "Practical Issues in Glaucoma Management", Indiana Optometric Association, Indianapolis, January 1994 605. "New Ophthalmic Medications", Indiana Optometric Association, Indianapolis, January 1994 606. "Oral Analgesics in Primary Eye Care", Indiana Optometric Association, Indianapolis, January 1994 607. "Current Treatment Strategies in Glaucoma and Disorders of the Cornea", Texas Association of Optometrists, Dallas, February 1994 608. "A Practical Approach to Oral Analgesic Therapy", Southern Educational Congress of Optometry, Atlanta, February 1994 609. "Practical Tips and Pearls in Ocular Drug Use", Southern Educational Congress of Optometry, Atlanta, February 1994 610. "Pharmacological Issues in Geriatrics", Southern Educational Congress of Optometry, Atlanta, February 1994 611. "New Drugs on the Horizon", Southern Educational Congress of Optometry, Atlanta, February 1994 "Practical Management of External Disease and Glaucoma", California 612. Optometric Association, Long Beach, March 1994 Case 3:12-cv-01141-SMY-DGW Document 176-33 *SEALED* Filed 12/01/14 Page 77 of 126 Page ID #3090 Case: 16-3334 Document: 55-19 Filed: 02/08/2017 Pages: 126 (711 of 1511) Curriculum Vitae Jimmy D. Bartlett 43 613. "Pharmacology of Antiglaucoma Medication", University of Alabama at Birmingham, March 1994 614. "Contemporary Pharmacology of the Antibiotics", University of Alabama at Birmingham, April 1994 "Anterior Segment Disease Grand Rounds", University of Alabama at 615. Birmingham, April 1994 616. "Current Problems and Controversies in Glaucoma", Kentucky Optometric Association, Louisville, April 1994 "Oral Medications in Optometry", Kentucky Optometric Association, Louisville, 617. April 1994 618. Bartlett JD. Ocular toxicity of topically applied insulin (Invited paper delivered at International Symposium on Ocular Pharmacology, Detroit, August 1993) 619. White K, Bartlett JD. Foveomacular vitelliform dystrophy, adult type: a case report. (Poster at Southern Educational Congress of Optometry, Atlanta, February 1994). 620."Prescription Oral Medications", Florida Optometric Association, Orlando, June 1994 621."New Ophthalmic Drug Update", American Optometric Association, Minneapolis, June 1994 622."New FDA-Approved Ophthalmic Drugs", OcuCenter of San Antonio, San Antonio, Texas, July 1994 623."Nonnarcotic Analgesics for Acute Ocular Pain", OcuCenter of San Antonio,San Antonio, Texas, July 1994 624."Current Management of Herpes Zoster Ophthalmicus", OcuCenter of San Antonio,San Antonio, Texas, July 1994 625."Overview of Ophthalmic Medications", University of California, Berkeley, August 1994 626."Ocular Anti-inflammatory Agents", University of California, Berkeley, August 1994 627."Current Diagnosis and Medical Management of Glaucoma", Baptist Eye Institute, Knoxville, August 1994 628."Pharmacology and Clinical Uses of Oral Analgesics", Georgia Optometric Association, Atlanta, August 1994 629."Prescribing Considerations for Opioid Analgesics", Georgia Optometric Association, Atlanta, August 1994 630."Management of Acute Ocular Pain", Southern College of Optometry, Memphis, September, 1994 631."Tips and Pearls in Ocular Drug Use", Southern College of Optometry, Memphis, September, 1994 632."Practical Tips and Pearls in Ocular Drug Use", California Optometric Association, Newport Beach, September 1994 633."Mechanisms and Clinical Uses of Therapeutic Pharmaceutical Agents", California Optometric Association, Newport Beach, September 1994 634."New and Investigational Drugs for Glaucoma", National Glaucoma Symposium, Iowa Optometric Association, Cedar Rapids, October 1994 Case 3:12-cv-01141-SMY-DGW Document 176-33 *SEALED* Filed 12/01/14 Page 78 of 126 Page ID #3091 Case: 16-3334 Document: 55-19 Filed: 02/08/2017 Pages: 126 (712 of 1511) Curriculum Vitae Jimmy D. Bartlett 44 635."Prescription Writing and Regulatory Issues", Alabama Optometric Association, Birmingham, October 1994 636."Topical Ocular Anti-infective Agents", Omega Eye Care Center, Birmingham, October 1994 637."Oral Antihistamines, Anti-infective, and Analgesic Agents in Optometric Practice", New Mexico Optometric Association, Albuquerque, November 1994 638."Controlled Substances, Oral Hi Antihistamines, Drugs in Pregnancy, New Glaucoma Drugs, and Drug Interactions", Alabama Optometric Association, Birmingham, November 1994 639."Ocular Anti-inflammatory Therapy", UAB Faculty In-Service, November 1994 640."Tips and Pearls in Ocular Drug Use", American Academy of Optometry, San Diego, California, December 1994 641."Drug Delivery Systems and Practical Considerations in Ocular Pharmacology", UAB School of Optometry, December 1994 642."Practical Diagnostic Ocular Applications", UAB School of Optometry, December 1994 643."Pupillary Drug Tests for Anisocoria", UAB School of Optometry, December 1994 644."Diagnosis of the Glaucomas", UAB School of Optometry, December 1994 645."Review of Anterior Segment Disease", UAB School of Optometry, December 1994 646."New Drugs for Glaucoma", Society for Therapeutic Optometry, Dallas, February 1995 647."New Drugs for External Disease", Society for Therapeutic Optometry, Dallas, February 1995 648."External Disease Grand Rounds", Society for Therapeutic Optometry, Dallas, February 1995 649."New Drugs for External Disease and Glaucoma", Southern Educational Congress of Optometry, Atlanta, February 1995 650."Narcotic Analgesics in Optometric Practice", Southern Educational Congress of Optometry, Atlanta, February 1995 651."Topically Active Carbonic Anhydrase Inhibitors", Grand Rounds, Department of Ophthalmology, University of South Alabama, Mobile, April 1995 652."Pupillary Drug Tests - Review and New Developments", Grand Rounds, Department of Ophthalmology, University of South Alabama, Mobile, April 1995 653."Clinical Uses of New Ophthalmic Drugs", San Diego County Optometric Society, San Diego, April 1995 654."Practical Issues in Glaucoma Management", San Diego County Optometric Society, San Diego, April 1995 655.Bartlett JD, Guthrey P. Assessment of pharmacists' knowledge and experiences with ophthalmic drugs and products. Optom Vis Sci 1994; 71 (suppl): 115 (American Academy of Optometry poster) 656. "Bartlett JD, Wesson M, Swiatocha J, Woolley T. Ophthalmic sprays for topical drug delivery. "Scientific paper given at the Annual Meeting of the Case 3:12-cv-01141-SMY-DGW Document 176-33 *SEALED* Filed 12/01/14 Page 79 of 126 Page ID #3092 Case: 16-3334 Document: 55-19 Filed: 02/08/2017 Pages: 126 (713 of 1511) Curriculum Vitae Jimmy D. Bartlett 45 Association for Ocular Pharmacology and Therapeutics, New Orleans, January 1995 657. "Bartlett JD, Guthrey P, Singh K. Assessment of pharmacists' knowledge and experiences with ophthalmic drug formulations - implications for pharmacy education." Scientific paper given at the Annual Meeting of the Association for Ocular Pharmacology and Therapeutics, New Orleans, January 1995 658."Pain Management in Primary Care Optometry", Minnesota Optometry Association, Minneapolis, April 1995 659."Oral Antihistamines in Allergic Eye Disease", Minnesota Optometric Association, Minneapolis, April 1995 660."New Ophthalmic Medications", Minnesota Optometric Association, Minneapolis, April 1995 661."Anti-Glaucoma Drugs", Australian Optometric Association, Brisbane, May 1995 662."Medical Management of the Glaucomas", Australian Optometric Association, Melbourne, May 1995 663."Pain Management in Primary Care Optometry", Australian Optometric Association, Melbourne, May 1995 664."Ocular Medication: What is the Latest?", Australian Optometric Association, Melbourne, May 1995 665.The Basics of Ocular Therapeutics", Australian Optometric Association, Melbourne, May 1995 666."Diagnosis and Management of Unequal Pupils", Optometric Association, Melbourne, May 1995 667."Clinical Grand Rounds", Australian Optometric Association, Melbourne, May 1995 668."Dilation Issues: Drugs and Dilation", Australian Optometric Association, Melbourne, May 1995 669."Clinical Procedures Workshop", Australian Optometric Association, Melbourne, May 1995 670."Pharmacology of Drugs Used in Primary Eye Care", Australian Optometric Association, Melbourne, May 1995 671."New Glaucoma Medications and Treatment Strategies", University of Alabama at Birmingham, June 1995 672."Angle-Closure Glaucoma", University of Alabama at Birmingham, June 1995 673."Pharmacology Update", Boston Summer Institute, New England College of Optometry, July 1995 674."New Drugs of Primary Eye Care", Vision America, Nashville, August 1995 675."Pearls and Pitfalls of Prescribing for Optometrists", Alabama Optometric Association, Montgomery, August 1995 676."Pharmacologic Management of Contact Lens-Related Eye Disease", Gilbert Cataract Center, Ponte Vedra Beach, Florida, September 1995 677."Ophthalmic Medications Update", Gilbert Cataract Center, Ponte Vedra Beach, Florida, September 1995 678."Grand Rounds-Cornea and External Disease", Gilbert Cataract Center, Ponte Vedra Beach, Florida, September 1995 Case 3:12-cv-01141-SMY-DGW Document 176-33 *SEALED* Filed 12/01/14 Page 80 of 126 Page ID #3093 Case: 16-3334 Document: 55-19 Filed: 02/08/2017 Pages: 126 (714 of 1511) Curriculum Vitae Jimmy D. Bartlett 46 679."Classification of the Glaucomas", Alabama Optometric Association, Birmingham, October 1995 680."Pharrnacology of Anti-Glaucoma Medications", Alabama Optometric Association, Birmingham, October 1995 681."Case Presentations in Glaucoma", Alabama Optometric Association, Birmingham, October 1995 682."Contemporary Pharmacology of the Antibiotics", University of Alabama at Birmingham, October 1995 683."Prescription Writing and Regulatory Issues for Optometrists", University of Alabama at Birmingham, October 1995 684."Prescription Writing Symposium", Alabama Optometric Association, Birmingham, October 1995 685."Pain Management in Primary Care Optometry", University of Alabama at Birmingham, November 1995 686."Contemporary Management of Glaucoma", Bond Eye Associates, Peoria, Illinois, November 1995 687."New Ophthalmic Medications (1995)", Bond Eye Associates, Peoria, Illinois, November 1995 688."New Ophthalmic Steroids - Loteprednol and Rimexolone", American Academy of Optometry, New Orleans, December 1995 689."Clinical Ocular Pharmacology", University of Alabama at Birmingham, December 1995 690."Differential Diagnosis and Management of Anisocoria", University of Alabama at Birmingham, December 1995 691."Diagnosis of Glaucoma", University of Alabama at Birmingham, December 1995 692."Anterior Segment Disease Grand Rounds", University of Alabama at Birmingham, December 1995 693."Mydriatics - Cycloplegics", Guest Lecturer in Basic Pharmacology, University of Alabama at Birmingham, February 1996 694."Local Anesthetics", Guest Lecturer in Basic Pharmacology, University of Alabama at Birmingham, February 1996 695."Pain Control", Guest Lecturer in Basic Pharmacology, University of Alabama at Birmingham, February 1996 696."Anti-Infective Agents", Guest Lecturer in Basic Pharmacology, University of Alabama at Birmingham, February 1996 697."Clinical Uses of Oral Anti-Infective Drugs", Heart of America Contact Lens and Primary Eye Care Congress, Kansas City, February 1996 698."Narcotic Analgesics in Optometric Practice", Heart of America Contact Lens and Primary Eye Care Congress, Kansas City, February 1996 699."New Anti-Allergy Medications", Heart of America Contact Lens and Primary Eye Care Congress, Kansas City, February 1996 700."New Anti-Glaucoma Medications", Heart of America Contact Lens and Primary Eye Care Congress, Kansas City, February 1996 701."New Ophthalmic Medications", Nevada Optometric Association, Lake Tahoe, February 1996 Case 3:12-cv-01141-SMY-DGW Document 176-33 *SEALED* Filed 12/01/14 Page 81 of 126 Page ID #3094 Case: 16-3334 Document: 55-19 Filed: 02/08/2017 Pages: 126 (715 of 1511) 401.11,, Curriculum Vitae Jimmy D. Bartlett 47 702."Oral Medications in Optometric Practice", Nevada Optometric Association, Lake Tahoe, February 1996 703."New Anti-Inflammatory and Anti-Glaucoma Medications", Southern Education Congress of Optometry, Atlanta, March 1996 704."Overview of Oral Medications in Optometry", Southern Educational Congress of Optometry, Atlanta, March 1996 705."New Ophthalmic Medications (1996)", California Optometric Association, Anaheim, March 1996 706."Systemic Medications in Optometric Practice", California Optometric Association, Anaheim, March 1996 707."Primary Care Medications and Their Clinical Uses", Vision Expo East, New York, New York, March 1996 708."Oral Analgesics, Antihistamines, and Anti-Infectives", Vision Expo East, New York, New York, March 1996 709."Medical Management of Primary Open-Angle Glaucoma", Vision Expo East, New York, New York, March 1996 710."Oral Anti-Infective Therapy", Eye Tech '96, Chicago, April 1996 711."Oral Analgesics In Optometric Practice", Eye Tech '96, Chicago, April 1996 712."Medical Management of Primary Open-Angle Glaucoma", Eye Tech '96, Chicago, April 1996 713.Bartlett JD. Local Ocular Toxicity of Topical Insulin - Preliminary Human Studies. International Symposium on Experimental and Clinical Ocular Pharmacology and Pharmaceutics, Geneva, Switzerland, September 28October 1, 1995. 714.Bartlett JD, Zeise MM, McDougall BWJ, Corliss D. Mydriatic and Cycloplegic Efficacy and Patient Tolerance Comparison Between Paremyd and 0.5% Tropicamide Combined with 2.5% Phenylephrine. International Symposium on Experimental and Clinical Ocular Pharmacology and Pharmaceutics, Geneva, Switzerland, September 28-October 1, 1995. 715.Bartlett JD. Conjunctival Inflammation - Response to a Novel Steroid, Loteprednol Etabonate. Quantitative and Clinical Aspects. American Academy of Optometry, New Orleans, December 1995. 716.Bartlett JD, Nelson MD, Corliss D, Voce M. Ocular Tolerability of Timolol in Gelrite. Invest Ophthalmol Vis Sci 1996; 37(suppl):S833(ARVO poster) 717."Ophthalmic Pharmaceutical Update", Texas Optometric Association, Dallas, May 1996 718."Systemic Pharmaceutical Update", Texas Optometric Association, Dallas, May 1996 719."Beyond Basic Therapeutics: Solving the Mystery of TPA Implementation", Eye Quest, Chicago, May 1996 720."New FDA-Approved Ophthalmic Drugs for External Disease and Glaucoma", Eye Group, Ft. Smith, Arkansas, June 1996 721."Ophthalmic Drugs for Today and the 21st Century", Gilbert Cataract Center, Amelia Island, Florida, August 1996 722."Drug Therapy in Special Patient Populations", Gilbert Cataract Center, Amelia Island, Florida, August 1996 Case 3:12-cv-01141-SMY-DGW Document 176-33 *SEALED* Filed 12/01/14 Page 82 of 126 Page ID #3095 Case: 16-3334 Document: 55-19 Filed: 02/08/2017 Pages: 126 (716 of 1511) Curriculum Vitae Jimmy D. Bartlett 48 723."Medical Management of Primary Open-Angle Glaucoma", Gilbert Cataract Center, Amelia Island, Florida, August 1996 724."Diagnosis and Medical Management of Preseptal Cellulitis", Connecticut Optometric Association, Hartford, September 1996 725."Diagnosis and Medical Management of Herpes Zoster Ophthalmicus", Connecticut Optometric Association, Hartford, September 1996 726."Pain Management in Primary Eye Care", Connecticut Optometric Association, Hartford, September 1996 727."Contemporary Developments and Future Perspectives on Ophthalmic Pharmacotherapy", University of Alabama at Birmingham, November 1996 728."Drug Therapy in Special Patient Populations", University of Alabama at Birmingham, November 1996 729."Recently FDA-Approved Ophthalmic Medications", Lunch and Learn Series, University of Alabama at Birmingham, November 1996 730."New Ophthalmic Drug Products", American Academy of Optometry, Orlando, Florida, December 1996 731."Investigational Drugs for Tomorrow's Ophthalmic Practice", American Academy of Optometry, Orlando, Florida, December 1996 732."Bacterial Resistance Patterns in Ocular Surface Infections", American Academy of Optometry, Orlando, Florida, December 1996 733."Antibiotic Pharmacology", University of Alabama at Birmingham, December 1996 734."Anti-Inflammatory Drugs - Steroids, NSAIDs, Anti-Allergy Medications", University of Alabama at Birmingham, December 1996 735."Glaucoma Pharmacology", University of Alabama at Birmingham, December 1996 736."Classification of Glaucoma and Principles of Treatment", University of Alabama at Birmingham, December 1996 737."Pain Management in Optometry", University of Alabama at Birmingham, December 1996 738."Prescription Writing and Regulatory Issues", University of Alabama at Birmingham, December 1996 739."New TPAs for Optometry", American Optometric Student Association, Birmingham, January 1997 740."Ophthalmic Drugs for Today and Tomorrow", Southern Educational Congress of Optometry, Atlanta, February 1997 741."Drug Therapy for Special Patient Populations", Southern Educational Congress of Optometry, Atlanta, February 1997 742."Ophthalmic Drug Development and New FDA-Approved Drugs", Center for Sight, Venice, Florida, March 1997 743."Medical Management of Primary Open-Angle Glaucoma", Center for Sight, Venice, Florida, March 1997 744."New Ophthalmic Medications", Wisconsin Optometric Association, Green Bay, April 1997 745."Pain Management in Primary Care Optometry", Wisconsin Optometric Association, Green Bay, April 1997 Case 3:12-cv-01141-SMY-DGW Document 176-33 *SEALED* Filed 12/01/14 Page 83 of 126 Page ID #3096 Case: 16-3334 Document: 55-19 Filed: 02/08/2017 Pages: 126 (717 of 1511) Curriculum Vitae Jimmy D. Bartlett 49 746."Drug Therapy in Special Patient Populations", Wisconsin Optometric Association, Green Bay, April 1997 747."Glaucoma Grand Rounds", Wisconsin Optometric Association, Green Bay, April 1997 Tunnel Vision Conference, "New Ophthalmic Medications", Vancouver to 748. Banff, Canada, May 1997 749. Tunnel Vision Conference, "Drug Use in Special Patient Populations", Vancouver to Banff, Canada, May 1997 750. Tunnel Vision Conference, "Oral Antibiotics in Optometry", Vancouver to Banff, Canada, May 1997 751. Eye Group, "New FDA-Approved Ophthalmic Drugs", Ft. Smith, Arkansas, June 1997 Eye Group, "Oral Antiviral and Antibacterial Drugs in Optometric Practice", Ft. 752. Smith, Arkansas, June 1997 753. Omni Eye Services, "Ocular Therapy Update — 1997", Atlanta, Georgia, July 1997 754. Colorado Optometric Association/Mountain States Optometric Society, "New Concepts in Ocular Therapeutics", Snowmass, Colorado, July 1997 755. Colorado Optometric Association/Mountain States Optometric Society, "Drug Therapy in Special Patient Populations", Snowmass, Colorado 756. VisionAmerica, "What to Do When the First Medication Fails ...", Nashville, Tennessee, August 1997 Maryland Optometric Association, "Ocular Therapy Update — 1997", Baltimore, 757. Maryland, August 1997 758. Maryland Optometric Association, "Medical Management of Primary OpenAngle Glaucoma", Baltimore, Maryland, August 1997 759. Eye Sight 20/20, "Ocular Therapeutics Update — 1997", Boston, Massachusetts, September 1997 760. Eye Sight 20/20, "Glaucoma Grand Rounds", Boston, Massachusetts, September 1997 761. South Bay Optometric Society, "New Medications for Optometric Practice", Los Angeles, California, November 1997 762. South Bay Optometric Society, "External Disease Grand Rounds", Los Angeles, California, November 1997 763. South Bay Optometric Society, "Diagnosis and Management of Anisocoria", Los Angeles, California, November 1997 764. Alabama Optometric Association, "Ocular Therapy Update 1997", Birmingham, Alabama, November 1997 765. South Carolina Optometric Association, "Do's and Don't's in Prescribing Systemic Medications in Optometry", Hilton Head Island, South Carolina, December 766. Tropical Sea E, "New Topical and Systemic Medications", Belize, January 1998 767. Tropical Sea E, "Pain Management in Optometry", Belize, January 1998 768. Tropical Sea E, "New Oral Antibiotics for Optometric Practice", Belize, January 1998 Case 3:12-cv-01141-SMY-DGW Document 176-33 *SEALED* Filed 12/01/14 Page 84 of 126 Page ID #3097 Case: 16-3334 Document: 55-19 Filed: 02/08/2017 Pages: 126 (718 of 1511) Curriculum Vitae Jimmy D. Bartlett 50 769. Tropical Sea E, "Medical Management of Primary Open-Angle Glaucoma", Belize, January 1998 770. Southern Educational Congress of Optometry, "Future Therapy in Glaucoma", Atlanta, Georgia, February 1998 771. Southern Educational Congress of Optometry, "Issues and Controversies in Glaucoma - Panel Discussion", Atlanta, Georgia, February 1998 772. Southern Educational Congress of Optometry, "Increasing Your Comfort with Beta Blockers", Atlanta, Georgia, February 1998 773. Southwest Council of Optometry, "Pearls in Medical Management of Glaucoma", Dallas, Texas, March 1998 774. Southwest Council of Optometry, "Oral Antibiotics in Optometric Practice", Dallas, Texas, March 1998 775. Southwest Congress of Optometry, "External Disease Grand Rounds", Dallas, Texas, March 1998 776. Bartlett JD, Gordon A, Linn M, Corliss D. "Short-Term Toxicity of Topical Diclofenac Sodium Used to Improve Adaptation to Rigid Contact Lenses." Second International Symposium on Experimental and Clinical Ocular Pharmacology and Pharmaceutics. Munich, Germany, September 1997 777."Medical Management in Primary Open-Angle Glaucoma", Kentucky Optometric Association, Louisville, April 1998 778."New Ophthalmic Medications for Today and Tomorrow", Kentucky Optometric Association, Louisville, April 1998 779."New Ophthalmic Drugs for 1998", Post Eye Center, Plymouth, Massachusetts, May 1998 780."External Disease Grand Rounds", Post Eye Center, Plymouth, Massachusetts, May 1998 781."Update on Medical and Legal Issues in Primary Open-Angle Glaucoma", Indiana Optometric Association, Indianapolis, June 1998 782."Current Trends in Medical Management of Primary Open-Angle Glaucoma", Middle Atlantic Educational Conference/Virginia Optometric Association, Wintergreen, Virginia, June 1998 783."Systemic Medications for Ophthalmic Therapy", American Optometric Association, Orlando, June 1998 784."Pain Management in Optometric Practice", American Optometric Association, Orlando, June 1998, 2 hours 785 "Immunosuppressive Treatment in Primary Eye Care", American Optometric Association, Orlando, June 1998 786."Glaucoma Refresher Course", Nebraska Optometric Association, Omaha, July 1998 787."Future Treatment of Glaucoma", Diversified Ophthalmics, Cincinnati, Ohio, August 1998 788."New Ophthalmic Medications (1998)", Diversified Ophthalmics, Cincinnati, Ohio, August 1998 789."External Disease Grand Rounds", Diversified Ophthalmics, Cincinnati, Ohio, August 1998 Case 3:12-cv-01141-SMY-DGW Document 176-33 *SEALED* Filed 12/01/14 Page 85 of 126 Page ID #3098 Case: 16-3334 Document: 55-19 Filed: 02/08/2017 Pages: 126 (719 of 1511) Curriculum Vitae Jimmy D. Bartlett 51 790."New Medications for Today and Tomorrow", San Diego Optometric Society, Holland American Line Cruise, Vancouver, BC to Anchorage, Alaska, September 1998 791."Drug Therapy for Special Patient Populations", San Diego Optometric Society, Holland American Line Cruise, Vancouver, BC to Anchorage, Alaska, September 1998 New in Medical Management of Primary Open-Angle Glaucoma?" San "What's 792. Diego Optometric Society, Holland American Line Cruise, Vancouver, BC to Anchorage Alaska, September 1998 Anti-Infective Agents for Optometric Practice", San Diego Optometric "Oral 793. Society, Holland American Line Cruise, Vancouver, BC to Anchorage Alaska, September 1998 794."Current Trends in Medical Management of Glaucoma", Omega Health Systems, Memphis, Tennessee, September 1998 795."What's New in Glaucoma", University of Alabama at Birmingham, September 1998 796."New Ophthalmic and Systemic Medications on the Horizon", Kansas Optometric Association, Wichita, October 1998 797."New Anti-Glaucoma Drugs and the "New" Management of Glaucoma", Kansas Optometric Association, Wichita, October 1998 798."New Anti-Glaucoma Medications", New England College of Optometry, Boston, October 1998 799."Systemic Treatment of Infectious Ocular Diseases", New England College of Optometry, Boston, October 1998 and Developing Ophthalmic Medications", SeaVision Conference, Athens, "New 800. Greece, November 1998 801."Contemporary Management of Difficult Red Eyes", SeaVision Conference, Athens, Greece, November 1998 802."New Treatment of Ophthalmic Zoster and Ocular Rosacea", SeaVision Conference, Athens, Greece, November 1998 803."Current Trends in Medical Management of Glaucoma", SeaVision Conference, Athens, Greece, November 1998 804."Current Trends in Medical Management of Glaucoma", South Carolina Optometric Association, Hilton Head Island, December 1998 805."New Drug Panel", Southern Educational Congress of Optometry, Atlanta, February 1999 806."Management of Ocular Pain", Southern Educational Congress of Optometry, Atlanta, February 1999 807."New Ophthalmic Anti-Inflammatory Medications for Optometric Use", St. Louis Optometric Society, St. Louis, March 1999 808."What's the Latest in New Ocular Medication?" Vision Expo East, New York, March 1999 809."Medical Management of Ocular Inflammation", Vision Expo East, New York, March 1999 810."Future Therapy in Glaucoma", Vision Expo East, New York, March 1999 Case 3:12-cv-01141-SMY-DGW Document 176-33 *SEALED* Filed 12/01/14 Page 86 of 126 Page ID #3099 Case: 16-3334 Document: 55-19 Filed: 02/08/2017 Pages: 126 (720 of 1511) Curriculum Vitae Jimmy D. Bartlett 52 811."Pain Management in Optometric Practice", Vision Expo East, New York, March 1999 812."Pharmacology and Ocular Therapeutics", Optometry '99, Birmingham, England, April 1999 813."Red Eyes", Optometry '99, Birmingham, England, April 1999 814."Medical Management of Ocular Inflammation", Optometry '99, Birmingham, England, April 1999 815."Association for Research in Vision and Ophthalmology, Ft. Lauderdale, Florida; "Ocular and Systemic Tolerability of Carteolol and Timolol in Postmenopausal Black Women with Primary Open-Angle Glaucoma or Ocular Hypertension. M. Olivier (presenter), J. Bartlett, T. Richardson, R. Whitaker, K. Greenidge, D. Pensyl. Invest Ophthalmol Vis Sci 1998;39:S200 816."American Academy of Optometry, San Francisco, California; The New Soft Steroids-Can They Live Up to Their Early Promise?" J. Bartlett (presenter), Optom Vis Sci 1998;75(125):181. 817."Association for Ocular Pharmacology and Therapeutics, January 1999, Irvine, California; "Central Nervous System Effects of Carteolol Hydrochloride and Timolol Maleate in Postmenopausal Black Women With Primary OpenAngle Glaucoma or Hypertension". 818."Glaucoma Medications Update - 1999", 2 hours, University of Alabama at Birmingham, Birmingham, AL, May 1999. 819."Oral Anti-Infective Agents for Optometric Practice", North Carolina State Optometric Society, Myrtle Beach, South Carolina, June 1999. 820. "Selection and Clinical Uses of New Oral Analgesics", North Carolina State Optometric Society, Myrtle Beach, South Carolina, June 1999. 821."New Oral Medicines for Optometric Practice", North Central States Optometric Conference, Minneapolis, June 1999. 822."Neuroprotection - A New Paradigm for Glaucoma Management", North Central States Optometric Conference, Minneapolis, June 1999. 823."Ocular Therapeutics - Panel Discussion", North Central States Optometric Conference, Minneapolis, June 1999. 824."Current Concepts and Future Perspective in Glaucoma Diagnosis and Management", Vision America, Nashville, Tennessee. 825."New Oral and Topical Medications for Optometric Practice", Vision America, Nashville, Tennessee, July 1999. 826."Loteprednol - A Novel Steroid for Ophthalmic Inflammation", Aran Eye Associates, Key West, Florida, July 1999. 827."New FDA-Approved Ophthalmic Medications", Aran Eye Associates, Key West, Florida, July 1999. 828."New Ophthalmic Steroids for Optometric Practice", Eye Group, Ft. Smith, Arkansas, August 1999. 829."New Strategies for Glaucoma Management", Eye Group, Ft. Smith, Arkansas, August 1999. 830."Clinical Neuroprotection in Glaucoma", Department of Pharmacology and Toxicology, UAB School of Medicine, September 1999. Case 3:12-cv-01141-SMY-DGW Document 176-33 *SEALED* Filed 12/01/14 Page 87 of 126 Page ID #3100 Case: 16-3334 Document: 55-19 Filed: 02/08/2017 Pages: 126 (721 of 1511) Curriculum Vitae Jimmy D. Bartlett 53 831."New Diagnostic and Therapeutic Strategies for the New Millennium", Kaiser Permanente Northwest Ocular Disease Forum, Portland, Oregon, September 1999. 832. "New Diagnostic and Therapeutic Interventions in Glaucoma", Kaiser Permanente Northwest Ocular Disease Forum, Portland, Oregon, September 1999. 833."Pain Management in Optometry", Kaiser Permanente Northwest Ocular Disease Forum, Portland, Oregon, September 1999. 834."Contemporary Developments in the Pharmacologic Management of Glaucoma", Cataract and Laser Institute, San Antonio, Texas, September 1999. 835."Difficult Problems and Challenges in the Use of Oral Analgesics and Anti-Infective Agents", Hunkeler Eye Center, Kansas City, Missouri, October 1999. 836."New Therapeutic Strategies for the Next Millennium", Federal Service Optometry Seminar, Sheppard Air Force Base, Texas, October 1999. 837."Anterior Segment Challenges in Primary Eye Care", Federal Service Optometry Seminar, Sheppard Air Force Base, Texas, October 1999. 838."New Oral Medications for Optometric Practice", Alabama Optometric Association, Birmingham, November 1999. 839."New Drugs and Therapeutic Strategies in Glaucoma Management", Alabama Optometric Association, Birmingham, November 1999. 840. "The New Soft Steroids - Can They Live Up to Their Early Promise", Alabama Optometric Association, Birmingham, November 1999. 841."New Therapeutic Strategies for the New Millennium", NOVA Southeastern University, Ft. Lauderdale, Florida, November 1999. 842."The Role of "Soft Steroids" in Optometric Practice", NOVA Southeastern University, Ft. Lauderdale, Florida, November 1999. 843. "New Therapeutic Strategies for the New Millennium", SnowVision Conference, Steamboat Springs, Colorado, January 2000. 844."Current Trends in the Medical Management of Glaucoma", SnowVision Conference, Steamboat Springs, Colorado, January 2000. 845."Oral Anti-Infectives for Optometric Practice", SnowVision Conference, Steamboat Springs, Colorado, January 2000. 846."Sorting Out Steroids", SECO International, Atlanta, Georgia, February 2000. 847."Ocular Pain Management", SECO International, Atlanta, Georgia, February 2000. 848."Drug Pearls in Primary Eye Care", SECO International, Atlanta, Georgia, February 2000. 849."The Red, Puffy, Swollen Eyelid", SECO International, Atlanta, Georgia, February 2000. 850. "New Drugs and Therapeutic Strategies for the New Millennium", Internet Course Sponsored by Vision Service Plan. 851."New Treatment Paradigms in Glaucoma Management", UAB School of Optometry, Birmingham, March 2000. Case 3:12-cv-01141-SMY-DGW Document 176-33 *SEALED* Filed 12/01/14 Page 88 of 126 Page ID #3101 Case: 16-3334 Document: 55-19 Filed: 02/08/2017 Pages: 126 (722 of 1511) Curriculum Vitae Jimmy D. Bartlett 54 852."New Anti-Glaucoma and Anti-Allergy Drugs", South Dakota Optometric Society, Chamberlain, South Dakota, April 2000. 853. "New Treatment Paradigms in Glaucoma Management", South Dakota Optometric Society, Chamberlain, South Dakota, April 2000. 854."Oral Antibiotic, Analgesic, and Antihistaminic Therapy in Primary Eye Care", South Dakota Optometric Society, Chamberlain, South Dakota, April 2000. 855."New FDA-Approved Ophthalmic Medications", New Mexico Optometric Association, Albuquerque, April 2000. 856."New Approaches in Glaucoma Management", New Mexico Optometric Association, Albuquerque, April 2000. 857. International Symposium on Ocular Pharmacology and Pharmaceutics, Lisbon, Portugal; "Hypercapnia Invokes an Acute Contrast Sensitivity Loss in Glaucoma Patients but not Normal Subjects". D. Evans (presenter), B. Houde, J. Bartlett. February 2000 858.International Symposium on Ocular Pharmacology and Pharmaceutics, Lisbon, Portugal. "Toxokinetics of Ophthalmic Drug Interactions". J. Bartlett (presenter). February 2000 859.Valley Forge Pharmaceuticals Symposium on Pirenzepine. "Pirenzepine Ophthalmic Gel - Protocol and Preliminary Results of Phase II Clinical Trials". San Diego, California. March 2000 860."New Drugs and Clinical Pearls", Omni Eye Services of Chattanooga, Chattanooga, Tennessee, July 2000. 861."Glaucoma Grand Rounds", Southwest Florida Educational Retreat, Captiva Island, Florida, August 2000 862.Association of Ocular Pharmacology and Therapeutics; "Pirenzepine-A New MI Antagonist for Myopia Progression". J. Bartlett (presenter). Birmingham, Alabama, November 2000 863.Association of Ocular Pharmacology and Therapeutics, "Evidence that Brimonidine may have Neuroprotective Activity in Human Eyes with Early Primary Open-Angle Glaucoma". D. Evans (presenter) J. Bartlett, B. Houde. Birmingham, Alabama. November 2000 864. Case Challenges in Ocular Disease", Southwest Florida Educational Retreat, Captiva Island, Florida, August 2000, 2 hours 865."Clinical Drug Pearls" Southwest Florida Educational Retreat, Captiva Island, Florida, August 2000. 866."New Concepts in Diagnosis and Management of Glaucoma", Southwest Florida Educational Retreat, Captiva Island, Florida, August 2000. 867. "Neuroprotection in Glaucoma - A New Therapeutic Paradigm", Department of Pharmacology and Toxicology, University of Alabama at Birmingham, September 2000. 868."New Drugs for Optometric Practice", EyeSight 20/20, Boston, September 2000. 869."Current Trends in Glaucoma Management", EyeSight 20/20, Boston, September 2000. 870."New Therapeutic Strategies for Ocular Disease", Aston University, Birmingham, England, September 2000. Case 3:12-cv-01141-SMY-DGW Document 176-33 *SEALED* Filed 12/01/14 Page 89 of 126 Page ID #3102 Case: 16-3334 Document: 55-19 Filed: 02/08/2017 Pages: 126 (723 of 1511) Curriculum Vitae Jimmy D. Bartlett 55 871."Current Trends in Glaucoma Management", Aston University, Birmingham, England, September 2000. 872."Sorting Out Unequal Pupils", Aston University, Birmingham, England, September 2000. 873."New Anti-Inflammatory Medications", VisionExpo West, Las Vegas, September 2000. 874."Contemporary Management of Glaucoma", VisionExpo, Las Vegas, September 2000. 875."Ophthalmic Drug Pearls", VisionExpo West, Las Vegas, September 2000. 876."Medical Management of Ocular Inflammation", VisionExpo West, Las Vegas, September 2000. 877."New Strategies in Systemic Treatment of Eye Disease, Part I", Kansas Optometric Association, Wichita, Kansas, October 2000. 878."New Strategies in Systemic Treatment of Eye Disease, Part II", Kansas Optometric Association, Wichita, Kansas, October 2000. 879."New Drugs for Ocular Inflammatory Disease", Michigan Eye Center, Detroit, October 2000. 880."Systemic Treatment of Eye Disease", Michigan Eye Center, Detroit, October 2000. 881."Pirenzepine-A New MI Antagonist for Myopia Progression", American Academy of Optometry, Orlando, Florida, December 2000. 882."Contemporary Ocular Hypotensive Medications", American Academy of Optometry, Orlando, Florida, December 2000. 883."Ocular Hypotensive Medications of the Future", American Academy of Optometry, Orlando, Florida, December 2000. 884."The Red, Swollen or Inflamed Eyelid", SnowVision Conference, Breckenridge, Colorado, January 2001. 885."New and Investigational Ocular Hypotensive Medications", SnowVision Conference, Breckenridge, Colorado, January 2001. 886."New Treatment Strategies for the New Millennium", SnowVision Conference, Breckenridge, Colorado, January 2001. 887. "Case Challenges in Grand Rounds", Palm Beach Winter Seminar, West Palm Beach, Florida, February 2001. 888."Ophthalmic Drug Pearls", Palm Beach Winter Seminar, West Palm Beach, Florida, February 2001. 889."Contemporary Trends in Medical Management of Glaucoma", Palm Beach Winter Seminar, West Palm Beach, Florida, February 2001. 890."Oral Medicines in Optometric Practice", Palm Beach Winter Seminar, West Palm Beach, Florida, February 2001. 891."Neuroprotection in Glaucoma", SECO International, Atlanta, Georgia, February 2001. 892."Oral Medications in Optometric Practice, SECO International, Atlanta, Georgia, February 2001. 893."Ocular Anti-Inflammatory Therapy", SECO International, Atlanta, Georgia, February 2001. Case 3:12-cv-01141-SMY-DGW Document 176-33 *SEALED* Filed 12/01/14 Page 90 of 126 Page ID #3103 Case: 16-3334 Document: 55-19 Filed: 02/08/2017 Pages: 126 (724 of 1511) Curriculum Vitae Jimmy D. Bartlett 56 894. "Systemic Medications in Optometry", Indiana Optometric Association, Indianapolis, April 2001 895. "Current Trends in Glaucoma Management", Tropical SeaE, Aruba, April 2001 896."External Disease Grand Rounds", Tropical SeaE, Aruba, April 2001 897."New Ophthalmic Medications", Tropical SeaE, Aruba, April 2001 898."Oral Medications in Optometry", Tropical SeaE, Aruba, April 2001 899."Prescription Writing Workshop" Tropical SeaE, Aruba, April 2001 900."Systemic Medications in Optometry", Washington Association of Optometric Physicians, Ocean Shores, Washington, May 2001 901. "New Drugs for Optometric Practice, Washington Association of Optometric Physicians, Ocean Shores, Washington, May 2001 902. "Contemporary Medical Management of Ocular Inflammation", British Contact Lens Association, Brighton, United Kingdom, May 2001 903."Diagnosis and Treatment of Ocular Allergic Diseases", British Contact Lens Association, Brighton, United Kingdom, May 2001 904."Panel Discussion — Treatment and Management of Ocular Disease", British Contact Lens Association, Brighton, United Kingdom, May 2001 905."Pharmacologic Considerations in Eldercare", Omni Eye Services of Chattanooga, Chattanooga, Tennessee, June 2001 906."Treatment of Glaucoma in 2001", Birmingham Ophthalmology (Allergan), June 2001 907."Pharmaceutical Update 2001", American Optometric Association, Boston, June 2001 908."Pharmacologic Aspects of Eldercare", American Optometric Association, Boston, June 2001 909."Contemporary Medical Management of Glaucoma", Gulf Coast Summer Conference, Alabama Optometric Association, San Destin, Florida, July 2001 910."Ocular Hypotensive Activity of New Prostaglandins, Docosanoids, and Prostamides", Duke Eye Center, Department of Ophthalmology, Duke University, Durham, North Carolina, September 2001 911."Contemporary Trends in Medical Management of Glaucoma", Duke Eye Center, Winston-Salem, North Carolina, September 2001 912."New Therapeutic Strategies for the New Millennium", Duke Eye Center, Winston-Salem, North Carolina, September 2001 913."New Therapeutic Strategies" New Jersey Optometric Association", Atlantic City, October 2001 914."Systemic Medications in Optometric Practice", New Jersey Optometric Association, Atlantic City, October 2001 915."Contemporary Medical Management of Glaucoma", New Jersey Optometric Association, Atlantic City, October 2001 916."Special Considerations in Glaucoma Management", Omni Eye Services of Atlanta, November 2001 917."Sorting Out Glaucoma Drugs", SECO International, Atlanta, Georgia, February 2002 Case 3:12-cv-01141-SMY-DGW Document 176-33 *SEALED* Filed 12/01/14 Page 91 of 126 Page ID #3104 Case: 16-3334 Document: 55-19 Filed: 02/08/2017 Pages: 126 (725 of 1511) Curriculum Vitae Jimmy D. Bartlett 57 918 "Early Diagnosis and Treatment of Glaucoma — Evaluating Ocular Blood Flow", SECO International, Atlanta, February 2002 919."Oral Medications in Eye Care", SECO International, Atlanta, Georgia, February 2002 American Academy of Optometry; "Efficacy and Safety of Travoprost 920. Compared to Latanoprost and Timolol in Patients with Open-Angle Glaucoma or Ocular Hypertension". J Bartlett (presenter). Philadelphia, Pennsylvania, December 2001 921. Panel Discussion, "Treatment and Management of Ocular Disease", British Contact Lens Association, Brighton, United Kingdom, May 2001. "Sorting Out Steroids", Vision Expo East, New York, New York, March 2002, 2 hours 922. "Sorting Out Steroids", Vision Expo East, New York, New York, March 2002, 2 hours 923. "The Inflamed Eyelid", Vision Expo East, New York, New York, March 2002 924. "New Drugs 2002", Vision Expo East, New York, New York, March 2002 925. "Practical Applications of Blood Flow in Glaucoma", UAB School of Optometry, March 2002 "New Glaucoma Medications and New Treatment Paradigms, UAB School of 926. Optometry, March 2002 927. "New Glaucoma Treatment Strategies", West Tennessee Optometric Society, Memphis, Tennessee, April 2002 928. "Medical Management of Glaucoma in 2002", North West Tennessee Optometric Society, Jackson, Tennessee, April 2002 929. "New Treatment Paradigms in Glaucoma", University of Notre Dame, South Bend, Indiana, May 2002 930. "Oral Medications in Eyecare", University of Notre Dame, South Bend, Indiana, May 2002 931. Evans DW, Bartlett J, Houde B, Than T. Effect of latanoprost on contrast sensitivity in glaucoma patients. Association for Research in Vision and Ophthalmology, Fort Lauderdale, Florida, May 5-10, 2002 932.Bartlett JD, Evans DW. Contrast sensitivity improvements in brimonidinetreated primary open-angle glaucoma patients suggest a neuroprotective mechanism. Association for Research in Vision and Ophthalmology, Fort Lauderdale, Florida, May 5-10, 2002. 933. "The Red, Puffy, Inflamed Eyelid", Maine Optometric Association, Boothbay Harbor, June 2002 "New Treatment Paradigms in Glaucoma Management" Maine Optometric 934. Association, Boothbay Harbor, June 2002 935. "Systemic Medications in Optometric Practice", Maine Optometric Association, Boothbay Harbor, June 2002 936. "New Drugs and Treatment Strategies", Maine Optometric Association, Boothbay Harbor, Maine, June 2002 937. "Contemporary Medical Management of Glaucoma", American Optometric Association, New Orleans, Louisiana, June 2002 Case 3:12-cv-01141-SMY-DGW Document 176-33 *SEALED* Filed 12/01/14 Page 92 of 126 Page ID #3105 Case: 16-3334 Document: 55-19 Filed: 02/08/2017 Pages: 126 (726 of 1511) Curriculum Vitae Jimmy D. Bartlett 58 938. "Ocular Blood Flow in Diagnosis and Management of Glaucoma", American Optometric Association, New Orleans, Louisiana, June 2002 939. "Ocular Blood Flow Workshop", American Optometric Association, New Orleans, Louisiana, June 2002 940. "Oral Anti-Infective Agents in Optometric Practice", Ohio State University, Columbus, July 2002 941. "New Treatment Paradigms in Glaucoma", Ohio State University, Columbus, July 2002 942. "Diagnosis and Treatment of the Inflamed or Infected Eyelid", Ohio State University, Columbus, July 2002 943. "Neuroprotection and Other Novel Strategies in Glaucoma Management", UAB Department of Pharmacology and Toxicology, September 2002 944. "New Glaucoma Treatment Strategies for 2002", EyeSight 20/20, Boston, Massachusetts, September 2002 945. "Oral Medications in Eyecare", EyeSight 20/20, Boston, Massachusetts, September 2002 946. "Systemic Medications in Optometry", Wisconsin Optometric Association, Madison, September 2002 947. "New Drugs and Treatment Strategies for Optometric Practice", Wisconsin Optometric Association, Madison, September 2002 948. "Contemporary Medical Management of Normal Tension Glaucoma", UAB School of Optometry, October 2002 949. "Medical Management of Glaucoma", Oklahoma Association of Optometric Physicians, Tulsa, October 2002 950. "The Red, Puffy, or Inflamed Eyelid", Oklahoma Association of Optometric Physicians, Tulsa, October 2002 951. "Prostaglandins in Glaucoma Management", Review of Optometry/Pharmacia, Kansas City, Missouri, October 2002 952. "New Treatment Paradigms in Glaucoma Management", East-West Eye Conference, Cleveland, Ohio, November 2002 953. "Ocular Disease Round Table", East-West Eye Conference, Cleveland, Ohio, November 2002 954. "Systemic Medications in Optometry", East-West Eye Conference, Cleveland, Ohio, November 2002 955. "Ocular Blood Flow and Neuroprotection in Glaucoma", East-West Eye Conference, Cleveland, Ohio November 2002 956. "Blood Flow and Neuroprotection in Glaucoma", South Carolina Optometric Association, Hilton Head, December 2002 957. Optometric Glaucoma Society; "Brimonidine-associated Neuroprotection in Glaucoma". J Bartlett (presenter). San Diego, California, December 2002 958. "Contemporary Medical Management of Primary Open-Angle Glaucoma", South Carolina Optometric Association, Hilton Head, December 2002, 2 hours 959. "Sorting out Glaucoma Drugs", SnowVision, Steamboat Springs, Colorado, January 2003 Case 3:12-cv-01141-SMY-DGW Document 176-33 *SEALED* Filed 12/01/14 Page 93 of 126 Page ID #3106 Case: 16-3334 Document: 55-19 Filed: 02/08/2017 Pages: 126 (727 of 1511) ....., olillbsw Curriculum Vitae Jimmy D. Bartlett 59 960. "New Ophthalmic Medication and Treatment Strategies for Optometric Practice", SnowVision, Steamboat Springs, Colorado, January 2003 "Ocular Blood Flow and Neuroprotection in Glaucoma", SnowVision, 961. Steamboat Springs, Colorado, January 2003 962. "New Glaucoma Diagnostic Imaging Technologies", SnowVision, Steamboat Springs, Colorado, January 2003 Association for Ocular Pharmacology and Therapeutics; "Electronic Monitoring 963. System for Assessment of Compliance in a Pediatric Drug Clinical Trial". J Bartlett (presenter), Kona, Hawaii. January 2003 964. "Pharmaceutical Update 2003", Heart of America Contact Lens and Primary Care Congress, Kansas City, Missouri, February 2003 "Sorting Out Glaucoma Drugs", Heart of America Contact Lens and Primary 965. Care Congress, Kansas City, Missouri, February 2003 966. "Oral Medications in Optometric Practice", Heart of America Contact Lens and Primary Care Congress, Kansas City, Missouri, February 2003 967. "Contemporary Medical Management of Glaucoma", SECO, Atlanta, Georgia, February 2003 968. "New Drugs and Treatment Strategies for Optometric Practice", SECO, Atlanta, Georgia, February 2003 "Eye Examination in the ER", Department of Emergency Medicine, University 969. of Alabama at Birmingham, March 2003 970. "Glaucoma Medications — A New Treatment Paradigm", University of Alabama at Birmingham, March 2003 971. "New Treatment Paradigms for Glaucoma", Allergan Pharmaceuticals, Little Rock, Arkansas, April 2003 972. "Immunosuppressive Treatment for Dry Eye", Allergan Pharmaceuticals, Little Rock, Arkansas, April 2003 973. "The Glaucoma Continuum — Landmark Clinical Trials", Pfizer Ophthalmics, Dallas, Texas, May 2003 "Sorting Out Glaucoma Drugs", American Optometric Association, San Diego, 974. California, June 2003 975. "New Drugs and Treatment Strategies For Optometric Practice", American Optometric Association, San Diego, California, June 2003 "Pirenzepine — A Novel Mi Antagonist for Myopia Control", Visiting Lecturer, 976. University of California, Berkeley, June 2003 977. "New Drugs for External Disease", Alabama Optometric Association Gulf Coast Summer Conference, July 2003 978. "Glaucoma and Ocular Hypertension in Optometric Practice — 2003 Update", Pfizer Ophthalmics, Memphis, Tennessee, July 2003 979. "New Treatment Paradigms in the Medical Management of Primary OpenAngle Glaucoma", University of Houston Continuing Education, Banff, Alberta, Canada, July 2003 "New Drugs for Optometric Practice", University of Houston Continuing 980. Education, Banff, Alberta, Canada July 2003 981. "New Drugs for Dry Eye and Ocular Infection", University of Alabama at Birmingham, October 2003 Case 3:12-cv-01141-SMY-DGW Document 176-33 *SEALED* Filed 12/01/14 Page 94 of 126 Page ID #3107 Case: 16-3334 Document: 55-19 Filed: 02/08/2017 Pages: 126 (728 of 1511) Curriculum Vitae Jimmy D. Bartlett 60 982. "Sorting Out Unequal Pupils", Conference on New Eyecare Technologies, Dallas, Texas, October 2003 983. "Contemporary Therapeutic Strategies for Optometric Practice", Conference on New Eyecare Technologies, Dallas, Texas, October 2003 984. "Eye Examination in the ER", Department of Emergency Medicine, University of Alabama at Birmingham, October 2003 985. "Cyclosporin in Dry Eye Syndrome — A New Therapeutic Paradigm", Allergan Pharmaceuticals, Huntsville, Alabama, October 2003 986. "New Drugs for Dry Eye and Ocular Infection", Iowa Optometric Association, Cedar Rapids, October 2003 987. "New Treatment Paradigms for the Medical Management of Glaucoma", Iowa Optometric Association, Cedar Rapids, October 2003 988. "Systemic Medicines for Optometric Practice", Iowa Optometric Association, Cedar Rapids, October 2003 989. "Cyclosporin — A Novel Immunomodulatory Agent for Dry Eye", Eyesight 20/20, Boston, November 2003 990. "The Patient With Unequal Pupils", Eyesight 20/20, Boston, November 2003 991. "New Therapeutic Strategies for Optometric Practice", Eyesight 20/20, Boston, November 2003 992. "Current Management of Dry Eye", Allergan Pharmaceuticals, Dothan, Alabama, December 2003 993. "Highlights of Ophthalmic Meetings", American Academy of Optometry, Dallas, Texas, December 2003 "New 994. Drugs for External Disease", University of Houston, Santa Fe, New Mexico, January 2004 995. "Ocular Blood Flow and Neuroprotection", University of Houston, Santa Fe, New Mexico, January 2004 996. "New Glaucoma Treatment Strategies", University of Houston, Santa Fe, New Mexico, January 2004 "What is New and Hot in Ocular Therapeutics", Armed Forces Optometric 997. Society, Atlanta, Georgia, February 2004 998. "Impact of Dry Eye on Quality of Life", Symposium on Dry Eye, Allergan Pharmaceuticals, Atlanta, Georgia, February 2004 999. "New Drugs for Dry Eye and Ocular Infection", SECO International, Atlanta, Georgia, February 2004 1000."Sorting out Glaucoma Drugs", SECO International, Atlanta, Georgia, February 2004 1001."Topical Steroids in the Baby Boomer", SECO International, Atlanta, Georgia, February 2004 1002."Systemic Medications in Optometry", Tropical Sea E, Saint Kitts, West Indies, March 2004 1003."Contemporary Medical Management of Glaucoma", Tropical Sea E, Saint Kitts, West Indies, March 2004 1004."Ocular Blood Flow and Neuroprotection in Glaucoma", Tropical Sea E, Saint Kitts, West Indies, March 2004 Case 3:12-cv-01141-SMY-DGW Document 176-33 *SEALED* Filed 12/01/14 Page 95 of 126 Page ID #3108 Case: 16-3334 Document: 55-19 Filed: 02/08/2017 Pages: 126 (729 of 1511) Curriculum Vitae Jimmy D. Bartlett 61 1005."Sorting Out Unequal Pupils", Tropical Sea E, Saint Kitts, West Indies, March 2004 1006." "New Treatment Strategies for Dry Eye and Ocular Infection", Tropical Sea E, Saint Kitts, West Indies, March 2004 1007."What's New with Glaucoma Medications — 2004?", University of Alabama at Birmingham, March 2004 1008."New Drugs for Dry Eye and Ocular Infection", Minnesota Optometric Association, Minneapolis, April 2004 1009."Systemic Medicines in Optometric Practice", Minnesota Optometric Association, Minneapolis, April 2004 1010."Blood Flow and Neuroprotection in Glaucoma", Arizona Optometric Association, Phoenix, May 2004 1011."Therapeutic Update 2004", Arizona Optometric Association, Phoenix, May 2004 1012."New Strategies in the Medical Management of Glaucoma", Arizona Optometric Association, Phoenix, May 2004 1013."Diagnosis and Management of Unequal Pupils", Arizona Optometric Association, Phoenix, May 2004 1014."Contemporary Diagnosis and Medical Management of Glaucoma", Geriatric Conference, Birmingham — Atlanta VA Geriatric Research Education and Clinical Center, Division of Gerontology and Geriatric Medicine, Center for Aging, University of Alabama at Birmingham, May 2004 1015."Systemic Medications in Optometric Practice", AOA Optometry's Meeting, June 2004 1016."Assessment and Management of Blood Flow in Glaucoma", Southwest Florida Optometric Association, Captiva Island, July 2004 1017."Sorting Out Unequal Pupils", Southwest Florida Optometric Association, Captiva Island, July 2004 1018."New Treatment for Dry Eye and Ocular Infection", Southwest Florida Optometric Association, Captiva Island, July 2004 1019."Contemporary Medical Management of Glaucoma", Southwest Florida Optometric Association, Captiva Island, July 2004 1020."New Drugs and Therapeutic Procedures", Vision Expo West, Las Vegas, September 2004 1021."Pharmacologic Management of Glaucoma" National Glaucoma Symposium, Vision Expo West, Las Vegas, September 2004 1022."Sorting out Unequal Pupils", Vision Expo West, Las Vegas, September 2004 1023."Oral Medications in Optometry", Vision Expo West, Las Vegas, September 2004 1024."Pharmacology Update", Omni Eye Services, Atlanta, October 2004 1025."Ocular Blood Flow and Neuroprotection in Glaucoma", East-West Eye Conference, Cleveland, October 2004 1026."Contemporary Medical Management of Glaucoma", East-West Eye Conference, Cleveland, October 2004 1027."Oral Medications in Optometric Practice", East-West Eye Conference, Cleveland, October 2004 Case 3:12-cv-01141-SMY-DGW Document 176-33 *SEALED* Filed 12/01/14 Page 96 of 126 Page ID #3109 Case: 16-3334 Document: 55-19 Filed: 02/08/2017 Pages: 126 (730 of 1511) Curriculum Vitae Jimmy D. Bartlett 62 1028."Autonomic Drugs in Glaucoma Practice", Massachusetts Society of Optometrists, Boston, November 2004 1029."Prostaglandin Analogs", Massachusetts Society of Optometrists, Boston, November 2004 1030."Contemporary Medical Management of Glaucoma", Massachusetts Society of Optometrists, Boston, November 2004 1031."Systemic Medications in Optometry", New Jersey Society of Optometric Physicians, Newark, New Jersey, November 2004 1032."The Importance of a Healthy Tear Film", American Academy of Optometry, Tampa, December 2004 1033."Highlights from Ophthalmic Meetings — ARVO", American Academy of Optometry, Tampa, December 2004 1034.Bartlett JD. "Prevalence and Pathophysiology of Dry Eye, American Optometric Association/Allergan Webcast in Advanced Principles in the Treatment of Ocular Surface Disorders", 2004 1035.Bartlett JD, Shaikh A, Semes L, et. al. "The Influence of Race on Pulsatile Ocular Blood Flow", Association for Ocular Pharmacology and Therapeutics, Catania, Sicily, February 2005 1036."New Strategies for Treating Ocular Infection", Hawaii Ocular Disease Symposium, Honolulu , January 2005 1037."Contemporary Medical Management of Glaucoma", Hawaii Ocular Disease Symposium, Honolulu, January 2005 1038."Oral Medications in Optometric Practice", Hawaii Ocular Disease Symposium, Honolulu, January 2005 1039."Ocular Blood Flow Workshop", Hawaii Ocular Disease Symposium, Honolulu, January 2005 1040."NEI Landmark Trials in Glaucoma — Clinical Applications", SECO International, Atlanta, February 2005 1041."Systemic Medications in Optometry", New Orleans Contact Lens Society, New Orleans, March 2005 1042."Sorting Out Unequal Pupils", New Orleans Contact Lens Society, New Orleans, March 2005 1043."Bloodflow and Neuroprotection in Glaucoma", New Orleans Contact Lens Society, New Orleans, March 2005 1044."Oral Anti-infective Agents and Analgesics in Optometric Practice", Massachusettes Society of Optometry, Boston, April 2005 1045."Oral Medications in Treatment of Eye Disease", University of Waterloo, Ontario, Canada, June 2005 1046."Deciphering Unequal Pupils with Drugs", University of Waterloo, Ontario, Canada, June 2005 1047."Contemporary Glaucoma Therapy", University of Waterloo, Ontario, Canada, June 2005 1048."Application of Newer Steroids in Anti-inflammatory Therapies", University of Waterloo, Ontario, Canada, June 2005 1049."Systemic Medications in Optometry—Anti-infectives and Analgesics", Michigan Optometric Association, Mackinac Island, Michigan, July 2005 Case 3:12-cv-01141-SMY-DGW Document 176-33 *SEALED* Filed 12/01/14 Page 97 of 126 Page ID #3110 Case: 16-3334 Document: 55-19 Filed: 02/08/2017 Pages: 126 (731 of 1511) Curriculum Vitae Jimmy D. Bartlett 63 1050."Contemporary Pharmacologic Management of Glaucoma", Allergan Pharmaceuticals, Tupulo, Mississippi, August 2005 1051."Prostaglandin Analogs in Glaucoma—An Evidence-based Approach", Pfizer Ophthalmics, Phoenix, Arizona, September 2005 I 052."Therapeutic Strategies in Primary Eyecare", Southern College of Optometry, September 2005 1053."Evidence-based Approach to Glaucoma Therapy", Pfizer Ophthalmics, Little Rock, Arkansas, October 2005 1054."Comparative Efficacy Assessments of Prostaglandins", Birmingham Area Optometric Society, October 2005 1055."Systemic Medications in Optometry", New Hampshire Optometric Association, Portsmith, October 2005 1056."Contemporary Medical Management of Glaucoma", New Hampshire Optometric Association, Portsmith, October 2005 1057."Oral Anti-infective Agents in Optometric Practice", EyeSight 20/20, Groton, Connecticut, November 2005 1058."New Treatment Strategies for Dry Eye and Ocular Infection", EyeSight 20/20, Groton, Connecticut, November 2005 1059."Clinical Drug Trials in Optometry—Past Successes and Future Opportunities", in Symposium on Drug Trials in Optometry, American Academy of Optometry, San Diego, December 2005 1060."Therapeutic Strategies in Primary Eye Care", Eye Center South, Dothan, Alabama, January 2006 1061."Anisocoria 2006", Eye Center South, Dothan, Alabama, January 2006 1062."Evidence-based Glaucoma Care", Allergan Optometry Leaders Conference, Atlanta, Georgia, February 2006 1063."What You Do Makes a Difference", SECO International, Atlanta, February 2006 1064."Therapeutic Strategies in Primary Care Practice", New Orleans Contact Lens Society, New Orleans, March 2006 1065."Contemporary Treatment Strategies for Primary Care", Suncoast Seminar, Pinellas Optometric Association, Clearwater Beach, Florida, May 2006 1066."Oral Medications in Optometry", Suncoast Seminar, Pinellas Optometric Association, Clearwater Beach, Florida, May 2006 1067."New Treatment Strategies for Dry Eye and Ocular Infection", Suncoast Seminar, Pinellas Optometric Association, Clearwater Beach, Florida, May 2006 1068."Pharmacotherapeutic Update for Primary Care Practice, American Optometric Association, Las Vegas, July 2006 1069."New Treatment Strategies for Dry Eye and Ocular Infection", Wisconsin Optometric Association, Madison, September 2006 1070."Contemporary Medical Management of Glaucoma", Wisconsin Optometric Association, Madison, September 2006 1071."Systemic Medicines in Optometric Practice", Wisconsin Optometric Association, Madison, September 2006 Case 3:12-cv-01141-SMY-DGW Document 176-33 *SEALED* Filed 12/01/14 Page 98 of 126 Page ID #3111 Case: 16-3334 Document: 55-19 Filed: 02/08/2017 Pages: 126 (732 of 1511) Curriculum Vitae Jimmy D. Bartlett 64 1072."Pharmacotherapeutic Update 2006, University of Alabama at Birmingham, October 2006 1073."Contemporary Medical Management of Glaucoma", Rhode Island Optometric Association, Providence, October 2006 1074."New Treatment Approaches in Primary Care Optometry", Rhode Island Optometric Association, Providence, October 2006 1075."Oral Medications in Optometric Practice", Rhode Island Optometric Association, Providence, October 2006 1076."Hot Topics in Pharmacology—ARVO 2006", American Academy of Optometry", Denver, December 2006 1077."Management of Ocular Inflammation and Allergy 2007", Southeast Eye Specialists, Chattanooga, Tennessee, March 2007 1078."Management of Infectious Ocular Inflammatory Conditions-Novel Combination Therapy," Bausch & Lomb, Birmingham, Alabama, March 2007 1079."Oral Medications in Optometry," Massachusetts Society of Optometrists, Boston, April 2007 1080."Systemic Medications in Pregnancy and Pediatrics," Southern College of Optometry, Memphis, Tennessee, April 2007 1081."Contemporary Pharmacotherapeutic Strategies in Primary Care Optometry," Florida Chapter, American Academy of Optometry, Orlando, Florida, May 2007 1082."New Treatment Approaches to Dry Eye and Ocular Infection," Florida Chapter, American Academy of Optometry, Orlando, Florida, May 2007 1083."Contemporary Treatment of Ocular Inflammation and Allergy," Florida Chapter, American Academy of Optometry, Orlando, Florida, May 2007 1084."Treatment Strategies for the New Millennium," Louisiana Optometric Association, Baton Rouge, Louisiana, June 2007 1085."Safe and Effective Use of Oral Medications in Optometry," Louisiana Optometric Association, Baton Rouge, Louisiana, June 2007 1086."New Therapeutic Approaches for the Twenty-First Century," Canadian Association of Optometrists, Saskatoon, Saskatchewan, Canada, July 2007 1087."Dry Eye and Ocular Infection — New Therapeutic Interventions," Canadian Association of Optometrists, Saskatoon, Saskatchewan, Canada, July 2007 1088."Contemporary Pharmacotherapeutic Strategies in Optometric Practice," Gulf Coast Optometric Conference, Destin, Florida, July 2007 1089."Regulation and Effective Prescribing of Controlled Substances," Nurse Practitioner Alliance of Alabama, Birmingham, August 2007 1090."Oral Medications in Optometry," Virginia Optometric Association, Tysons Corner, September 2007 1091."Contemporary Management of Ocular Inflammation and Allergy," Rhode Island Optometric Association, Newport, October 2007 1092."New Therapeutic Strategies in Primary Care Optometry," Rhode Island Optometric Association, Newport, October 2007 1093."Safety Precautions in Oral Pharmacotherapy," Clayton Eye Center, Atlanta, Georgia, November 2007 Case 3:12-cv-01141-SMY-DGW Document 176-33 *SEALED* Filed 12/01/14 Page 99 of 126 Page ID #3112 Case: 16-3334 Document: 55-19 Filed: 02/08/2017 Pages: 126 (733 of 1511) Curriculum Vitae Jimmy D. Bartlett 65 1094."Safety Precautions in Oral Pharmacotherapy," Georgia Optometric Association, Macon, Georgia, January 2008 1095."Prescribing Oral Antibacterial and Antiviral Drugs," Georgia Optometric Association, Macon, Georgia, January 2008 1096."Effective Prescribing of Nonopioid and Opioid Analgesics," Georgia Optometric Association, Macon, Georgia, January 2008 1097."Prescribing Oral Antihistamines, Carbonic Anhydrase Inhibitors, and Steroids," Georgia Optometric Association, Macon, Georgia, January 2008 1098."Ocular Adverse Drug Reactions to Systemic Medications," Georgia Optometric Association, Macon, Georgia, January 2008 1099."Safe and Effective Prescribing of Oral Medications in Optometric Practice", New England College of Optometry, Boston, February 2008 1100."Prescribing Oral Antibiotics, Antivirals, and Narcotics," SECO International, Atlanta, Georgia, March 2008 1101."Ocular Pharmacology Rounds," SECO International, Atlanta, Georgia, March 2008 1102. "Systemic Medications in Optometry", New Jersey Academy of Optometry, Myrtle Beach, South Carolina, April 2008 1103."Therapeutic Strategies in Primary Care Practice", New Jersey Academy of Optometry, Myrtle Beach, South Carolina, April 2008 1104."Contemporary Medical Management of Glaucoma", New Jersey Academy of Optometry, Myrtle Beach, South Carolina, April 2008 1105."New Treatment Strategies for Dry Eye and Ocular Infection", New Jersey Academy of Optometry, Myrtle Beach, South Carolina, April 2008 1106."Contemporary Issues in Medical Management of Glaucoma", Colorado Optometric Glaucoma Society, Denver, May 2008 1107."Ocular Blood Flow and Neuroprotection — Has Their Time Yet Arrived?", Colorado Optometric Glaucoma Society, Denver, May 2008 1108."Contemporary Medical Management of Glaucoma", American Optometric Association, Seattle, June 2008 1109."Pharmacotherapeutic Strategies in Optometric Practice", American Optometric Association, Seattle, June 2008 1110."Safety Issues in Oral Pharmacotherapy", American Optometric Association, Seattle, June 2008 1111.Webinar Recording of "The Role and Toxicity of Preservatives in Prostaglandin Analogs for Treatment of Glaucoma", Pfizer Ophthalmics, New York City, July 2008 1112."Contemporary Medical Management of Glaucoma", Southwest Florida Optometric Association, Captiva Island, Florida, August 2008 1113."Ocular Pharmacology Rounds", Southwest Florida Optometric Association, Captiva Island, Florida, August 2008 1114."Systemic Medications in Optometry — Antibacterial and Antiviral", Southwest Florida Optometric Association, Captiva Island, Florida, August 2008 1115."Pharmacology Rounds", Eyesight 20/20, Boston, September 2008 1116."Ocular Adverse Drug Reactions to Systemic Medications", Eyesight 20/20, Boston, September 2008 Case 3:12-cv-01141-SMY-DGW Document 176-33 *SEALED* Filed 12/01/14 Page 100 of 126 Page ID #3113 Case: 16-3334 Document: 55-19 Filed: 02/08/2017 Pages: 126 (734 of 1511) Curriculum Vitae Jimmy D. Bartlett 66 1117."Safety Considerations in Oral Pharmacotherapy", Eyesight 20/20, Boston, September 2008 I118."Systemic Medications in Optometric Practice", New England College of Optometry, September 2008 1119."Advances in the Treatment of Ocular Surface Inflammatory Disease", Bausch & Lomb, Cape Girardeau, Missouri, November 2008 1120."Ocular Pharmacology Rounds", South Carolina Optometric Association, Hilton Head, December 2008 1121."Safety Precautions in Oral Pharmacotherapy", South Carolina Optometric Association, Hilton Head, December 2008 1122."Importance of Ocular Surface Inflammatory Disease in Optometric Practice", Bausch & Lomb, Chattanooga, Tennessee, February 2009 1123."Therapeutic Update 2009", UAB School of Optometry, February 2009 1124."Pharmacology Update 2009", SECO International, Atlanta, March 2009 1125."Ocular Surface Inflammation — Focus on Loteprednol", Bausch & Lomb, Tuscaloosa, Alabama, March 2009 1126."Oral Antibacterial and Antiviral Agents in Optometric Practice", Diversified Ophthalmics, Cincinnati, Ohio, March 2009 1127."Pharmacology Update 2009", Diversified Ophthalmics, Cincinnati, Ohio, March 2009 1128."Ocular Surface Inflammation - Focus on Loteprednol", Richmond Optometric Society, Richmond, Virginia, March 2009 1129."Ocular Surface Inflammation - Focus on Loteprednol", Birmingham Area Optometric Society, March 2009 1130."Safety Precautions in Oral Pharmacotherapy", New Jersey Society of Optometric Physicians, Newark, New Jersey, April 2009 1131."Effective Prescribing of Nonopioid and Opioid Analgesics", New Jersey Society of Optometric Physicians, Newark, New Jersey, April 2009 1132."Oral Antiviral and Antibacterial Agents in Optometric Practice", New Jersey Society of Optometric Physicians, Newark, New Jersey, April 2009 1133."Steroids in Ocular Inflammation", Central Tennessee Optometric Society, Nashville, April 2009 1134."Prescribing Oral Antibiotic, Antiviral, and Narcotic Agents", Eyesight 20/20, Groton, Connecticut, April 2009 1135."Contemporary Management of Ocular Inflammation and Allergy", Eyesight 20/20, Groton, Connecticut, April 2009 1136."Contemporary Management of Ocular Inflammation", East Central Alabama Optometric Society, Montgomery, Alabama, May 2009 1137."Contemporary Management of Ocular Inflammation", Northeast Alabama Optometric Society, Anniston, Alabama, May 2009 1138."Pharmacologic Management of Ocular Surface Inflammation", Piedmont Triad-Winston Salem Optometric Societies, Winston Salem, North Carolina, June 2009 1139."Contemporary Management of Ocular Surface Disease", North Atlanta Optometric Society, Atlanta, Georgia, June 2009 1140."Treatment Algorithms for Anterior Segment Inflammatory Disease", Chicago, Illinois, July 2009 Case 3:12-cv-01141-SMY-DGW Document 176-33 *SEALED* Filed 12/01/14 Page 101 of 126 Page ID #3114 Case: 16-3334 Document: 55-19 Filed: 02/08/2017 Pages: 126 (735 of 1511) Curriculum Vitae Jimmy D. Bartlett 67 1141."New Insights in Glaucoma Management", Pfizer Ophthalmics, Tallahassee, Florida, July 2009 1142."Safe and Effective Use of Systemic Medications in Optometry", Colorado Vision Summit, Denver, August 2009 1143."Ocular Pharmacology Rounds", Colorado Vision Summit, Denver, August 2009 1144."PG Analogs in Glaucoma Management: Evaluating the Scientific Evidence", New Orleans Optometric Society, September 2009 1145."Steroids for Treatment of Ocular Inflammation in Optometric Practice", Tidewater Optometric Society, Virginia Beach, Virginia, September 2009 1146."Contemporary Medical Management of Glaucoma", Maine Optometric Association, Northport, Maine, September 2009 1147."Ocular Pharmacology Rounds", Maine Optometric Association, Northport, Maine, September 2009 1148."Ocular Adverse Drug Reactions to Systemic Medications", Maine Optometric Association, Northport, Maine, September 2009 1149."Safety Precautions in Oral Pharmacotherapy", Maine Optometric Association, Northport, Maine, September 2009 1150."Systemic Antibacterials, Antivirals, and Opioid Analgesics in Optometric Practice", New England College of Optometry, Boston, September 2009 1151."Safety Precautions in Systemic Pharmacotherapy", Therapy by the Sea, New Jersey Society of Optometric Physicians, Atlantic City, October 2009 1152."Effective Prescribing of Nonopioid and Opioid Analgesics", Therapy by the Sea, New Jersey Society of Optometric Physicians, Atlantic City, October 2009 1153."Oral Antibacterial and Antiviral Medications in Optometric Practice", Therapy by the Sea, New Jersey Society of Optometric Physicians, Atlantic City, October 2009 1154."Treatment Algorithms for Anterior Segment Ocular Diseases", Newport Beach, California, November 2009 1155."Pharmacology Update", American Academy of Optometry, Orlando, November 2009 1156."Research for Today's Practice —Dry Eye", American Academy of Optometry, Orlando, November 2009 1157."Managing Ocular Infection and Inflammatory Conditions", American Academy of Optometry, Orlando, November 2009 1158."Loteprednol: Ten years of Innovation and Discovery", North Alabama Optometric Society, Huntsville, January 2010 1159."Contemporary Management of Ocular Infection and Inflammation", Walker County Optometric Society, Jasper, Alabama, February 2010 1160."Pharmacology Update", SECO, Atlanta, Georgia, February 2010 1161."Enhancing Patient Safety When Using Oral Medications", SECO, Atlanta, Georgia, February 2010 1162."An Emerging Therapeutic Option for Bacterial Conjunctivitis", Birmingham Area Optometric Society, February 2010 Case 3:12-cv-01141-SMY-DGW Document 176-33 *SEALED* Filed 12/01/14 Page 102 of 126 Page ID #3115 Case: 16-3334 Document: 55-19 Filed: 02/08/2017 Pages: 126 (736 of 1511) Curriculum Vitae Jimmy D. Bartlett 68 1163."Besifloxacin", East Central Alabama Optometric Society, Montgomery, February 2010 1164."Loteprednol", Northwest Alabama Optometric Society, Florence, Alabama, February 2010 1165."Diagnostic and Treatment Algorithms for Ocular Surface Disease States", Fort Lauderdale, Florida, March 2010 1166. "New Strategies for Managing Blepharokeratoconjunctivitis." Baton Rouge Optometric Society, March 2010. 1167."Treatment of Ocular Inflammation and Infection in Optometric Practice." Northwest Florida Optometric Society, Destin, March 2010. 1168."New Approaches to Ocular Surface Inflammatory Disease." West Central Alabama Optometric Society, Tuscaloosa, March 2010. 1169."Pharmacology Update." Florida Chapter, American Academy of Optometry, Orlando, April 2010. 1170."Prescribing Oral Antibacterials and Antivirals." Florida Chapter, American Academy of Optometry, Orlando, April 2010. 1171."Adverse Ocular Reactions to Systemic Medications." Florida Chapter, American Academy of Optometry, Orlando, April 2010. 1172."Diagnostic and Treatment Algorithms for Ocular Surface Disease States", Phoenix, Arizona, June 2010. 1173."Pharmacology Update." American Optometric Association, Orlando, Florida, June 2010. 1174."Adverse Ocular Reactions to Systemic Medications." American Optometric Association, Orlando, Florida, June 2010. 1175."Pharmacology Update." Northern Rockies Optometric Conference, Jackson Hole, Wyoming, July 2010. 1176."Prescribing Oral Antibacterials and Antivirals." Northern Rockies Optometric Conference, Jackson Hole, Wyoming, July 2010. 1177."New Topical Anti-infective Agents for Primary Eye Care." North Atlanta Optometric Society, July 2010. 1178."Prescribing Oral Antibacterials and Antivirals." Phillips Eye Foundation, West Orange, New Jersey, September 2010. 1179."Effective Use of Oral Opioid and Nonopioid Analgesics in Optometric Practice." Phillips Eye Foundation, West Orange, New Jersey, September 2010. 1180."Phannacology Update." New Hampshire Optometric Association, Nashua, October 2010. 1181."Prescribing Oral Narcotic Analgesics." New Hampshire Optometric Association, Nashua, October 2010. 1182."Contemporary Medical Management of Glaucoma." New Hampshire Optometric Association, Nashua, October 2010. 1183."Adverse Ocular Reactions to Systemic Medications." New Hampshire Optometric Association, Nashua, October 2010. 1184."Pharmacology Update." American Academy of Optometry, San Francisco, California, November 2010. 1185 ."Pharmacology Update." China Tour, Beijing and Shanghai, June 2011. Case 3:12-cv-01141-SMY-DGW Document 176-33 *SEALED* Filed 12/01/14 Page 103 of 126 Page ID #3116 Case: 16-3334 Document: 55-19 Filed: 02/08/2017 Pages: 126 (737 of 1511) ...., Curriculum Vitae Jimmy D. Bartlett 69 1186."Prescribing Oral Narcotic Analgesics." China Tour, Beijing and Shanghai, June 2011 1187."Contemporary Medical Management of Glaucoma." China Tour, Beijing and Shanghai, June 2011. 1188."Adverse Ocular Reactions to Systemic Medications." China Tour, Beijing and Shanghai, June 2011. 1189."Pharmacology Update." St. Thomas, US Virgin Islands, March 2012. 1190."Prescribing Oral Narcotic Analgesics." St. Thomas, US Virgin Islands, March 2012. 1191."Contemporary Medical Management of Glaucoma." St. Thomas, US Virgin Islands, March 2012. 1192."Adverse Ocular Reactions to Systemic Medications." St. Thomas, US Virgin Islands, March 2012. 1193."Ocular Adverse Drug Reactions to Systemic Medications." Virginia Academy of Optometry, Fredericksburg, November 2012. 1194."Pharrnacology Update." Virginia Academy of Optometry, Fredericksburg, November 2012. 1195. "Clinical Pearls for Therapeutic Prescribing." Virginia Academy of Optometry, Fredericksburg, November 2012. 1196."Pharmacology Update." Alabama Optometric Association, Birmingham, November 2012. 1197."Ocular Therapeutics-A Look Back, a Look Ahead", SECO International, Atlanta, March 2013. 1198."Ocular Adverse Drug Reactions to Systemic Medications." SECO International, Atlanta, March 2013. 1199."Contemporary Management of Ocular Inflammation and Allergy." University of Alabama at Birmingham, April 2013. 1200."Ocular Adverse Drug Reactions to Systemic Medications." Filutowski Cataract and LASH( Institute, Orlando, Florida, March 2013. 1201."Contemporary Management of Ocular Inflammation and Allergy." Filutowski Cataract and LASIK Institute, Orlando, Florida, March 2013. 1202."Contemporary Management of Ocular Inflammation and Allergy." Virginia Optometric Association, Wintergreen Resort, June 2013. 1203."Safety Precautions in Systemic Pharmacotherapy." Virginia Optometric Association, Wintergreen Resort, June 2013. 1204."Effective Prescribing of Nonopioid and Opioid Analgesics." Virginia Optometric Association, Wintergreen Resort, June 2013. 1205."Pharmacology for the Optometric Office." Virginia Optometric Association, Wintergreen Resort, June 2013. 1206."New Developments in Glaucoma Pharmacology." National Glaucoma Society, Cape Cod, Massachusetts, July 2013. 1207."Clinical Pearls for Therapeutic Prescribing in Glaucoma Practice." National Glaucoma Society, Cape Cod, Massachusetts, July 2013. 1208."Systemic Drugs That Can Impact Glaucoma Therapy." National Glaucoma Society, Cape Cod, Massachusetts, July 2013. Case 3:12-cv-01141-SMY-DGW Document 176-33 *SEALED* Filed 12/01/14 Page 104 of 126 Page ID #3117 Case: 16-3334 Document: 55-19 Filed: 02/08/2017 Pages: 126 (738 of 1511) Curriculum Vitae Jimmy D. Bartlett 70 1209."Effective Prescribing of Nonopioid and Opioid Analgesics." Vision Expo West, Las Vegas, Nevada, October 2013. 1210."Ocular Adverse Drug Reactions to Systemic Medications." Vision Expo West, Las Vegas, Nevada, October 2013. 1211."Prescribing Oral Antibacterials and Antivirals." Vision Expo West, Las Vegas, Nevada, October 2013. 1212. "New Therapeutics." Review of Optometry's New Technologies in Vision Care. Aruba, January 2014. 1213. "Anterior Segment Grand Rounds." Review of Optometry's New Technologies in Vision Care. Aruba, January 2014. 1214. "Pharmacology Update." Eye Center South. Dothan, Alabama, January 2014. 1215. "Clinical Pearls in Therapeutic Prescribing." Eye Center South. Dothan, Alabama, January 2014. 1216. "Adverse Ocular Effects of Systemic Medications." Eye Center South. Dothan, Alabama, January 2014. 1217. "Safety Precautions in Oral Pharmacotherapy." Eye Center South. Dothan, Alabama, January 2014. 1218. "Anterior Segment Grand Rounds." Connecticut Association of Optometrists, Hartford, March 2014. Management of Ocular Inflammation and Allergy." "Contemporary 1219. Connecticut Association of Optometrists, Hartford, March 2014. NAMED LECTURES "Legislative Strategies for Therapeutic Drug Laws", Nielsen Lecture", Mountain States Congress of Optometry/Colorado Optometric Association, Denver, August 1986. "Today's Drugs and Tomorrow's Drugs", Meredith Morgan Lecture, University of California at Berkeley, May 1996 "Contemporary Ocular Therapeutics - What's New in Ocular Drugs and Glaucoma Management?" Distinguished Lectureship Series, Illinois Society for the Prevention of Blindness, Chicago, October 1996 th "Pirenzepine—A Novel Mi Antagonist for Treatment of Myopia Progression", 11 Annual Woodruff Lecture, University of Waterloo, Ontario, Canada, June 2005 "New Optometric Therapeutic Opportunities and Strategies for the 21' Century", Allan Freid Lecture for 103rd Alumni Reunion, Southern California College of Optometry, Fullerton, California, October 2007 Case 3:12-cv-01141-SMY-DGW Document 176-33 *SEALED* Filed 12/01/14 Page 105 of 126 Page ID #3118 Case: 16-3334 Document: 55-19 Filed: 02/08/2017 Pages: 126 (739 of 1511) Curriculum Vitae Jimmy D. Bartlett 71 "New Developments in Glaucoma Pharmacology", Sullins Memorial Lecture, National Glaucoma Society, Cape Cod, Massachusetts, July 2013 COMMUNITY PRESENTATIONS Cub Scout Den 21, Pack 352, presentation on Vision and Optical Illusions, April, 1998 WBHM Radio Interview, "Medical Treatment of Glaucoma", February, 1998 "How Medicines Can Affect Your Eyes", UAB Elderhostel, May 1993 "Insulin Eyedrops for Treatment of Diabetes Mellitus", WBMG Television, Birmingham, Alabama, April 1993 "Insulin Eyedrops for Treatment of Diabetes Mellitus", WBRC Television, Birmingham, Alabama, April 1993 "Insulin Eyedrops for Treatment of Diabetes Mellitus", WVTM Television, Birmingham, Alabama, April 1993 "Insulin Eyedrops for Treatment of Diabetes Mellitus", Alabama Public Radio, April 1993 "How Medicines Can Affect the Eyes", Channel 6, WBRC-TV Morning Show, January 1991 "Ocular Side Effects of Systemic Drugs", Channel 6, WBRC (Birmingham, Alabama), January 1987 "Medication Effects on the Eye", Cable News Network (CNN), March 1987 "Retinitis Pigmentosa", Alabama Institute for the Deaf and Blind, Talladega, October 1985 "Marijuana and Glaucoma", WBRC Television (Birmingham, Alabama), October 1982 "National Save Your Vision Week", WBRC Television (Birmingham, Alabama), March 1981 "Eye Safety in Industry", Alabama Surface Mining Safety Assoc., May 1980 "Eye Safety in Industry", Jefferson Health Foundation, May 1980 "National Save Your Vision Week", WBIQ Television (Birmingham, Alabama), February 1980 Case 3:12-cv-01141-SMY-DGW Document 176-33 *SEALED* Filed 12/01/14 Page 106 of 126 Page ID #3119 Case: 16-3334 Document: 55-19 Filed: 02/08/2017 Pages: 126 (740 of 1511) Curriculum Vitae Jimmy D. Bartlett 72 "Blindness and Its Prevention," WEDU Television (Tampa, Florida), May 1977 "Low Vision Rehabilitation," North Tampa Lions Club, Tampa, Florida, July 1976 "Low Vision Care," Central Florida Lions Eye Bank Foundation, Tampa, Florida, June 1976 "Your Vision After Forty," Business and Professional Women's Club, St. Petersburg, Florida, April 1976 "Your Vision After Forty," Rochester, NY and Vicinity Club, Clearwater, Florida, November 1975 "Low Vision Services in the Veterans Administration," WIMP Radio, (Tampa, Florida), September 1975 "Eye Safety for the Family," Kiwanis Club, Seminole, Florida, August 1976 "Emergency Removal of Contact Lenses," Hillsborough County (Florida) Division of Emergency Ambulance Service, November 1974 PUBLICATIONS and ABSTRACTS 1. 2. 3. 4. 5. 6. 7. 8. 9. 10. 11. Bartlett JD. Why drugs? American Optometric Student Review, September 1973. Bartlett JD. Isometropic meridional aniseikonia - A case report. J Am Optom Assoc 1975; 46(2): 174-176. Bartlett JD. Opening the eyes of the visually impaired. Paraplegia News 1975; 28(323). Bartlett JD. A clinical comparison of three high-plus hydrophilic spin-cast contact lens designs. Int Cont Lens Clin 1977; 4(2): 28-33. Bartlett JD. Administration of and adverse reactions to cycloplegic agents. Am J Optom Physiol Optics 1978; 55(4): 227-233. Bartlett JD. (Book Review) So, you have a retinal detachment - A guide for patients. Fred M. Wilson, Charles C. Thomas, December 1977, in Rev Optom 1978; 115(7): 22-23. Bartlett JD. (Letter). J Am Optom Assoc 1979; 50(1): 16. Bartlett JD. Congenital cone dysfunction. Am J Optom Physiol Optics 1979; 56(3): 206-210. Bartlett JD. Slab-off prism compensation for anisometropic vertical imbalance induced by disease. Rev Optom 1979; 116(7): 65-71. Bartlett JD, Alexander LJ. Construction of a Fresnel_e_ membrane telemicroscopic system. J Am Optom Assoc 1979; 50(9): 1031-1034. Bartlett JD, Peters HB. Ocular fundus in diagnosis. In Physifax - Physicians pocket compendium of normal values, tests, diagnostic criteria, drug therapy, and Case 3:12-cv-01141-SMY-DGW Document 176-33 *SEALED* Filed 12/01/14 Page 107 of 126 Page ID #3120 Case: 16-3334 Document: 55-19 Filed: 02/08/2017 Pages: 126 (741 of 1511) AMIN, Curriculum Vitae Jimmy D. Bartlett 73 other useful data. Montclair, New Jersey, Meducation International, 1980, pps. 97-136. 12. Blume AJ, Bartlett JD, Alexander LJ. The optometric model. J Am Optom Assoc 1980; 51(1): 13-14. 13. Bartlett JD. Pitfalls encountered in the clinical utilization of mydriatic drugs. South J Optom 1980; 22(2): 8-14. 14. Bartlett JD. (Letter) Optom Manage 1980; 16(4): 13. 15. Interviewed by Milton J. Eger in The many faces of the optometry residency program. J Am Optom Assoc 1980; 51(10): 923-931. 16. Bartlett JD. Ocular pharmacology: Self assessment, Vol. 1. American Academy of Optometry, 1980. 17. Brooks DN, Potter JW, Bartlett JD, Nowakowski R. Pigmented paravenous retinochoroidal atrophy. J Am Optom Assoc 1980; 51(12): 1097-1101. 18. Bartlett JD, JW Wood. Optometry and the Drug Enforcement Administration. J Am Optom Assoc 1981; 52(6):495-498. 19. Bartlett JD. Ocular pharmacology: Self-Assessment, Vol 2. American Academy of Optometry, 1981. 20. Bartlett JD. (Letter). South J Optom 1981; 23(4):4. 21. Semes L, Bartlett JD. Mydriatic effectiveness of hydroxyamphetamine. J Am Optom Assoc 1982; 53(1):899-904. 22. Horton RO, Bartlett JD. Presumed ocular vitelliform macular giardiasis and lesions. J Am Optom Assoc 1983; 54(1):23-27. 23. Jaanus S, Pagano V, Bartlett JD. Drugs affecting the autonomic nervous system. In Bartlett JD, Jaanus S, ed., Clinical ocular pharmacology, Boston: Butterworths, pp. 37-130, 1984. 24. Jaanus S, Bartlett JD. Adverse ocular effects of systemic drug therapy. In Bartlett JD, Jaanus S, ed., Clinical ocular pharmacology, Boston: Butterworths, pp. 917939, 1984. 25. Eskridge JB, Bartlett JD. The glaucomas. In Bartlett JD, Jaanus S, ed., Clinical ocular pharmacology, Boston: Butterworths, pp. 845-914, 1984. 26. Bartlett JD, Gaitan E. Thyroid eye disease. In Bartlett JD, Jaanus S, ed., Clinical ocular pharmacology, Boston: Butterworths, pp. 803-833, 1984. 27. Bartlett JD. Diseases of the eyelids. In Bartlett JD, Jaanus S, ed., Clinical ocular pharmacology, Boston: Butterworths, pp. 523-561, 1984. 28. Bartlett JD. Pupillary abnormalities. In Bartlett JD, Jaanus S, ed., Clinical ocular pharmacology, Boston: Butterworths, pp. 483-521, 1984. 29. Bartlett JD. Pupillary dilation. In Bartlett JD, Jaanus S, ed., Clinical ocular pharmacology, Boston: Butterworths, pp. 431-467, 1984. 30. Bartlett JD. Topical anesthesia. In Bartlett JD, Jaanus S, ed., Clinical ocular pharmacology, Boston: Butterworths, pp. 419-428, 1984. 31. Bartlett JD, Cullen A. Clinical administration of ocular drugs. In Bartlett JD, Jaanus S, ed., Clinical ocular pharmacology, Boston: Butterworths, pp. 365-418, 1984. 32. Bartlett JD, Jaanus S, ed., Clinical ocular pharmacology, Boston: Butterworths, 1984. Case 3:12-cv-01141-SMY-DGW Document 176-33 *SEALED* Filed 12/01/14 Page 108 of 126 Page ID #3121 Case: 16-3334 Document: 55-19 Filed: 02/08/2017 Pages: 126 (742 of 1511) Curriculum Vitae Jimmy D. Bartlett 74 33. Bartlett JD. Clinical ocular microbiology and cytology. In Terry J, ed., Ocular disease diagnosis and treatment, Springfield: Charles Thomas, pp. 402-435, 1984. 34. Bartlett JD (Book Review). Terry JE. Ocular disease diagnosis and treatment. Springfield: Charles Thomas, 1984, in Current Eye Research 1984; 3: 1361-2. 35. Bartlett JD. The microbiological benefits of cleaning and rinsing contact lenses Clinical implications. Int Cont Lens Clin 1985;12:248. 36. Bartlett JD. Legacies (editorial). J Am Optom Assoc 1985; 56: 435-436. 37. Bartlett JD. Optometric impact of intraocular lenses (editorial). J Am Optom Assoc 1985; 56: 520-521. 38. Bartlett JD. Development of human vision (editorial). J Am Optom Assoc 1985; 56: 596. 39. Bartlett JD. Role of the optometrist in disease prevention and health promotion (editorial). J Am Optom Assoc 1985; 56: 681-682. 40. Bartlett JD. How progressive is your practice? (editorial). J Am Optom Assoc 1985; 56: 765-766. 41. Potter JW, Bartlett JD, Alexander et al. Oral fluorography. J Am Optom Assoc 1985; 56: 784-92. 42. Bartlett JD. Happy birthday, JAOA (editorial). J Am Optom Assoc 1985; 56: 840-841. 43. Bartlett JD. I had a patient (editorial). J Am Optom Assoc 1985; 56: 908. 44. Bartlett JD. Visually-related learning disabilities -Fact or fiction? (editorial). J Am Optom Assoc 1986; 57: 7. 45. Bartlett JD. The didactic therapeutics curriculum -The broader issues. J Optom Educ (in press), 1986 46. Bartlett JD. Optometry's role in retinal disease (editorial). J Am Optom Assoc 1986; 57: 92. 47. Bartlett JD. The remarkable evolution of contact lens care (editorial). J Am Optom Assoc 1986; 57: 168. 48. Bartlett JD. The importance of periodic clinical review (editorial). J Am Optom Assoc 1986; 57: 344. 49. Bartlett JD. Vision care in third world nations (editorial). J Am Optom Assoc 1986; 57: 420. 50. Bartlett, JD. Optometry: The primary eye and vision care profession (editorial). J Am Optom Assoc 1986; 57: 495-6. 51. Bartlett JD. Radial keratotomy: An idea whose time has come? (editorial). J Am Optom Assoc 1986; 57: 571-2. 52. Bartlett JD. Drug-induced ocular manifestations in patients treated for rheumatoid arthritis. IM-Intern Med Special 1986; 7: 113-23. JD. Optometry and law enforcement (editorial). J Am Optom Assoc Bartlett 53. 1986; 57: 646. 54. Bartlett JD. Women in optometry (editorial). J Am Optom Assoc 1986; 57: 722. 55. Bartlett JD. Career satisfaction in optometry (editorial). J Am Optom Assoc 1986; 57: 799-800. 56. Bartlett JD. Are we prepared for geriatric eye and vision care? (editorial). J Am Optom Assoc 1986; 57: 875-6. Case 3:12-cv-01141-SMY-DGW Document 176-33 *SEALED* Filed 12/01/14 Page 109 of 126 Page ID #3122 Case: 16-3334 Document: 55-19 Filed: 02/08/2017 Pages: 126 (743 of 1511) ..4■111, Curriculum Vitae Jimmy D. Bartlett 75 57. Bartlett JD. The didactic therapeutics curriculum. J Optom Educ 1986; 12: 4950. 58. Bartlett JD. Toward better eye and vision care for the mentally handicapped (editorial). J Am Optom Assoc 1987; 58: 6-7. 59. Bartlett JD. The "P" is for management (editorial). J Am Optom Assoc 1987; 58: 82-3. 60. Bartlett JD. Are extended wear lenses safe? (editorial). J Am Optom Assoc 1987; 58: 159-60. 61. Bartlett JD. Medicare...at last! (editorial). J Am Optom Assoc 1987; 58: 282. 62. Bartlett JD. Optometric residency programs: a sleeping giant (editorial). J Am Optom Assoc 1987; 58: 358-9. 63. Wilcox T, Bartlett JD. Systemic drug profiles in adult optometric outpatients. J Am Optom Assoc 1988; 59:78-84. 64. Bartlett JD. Anisometropia and aniseikonia. In: Amos IF, ed. Diagnosis and management in vision care. Boston: Butterworth, 1987:173-202. 65. Bartlett JD, Brown B, Eger MJ, et al. Uniform requirements for manuscripts submitted to optometric journals. J Am Optom Assoc 1987; 58-915-19. 66. Bartlett TD. Some predictions of optometry's future. I Am Optom Assoc 1987; 58:450-1. 67. Bartlett JD. Political attacks on vision therapy. J Am Optom Assoc 1987; 58:534. 68. Bartlett JD. Vision screening by opticians. J Am Optom Assoc 1987; 58:618. 69. Bartlett JD. Why optometrists should treat glaucoma. J Am Optom Assoc 1987; 58:694-5. 70. Bartlett JD. Toward problem-free contact lenses. J Am Optom 1987; 58:786. 71. Bartlett JD. Diabetes and optometry's contributions to the clinical archives. J Am Optom Assoc 1987; 58:870. 72. Bartlett JD. Back to the future. J Am Optom Assoc 1987; 58:946. 73. Bartlett JD. Optometry and the public health. J Am Optom Assoc 1988; 59:6. 74. Bartlett TD. Welcome to the real world. J Am Optom Assoc 1988; 59:82. 75. Bartlett JD. Who decides which lens is best? J Am Optom Assoc 1988; 59:160. 76. Bartlett JD. Vision care for our elderly. J Am Optom Assoc 1988; 59:274. 77. Bartlett JD. The new AOA Congress. J Am Optom Assoc 1988; 59:358. 78. Bartlett TD, Jaanus SD, eds. Clinical Ocular Pharmacology, second ed., Boston: Butterworths, 1989. 79. Bartlett JD, Ghormley NR, Jaanus SD, et al, eds. Ophthalmic Drug Facts. St. Louis: Facts and Comparisons, Inc./J.B. Lippincott Co., 1989. 80. Bartlett JD. New instrumentation in optometric practice. J Am Optom Assoc 1988; 59:434. 81. Bartlett JD. Home remedies. J Am Optom Assoc 1988; 59:510. 82. Bartlett JD. Optometry in the multidisciplinary setting. J Am Optom Assoc 1988; 59:586-587. 83. Bartlett JD. Employment of optometrists by ophthalmologists. J Am Optom Assoc 1988; 59:662. 84. Bartlett JD. Optometric co-management centers: are they working? J Am Optom Assoc 1988; 59:754. Case 3:12-cv-01141-SMY-DGW Document 176-33 *SEALED* Filed 12/01/14 Page 110 of 126 Page ID #3123 Case: 16-3334 Document: 55-19 Filed: 02/08/2017 Pages: 126 (744 of 1511) Curriculum Vitae Jimmy D. Bartlett 76 85. Bartlett JD. Follow or refer? J Am Optom Assoc 1988; 59:830. 86. Bartlett JD. Preventing eye injuries. J Am Optom Assoc 1988; 59:914. 87. Bartlett JD. The Journal-behind the scenes. J Am Optom Assoc 1989; 60:6. 88. Bartlett JD. The educated clinician. J Am Optom Assoc 1989; 60:82. 89. Bartlett JD. Disposable contact lenses-boon or boondoggle? J Am Optom Assoc 1989; 6 0:158. 90. Bartlett JD. Personal communications. J Am Optom Assoc 1989; 60:266. 91. Bartlett JD. Scholarship in optometry. J Am Optom Assoc 1989; 60:342. 92. Bartlett ID. Ocular therapeutics-the next 10 years. J Am Optom Assoc 1989; 60:418-419. 93. Bartlett JD. Remembering Milton J. Eger, O.D. J Am Optom Assoc 1989;60:570571. 94. Bartlett JD. The menace of UV radiation. J Am Optom Assoc 1989;60:646. 95. Bartlett JD. The environment and the eye. J Am Optom Assoc 1989; 60:722. 96. Bartlett JD. The optometrist as ophthalmic gatekeeper. J Am Optom Assoc 1989; 60:798. 97. Bartlett M. Automated visual fields: What do they mean? J Am Optom Assoc 1989; 60:874. Bartlett JD. A new decade, a new design. J Am Optom Assoc 1989; 61:6-7. 98. 99. Bartlett JD. Optometry and literacy. J Am Optom Assoc 1990; 61:82. 100. Bartlett JD. Contact lens compliance. J Am Optom Assoc 1990; 61:159-160. 101. Bartlett JD. Office image. Does it really make a difference? J Am Optom Assoc 1990; 61:268. 102. Bartlett JD. Deja vu, all over again! J Am Optom Assoc 1990; 61:344. 103. Bartlett JD, Ross RN, eds. Primary care of ocular allergy, J Am Optom Assoc 1990; 61: S3-S46. 104. Bartlett JD. Pharmacology of allergic eye disease. J Am Optom Assoc 1990; 61: S23-S31. 105. Bartlett JD. Adverse effects of anti-glaucoma medications. Optom Clin 1991; 1: 103-126. 106. Bartlett JD, Ghormley NR, Jaanus SD, Rowsey JJ, Zimmerman TJ, eds. Ophthalmic drug facts. St. Louis: Facts and Comparisons/JB Lippincott, 2nd edition, 1991. 107. Bartlett JD (book review). Ritch R, Shields MB, Krupin T, eds. The glaucomas. St. Louis: C.V. Mosby Company, 1989, in Clin Eye Vis Care 1991; 3:44-45. 108. Pillion DJ, Yang M, Meezan E, Bartlett JD, Crain JR, Grizzle WE. Treatment of diabetic rats with eyedrops containing insulin. Invest Ophthalmol Vis Sci 1991; 32(suppl):1295. 109. Eskridge JB, Amos JF, Bartlett JD, eds. Clinical procedures in optometry. Philadelphia: J.B. Lippincott, 1991 110. Bartlett JD. Slit lamp. In: Eskridge JB, Amos JF, Bartlett JD, eds. Clinical procedures in optometry. Philadelphia: J.B. Lippincott, 1991: 206-220. Bartlett JD. Eyelid procedures. In: Eskridge JB, Amos JF, Bartlett JD, eds. 111. Clinical procedures in optometry. Philadelphia: J.B. Lippincott, 1991: 397-400. Case 3:12-cv-01141-SMY-DGW Document 176-33 *SEALED* Filed 12/01/14 Page 111 of 126 Page ID #3124 Case: 16-3334 Document: 55-19 Filed: 02/08/2017 Pages: 126 (745 of 1511) Asek, Curriculum Vitae Jimmy D. Bartlett 77 112. London R, Bartlett JD. Anisocoria evaluation. In: Eskridge JB, Amos JF, Bartlett JD, eds. Clinical procedures in optometry. Philadelphia: J.B. Lippincott, 1991: 414-419. 113. Bartlett JD, Amos JF. Evaluation of motivating factors for choosing optometry residency education. Optom Vis Sci 1991; 68 (suppl): 117. 114. Bartlett JD, Amos JF, Ghormley NR, Lowther GE, Laibovitz R, Horwitz B, Howes JF. Evaluation of loteprednol etabonate, a novel corticosteroid, for treatment of giant papillary conjunctivitis. Optom Vis Sci 1991; 68 (suppl): 111. 115. Bartlett JD, Amos JF, Woolley TW. Evaluation of motivating factors for selecting optometric residency education. J Am Optom Assoc 1992; 63: 131-134. 116. Bartlett JD, Ghormley NR, Jaanus SD, Rowsey JJ, Zimmerman TJ, eds. Ophthalmic drug facts. St Louis: Facts and Comparisons/JB Lippincott, 3rd edition, 1992. Pillion DJ, Bartlett JD, Meezan E, Yang M, Crain RJ, Grizzle WE. Systemic 117. absorption of insulin delivered topically to the rat eye. Invest Ophthalmol Vis Sci 1991; 32: 3021-3027. 118. Wesson MD, Bartlett JD, Swiatocha J, Woolley T. Mydriatic efficacy of a cycloplegic spray in the pediatric population. Invest Ophthalmol Vis Sci 1992; 33 (suppl): 1095. 119. Bartlett JD, Woolley T, Adams CM. A model for identifying high intraocular pressure responders to topical ophthalmic corticosteroid. Invest Ophthalmol Vis Sci 1992; 33(suppl): 1121. 120. Laibovitz R, Howes JF, Bartlett JD. Safety evaluation of the intraocular pressure response to loteprednol etabonate in high steroid responders. Invest Ophthalmol Vis Sci 1992; 33(suppl): 1121. 121. Howes JF, Bartlett JD, Ghormley NR, Amos JF, Laibovitz R, Horwitz B. Safety and efficacy of loteprednol etabonate for treatment of giant papillary conjunctivitis. Invest Ophthalmol Vis Sci 1992; 33(suppl): 1294. 122. Holt GA, Covington T, Bartlett JD, Hollon J, Liden D. Giant papillary conjunctivitis. U.S. Pharmacist 1992; 17: 68-80. 123. Sharir M, Bartlett JD, Zimmerman TJ. Unilateral map-dot-fingerprint dystrophy after acute angle-closure glaucoma. Ann Ophthalmol 1993; 25: 35-36. 124. Bartlett JD. What you need to know about ocular surface disease. Optom Manage 1992; 27: 49-56. 125. Bartlett JD, Class JG. Dapiprazole: Will it affect the standard of care for pupillary dilation? Optom Clin 1992; 2: 113-120. 126. Bartlett JD, Swanson M. Ophthalmic products. In: Covington T, ed. Handbook of nonprescription drugs. Washington DC: American Pharmaceutical Association, 10th edition, 1993: 351-365. 127. Bartlett JD. Medications and contact lens wear. In: Silbert J, ed. Anterior segment complications of contact lens wear. New York: Churchill Livingston, Inc., 1993: 473-485. 128. Bartlett JD. Ophthalmic toxicity by systemic drugs. In: Chiou G, ed. Ophthalmic toxicology. New York: Raven Press, 1992: 167-217. Case 3:12-cv-01141-SMY-DGW Document 176-33 *SEALED* Filed 12/01/14 Page 112 of 126 Page ID #3125 Case: 16-3334 Document: 55-19 Filed: 02/08/2017 Pages: 126 (746 of 1511) Curriculum Vitae Jimmy D. Bartlett 78 129. Bartlett JD, Ghormley NR, Jaanus SD, Rowsey JJ, Zimmerman TJ, eds. Ophthalmic drug facts. St. Louis: Facts and Comparisons/JB Lippincott, 4th edition, 1993 130. Bartlett JD, Wesson MD, Swiatocha J, Wooley T. Efficacy of a pediatric cycloplegic administered as a spray. Optom Vis Sci 1992; 69 (suppl): 101 131. Bartlett JD, Woolley TW, Adams CM. Identification of high intraocular pressure responders to topical ophthalmic corticosteroids. J Ocular Pharmacol 1993; 9: 3545 132. Bartlett JD, Howes JF, Ghormley NR, Amos JF, Laibovitz R, Horowitz B. Safety and efficacy of loteprednol etabonate for treatment of papillae in contact lensassociated giant papillary conjunctivitis. Curr Eye Res 1993; 12: 313-321. 133. Bartlett JD, Horwitz B, Laibovitz R, Howes JF. Intraocular pressure response to loteprednol etabonate in known steroid responders. J Ocular Pharmacol 1993; 9: 157-165. 134. Bartlett JD, Turner-Henson A, Atchison JA, Wooley TW, Covington TR, Pillion DJ. Toxicity of insulin administered to the human eye in vivo. Invest Ophthalmol Vis Sci 1993; 34 (suppl): 1492. 135. Adams CM, Alexander LJ, Bartlett JD, Classe JG. Co-management of patients with glaucoma. Optom Clin 1992; 2: 143-156. 136. Bartlett JD, Wesson MD, Swiatocha J, Woolley T. Efficacy of a pediatric cycloplegic administered as a spray. J Am Optom Assoc 1993; 64: 617-621. 137. Wesson MD, Bartlett JD, Swiatocha J, Woolley T. Mydriatic efficacy of a cycloplegic spray in the pediatric population. J Am Optom Assoc 1993; 64: 637640. 138. Bartlett JD, Slusser TG, Turner-Henson A, et al. Toxicity of insulin administered chronically to human eyes in vivo. J Ocular Pharmacol 1994; 10: 26-34. 139. Leibowitz HM, Rich R, Crabb JL, Stewart R, Fox K, Bartlett JD, et al. Intraocular pressure raising potential of rimexolone 1.0% in steroid responders. Invest Ophthalmol Vis Sci 1994; 35 (suppl): 1508. 140. Bartlett JD, Hogan T, McDaniel D, Voce M. Study of three different treatment regimens of dapiprazole HC1 in the reversal of mydriasis induced by 2.5% phenylephrine. Invest Ophthalmol Vis Sci 1994; 35 (suppl):1546. 141. Paggiarino D, Bartlett JD, Stumer S, et al. Can dapiprazole HC1 improve contrast sensitivity in patients with cataract? Invest Ophthalmol Vis Sci 1994; 35 (suppl): 1964. 142. Bartlett JD, Ghormley NR, Jaanus SD, Rowsey II, Zimmerman TJ, eds. Ophthalmic drug facts. St. Louis: Facts and Comparisons, 5th edition, 1994. 143. Bartlett JD, Turner-Henson A, Atchison JA, et al. Insulin administration to the eyes of normoglycemic human volunteers. I Ocular Pharmacol 1994; 10:683-690. 144. Bartlett JD, Nowakowski R, Swanson M. Grand Rounds. Management of the patient with diabetes mellitus. Optom Clin 1994; 3:175-185. 145. Bartlett JD. Pediatric drug therapy. Are we providing the best care possible? J Am Optom Assoc 1994; 65:687-688. 146. Bartlett JD, Ghormley NR, Jaanus SD, et al, eds. Ophthalmic drug facts. St. Louis: Facts and Comparisons, 1995. Case 3:12-cv-01141-SMY-DGW Document 176-33 *SEALED* Filed 12/01/14 Page 113 of 126 Page ID #3126 Case: 16-3334 Document: 55-19 Filed: 02/08/2017 Pages: 126 (747 of 1511) Curriculum Vitae Jimmy D. Bartlett 79 147. Bartlett JD, Ghormley NR, Jaanus SD, et al, eds. Ophthalmic Drug Facts. St. Louis: Facts and Comparisons, 1996. 148. Leibowitz H, Bartlett JD, Rich R, et al. Intraocular pressure-raising potential of 1% rimexolone in patients Responding to corticosteroids. Arch Ophthalmol 1996; 114:933-937. 149. Bartlett JD, Jaanus SD, eds. Clinical Ocular Pharmacology, Third Edition. Boston:Butterworth-Heinemann, 1995. 150. Bartlett JD, Jaanus SD, Ross RN, eds. Clinical Ocular Pharmacology-Pocket Companion. Boston:Butterworth-Heinemann, 1997. 151. Swanson M, Bartlett JD. Ophthalmic Products. In: Covington T, ed. Handbook of Nonprescription Drugs, 11th Edition. Washington,D.C.:American Pharmaceutical Association; 1996:447-463. 152. Guthrey P, Bartlett JD, Singh KP. Assessment of Pharmacists' Experience With Ophthalmic Drug Products. J Am Optom Assoc 1995; 66:334-337. 153. Shimmick JK, Telfair WB, Munnerlyn CR, Bartlett JD, Trokel SL. Corneal Ablation Profilometry and Steep Central Islands. J Refract Surg 1997;13:235245. 154. Bartlett JD. Pain Management in Optometry. Optom Cur Lit Perspec 1996; 6:7-8. 155. Friedlander M, Bartlett JD. Pullout Guide to Glaucoma Drugs. Eye Care Tech 1996; Volume 6. 156. Friedlander M, Bartlett JD. Pullout Guide to Anti-Allergic and Anti-Inflammatory Drugs. Eye Care Tech 1996; Volume 6. 157. Bartlett JD. Putting NSAIDs to Unlabeled Uses. Optom Manage 1996; 31:56. 158. Nelson MD, Bartlett JD, Corliss D, et. al. Ocular tolerability of timolol in Gelrite in young glaucoma patients. J Am Optom Assoc 1996; 67:659-663. 159. Zeise MM, McDougall BWJ, Bartlett JD, et. al. Comparison of efficacy and tolerance between 1% hydroxyamphetamine plus 0.25% tropicamide (Paremyd) and 0.5% tropicamide combined with 2.5% phenylephrine. J Am Optom Assoc 1996; 67:681-689. 160. Bartlett, JD, Boan K, Corliss D, et. al. Efficacy of silicone punctal plugs as adjuncts to topical pharmacotherapy of glaucoma - a pilot study. J Am Optom Assoc 1996; 67:664-668. 161. Hogan TS, McDaniel DD, Bartlett JD, et. al. Dose-response study of dapiprazole HCI in the reversal of mydriasis induced by 2.5% phenylephrine. J Ocul Pharmacol Ther 1997; 13:297-302. 162. Bartlett JD. New drug therapies for glaucoma. J Am Optom Assoc 1996; 67:648653. 163. Niemann KK, Bartlett JD, Heck LW, McCollum J. Nodular Scleritis: Case Report Involving Immunosuppressive Therapy. J Am Optom Assoc 1997;68:782787. 164. Bartlett JD. Ocular side effects of systemic drugs. In: Amos J, Casser L, Classe' J, eds. Handbook of primary care optometry. Philadelphia; W.B. Saunders (in press) 165. Bartlett JD. Management of allergic conjunctivitis (letter). Ophthalmology 1997; 104:345-346. Case 3:12-cv-01141-SMY-DGW Document 176-33 *SEALED* Filed 12/01/14 Page 114 of 126 Page ID #3127 Case: 16-3334 Document: 55-19 Filed: 02/08/2017 Pages: 126 (748 of 1511) Curriculum Vitae Jimmy D. Bartlett 80 166. Bartlett JD. Ocular Allergy Update - Taking Care of Red, Swollen, Itchy Eyes. Optom Manage 1998;33:77-84. 167. Bartlett JD. Why a Pocket-Sized Ophthalmic Drug Guide? Optom Manage 1997;32:25. 168. Bartlett JD. Hard Pill to Swallow. Optom Manage 1997;32(6):56-58. 169. Bartlett JD. Drug Update. Optom Manage 1997;32(8):41-49. 170. Bartlett JD. Textbook of Ocular Pharmacology (Zimmerman et al, eds.) (Book Review). Optom Vis Sci 1998;75:169-170. 171. Bartlett JD, Fiscella RG, Ghormley NR, et al, eds. Ophthalmic Drug Facts. St. Louis: Facts and Comparisons, 1998. 172. Bartlett JD, Bessant BS, Guthrie P. Compliance with Timolol Therapy as Determined by Prescription Refill Records. Invest Ophthalmol Vis Sci 1997;38:S826) (abstract). 173. Gordon A, Bartlett JD, Lin M, Corliss D. The Effect of Diclofenac Sodium on the Initial Comfort of RGP Contact Lenses: A Pilot Study. Optom Vis Sci 1997;74(12):S190 (abstract). 174. Bartlett JD. Ocular allergy update. Optom Manage 1998;33:55-59. 175. Bartlett JD. Growing your therapeutic practice from the ground up. Optom Manage 1998;13:35. 176. Bartlett JD. Need a quick prescribing resource? Optom Manage 1999:34:99. 177. Bartlett JD. Loteprednol Etabonate: a novel new ophthalmic corticosteroid. Primary Care Optom News 1999;4:23-24. 178. Bartlett M. Ophthalmic toxicity by systemic drugs. In: Chiou GCY, ed. Ophthalmic Toxicology, 2nd ed. Philadelphia, Taylor & Francis, 1999:225-283. 179. Bartlett JD. Medications in contact lens wear. In: Silbert JA, ed. Anterior segment complications of contact lens wear, 2nd ed. Boston, ButterworthHeinemann, 1999 180. Bartlett JD, Jaanus SD, Ross R. Terapeutica en oftalmologia. Bogota: McGrawHill Interamericana, 1998. 181. Bartlett JD, Fiscella RG, Ghormley NR, et al, eds. Ophthalmic drug facts. St. Louis: Facts and Comparisons, 1999. 182. Fiscella RG, Bartlett JD. Pharmacotherapy of the ophthalmic patient. In: Bartlett JD, Jaanus SD, eds. Clinical ocular pharmacology, 4th ed. Boston: ButterworthHeinemann, 2000. 183. Bartlett JD. Ophthalmic drug delivery. In: Bartlett JD, Jaanus SD, eds. Clinical ocular pharmacology, 4th ed. Boston: Butterworth-Heinemann, 2000. 184. Bartlett JD, Jaanus SD, Fiscella RG, Sharir M. Antiglaucoma drugs. In: Bartlett M, Jaanus SD, eds. Clinical ocular pharmacology, 4th ed. Boston: ButterworthHeinemann, 2000. 185. Bartlett JD, Jaanus SD. Ocular effects of systemic drugs. In: Bartlett JD, Jaanus SD, eds. Clinical ocular pharmacology, 4th ed. Boston: Butterworth-Heinemann, 2000. 186. American Academy of Optometry, San Francisco, California; "Corneal Limbal Stem Cells: Concepts and Therapeutic Applications", Wang SE, Bartlett M. Optom Vis Sci 1998;75(12suppl):48. Case 3:12-cv-01141-SMY-DGW Document 176-33 *SEALED* Filed 12/01/14 Page 115 of 126 Page ID #3128 Case: 16-3334 Document: 55-19 Filed: 02/08/2017 Pages: 126 (749 of 1511) AMMO, Curriculum Vitae Jimmy D. Bartlett 81 187. Bartlett JD, Olivier M, Richardson T, et.al. Central nervous system and plasma lipid profiles associated with carteolol and timolol in postmenopausal black women. J Glaucoma 1999;8:388-395 188. Gordon A, Bartlett JD, Lin M. The effect of diclofenac sodium on the initial comfort of RGP contact lenses. J Am Optom Assoc 1999; 70-509-513. 189. Bartlett JD. Quick Drug Guide 2000. Optom Manage 2000;35:99-100 190. Bartlett JD. Medications in contact lens wear. In: Sibert JA, ed. Anterior segment complications of contact lens wear, 2nd ed. Boston: ButterworthHeinemann, 2000:419-431. 191. Bartlett JD. Ophthalmic toxicity by systemic drugs. In: Chiou GCY, ed. Ophthalmic toxicology, rd ed. Philadelphia: Taylor & Francis, 1999:225-283. 192. Bartlett JD, Fiscella RG, Bennett E, et.al., eds. Ophthalmic Drug Facts. St. Louis. Facts and Comparisons, 2000. 193. Association for Research in Vision and Ophthalmology, Ft. Lauderdale, Florida; "CNS Effects of Carteolol HCL and Timolol Maleate in Black Women". Bartlett JD, Olivier M, Richardson T, et.al. Invest Ophthalmol Vis Sci 1999; 40:S513. 194. Association for Research in Vision and Ophthalmology, Ft. Lauderdale, Florida; "Spectral Content of IOP Pulse Wave Reveals Differences Between Glaucoma Patients and Normal Subjects". Hosking SL, Evans DW, Embleton S, Good D, Houde B, Bartlett J. Invest Ophthalmol Vis Sci 2000; 41:S556. 195. Association for Research in Vision and Ophthalmology, Ft. Lauderdale, Florida. "Ocular Hypotensive Effect of Topical Verapamil HCL in Combination with Low-Dose Pilocarpine in Patients with Ocular Hypertension." B. Houde, J. Bartlett, D. Evans, K. Erickson. Invest Ophthalmol Vis Sci 2000;41:S281 196. Association for Research in Vision and Ophthalmology, Ft. Lauderdale, Florida. "Safety and Tolerability of Pirenzepine Ophthalmic Gel in Pediatric Myopic Patients." J. Bartlett, K. Niemann, B. Houde, T. Allred, M. Edmondson. Invest Ophthalmol Vis Sci 2000;41:S303 197. Bartlett JD, Fiscella RG, Bennett E, et. al., eds. Ophthalmic Drug Facts. St. Louis: Facts and Comparisons, 2001. 198. Fiscella RG, Bartlett JD. Pharmacotherapy of the ophthalmic patient. In: Bartlett JD, Jaanus SD, eds. Clinical ocular pharmacology, 4th ed. Boston: ButterworthHeinemann, 2001. 199. Bartlett JD. Ophthalmic drug delivery. In: Bartlett JD, Jaanus SD, eds. Clinical ocular pharmacology, 4th ed. Boston: Butterworth-Heinemann, 2001. 200. Bartlett JD, Jaanus SD, Fiscella RG, Sharir M. Ocular hypotensive drugs. In Bartlett JD, Jaanus SD, eds. Clinical ocular pharmacology, 4th ed. Boston: Butterworth-Heinemann, 2001. 201. Bartlett JD, Jaanus SD. Ocular effects of systemic drugs. In: Bartlett JD, Jaanus SD, eds. Clinical ocular pharmacology, 4th ed. Boston: Butterworth-Heinemann, 2001. 202. Bartlett JD, Jaanus SD, eds. Clinical ocular pharmacology, 4th ed. Boston: Butterworth-Heinemann, 2001 203. Hosking SL, Evans DW, Embleton SJ, Houde B, Amos JF, Bartlett JD. Hypercapnia evokes an acute loss of contrast sensitivity in untreated glaucoma patients. Br J Ophthalmol 2001; 85:1352-1356 Case 3:12-cv-01141-SMY-DGW Document 176-33 *SEALED* Filed 12/01/14 Page 116 of 126 Page ID #3129 Case: 16-3334 Document: 55-19 Filed: 02/08/2017 Pages: 126 (750 of 1511) Curriculum Vitae Jimmy D. Bartlett 82 204. Bartlett JD. Pocket-sized ophthalmic drug guide. Optom Manage 2001; 36:45-46 205. Depaolis MD, Bartlett JD, Eldridge D, et al. Optometric applications of fluoroquinolones. Primary Care Optometry News, 2001; S 1-15. 206. Bartlett JD. 2001: The Year of Glaucoma. Optom Manage, 2001; 36:99-100 207. Bartlett JD, Jaanus SD, eds. Pocket companion to Clinical Ocular Pharmacology, 4th edition. Boston: Butterworth-Heinemann, 2002. 208. Hosking SL, Evans DW, Embleton SJ, Morgan AJ, Bartlett JD. Spectral content of the intraocular pressure pulse wave: Glaucoma patients versus normal subjects. Graefe's Arch Clin Exp Ophthalmol 2002; 240:475-480 209. Bartlett JD, Niemann K, Houde B, Allred T, Edmondson M, Crockett RS. A tolerability study of pirenzepine ophthalmic gel in myopic children. J Ocul Pharmacol Ther 2003; 19(3): 271-279 210. Bartlett JD, Semes L, Fingeret M, Thomas R, Melton R, Woodridge R. What landmark research tells us about glaucoma management. Rev Optom 2002; 163(Suppl): S1-S26. 211. Bartlett JD, Fiscella RG, Bennett E, et. al., eds. Ophthalmic Drug Facts. St. Louis: Facts and Comparisons, 2003 212. Bartlett JD. Pharmacotherapeutic agents: Basic principles and clinical applications. In: Stapleton F, ed. The anterior eye and therapeutics: Diagnosis and management. Edinburgh, United Kingdom: Butterworth-Heinemann, 2003: 167-208 213. Bartlett JD, Voce M, Than T, Edmondson M, Novack, G. Electronic monitoring system to assess patient adherence in pediatric drug studies (ARVO Abstract) 214. Bartlett JD. Ophthalmic Drug Facts. Facts and Comparisons. St. Louis, 2004. 215. Bartlett JD. New prescription treatment strategies for external disease. Optom Manage 2003; 38:48. 216. Evans DW, Hosking SL, Gherghel D, Bartlett JD. Contrast sensitivity improves after brimonidine therapy in primary open-angle glaucoma. Br J Ophthalmol 2003; 87:1463-14 217. Bartlett JD, Shaikh A, Semes L, McGwin G. "The Relationship Among Race, Iris Color, Central Corneal Thickness and Intraocular Pressure". Association for Research in Vision and Ophthalmology, 2004 218. Semes L, Shaikh A, Bartlett JD. "Pulsatile Ocular Blood Flow and the Influence of Race", American Academy of Optometry, Tampa, 2004 219. Karpecki P, Bartlett JD, Bloomenstein M, et al. New advances in combination corticosteroid/anti-infective therapy for the management of acute and chronic ocular disease. Optom Manage 2005 (suppl) 40 (3): 1-43. 220. Bartlett JD, Fiscella RG, Bennett E, et.al., eds. Ophthalmic Drug Facts. St. Louis: Facts and Comparisons, 2006 221. Bartlett JD, Holland E, Pribadi-Behm M, et al. Ocular tolerance and IOP effects of tobramycin/loteprednol compared to tobramycin/dexamethasone. ARVO abstract 5559, Fort Lauderdale, Florida, April 30-May 4, 2006 222. Semes L, Shaikh A, McGwin G, Bartlett JD. The relationship among race, iris color, central corneal thickness, and intraocular pressure. Optom Vis Sci 2006; 83: 512-515 Case 3:12-cv-01141-SMY-DGW Document 176-33 *SEALED* Filed 12/01/14 Page 117 of 126 Page ID #3130 Case: 16-3334 Document: 55-19 Filed: 02/08/2017 Pages: 126 (751 of 1511) Curriculum Vitae Jimmy D. Bartlett 83 223. Bartlett JD, Fiscella RG, Bennett E, et.al., eds. Ophthalmic Drug Facts, 18th edition, St. Louis: Facts and Comparisons, 2007 224. Holland EJ, Bartlett JD, Paterno MR, et.al. Effects of loteprednol/tobramycin versus dexamethasone/tobramycin on intraocular pressure in healthy volunteers. Cornea 2008; 27:50-55. 225. Evans DW, Bartlett JD, Houde B, et.al. Latanoprost-induced stablization of central visual function in patients with primary open-angle glaucoma. J Ocul Pharmacol Ther 2008; 24:224-229. 226. Bartlett JD, Fiscella RG, Bennett E, et. al., eds. Ophthalmic drug facts, 19th ed., St. Louis: Wolters Kluwer Health, 2008. 227. Bartlett JD, Jaanus SD, eds. Clinical ocular pharmacology, 5th ed., St. Louis: Elsevier, 2008. 228. Coulter RA, Bartlett JD, Fiscella RG. Pharmacotherapy of the ophthalmic patient. In: Bartlett JD, Jaanus SD, eds. Clinical ocular pharmacology, 5th ed., St. Louis: Elsevier, 2008:3-15. 229. Bartlett JD. Ophthalmic drug delivery. In: Bartlett JD, Jaanus SD, eds. Clinical ocular pharmacology, 5th ed., St. Louis: Elsevier, 2008:39-52. 230. Than TP, Bartlett JD. Local anesthetics. In: Bartlett JD, Jaanus SD, eds. Clinical ocular pharmacology, 5th ed., St. Louis: Elsevier, 2008:85-95. 231. Bartlett JD, Holdeman NR. Analgesics for treatment of acute ocular pain. In: Bartlett JD, Jaanus SD, eds. Clinical ocular pharmacology, 5th ed., St. Louis: Elsevier, 2008:97-111. 232. Bartlett JD, Fiscella RG, Jaanus SD, Barnebey H. Ocular hypotensive drugs. In: Bartlett JD, Jaanus SD, eds. Clinical ocular pharmacology, 5th ed., St. Louis: Elsevier, 2008:139-174. 233. Prokopich CL, Bartlett JD, Jaanus SD. Ocular adverse drug reactions to systemic medications. In: Bartlett JD, Jaanus SD, eds. Clinical ocular pharmacology, 5th ed., St. Louis: Elsevier, 2008:701-759. 234. Bartlett JD, Holland EJ, Usner D, et.al. Tolerability of loteprednol/tobramycin vs dexamathasone/tobramycin in healthy volunteers: Results of a four-week, randomized, double-masked, parallel-group study. Curr Med Res Opin 2008; 24:2219-2227. 235. Bartlett JD, Karpecki PM, Melton R, Thomas RK. Diagnostic and treatment algorithms for ocular surface disease states - allergy. Rev Optom 2008; 145:S1S12. 236. Bartlett JD, Fiscella RG, Bennett E, et.al., eds. Ophthalmic drug facts, 20th ed., St. Louis: Wolters Kluwer Health, 2009. 237. Bartlett JD, Karpecki PM, Melton R, Thomas RK. Diagnostic and Treatment Algorithms for Ocular Surface Disease States: Dry Eye. Rev Optom 2009; 146(6) suppl: 1-11. 238. Bartlett JD, Clinical Ocular Toxicology (book review) Optom Vis Sci 2009; 86: 1128. 239. Bartlett JD, Karpecki PM, Melton R, Thomas RK. Diagnostic and Treatment Algorithms for Ocular Surface Disease States: Keratitis. Rev Optom 2009; 146(10) suppl: 1-12. Case 3:12-cv-01141-SMY-DGW Document 176-33 *SEALED* Filed 12/01/14 Page 118 of 126 Page ID #3131 Case: 16-3334 Document: 55-19 Filed: 02/08/2017 Pages: 126 (752 of 1511) Curriculum Vitae Jimmy D. Bartlett 84 240. Bartlett JD, ed. Ophthalmic Drug Facts. 21st ed, St. Louis: Wolters Kluwer Health; 2010. 241. Bartlett JD, Snyder C. Overview of methicillin-resistent Staphylococcus aureus (MRSA). Cont Lens Spectrum 2010; February (suppl): 3-9. 242. Sheppard J, Bartlett J. Loteprednol etabonate in ocular inflammation. US Ophthalmic Rev 2011; 4(1): 57-62. 243. Bartlett JD. Managing ocular infection and inflammatory conditions-HSV keratitis in a college student. Optom Times 2010; May (suppl): 1-10. 244. Bartlett JD, Fiscella RG, Bennett E, et.al., eds. Ophthalmic drug facts, 22nd ed., St. Louis: Wolters Kluwer Health, 2011. 245. Bartlett JD. Clinical pearls in seasonal allergy management. Rev Optom 2012; 149(2): 100-101. 246. Bartlett JD. Making the most of antivirals for treating herpes simplex keratitis. Rev Optom 2012; 149(4): 92-95. 247. Bartlett JD. New developments in the pharmacologic management of MGD. Rev Optom 2012; 149(9): 28-31. 248. Bartlett JD. Maximize MRSA management. Rev Optom 2012; 149(11): 26-27. 249. Bartlett JD, Fiscella RG, Bennett E, et.al., eds. Ophthalmic drug facts, 24th ed., St. Louis: Wolters Kluwer Health, 2013. 250. Melton R, Thomas RK, Bartlett JD, et al. Pharmacologic management of allergic conjunctivitis: an evidence-based algorithm. Optom Manage 2013; 48(6): S1-19. 251. Bielory L, Meltzer EO, Nichols KK, Melton R, Thomas RK, Bartlett JD. An algorithm for the management of allergic conjunctivitis. Allergy Asthma Proc 2013; 34: 408-420. 252. Bartlett JD, Fiscella RG, Bennett E, et.al., eds. Ophthalmic drug facts, 25th ed., St. Louis: Wolters Kluwer Health, 2014 MULTIMEDIA PRESENTATIONS 1. 2. 3. 4. Bartlett JD. "Glaucoma Medications". In Catania L, Lewis T, eds. Primary care of glaucoma, Primary Eye Care, 1986. Bartlett JD. "Clinical Pharmacology of the Eye". In audio tape series, "Conversations in Eye Care". Published by Anadem, Inc., Columbus, Ohio, 1989. Bartlett JD. Bacterial Resistance Patterns in Ocular Surface Infections. In: Symposium on Keratoconjunctivitis, American Academy of Optometry. Ophthalmology Interactive CD-ROM 1997. Bartlett JD. "Prevalence and Pathophysiology of Dry Eye". American Optometric Association/Allergan Webcast in "Advanced Principles in the Treatment of Ocular Surface Disorders", 2004 GRANTS AND CONTRACTS AWARDED Case 3:12-cv-01141-SMY-DGW Document 176-33 *SEALED* Filed 12/01/14 Page 119 of 126 Page ID #3132 Case: 16-3334 Document: 55-19 Filed: 02/08/2017 Pages: 126 (753 of 1511) Curriculum Vitae Jimmy D. Bartlett 85 1. 2. 3. 4. 5. 6. 7. 8. 9. 10. 11. 12. 13. 14. 15. 16. 17. 18. 19. Pilot Efficacy and Safety Evaluation of Loteprednol Etabonate in Giant Papillary Conjunctivitis (Xenon Vision, Inc.) Identification of High Steroid Responders to Topical Ophthalmic Prednisolone (Biomedical Research Support Grant, UAB) Intraocular Pressure Raising Potential of Rimexolone in High Steroid Responders (Alcon Laboratories, Inc.) Safety Evaluation of the Intraocular Pressure Response to Loteprednol Etabonate in Known Steroid Responsive Individuals (Xenon Vision, Inc.) A Multicenter Evaluation of the Efficacy and Safety of Ciprofloxacin Ophthalmic Ointment vs Tobrex Ophthalmic Ointment in the Treatment of Acute Bacterial Conjunctivitis (Alcon Laboratories, Inc.) Evaluation of the Safety and Efficacy of a Cycloplegic Spray in the Pediatric Population (Biomedical Research Support Grant, UAB) Efficacy of 0.3% Carbomer Ophthalmic Gel vs. Hypotears in Dry Eye Patients (Alcon Laboratories, Inc.) Visual Effects of Dapiprazole (Angelini Pharmaceuticals, Inc.) Dose-Response Study of Dapiprazole HCl in the Reversal of Mydriasis Induced by 2.5% Phenylephrine (Angelini Pharmaceuticals, Inc.) Efficacy and Safety of Insulin Eyedrops for Treatment of Diabetes Mellitus (American Foundation for Vision Awareness) Efficacy and Safety Evaluation of Loteprednol Etabonate in Giant Papillary Conjunctivitis--Phase III Study (Pharmos Corporation) Pilot Study of Punctal Plugs as Adjuncts to Medical Treatment of Glaucoma--A Multicenter Clinical Trial (Eagle Vision, Inc.) A Study of Two Different Formulations of Dapiprazole HCI in the Reversal of Mydriasis Induced by 2.5% Phenylephrine and 0.5% Tropicamide (Angelini Pharmaceuticals, Inc.) Mydriatic and Cycloplegic Efficacy and Patient Tolerance Comparison Between Paremyd and 0.5% Tropicamide Combined with 2.5% Phenylephrine (Allergan Pharmaceuticals) Intraocular Pressure Raising Potential of 0.25% Rimexolone Versus 0.1% Fluorometholone in Steroid Responders (Alcon Laboratories) Identification of High Steroid Responders to Topical Prednisolone. Alcon Laboratories, Inc. ($4,074.00) Ocular and Systemic Tolerability Comparison Between Timolol and Carteolol in Post-Menopausal African-American Women with Primary Open-Angle Glaucoma. Otsuka America Pharmaceutical ($25,707.00). Placebo-controlled, Randomized, Triple-Masked Prospective Study of AL-4862 Adjunctive to Timolol Therapy in Patients with Primary Open-Angle Glaucoma. Alcon Laboratories, Inc. ($19,800.00) A 3-Month, Multicenter, Triple-Masked, Parallel Study of the Safety and Efficacy of Timolol Gel Forming Solution 0.25%, Dosed Once-Daily, Compared to Timoptic 0.25% Ophthalmic Solution, Dosed Twice-Daily, in Patients with Primary Open-Angle Glaucoma or Ocular Hypertension (Alcon Laboratories, Inc., $28,200) Case 3:12-cv-01141-SMY-DGW Document 176-33 *SEALED* Filed 12/01/14 Page 120 of 126 Page ID #3133 Case: 16-3334 Document: 55-19 Filed: 02/08/2017 Pages: 126 (754 of 1511) Curriculum Vitae Jimmy D. Bartlett 86 20. Genentech, "Phase III, Randomized, Double-Blind, Placebo-Controlled, Multicenter, Multidose Study of the Combined Effects of Subcutaneously Administered Insulin and rhIGF-I in Subjects with Insulin Dependent Diabetes Mellitus", Subinvestigator to Joycelyn A. Atchison (PI), $2,464.00 21. Alcon Laboratories, Inc., "A Six-Month, Triple-Masked, Parallel Group, Primary Therapy Study of the Safety and Efficacy of Travoprost 0.0015% and Travoprost 0.004% Compared to Timoptic 0.5% in Patients with Open-Angle Glaucoma or Ocular Hypertension", Jimmy D. Bartlett (PI), $58,855.00 22. Vision Service Plan, "VSP Glaucoma Fellowship Proposal"; Bartlett JD, Principal Investigator; $70,000; 4-99 to 3-00. 23. Clinical Research Advisory Committee, "Intraocular Pressure and Visual Function in Primary Open-Angle Glaucoma During Hyperoxia and Hypercapnia", David Evans, Ph.D. (PI), Jimmy D. Bartlett, O.D. (co-PI), $5,000, 4-99 to 3-00. 24. Pharmacia & Upjohn, "Effect of Latanoprost Therapy on Contrast Sensitivity in Glaucoma Patients", David Evans, Ph.D. (PI), Jimmy D. Bartlett, O.D. (co-PI), $26,000 25. Allergan Pharmaceuticals, Inc., "Effect of Brimonidine Therapy on Visual Function Recovery in Glaucoma Patients", David Evans, Ph.D. (PI), Jimmy D. Bartlett, O.D. (Co-PI), $26,000 26. Valley Forge Pharmaceuticals, Inc., "A One-Year, Multicenter, Double-Masked, Placebo-Controlled Safety and Efficacy Study of 0.5% and 2.0% Pirenzepine Ophthalmic Gel in Children With Myopia", Jimmy D. Bartlett, O.D. (PI), $65,800 27. Vision Service Plan, "VSP Glaucoma Fellowship Renewal"; Bartlett JD, Principal Investigator; $70,000; 5% effort, April 2000 to March 2001. 28. Allergan Pharmaceuticals, Inc., "Effect of Brimonidine Therapy on Visual Function Recovery in Glaucoma Patients". (unrestricted grant), David Evans (P.I.) J. Bartlett (Co-P.I.) $28,700, 5% effort, August 1999 to July 2000 29. New England College of Optometry, "Single Instillation Evaluation of an Ophthalmic Calcium Channel Blocker, Verapamil HC1, in Combination with Low Dose Pilocarpine in Subjects with Elevated Intraocular Pressure." J. Bartlett (P.I.), $1,000, 5% effort, August 1999 to July 2000. 30. Pharmacia & UpJohn, Inc. "Effect of Latanoprost Therapy on Central Visual Function in Glaucoma Patients", David Evans (P.I.), J. Bartlett (Co-P.I.) $26,000, November 1999 to October 2000. 31. University of Alabama Health Services Foundation, "Optic Nerve and Retinal Imaging Center". C. Girkin (P.I.), L. Kline, R. Morawetz, A. Mays, J. Bartlett, C. Owsley. $80,000, 5% effort, February 2000 to January 2001 32. Valley Forge Pharmaceuticals, Inc., "An Ascending, Multiple-Dose, DoubleMasked, Parallel Placebo-Controlled (4 week) Tolerability Study of Pirenzepine Ophthalmic Gel with an Extension Providing One Year of Treatment in Myopic Children". Jimmy D. Bartlett (P.I.), $65,125, 10% effort, May 1999 to April 2000 33. UAB Educational Foundation, "Development of a Comprehensive Low Vision Rehabilitation Center". Bartlett JD, Klein L(Co-PIs), $25,000, January 2001 to December 2001 Case 3:12-cv-01141-SMY-DGW Document 176-33 *SEALED* Filed 12/01/14 Page 121 of 126 Page ID #3134 Case: 16-3334 Document: 55-19 Filed: 02/08/2017 Pages: 126 (755 of 1511) Curriculum Vitae Jimmy D. Bartlett 87 34. Valley Forge Pharmaceuticals, "An Additional OneYear of Treatment in a Double-Masked, Parallel Placebo-Controlled Tolerabilit y Study of Pirenzepine Ophthalmic Gel in the Treatment of Myopic Children". J. Bartlett (PI), T Than, (CO-PI), $27,434.00, October 2000 — September 2001 . 35. Alcon Laboratories Inc. "A Six Week, Rand omized, Double-Masked, Primary Therapy Study to Compare I0P-Lowering Efficacy of Travatan 0.004% and Xalatan 0.005% in African-American Patients with Open -Angle Glaucoma or Ocular Hypertension." I Bartlett (PI), T. Than (Co-PI), $32,200, February 2001 — January 2002 36. Valley Forge Pharmaceuticals; "A third year of treatment in a double-masked, parallel, placebo-controlled tolerability study of piren zepine ophthalmic gel in the treatment of myopic children". J Bartlett (PI), T Than (Co-PI), $19,600.00, October 2001-September 2002 37. Alcon Laboratories, Inc.; "A 4-week, randomize d, double-masked, parallel group, primary therapy study of the IOP lowering effica cy of Travatan 0.004% compared to Lumigan 0.03% in African-American subje cts with open-angle glaucoma or ocular hypertension". J Bartlett (PI), T Than (Co-PI), $35,700.00 , October 2001 to October 2002 38. Valley Forge Pharmaceuticals; "A third year of treatment in a double-masked, parallel, placebo-controlled tolerability study of piren zepine ophthalmic gel in the treatment of myopic children (open-label safety study )" J Bartlett (PI), $8120.00, May 1, 2002- April 30, 2003 39. Bausch and Lomb, Inc. "A double-masked, rando mized, prospective study of the intraocular pressure effects of Zylet compared with Tobr adex. J. Bartlett (PI), $33,000, February 2005-January 2006 40. Alcon Research, Ltd. "A Clinical Comparis on of Acute Corneal Staining and Comfort Associated with Marketed Multi-Purpose Lens Care Solutions". J. Bartlett (PI), $6944, February 2007-January 2008 SPECIAL PROFESSIONAL AND CLINICAL INTE REST S Special interests lie in ocular pharmacology, toxicology , and investigational drugs, with emphasis in external disease and glaucoma. Case 3:12-cv-01141-SMY-DGW Document 176-33 *SEALED* Filed 12/01/14 Page 122 of 126 Page ID #3135 Case: 16-3334 Document: 55-19 Filed: 02/08/2017 Pages: 126 (756 of 1511) APPENDIX B Case 3:12-cv-01141-SMY-DGW Document 176-33 *SEALED* Filed 12/01/14 Page 123 of 126 Page ID #3136 Case: 16-3334 Document: 55-19 Filed: 02/08/2017 Pages: 126 (757 of 1511) ADDITIONAL MATERIALS CONSIDERED First Amended Class Action Complaint for Damages, Punitive Damages, and Injunctive Relief Expert Report of Alan Robin, MD and referenced materials (May 30, 2014) Supplemental Expert Report of Alan Robin, MD (June 9, 2014) Deposition of Alan Robin, MD and exhibits (August 6, 2014) Deposition of Charlene Eike and exhibits (March 7, 2014) Deposition of Shirley Fisher and exhibits (February 24, 2014) Deposition of Jordan Pitler and exhibits (February 10, 2014) Deposition of Alan Raymond and exhibits (February 27, 2014) Deposition of Lon Spada, Ph.D. (March 26, 2014) Center for Drug Evaluation and Research, Application Number: 22-184, Summary Review, July 13, 2010. Petursson G, Cole R, Hanna C. Treatment of Glaucoma Using Minidrops of Clonidine, Arch Ophthalmology. 1984; 102: 1180-1181. Lynch MG, Brown RH, Goode SM, Schoenwald RD, Chien DS. Reduction of Phenylephrine Drop Size in Infants Achieves Equal Dilation with Decreased Systemic Absorption. Arch Ophthalmology. 1987; 105: 1364-1365. Alcon video study Case 3:12-cv-01141-SMY-DGW Document 176-33 *SEALED* Filed 12/01/14 Page 124 of 126 Page ID #3137 Case: 16-3334 Document: 55-19 Filed: 02/08/2017 Pages: 126 (758 of 1511) APPENDIX C • Single dose Single dose 3 months 7 days Kelly, et al. Br J Ophthalmol 1989 (Pilocarpine) Charap, et al. Ann Ophthalmol 1989 (Levobunolol) Vocci, et al. Am J Ophthalmol 1992 (Apraclonidine) Duration Petursson, et al. Arch Ophthalmol 1984 (Clonidine) Study (Drug) Investigatorand volunteerinstilled; smallest size was 16 EIL Investigatorand patientinstilled; smallest size was 204 Novel ophthalmic delivery system (NODS) Drug Delivery Method Investigatorinstilled dose of 15 uL 29 healthy volunteers ages 21-55 12 healthy volunteers; 117 patients with glaucoma or ocular hypertension 8 healthy volunteers ages 19-36 16 patients with glaucoma Subjects Results Day-7 diurnal 10P and systemic side effects 16 µ1. drop of apraclonidine 0.5% reduced 10P but was not tolerated better than 30 µL. 15 µL clonidine reduced 1013 and had less effect on blood pressure Pupil size Pilocarpine (10P was has 8-fold not greater assessed in bioavailability this study) from NODS than from eyedrop Four 10P 20 pL drop of assessments levobunolol (not diurnal) provided and equal efficacy systemic but not better safety safety 1013 and blood pressure over 5 hours Outcome Measures Summary of "Microdrop" Glaucoma Studies Inadequate study and statistical design to meet FDA requirements for glaucoma drug efficacy and safety study (patient self-dosing, diurnal 10P, study duration, 95% CI) FN Inad equate study and statistical design to meet FDA requirements for glaucoma drug efficacy and safety study (diurnal 10P, study duration, 95% CI)FN Inadequate study and statistical design to meet FDA requirements for glaucoma drug efficacy and safety study (patient self-dosing, diurnal 10P, study duration, 95% FN CI) Inadequate study and statistical design to meet FDA requirements for glaucoma drug efficacy and safety study (patient self-dosing, diurnal 10P, study duration, 95% FN CI) Comment Case 3:12-cv-01141-SMY-DGW Document 176-33 *SEALED* Filed 12/01/14 Page 125 of 126 Page ID #3138 Case: 16-3334 Document: 55-19 Filed: 02/08/2017 Pages: 126 (759 of 1511) • 14 days Allergan Microdrop Study (unpublished) 2003 (Bimatoprost) Investigatorinstilled drops ranging from 5 to 30 IA Patientinstilled drops of 35 or 26 pL 167 patients with glaucoma or ocular hypertension Single-site study of 67 patients with glaucoma or ocular hypertension Diurnal 10P and safety Diurnal 10P and safety Both drop sizes of brimonidine 0.5% were equally effective in reducing 1013. Smaller drop did not improve safety. Bimatoprost 0.03% in 5 and 10 pl. drops had less 10P lowering efficacy than volumes of 20 and 30 IA; eye redness occurred with all drop sizes Inadequate study design to meet FDA requirements for glaucoma drug efficacy and safety study (patient self-dosing, study duration, 95% CI) FN Inadequate study and statistical design to meet FDA requirements for glaucoma drug efficacy and safety study (study duration, 95% FN CI) CI = confidence interval statistics FN: FDA's Ophthalmology Group uses a fairly strict definition for clinical equivalence. For one product to be clinically equivalent to another product in 1013 reduction the difference must be within a 95% confide nce interval of 1.5 mmHg for all timepoints and within a 95% confide nce interval of 1 mmHg for the majority of timepoints. (Page 9 of FDA CDER Summary Review of Lumigan 0.01%, Application Number 22-184, July 13, 2010). FDA requires studies to include at least 100 patients with glaucoma or ocular hypertension evaluated for at least 3 months for efficacy and 12 months for safety using self-instilled medication in a "real-world" setting. (Weinreb RN, Kaufman PL. The glaucoma researc h community and FDA look to the future: a report from the NEI/FDA CDER Glaucoma Clinical Trial Design and Endpoints Symposium. Invest Ophthalmol Vis Sci 2009; 50: 1497-505). 7 days Allergan Microdrop Study (unpublished) 1994 (Brimonidine) Case 3:12-cv-01141-SMY-DGW Document 176-33 *SEALED* Filed 12/01/14 Page 126 of 126 Page ID #3139 Case: 16-3334 Document: 55-19 Filed: 02/08/2017 Pages: 126 (760 of 1511) Case 3:12-cv-01141-SMY-DGW Document 176-8 *SEALED* Filed 12/01/14 Page 1 of 40 Page ID #2378 Case: 16-3334 Document: 55-20 Filed: 02/08/2017 Pages: 40 (761 of 1511) Case 3:12-cv-01141-SMY-DGW Document 176-8 *SEALED* Filed 12/01/14 Page 2 of 40 Page ID #2379 Case: 16-3334 Document: 55-20 Filed: 02/08/2017 Pages: 40 (762 of 1511) Case 3:12-cv-01141-SMY-DGW Document 176-8 *SEALED* Filed 12/01/14 Page 3 of 40 Page ID #2380 Case: 16-3334 Document: 55-20 Filed: 02/08/2017 Pages: 40 (763 of 1511) Case 3:12-cv-01141-SMY-DGW Document 176-8 *SEALED* Filed 12/01/14 Page 4 of 40 Page ID #2381 Case: 16-3334 Document: 55-20 Filed: 02/08/2017 Pages: 40 (764 of 1511) Case 3:12-cv-01141-SMY-DGW Document 176-8 *SEALED* Filed 12/01/14 Page 5 of 40 Page ID #2382 Case: 16-3334 Document: 55-20 Filed: 02/08/2017 Pages: 40 (765 of 1511) Case 3:12-cv-01141-SMY-DGW Document 176-8 *SEALED* Filed 12/01/14 Page 6 of 40 Page ID #2383 Case: 16-3334 Document: 55-20 Filed: 02/08/2017 Pages: 40 (766 of 1511) Case 3:12-cv-01141-SMY-DGW Document 176-8 *SEALED* Filed 12/01/14 Page 7 of 40 Page ID #2384 Case: 16-3334 Document: 55-20 Filed: 02/08/2017 Pages: 40 (767 of 1511) Case 3:12-cv-01141-SMY-DGW Document 176-8 *SEALED* Filed 12/01/14 Page 8 of 40 Page ID #2385 Case: 16-3334 Document: 55-20 Filed: 02/08/2017 Pages: 40 (768 of 1511) Case 3:12-cv-01141-SMY-DGW Document 176-8 *SEALED* Filed 12/01/14 Page 9 of 40 Page ID #2386 Case: 16-3334 Document: 55-20 Filed: 02/08/2017 Pages: 40 (769 of 1511) Case 3:12-cv-01141-SMY-DGW Document 176-8 *SEALED* Filed 12/01/14 Page 10 of 40 Page ID #2387 Case: 16-3334 Document: 55-20 Filed: 02/08/2017 Pages: 40 (770 of 1511) Case 3:12-cv-01141-SMY-DGW Document 176-8 *SEALED* Filed 12/01/14 Page 11 of 40 Page ID #2388 Case: 16-3334 Document: 55-20 Filed: 02/08/2017 Pages: 40 (771 of 1511) Case 3:12-cv-01141-SMY-DGW Document 176-8 *SEALED* Filed 12/01/14 Page 12 of 40 Page ID #2389 Case: 16-3334 Document: 55-20 Filed: 02/08/2017 Pages: 40 (772 of 1511) Case 3:12-cv-01141-SMY-DGW Document 176-8 *SEALED* Filed 12/01/14 Page 13 of 40 Page ID #2390 Case: 16-3334 Document: 55-20 Filed: 02/08/2017 Pages: 40 (773 of 1511) Case 3:12-cv-01141-SMY-DGW Document 176-8 *SEALED* Filed 12/01/14 Page 14 of 40 Page ID #2391 Case: 16-3334 Document: 55-20 Filed: 02/08/2017 Pages: 40 (774 of 1511) Case 3:12-cv-01141-SMY-DGW Document 176-8 *SEALED* Filed 12/01/14 Page 15 of 40 Page ID #2392 Case: 16-3334 Document: 55-20 Filed: 02/08/2017 Pages: 40 (775 of 1511) Case 3:12-cv-01141-SMY-DGW Document 176-8 *SEALED* Filed 12/01/14 Page 16 of 40 Page ID #2393 Case: 16-3334 Document: 55-20 Filed: 02/08/2017 Pages: 40 (776 of 1511) Case 3:12-cv-01141-SMY-DGW Document 176-8 *SEALED* Filed 12/01/14 Page 17 of 40 Page ID #2394 Case: 16-3334 Document: 55-20 Filed: 02/08/2017 Pages: 40 (777 of 1511) Case 3:12-cv-01141-SMY-DGW Document 176-8 *SEALED* Filed 12/01/14 Page 18 of 40 Page ID #2395 Case: 16-3334 Document: 55-20 Filed: 02/08/2017 Pages: 40 (778 of 1511) Case 3:12-cv-01141-SMY-DGW Document 176-8 *SEALED* Filed 12/01/14 Page 19 of 40 Page ID #2396 Case: 16-3334 Document: 55-20 Filed: 02/08/2017 Pages: 40 (779 of 1511) Case 3:12-cv-01141-SMY-DGW Document 176-8 *SEALED* Filed 12/01/14 Page 20 of 40 Page ID #2397 Case: 16-3334 Document: 55-20 Filed: 02/08/2017 Pages: 40 (780 of 1511) Case 3:12-cv-01141-SMY-DGW Document 176-8 *SEALED* Filed 12/01/14 Page 21 of 40 Page ID #2398 Case: 16-3334 Document: 55-20 Filed: 02/08/2017 Pages: 40 (781 of 1511) Case 3:12-cv-01141-SMY-DGW Document 176-8 *SEALED* Filed 12/01/14 Page 22 of 40 Page ID #2399 Case: 16-3334 Document: 55-20 Filed: 02/08/2017 Pages: 40 (782 of 1511) Case 3:12-cv-01141-SMY-DGW Document 176-8 *SEALED* Filed 12/01/14 Page 23 of 40 Page ID #2400 Case: 16-3334 Document: 55-20 Filed: 02/08/2017 Pages: 40 (783 of 1511) Case 3:12-cv-01141-SMY-DGW Document 176-8 *SEALED* Filed 12/01/14 Page 24 of 40 Page ID #2401 Case: 16-3334 Document: 55-20 Filed: 02/08/2017 Pages: 40 (784 of 1511) Case 3:12-cv-01141-SMY-DGW Document 176-8 *SEALED* Filed 12/01/14 Page 25 of 40 Page ID #2402 Case: 16-3334 Document: 55-20 Filed: 02/08/2017 Pages: 40 (785 of 1511) Case 3:12-cv-01141-SMY-DGW Document 176-8 *SEALED* Filed 12/01/14 Page 26 of 40 Page ID #2403 Case: 16-3334 Document: 55-20 Filed: 02/08/2017 Pages: 40 (786 of 1511) Case 3:12-cv-01141-SMY-DGW Document 176-8 *SEALED* Filed 12/01/14 Page 27 of 40 Page ID #2404 Case: 16-3334 Document: 55-20 Filed: 02/08/2017 Pages: 40 (787 of 1511) Case 3:12-cv-01141-SMY-DGW Document 176-8 *SEALED* Filed 12/01/14 Page 28 of 40 Page ID #2405 Case: 16-3334 Document: 55-20 Filed: 02/08/2017 Pages: 40 (788 of 1511) Case 3:12-cv-01141-SMY-DGW Document 176-8 *SEALED* Filed 12/01/14 Page 29 of 40 Page ID #2406 Case: 16-3334 Document: 55-20 Filed: 02/08/2017 Pages: 40 (789 of 1511) Case 3:12-cv-01141-SMY-DGW Document 176-8 *SEALED* Filed 12/01/14 Page 30 of 40 Page ID #2407 Case: 16-3334 Document: 55-20 Filed: 02/08/2017 Pages: 40 (790 of 1511) Case 3:12-cv-01141-SMY-DGW Document 176-8 *SEALED* Filed 12/01/14 Page 31 of 40 Page ID #2408 Case: 16-3334 Document: 55-20 Filed: 02/08/2017 Pages: 40 (791 of 1511) Case 3:12-cv-01141-SMY-DGW Document 176-8 *SEALED* Filed 12/01/14 Page 32 of 40 Page ID #2409 Case: 16-3334 Document: 55-20 Filed: 02/08/2017 Pages: 40 (792 of 1511) Case 3:12-cv-01141-SMY-DGW Document 176-8 *SEALED* Filed 12/01/14 Page 33 of 40 Page ID #2410 Case: 16-3334 Document: 55-20 Filed: 02/08/2017 Pages: 40 (793 of 1511) Case 3:12-cv-01141-SMY-DGW Document 176-8 *SEALED* Filed 12/01/14 Page 34 of 40 Page ID #2411 Case: 16-3334 Document: 55-20 Filed: 02/08/2017 Pages: 40 (794 of 1511) Case 3:12-cv-01141-SMY-DGW Document 176-8 *SEALED* Filed 12/01/14 Page 35 of 40 Page ID #2412 Case: 16-3334 Document: 55-20 Filed: 02/08/2017 Pages: 40 (795 of 1511) Case 3:12-cv-01141-SMY-DGW Document 176-8 *SEALED* Filed 12/01/14 Page 36 of 40 Page ID #2413 Case: 16-3334 Document: 55-20 Filed: 02/08/2017 Pages: 40 (796 of 1511) Case 3:12-cv-01141-SMY-DGW Document 176-8 *SEALED* Filed 12/01/14 Page 37 of 40 Page ID #2414 Case: 16-3334 Document: 55-20 Filed: 02/08/2017 Pages: 40 (797 of 1511) Case 3:12-cv-01141-SMY-DGW Document 176-8 *SEALED* Filed 12/01/14 Page 38 of 40 Page ID #2415 Case: 16-3334 Document: 55-20 Filed: 02/08/2017 Pages: 40 (798 of 1511) Case 3:12-cv-01141-SMY-DGW Document 176-8 *SEALED* Filed 12/01/14 Page 39 of 40 Page ID #2416 Case: 16-3334 Document: 55-20 Filed: 02/08/2017 Pages: 40 (799 of 1511) Case 3:12-cv-01141-SMY-DGW Document 176-8 *SEALED* Filed 12/01/14 Page 40 of 40 Page ID #2417 Case: 16-3334 Document: 55-20 Filed: 02/08/2017 Pages: 40 (800 of 1511) Case 3:12-cv-01141-SMY-DGW Document 176-34 *SEALED* Filed 12/01/14 Page 1 of 64 Page ID #3140 Case: 16-3334 Document: 55-21 Filed: 02/08/2017 Pages: 64 (801 of 1511) UNITED STATES DISTRICT COURT SOUTHERN DISTRICT OF ILLINOIS EAST ST. LOUIS DIVISION CHARLENE EIKE, et al., on behalf of themselves and all other similarly situated, Plaintiffs, Case No. 3:12-cv-1141-SMY-DGW v. ALLERGEN, INC., et al., Defendants. EXPERT REPORT OF MICHAEL W. BELIN. M.D. Case 3:12-cv-01141-SMY-DGW Document 176-34 *SEALED* Filed 12/01/14 Page 2 of 64 Page ID #3141 Case: 16-3334 Document: 55-21 Filed: 02/08/2017 Pages: 64 (802 of 1511) Confidential — Subject to Protective Order Table of Contents Qualifications 1 Summary of Opinions 2 There Is No Basis for Dr. Robin's Opinion that Patients Can Safely and Efficaciously SelfAdminister a 15-16 j.11_, Eye Drop 4 The FDA Advisory Committee Would Require More Data to Approve Plaintiffs' Proposed Change 9 Patient Variability in Instilling Eye Drops 12 Case 3:12-cv-01141-SMY-DGW Document 176-34 *SEALED* Filed 12/01/14 Page 3 of 64 Page ID #3142 Case: 16-3334 Document: 55-21 Filed: 02/08/2017 Pages: 64 (803 of 1511) Confidential — Subject to Protective Order Expert Report of Michael W. Belin, M.D. I. Qualifications Education I am currently a Professor of Ophthalmology and Vision Science at University of 1. Arizona Health Sciences Center. I attended Northwestern University majoring in bio-mechanical engineering and graduated from Rutgers Medical School in 1978, after which I completed my internship and residency in ophthalmology at Albany Medical College. I then completed a fellowship at the University of Iowa Hospitals and Clinics in Corneal and External Eye Disease and subsequently completed (by invitation) a traveling fellowship from the Royal College of Surgeons of England Foundation before becoming an Assistant Professor of Ophthalmology at George Washington University in 1983. I left George Washington in 1989 to join the faculty at Albany Medical College where I was an Associate Professor and then full Professor and Director of the Cornea Service and Fellowship Director. In 2009, I assumed my current position at the University of Arizona. I additionally hold Adjunct Professorships at the University of Ottawa (Ottawa, Canada) and an Honorary Professorship at the Liaoning Province Northern Hospital in Shenyang, China. I am currently a member of the medical staff at Southern Arizona Veterans 2. Administration Healthcare System. I have been a member of the medical staff at George Washington University Hospitals, University of Iowa Hospitals and Clinics, Albany Medical Center Hospital, Stratton VA Medical Center, Albany, New York and the University of Arizona Medical Center. I have active medical licenses in Arizona, Washington State and New York. Clinical Practice I have been in continuous practice since 1983 and maintain an active clinical practice. 3. My ophthalmology practice concentrates on the anterior segment of the eye, as well as managing many patients with glaucoma. Currently, I treat and consult with patients three days a week in a clinical setting and perform approximately thirty surgeries per month. I specialize in cornea, external disease and refractive surgery. This includes all forms of corneal transplantation, treatment of infectious, inflammatory and external diseases of the eye and refractive surgery. Additionally, I am active in resident teaching both at the University of Arizona and the Southern Arizona Veterans Administration Healthcare System. 4. Nearly all of my patients use eye drops and a large percentage of my patients concurrently suffer from glaucoma. I regularly prescribe prescription eye drops for my patients, including anti-infective, anti-inflammatory and glaucoma medications. Corneal replacement surgery often creates or aggravates glaucoma-like conditions in patients that are treated with glaucoma medication and/or surgery. I regularly use and/or prescribe the following prescription eye drop medications: Brimonidine (Alphagan), Timolol (Timoptic), Ketorolac (Acular), Prednisolone (Pred Forte), Travaprost (Travatan), Olopatide (Patanol, Pataday), Difluprednole (Durezol), Moxifloxacin (Vigamox), Latanoprost (Xalatan), Dorzolamide (Trusopt), Loteprednole (Lotemax), Dorzolamide & Timolol (Cosopt), and Azithromycin (Azasite), among many others. Case 3:12-cv-01141-SMY-DGW Document 176-34 *SEALED* Filed 12/01/14 Page 4 of 64 Page ID #3143 Case: 16-3334 Document: 55-21 Filed: 02/08/2017 Pages: 64 (804 of 1511) Confidential — Subject to Protective Order 5. Additionally, I have treated countless patients with corneal abrasions. Corneal abrasions are one of the most commonly seen conditions on an emergency referral basis. Most abrasions are caused by ocular trauma (e.g., fingernail scratches, tree branches); others may be caused by a weakened surface epithelium (e.g., Map-Dot-Fingerprint dystrophy, corneal endothelial dysfunction). I have also seen, though less common, abrasions caused by the application of eye drops that are likely related to the patients accidentally scratching their cornea with the dropper tip. Appointments & Academic Research 6. My research expertise includes corneal disease, refractive surgery and corneal imaging. I have published in peer-reviewed literature or presented at major national and/or international meetings over 400 scholarly papers. 7. I was past President (2006-2008) and I am currently Vice-President of the International Development of the Cornea Society. I am the Vice-Chairman (Chair-elect) of the American University Professors of Ophthalmology Fellowship Compliance Committee which oversees Fellowship training in the United States. I am a Fellow of the American Academy of Ophthalmology and the Royal Australian & New Zealand College of Ophthalmology. I served on the Board of Directors, the Medical Advisory Board and the Executive Committee of the Eye Bank Association of America. I am a recipient of the American Academy of Ophthalmology's Honor Award, Senior Honor Award, Two Achievement Awards and the Lifetime Achievement Honor Award. I was appointed to be a consultant and committee member to the Food and Drug 8. Administration ("FDA") Anti-Infective Drugs Advisory Committee from 1989-1995. I was also appointed to be a consultant and committee member to the FDA Ophthalmic Device Advisory Committee from 1994-2002. I was a temporary voting member of the FDA Dermatologic and Ophthalmic Drugs Advisory Committee in 2009 and 2012 and currently serve as an active SGE (Special Government Employee) to the FDA. 9. My curriculum vitae is attached as Appendix A. I have considered the materials set forth in Appendix B, as well as the literature and research I have reviewed in the course of my career. My hourly fee for work in this case is $600 per hour. In the last four years, to the best of my knowledge, I have twice given testimony as an expert witness in medical malpractice cases. II. Summary of Opinions Assignments 10. I have reviewed Plaintiffs' First Amended Complaint. I understand Plaintiffs allege that the named prescription drug manufacturers and distributors should reduce the drop size of prescription eye drops to 15-16 µL because any volume in excess of that amount allegedly does not benefit patients and a smaller drop size allegedly can be delivered both safely and effectively. I have also reviewed the report and testimony of Plaintiffs' expert Dr. Alan Robin and depositions of the Plaintiffs. 11. Defendants have asked me to review Plaintiffs' claims that Defendants' prescription eye drop products emit drops that are too large such that the excess drop solution does not benefit 2 Case 3:12-cv-01141-SMY-DGW Document 176-34 *SEALED* Filed 12/01/14 Page 5 of 64 Page ID #3144 Case: 16-3334 Document: 55-21 Filed: 02/08/2017 Pages: 64 (805 of 1511) Confidential — Subject to Protective Order patients. Defendants have also asked me to review and respond to Dr. Robin's conclusions and opinions. Summary 12. I do not agree with Dr. Robin's conclusions and opinions contained in his report and deposition testimony. Among other things, Dr. Robin's conclusions are based on limited studies that do not simulate real-world patient instillation of prescription eye drops. Many of the studies do not involve the target patient population and the majority of the studies had either technicians or other medical personnel placing the study medication, such that is impossible to draw any conclusions that would relate to real-life clinical use. There is insufficient (if any) data to suggest that a redesigned dropper bottle can be 13. manufactured that can safely deliver a 15-16 pL drop in a manner that can be used by a patient without an increase in risk of contamination, infection, or possible corneal abrasions. Plaintiffs or Plaintiffs' expert presented absolutely no data to support this contention for non-glaucoma prescription eye drops such as anti-allergy, anti-infective, and anti-inflammatory medications. Plaintiffs and Plaintiffs' expert also presented no data to support their contention for prescription eye medications that are suspensions, emulsions or gels. 14. Defendants' eye drop medications have a long track record of safety and efficacy, and large scale studies would be required to show that a new delivery system would be equally safe and effective. Such data are currently not available. There are insufficient data to support Dr. Robin's conclusions that patients with glaucoma or other ophthalmic diseases could safely administer 15-16 .tL eye drops through redesigned eye dropper tips without causing eye trauma and there are insufficient data to show that a 15-16 µL eye drop would be otherwise safe and effective in real-life application. 15. Dr. Robin gives much weight to the Vocci papers and the term "potentially commercially available eyedrop bottle."2 The study, however, has very limited value and any extrapolations to real-life clinical usage are highly problematic. First, the study only looked at a single medication (Apraclonidine), which is a solution. Second, the subject number (29) is very small and significantly below what would normally be required for a drug approval study. Third, the study's participants were "normal" (healthy) with an average age of 33, which is not reflective of the glaucoma population. FDA Phase III studies mandate that the medication be used in the appropriate study population. Fourth, the investigators placed some of the medication into the participants' eyes. In other words, the study looked at young, healthy individuals where a study technician placed some of the smaller drops. There can be no conclusions drawn or inferred as to how elderly glaucoma patients would handle the dropper bottle or respond to smaller amounts of medications. The term "potentially commercially available/viable" is meaningless. Almost anything is potentially viable. There are in excess of a thousand "potentially viable drugs" that are investigated for every one drug that makes it through the FDA process and into clinical practice. ' Vocci MJ, Robin AL, Wahl JC, et. al. Reformulation and Drop Size of Apraclonidine Hydrochloride. Amer. J. Ophthal 1992; 113:154-160. 2 Expert Report of Alan Robin, M.D., May 30, 2014, pp. 7-9; deposition of Deposition of Alan Robin, M.D., August 6, 2014, pp. 107-108. 3 Case 3:12-cv-01141-SMY-DGW Document 176-34 *SEALED* Filed 12/01/14 Page 6 of 64 Page ID #3145 Case: 16-3334 Document: 55-21 Filed: 02/08/2017 Pages: 64 (806 of 1511) Confidential — Subject to Protective Order Each of these thousands is "potentially viable" but over 99.9% are not actually viable clinical products that will achieve FDA approval. 16. Based on my over a decade's experience on the FDA's advisory panel and past FDA actions, I believe that any modification to bottle design, tip design and the amount of medication delivered would require Phase III type studies. One of the requirements of Phase III studies is that the study population reflect the actual clinical patient population using the medication(s). Studies utilizing young, normal (i.e., non-glaucoma) patients or studies where technicians instilled some of the medication would never be considered suitable Phase III protocols. 17. Patients also do not instill eye drops in the same manner, regardless of the product or the dropper tip. This is because there is no standard method for instilling eye drops. Also, each human is a little different, and these individual characteristics, including health and age, affect the success with which a patient instills eye drops. As a result of these differences, drop sizes vary from patient to patient, as does the amount of product that makes it into the eye (or doesn't make it into the eye). Patients also miss their eyes, or emit multiple drops. Some patients risk contamination or eye trauma due to touching the dropper tip to the surface of their eye. These variables are known and predictable occurrences with patient administration. Companies must design a product that is safe and efficacious for all patients, notwithstanding the complicating variations in the patient population and their usage abilities. III. There Is No Basis for Dr. Robin's Opinion that Patients Can Safely and Efficaciously Self-Administer a 15-16 pl. Eye Drop Eye Trauma 18. Patients vary widely in their ability to self-administer eye drops without touching their eye. Characteristics such as health, age, vision quality, and experience impact the likelihood a patient will be able to self-administer eye drops without touching their eyes. 3 Studies of patient usage show that about 20-32% allow the dropper tip to touch their eyes when dispensing eye drops.' 19. The danger of a sharp object near the eye is real. Patients, especially those who are older, lack manual dexterity, or have poor vision, can and do harm their eyes while administering eye drops. A sharper tip, sometimes referred to as a "threatening tip," would cause additional risk of harm and pose a significant safety risk for patients. Corneal abrasions often require treatment with Kass MA, Dodapp E, Gordon M, Kolker AE, Goldberg I. Patient Administration of Eyedrops: Interview Part I. Ann Ophthalmol. 1982; 14(8):775-779; Kass MA, Dodapp E, Gordon M, Kolker AE, Goldberg I. Patient Administration of Eyedrops: Interview Part II. Ann Ophthalmol. 1982; 14(9):889-893; Gupta, R, Patil, B, Shah, BM, Bali, SJ, Mishra, SK, Dada, Evaluating Eye Drop Instillation Technique in Glaucoma Patients Journal of Glaucoma March 2012, Vol. 21, Issue 3; Hennessy, et. al., Eyedrop Instillation in Low-Vision Glaucoma Patients, 17 Ophthalmology Number 12 (2010); Stone et. al., An Objective Evaluation of eyedrop instillation in patients with glaucoma, Arch. Ophthalmology 2009; 127:732-6; Hennessy AL, Katz J, Covert D, Protzko C, Robin AL. Videotaped Evaluation of Eyedrop Instillation in Glaucoma Patients with Visual Impairment of Moderate to Severe Visual Field Loss. Ophthalmol. 2010; 117(12): 2345-2352. 4 Aptel F. Masset H, Burillon C, et. al. The influence of Disease Severity on Quality of Eye-Drop Administration in Patients with Glaucoma or Ocular Hypertension. Fr J Ophthalmol. 2009; 93:700-701; Hennessy AL, Katz J, Covert D, 3 Protzko C, Robin AL. Videotaped Evaluation of Eyedrop Instillation in Glaucoma Patients with Visual Impairment of Moderate to Severe Visual Field Loss. Ophthalmol. 2010; 117(12): 2345-2352. 4 Case 3:12-cv-01141-SMY-DGW Document 176-34 *SEALED* Filed 12/01/14 Page 7 of 64 Page ID #3146 Case: 16-3334 Document: 55-21 Filed: 02/08/2017 Pages: 64 (807 of 1511) Confidential — Subject to Protective Order anti-infective eye drops and potentially surgery. The abrasion would also cause discomfort and visual loss until healed. 20. In my clinical experience, I have consulted and treated many patients with corneal abrasions, including patients who caused themselves corneal abrasions while attempting to selfadminister preservative-free eye drops. As noted in Dr. Robin's expert report, the current eye drop design has a long history of both efficacy and safety, neither of which has been established for the proposed redesign. 21. From my decades of clinical experience, I have observed that the patient population can safely administer currently available prescription eye drops (in their current multi-use bottle and tip dimensions) without causing eye damage regardless of their health, age, vision, or experience. A safety profile for a redesigned tip has not been established. 22. Dr. Robin's "potentially commercially viable" 15-16 j.i.L multi-use eye drop dispenser utilizes a sharper dropper tip to create the 15-16 tL drop than tips currently marketed with multi-use bottles (Figure 1).5 While many factors enter into the final drop size, the overall outer tip diameter is the single most important factor.6 Smaller drops would necessitate a smaller (i.e., sharper or more pointed) tip, the safety of which has not been established. "Potentially commercially available" does not imply it is safe or approvable. Figure 17 23. If a safe eye drop delivery system delivering a 15-16 tL drop could be produced, it is very likely that a third party company would have already marketed such a bottle directly to patients to allow them to transfer their medication into these dropper bottles and have the bottle last longer. After-market devices are common outside of medicine and also common with systemic medications. 24. There are a number of after-market devices (e.g., DROPin Eye Drop Assist, E-Z Drops, Maddak Eye Drop Guide, Auto-Drop Eye Drop Guide) that assist the patient in placing the eye drop. There is another device, Simply Touch Eye Drop Applicator that necessitates touching the eye to deliver the eye drop. In light of the infrequency with which patients wash their hands prior to instilling drops (as directed), a device that necessitates actually touching the eye and cleaning before and after every use is ill advised. A large review article illustrates many dropper aids to assist Expert Report of Alan Robin, M.D., May 30, 2014, pp. 7-8. Van Santvliet L, Ludwig A. Influence of the Dropper Tip Design on the Size of Eye-Drops. Pharm Ind. 2001; 63:402409. Page 8 of Dr. Robin's report contains an enlarged version of this same photo. The photo in Figure 1, however, is a more accurate image of the actual size of the dropper tip used in the Vocci paper. 5 6 5 Case 3:12-cv-01141-SMY-DGW Document 176-34 *SEALED* Filed 12/01/14 Page 8 of 64 Page ID #3147 Case: 16-3334 Document: 55-21 Filed: 02/08/2017 Pages: 64 (808 of 1511) Confidential — Subject to Protective Order patients.' To my knowledge, however, there is no after-market dropper aid or device that reduces drop size to 15-16 µL. 25. There is likely a reason no company has manufactured such after-market devices. I am aware of no evidence showing a market for such a product, and there is no data available to suggest an after-market device emitting 15-16 µL drops can be produced that is safe for patient use. A paper acknowledges the difficulties in attempting to produce a commercially viable dropper bottle capable of delivering such a small drop, "Manufacturer 1 could not provide dropper tips with small outer otifice or inner aperture dimensions not possible due to frequent break-off of the pin under the high stress during the manufacturing process."' 26. There are no studies that I am aware of showing the eye drop patient population can safely self-administer 15-16 j..t.L prescription eye drops in a real-world setting. The vast majority of the studies cited in Dr. Robin's report utilized trained individuals, not the patients themselves, to administer the smaller drop size. Some studies utilized a pipette, not a dropper bottle, to deliver the smaller drop and others acknowledged that the device (Novel Ophthalmic Delivery System (NODS)) was never successfully marketed because of difficulty in using it. Additionally, the Vocci paper utilized healthy subjects with an average age of 33, which does not replicate the real-life situation, where the majority of eye drop users (outside of artificial tears users) are the elderly often with co-morbidities.1° 27. In my medical opinion, a 15-16 µL drop would increase the risk that patients would injure their eye when attempting to self-administer the drop. The degree of risk would vary depending on the patient's health, age, vision, and skill in administering eye drops. Extensive patient use studies would be needed to fully establish the degree of risk across the entire patient population if in fact a commercially viable bottle tip could be produced. Contamination 28. Patient instructions included in almost all eye drop medications include a statement similar to the following: "To apply eye drops, wash hands first. To avoid contamination, do not touch the dropper tip or let it touch your eye or any other surface."" In spite of these directions, real-life application of eye drops reveals that a large proportion of patients fails to properly instill Van Santvliet L, Ludwig A. Determinants of Eye Drop Size. Sun, Ophthalmol. 2004; 49:197-213. Van Santvliet L, Ludwig A. Influence of the Dropper Tip Design on the Size of Eye-Drops. Pharm Ind. 2001; 63:402409. 10 Expert Report of Alan Robin, M.D., May 30, 2014, pp. 7-8 (Vocci paper), 9 (Charap Study), 10-21 (Allergan Microdrop study), 22 (NODS) citing Charap A, Shin D, Petursson G, et al. Effect of Varying Drop Size on the Efficacy and Safety of a Topical Beta Blocker. Ann Ophthalmol. 1989; 21:351-357; Lynch MG, Brown RH, Goode SM, Schoenwald RD, Chien DS. Reduction of Phenylephrine Drop Size in Infants Achieves Equal Dilation with Decreased Systemic Absorption. Arch Ophthalmology 1987; 105:1364-1365; Petursson G, Cole R, Hanna C. Treatment of Glaucoma Using Minidrops of Clonidine, Arch Ophthalmology 1984; 102:1180-1181; Kelly JA, Molyneux PD, Smith SA, and Smith SE. Relative bioavailability of pilocarpine from a novel ophthalmic delivery system and conventional eyedrop formulations. British Journal of Ophthalmology. 1989; 73(5):360-362. 11 Package Insert — Highlights of Prescribing Information Zymaxid, Allergan Inc., 2012; Package Insert — Patient Information AzaSite, Merck & Co., Inc., 2012. 8 9 6 Case 3:12-cv-01141-SMY-DGW Document 176-34 *SEALED* Filed 12/01/14 Page 9 of 64 Page ID #3148 Case: 16-3334 Document: 55-21 Filed: 02/08/2017 Pages: 64 (809 of 1511) Confidential — Subject to Protective Order their drops with approximately 20-32% of patients potentially contaminating the eye-drop bottle by allowing the tip to touch their eyes.0 29. Many patients bring the bottle tip close to the ocular surface or have the drop touch the ocular surface to transfer the medication. With the drop sizes currently used for eye medications it has been shown that a significant number of patients actually touch the ocular surface and potentially contaminate the tip and/or bottle. A smaller drop size would potentially increase this risk. A smaller eye drop would also necessitate bringing the bottle even closer to the ocular surface. 30. Dr. Robin acknowledges another risk of contamination posed by extended bottle use: "Contamination of the bottle tip is a significant concern, especially in the chronic application of eyedrops as in glaucoma, because this may place the patient at risk, especially those who have prior filtration or cataract surgery, for vision threatening infection." In this same paper, Dr. Robin cited another study finding that the degree of contamination increased the longer the bottle was used: "The authors found contamination in 19% of drop bottles themselves that had been used for < 8 weeks versus 40% in those that had been used for > 8 weeks. Given that the most common population that has glaucoma is elderly, and that many also have ocular surface disease that could possibly predispose to infection, this is a potentially a serious issue."13 31. This paper, co-authored by Dr. Robin, raises serious concerns about drop contamination and bottle size. Even if a drop size of 15-16 1AL could be safely delivered (which has not been shown), extending the time a bottle would last, as Plaintiffs propose, would be ill-advised. I would not recommend extended bottle usage for my patients due to risk of contamination and other issues such as sterility. 32. Additionally, in another paper co-authored by Dr. Robin, the authors state that patients instill drops more poorly with larger bottle sizes: "The proportions of patients who were able to instill a single drop into the eye without touching the bottle to the eye were 21.9% with a 15-ml bottle and 30.8% with a 2.5-m1 bottle," again suggesting that contamination risk varies amongst the patient population, not only patient-to-patient, but bottle-to-bottle.14 33. The FDA has already voiced significant concern about increasing contamination rates due to patients touching the dropper tip to their eyes and due to extended bottle usage. Contamination can cause serious, vision-threatening complications. The concern was expressed for instance at a Dermatologic and Ophthalmic Drug Advisory Committee ("DODAC") meeting that I participated in on February 27, 2012.15 34. As with the risk of corneal abrasions, Dr. Robin fails to cite to any studies that establish that real-life patients can self-administer eye drops using an eye dropper capable of emitting a 15-16 tL drop without increasing the risk the patients would contaminate the dropper tip. 12 See 13 footnote 4. Hennessy AL, Katz J, Covert D, Protzko C, Robin AL. Videotaped Evaluation of Eyedrop Instillation in Glaucoma Patients with Visual Impairment or Moderate to Severe Visual Field Loss. Ophthalmology 2010; 117:2345-2352. 14 Stone JL, Robin AL, Novack GD, Covert DW, Cagle GD. An Objective Evaluation of Eyedrop Instillation in Patients with Glaucoma. Arch Ophthalmol. 2009;127(6):732-736. 15 For further explanation of the DODAC meeting findings see T141-48. 7 Case 3:12-cv-01141-SMY-DGW Document 176-34 *SEALED* Filed 12/01/14 Page 10 of 64 Page ID #3149 Case: 16-3334 Document: 55-21 Filed: 02/08/2017 Pages: 64 (810 of 1511) Confidential — Subject to Protective Order Efficacy 35. Plaintiffs' theory that the drop size of all of Defendants' products should be reduced across the board completely ignores the benefit a larger drop size has for some ophthalmic conditions. The contention that eye drop size in excess of 15-16 !IL is wasted and has no clinical benefit has not been proven and is not applicable across all medications and diseases. In allergic eye disease, for example, a larger drop volume has a potential benefit as it dilutes the allergen. A smaller drop size, while delivering medication, would not have this allergen washout potential. 36. Additionally, certain eye drop vehicles such as emulsions and/or gels are designed to increase the contact time with the ocular surface and a larger drop size may be beneficial. Many of the drugs listed in the First Amended Complaint are emulsion or gel products. (See Table 1). Reducing drop size with these medications may lower clinical efficacy. 37. Further, the normal ocular cul-de-sac only contains approximately 7 µL of tears, but the average eye can retain up to 30 µI. for a period of time. This is discussed on Dr. Robin's web page, where he instructs patients on how to maximize the amount of drug (drop) held by the eye.16 Decreasing the drop size would decrease the amount of active medication for those patients who can retain a drop volume larger than the 15-16 µL. Indeed, in some studies smaller drop sizes were less efficacious:7 38. Dr. Robin also observed that sometimes only a portion of the drop actually makes it to the ocular surface: "a portion of the drop landed on the eye and a portion on the lid; thus, a portion was dripping outside of the eye but eventual!), some of the drop made it to the ocular sulace.' Where patients only place a portion of the eye drop onto the ocular surface, a smaller drop size could result in suboptimal dosing and potentially allow disease progression in spite of the fact that the patients believed they were properly being treated. To my knowledge, there is no adequate and well-controlled study that demonstrates 39. that an eye drop bottle delivering the 15-16 µL drop can be self-administered by patients with the same efficacy as currently available drops. Additionally, there is no study, to my knowledge, that shows that such a bottle can deliver the wide spectrum of medications listed in the First Amended Complaint (solutions, suspensions, emulsions, and gels).19 40. I would not instruct my patients to use the "potentially commercially available" dropper tip Dr. Robin references from the Vocci paper because Dr. Robin cites no data establishing that actual patients can safely self-administer drops using that dropper tip, or any other dropper tip capable of emitting 15-16 1.1L drops, without an increased risk of eye trauma or contamination, or that 15-164 drops provide comparable efficacy for any of the currently marketed drugs in the First Amended Complaint. http://www.glaucomaexpert.com/glaucoma_treannent htrn (last visited September 12, 2014). SS, Makoid MC, Eriksen SP, Robinson JR. Drop Size and Initial Dosing Frequency Problems of Topically Applied Ophthalmic Drugs. / Pharm Sri. 1974; 63:333-338; Allergan Microdrop Study. 18 Hennessy AL, Katz J, Covert D, Protzko C, Robin AL. Videotaped Evaluation of Eyedrop Instillation in Glaucoma 16 17 Chrai Patients with Visual Impairment or Moderate to Severe Visual Field Loss. Ophthalmology 2010; 117:2345-2352. 19 For further explanation regarding problems with studies cited in Dr. Robin's report see ¶¶ 49-55. 8 Case 3:12-cv-01141-SMY-DGW Document 176-34 *SEALED* Filed 12/01/14 Page 11 of 64 Page ID #3150 Case: 16-3334 Document: 55-21 Filed: 02/08/2017 Pages: 64 (811 of 1511) Confidential — Subject to Protective Order IV. The FDA Advisory Committee Would Require More Data to Approve Plaintiffs' Proposed Change 41. The Anti-Infective Drugs Advisory Committee reviews and evaluates from existing clinical data the safety and effectiveness of marketed and investigational drugs that are intended to treat infectious diseases and disorders, and then makes recommendations to the Commissioner of Food and Drugs regarding the safety and effectiveness of the drugs. The Dermatologic and Ophthalmic Drugs Advisory Committee and the Ophthalmic Device Advisory Committee review and evaluate the safety and effectiveness of drugs and medical devices for ophthalmic uses based on existing clinical data and make recommendations to the Commissioner. 42. These committees consist of 9 to 15 voting members selected by the FDA Commissioner. The FDA typically provides data to committee members for the members to review in advance of the meetings. At the meetings, the committee members discuss and vote whether the available data support certain safety and efficacy determinations. 43. On February 27, 2012, for example, I was voting a member of the FDA Dermatologic and Ophthalmic Drug Advisory Committee that considered the following questions: Is it appropriate to use a single bottle of anti-inflammatory ophthalmic drops (a) to treat both eyes post-operatively? Should physician prescribing information for anti-inflammatory ophthalmic (b) drops with post-operative indications be revised to further address infection risk? What information should be communicated to the patient to mitigate (c) infection risk associated with post-operative use of anti-inflammatory ophthalmic drops? (d) ophthalmic drops. Please comment on the appropriate fill volume for anti-inflammatory 44. The FDA expressed significant reservations concerning extending the length of time a single bottle could be used due to the increasing risk of contamination with longer bottle life. The vast majority of studies document an increasing contamination rate with longer bottle usage, with rates as high as 70% reported. This concern was brought up both in the pre-meeting review materials and during the FDA's presentation at the 2012 FDA Ophthalmic Drug Panel. The concern was also discussed by the Advisory Committee, which shared the FDA's concern about contamination risk to the patient by having a longer time in which a single bottle could be used.2° At the same panel meeting both the FDA and the Advisory Committee discussed and agreed that bottle The following literature further discusses contamination risks. Nentwich MM et al. Microbial contamination of multiuse ophthalmic solutions. BrJ Ophthalmol. 2007; 91:1265-1268; Livingstone DJ, Hanlon GW, Dyke S. Evaluation of an extended period of use of preserved eye drops in hospital practice. BrJ Ophthalmol. 1998; 82:473-475; H-Kauffmann Jokl D. Bacterial contamination of ophthalmic solutions used in an extended care facility. Br J Ophthalmol. 2007; 91:13081310; Rahman et al. Microbial contamination of preservative-free eye drops in multiple application containers. Br Ophthalmol. 2006; 90:139-141; Porges Y et al. Sterility of Glaucoma Medications Among Chronic Users in the Community. J Ocular Pharm. 2004; 20:123-128; Geyer et. al. Microbial Contamination of Medications Used to Treat Glaucoma. BrJ Ophthalmol. 1995; 79:376-379. 20 9 Case 3:12-cv-01141-SMY-DGW Document 176-34 *SEALED* Filed 12/01/14 Page 12 of 64 Page ID #3151 Case: 16-3334 Document: 55-21 Filed: 02/08/2017 Pages: 64 (812 of 1511) Confidential — Subject to Protective Order fill volumes should be appropriate for their expected duration (e.g., 30-day fill volumes) while accounting for patient waste (e.g., multiple drops, missed drops). 45. One of the studies cited by the FDA at the Advisory Committee meeting describes the risk of contaminating the bottle tip as a "significant concern, especially in the chronic application of eyedrops as in glaucoma, because this may place the patient at risk, especially those who have prior filtration or cataract surgery, for vision-threatening infection."21 This study further states that, "[Oven that the most common population that has glaucoma is elderly, and that many also have ocular surface disease that could possibly predispose to infection, this is potentially a serious issue." 46. Another study referenced by the FDA regarding the risk of microbial contamination was Geyer, et al., Microbial Contamination of Medications Used to Treat Glaucoma, Br J Ophthalmol. 1995; 79: 376-379. Geyer, et al. recovered bacteria from 28% of medications used by study patients, 91% of which were gram positive. The investigators discovered that 40% of eye drop bottles used for more than eight weeks were contaminated, compared to only 19% of bottles used for less than eight weeks. 47. The FDA and the Advisory Committee also expressed significant concern that patients prescribed anti-inflammatory eye drops contaminate their droppers by touching the dropper tip to their eyes. The Advisory Committee recommended during its February 27, 2012 meeting that patients using these prescription ophthalmic drops should be told to avoid contacting the tip of the bottle, wash their hands before opening the bottle, and to not touch their eyes or any surface with the bottle tip. These directives are equally applicable to patients using prescription eye drops for other indications, including glaucoma. 48. The FDA's concerns regarding the risk of contamination are similarly posed by a new, smaller dropper that is capable of emitting 15-16 }AL eye drops. Any such dropper may increase contamination risks by extending the length of the bottle's use and also increase contamination risk by causing patients to bring the bottle tip closer to their eyes and therefore touching their eyes more often. 49. The FDA often asks advisory committee members to evaluate whether existing data demonstrate the safety and efficacy of a drug or device for a given use and to recommend what additional data, if any, are needed to establish safety and efficacy. FDA personnel actively participate in these advisory committee meetings. 50. In recent times, FDA decision making has been largely consistent with the recommendations of its advisory committees. 51. Based upon my experience on FDA advisory committees, the FDA would closely scrutinize the safety and efficacy profile of a redesigned dropper tip that delivers a 15-16 µL drop before permitting Defendants to market such a product. The FDA would likely require eye drop manufacturers to generate data demonstrating the safety and efficacy profile of the smaller drop and redesigned dropper tip for each individual prescription eye medication. The FDA typically requires data for each prescription eye medication; it is typically not a "one size fits all" review. None of the '1 Hennessy, et al., Videotaped Evaluation of Eyedrop Instillation in Glaucoma Patients With Visual Impairment or Moderate to Severe Visual Field Loss, Ophthalmol. 2010; 117:2345-2352. 10 Case 3:12-cv-01141-SMY-DGW Document 176-34 *SEALED* Filed 12/01/14 Page 13 of 64 Page ID #3152 Case: 16-3334 Document: 55-21 Filed: 02/08/2017 Pages: 64 (813 of 1511) Confidential — Subject to Protective Order studies identified by Plaintiffs or Dr. Robin come close to the type of studies that would normally be required by the FDA. The studies had insufficient numbers (subjects), were not designed to evaluate the dropper bottle, did not include subjects from the target populations (e.g., elderly glaucoma patients), and did not involve full self-administration of the medication.22 52. Based upon my experience on FDA advisory committees, it is my opinion that the FDA would likely require tests similar to Phase III clinical trials, in which the eye drop manufacturers collect data from a large number of patients who would self-administer the 15-16 µ1_, eye drops using the redesigned dropper tip over the course of many months for each prescription eye drop medication. This testing would be in addition to stability and shelf-life testing that would likely be needed. 53. Dr. Robin's report does not contain data establishing the safety and efficacy of a 15164 drop or redesigned dropper tip because the studies he cites in his report most closely resemble Phase I or Phase II trials. The studies involved a limited number of test subjects, often used healthy volunteers whose age and health characteristics did not reflect the actual patient population, and the test subjects were not required to self-administer in a real-world manner. He also fails to cite studies for each drug listed in the First Amended Complaint. Moreover, the Allergan Microdrop study that Dr. Robin cites revealed that 30 j.11, drops were comparably more effective in reducing IOP than smaller drops in a laboratory setting for the tested drugs (drops instilled in patients using micropipettes). Additionally, not showing a statistical difference between two drop sizes is not the same as showing they are statistically equivalent. Often, a lack of statistical significance is caused by the small number of study subjects (the majority of studies cited by Plaintiffs' had small study populations), which is one of the many reasons FDA mandates adequate study numbers before evaluating a new drug or device. 54. Dr. Robin's report contains inadequate data or scientific basis to support a claim that a 15-16 41, drop would deliver equivalent effectiveness as currently available eye drops when the actual patient population self-administers the 15-16 uL drop. Moreover, his report ignores major classes of medications cited in the complaint (anti-allergy, anti-inflammatories, anti-infectives, antivirals) and ignores the different vehicles for those drugs (solution vs suspension vs emulsion vs gels). Many more studies with much larger population groups done on appropriate target populations would be needed for each product listed in the Amended Complaint in order to reliably reach the conclusions Dr. Robin offers. 55. Dr. Robin does not have sufficient data to support his conclusion that 15-16 1.1.1drops emitted through redesigned dropper tips are safe and efficacious for patient use for any product listed in the Amended Complaint, much less all of them. It is my opinion that the FDA would require extensive safety and efficacy testing before permitting the Defendants to market a new 15-164 drops in a redesigned dropper tip. 22 See footnote 10 for studies relied on in Dr. Robin's report. 11 Case 3:12-cv-01141-SMY-DGW Document 176-34 *SEALED* Filed 12/01/14 Page 14 of 64 Page ID #3153 Case: 16-3334 Document: 55-21 Filed: 02/08/2017 Pages: 64 (814 of 1511) Confidential — Subject to Protective Order V. Patient Variability in Instilling Eye Drops Application and Bottle Fill 56. There is no standardized patient technique for instilling eye drops. Each of the Plaintiffs described a different method for how he or she instills eye drops, including different angles of administration, tilts of their head, and variations in sitting or standing.' It is well-documented that this instillation variation, among other factors, contributes to variation in eye drop instillation success and drop sizes. 57. Individual patient characteristics impact patients' ability to instill a single drop into their eyes—these characteristics include age, vision quality, and medical condition (e.g., arthritis, strokes, hand tremors, ischemic attacks).24 58. Much of the patient population struggles to instill a single eye drop into the eye, leading to large amounts of drug product missing the eye.25 The Plaintiffs in this case have described difficulties they had such as emitting multiple drops, missing their eye, and blinking as they instill drops, which are common difficulties across the patient population." 59. I agree with Dr. Robin that a patient who misses their eye with a drop, or emits multiple drops, or spills or leaks medication does not receive medical benefit from that medication and therefore wastes the medication." The FDA and DODAC agreed at the February 27, 2012 meeting that prescription eye drop fill volume should account for medication that patients waste due to their own instillation errors.28 I also agree with Dr. Robin that no amount of laboratory testing would determine 60. how much a specific patient wastes; it's an individual issue.' A survey would not work because patients do not accurately perceive their ability to instill eye drops. Deposition of Charlene Eike, March 7, 2014, pp. 38-39, 55; Deposition of Shirley Fisher, February 24, 2014, pp. 6064; Deposition of Jordan Pitler, February 10, 2014, pp. 28-29, 159-160; Deposition of Alan Raymond, February 27, 2014, pp. 35-37, 47. 24 Kass MA, Dodapp E, Gordon M, Kolker AE, Goldberg I. Patient Administration of Eyedrops: Interview Part I. Ann Ophthalmol1982; 14(8):775-779; Kass MA, Dodapp E, Gordon M, Kolker AE, Goldberg I. Patient Administration of Eyedrops: Interview Part II. Ann Ophthalmol 1982; 14(9):889-893; Gupta, R, Patil, B, Shah, BM, Bali, SJ, Mishra, SK, Dada, T (2012) Evaluating Eye Drop Instillation Technique in Glaucoma Patients Journal of Glaucoma March 2012, Vol. 21, Issue 3; Hennessy, et. al., Eyedrop Instillation in Low-Vision Glaucoma Patients, 17 Ophthalmology Number 12 (2010); Stone et. al., An Objective Evaluation of eyedrop instillation in patients with glaucoma, Arch. Ophthalmology 2009; 127:732-6; Hennessy, Amy L., Joanne Katz, David Covert, Colleen Protzko, and Alan L. Robin (2010), "Videotaped Evaluation of Eyedrop Instillation in Glaucoma Patients with Visual Impairment or Moderate to Severe Visual Field Loss", Ophthalmology 2010; 117(12):2345-2352. 25 See footnote 24. 26 Deposition of Charlene Eike, March 7, 2014, p. 47; Deposition of Jordan Pitler, February 10, 2014, p. 38-42, Deposition of Shirley Fisher, February 24, 2014, p. 63; Deposition of Alan Raymond, February 27, 2014, p. 43-44. 27 Deposition of Alan Robin, M.D., August 6, 2014, pp. 406-407. 23 28 See 1144. 29 Deposition of Alan Robin, M.D., August 6, 2014, p. 274; see footnote 24. 12 Case 3:12-cv-01141-SMY-DGW Document 176-34 *SEALED* Filed 12/01/14 Page 15 of 64 Page ID #3154 Case: 16-3334 Document: 55-21 Filed: 02/08/2017 Pages: 64 (815 of 1511) Confidential — Subject to Protective Order 61. In spite of the difficulty in applying drops and/or applying a single drop, none of the four Plaintiffs has reported running out of medication early, suggesting that pharmaceutical manufacturers account for this variable in their bottle fill and that current bottles provide sufficient volume to last their intended duration.3° This speaks strongly against any intent by the pharmaceutical company to deliberately deliver drops in a fashion that causes patients to run out of medication early. 62. In over 30 years of clinical and academic practice, I do not recall a single patient complaining of ophthalmic drops being too large or requesting a smaller drop size. Drop Size Variation 63. Eye drop size also varies amongst the patient population based upon patient-use characteristics. Factors such as angle of administration, method of administration, temperature of the medication, and pressure placed on the bottle all affect drop size.31 64. Company drop size testing pursuant to standardized testing procedures does not reflect how patients instill drops in the "real world." The company drop size tests use laboratory personnel emitting drops at certain specified angles pursuant to specific procedures. The testing often involves operators emitting numerous drops consecutively. The laboratory personnel do not emit drops into their eyes and there is no indication their age and health characteristics are representative of the prescription eye drop patient population. Real-life patients do not administer eye drops in this manner. 65. I agree with the literature that states "Laboratory methods . . . will not be precisely applicable to actual clinical experience because of the vagaries of patient self-administration of topical ocular medications."32 This is because individual patient use characteristics cannot be controlled for in laboratory testing. Poor correlation with laboratory testing and real-world clinical application is more the rule than the exception. 66. I am unaware of any data that measures the drop sizes prescription eye drop patients emit on average when they self-administer their prescriptions in real-world settings. Dr. Robin said he is also unaware of any such data.33 I am similarly unaware of any data that shows real-world drop sizes for any of the prescription eye medications identified in the First Amended Complaint. Michael W. Belin, M.D. Dated: September 12, 2014 Deposition of Charlene Eike, March 7, 2014, p. 69; Deposition of Jordan Pitler, February 10, 2014, p. 48, Deposition of Shirley Fisher, February 24, 2014, p. 73-74; Deposition of Alan Raymond, February 27, 2014, p. 43-44. 31 Santvliet LV, Ludwig A. Influence of the Dropper Tip Design on the Size of Eye-Drops. Pharm Ind. 2001; 63:402-409; Santvliet LV, Ludwig A. Determinants of Eye Drop Size. Sum Ophthalmol. 2004; 49:208-213. 32 Lederer, et. al., Drop Size of Glaucoma Medication, Am. J. of Opthalmology 1986; 101:691-694. 33 Deposition of Alan Robin, M.D., August 6, 2014, pp. 404, 417. 3" 13 Case 3:12-cv-01141-SMY-DGW Document 176-34 *SEALED* Filed 12/01/14 Page 16 of 64 Page ID #3155 Case: 16-3334 Document: 55-21 Filed: 02/08/2017 Pages: 64 (816 of 1511) Confidential — Subject to Protective Order TABLE 1 COMPANY ALLERGAN ALCON CHEM NAME Bimatoprost Brimonidine Brimonidine TRADE NAME Lumigan Alphagan Alphagan P USEAGE Glaucoma Glaucoma Glaucoma Brimonidine / Timolol Combigan Glaucoma Levobunolol Betagan Glaucoma B blocker Solution Ketorolac Nedocromil Epinastine Alcaftadine Acular Alocril Elestat Lastacaft Allergy Allergy Allergy Allergy NSAID Mast cell Antihistamine Antihistamine Solution Solution Solution Solution Ketorolac Prednisolone Acular LS Pred Forte Inflammation Inflammation NSAID Steroid Solution Suspension Gatifloxacin Zymar Anti-infective Quinolone Solution Gatifloxacin Zymaxid Anti-infective Quinolone Solution Travaprost Travaprost Brinzolamide Betaxolol Betaxolol Apraclonidine Travatan Travatan Z Azopt Betoptic Betoptic S lopidine Glaucoma Glaucoma Glaucoma Glaucoma Glaucoma GLaucoma Solution Solution Suspension Suspension Suspension Solution Brinzolamide / Brimonidine Simbrinza Glaucoma Prostaglandin Prostaglandin CAI B blocker B blocker A adrenergic agonist CAI / Alpha 2 agonist Olopatadine Olopatadine Patanol Pataday Allergy Allergy Antihistamine Antihistamine Solution Nepafenac Tobramycin / Dexamethasone Tobramycin / Dexamethasone Neomycin, Polymycin, Dexamethasone Difluprednate Nevanac TobraDex Inflammation Inflammation Suspension Suspension TobraDex ST Inflammation Maxitrol Inflammation NSAID Anti-infective / Steroid Anti-infective / Steroid Anti-infective / Steroid Durezol Inflammation Steroid Emulsion Moxifloxacin Vigamox Anti-infective Quinolone Solution Moxifloxacin Moxeza Anti-infective Quinolone Solution 14 CLASS Prostaglandin Alpha 2 agonist Alpha 2 agonist Alpha 2 agonist B blocker PROPERTY Solution Solution Solution Solution Suspension Solution Suspension Suspension Case 3:12-cv-01141-SMY-DGW Document 176-34 *SEALED* Filed 12/01/14 Page 17 of 64 Page ID #3156 Case: 16-3334 Document: 55-21 Filed: 02/08/2017 Pages: 64 (817 of 1511) Confidential — Subject to Protective Order COMPANY CHEM NAME Tobramycin / Dexamethasone TRADE NAME TobraDex USEAGE Anti-infective / Steroid CLASS PROPERTY Suspension Timolol Timolol GFS (Timoptic) (Timoptic) Glaucoma Glaucoma B blocker Solution ALCON GENERIC B blocker Gel B blocker Prostaglandin Solution Solution Solution Solution Solution Carteolol (Ocupress) Glaucoma Latanoprost Metipranolol Dorzolamide Dorzolamide / Timolol Ciprofloxacin Trifluridine (Xalatan) (OptiPranolol) (Trusopt) (Cosopt) Glaucoma (Cipro) (Viroptic) Anti-infective Anti-viral B blocker CAI CAI & B blocker Quinolone Anti-viral Brimonidine Dorzolamide Timolol (Alphagan) (Trusopt) Istalol Glaucoma Glaucoma Glaucoma Alpha 2 agonist CAI B blocker Solution Solution Solution Besifloxacin Tobramycin / Loteprednol Besivance Anti-infective Quinolone Zylet Anti-infective / Steroid Suspension Suspension Loteprednol Lotemax Steroid Suspension Bromfenac Bromaday Antiinflammatory Antiinflammatory NSAID Solution Loteprednol Bepotastine Alrex Bepreve Allergy Steroid antihistamine Suspension Allergy Latanoprost Xalatan Glaucoma Prostaglandin Solution Dorzolamide Dorzolamide & Timolol Trusopt Cosopt Glaucoma Glaucoma CAI CAI & B blocker Solution Solution Azithromycin Azasite Anti-infective Macrolide Gel Glaucoma Glaucoma Glaucoma Solution ** Solution BAUSCH & LOMB Solution PFIZER MERCK, SHARPE & DOHME 15 Case 3:12-cv-01141-SMY-DGW Document 176-34 *SEALED* Filed 12/01/14 Page 18 of 64 Page ID #3157 Case: 16-3334 Document: 55-21 Filed: 02/08/2017 Pages: 64 (818 of 1511) MICHAEL WELLINGTON BELIN, M.D., FACS, FRANZCO Professor of Ophthalmology & Vision Science University of Arizona Health Sciences 4232 West Summer Ranch Place Marana, AZ 85658-4741 Email MWBelineaol.com Cell (518) 527-1933 EDUCATION: Undergraduate Northwestern University, Evanston, Illinois - majored in BioMedical Engineering, 1971-1974 Medical School College of Medicine and Dentistry of New Jersey - Rutgers Medical School, Piscataway, New Jersey, 1974-1978 INTERNSHIP: Categorical-Diversified in Internal Medicine, Albany Medical College, Albany, New York, 1978-1979 RESIDENCY: Ophthalmology, Albany Medical College, Albany, New York, 1979-1982 Chief Resident 1981-1982 FELLOWSHIP: Corneal and External Disease, University of Iowa, Iowa City, Iowa, 1982-1983, Heed Fellow Jay H. Krachmer, M.D. - Medical Director, Iowa Lions Cornea Center Frederick D. Blodi, M.D. - Chairman Royal College of Surgeons of England Foundation, Travelling Fellowship recipient, 1990 Schaffer Fellowship recipient - Albany Medical College, 1990 APPOINTMENTS: Food and Drug Administration - Anti-Infective Drugs Advisory Committee - Consultant, 1989 Committee member, 1990 - 1992 Consultant (SGE), 1992 - 1995 Food and Drug Administration - Ophthalmic Device Committee Consultant (SGE), 1994- 2002 ANSI Z80 Committee American Academy of Ophthalmology 1 EXHIBIT A Case 3:12-cv-01141-SMY-DGW Document 176-34 *SEALED* Filed 12/01/14 Page 19 of 64 Page ID #3158 Case: 16-3334 Document: 55-21 Filed: 02/08/2017 Pages: 64 (819 of 1511) Honor Award 1988 Senior Honor Award 1998 Councilor 2002 to 2005 & 2007 to present Secretariat Achievement Award 2002 Secretariant Award 2009 Life Achievement Honor Award 2009 Honorary Professor of Ophthalmology, Liaoning Shenyang Northern Hospital, Shenyang, China Basic and Clinical Science Course Faculty, Section 8 - External Disease and Cornea. 1980 - 1992 Section Chairman, 1987 — 1992 Focal Points - Clinical Modules for Ophthalmologists - Editorial Review Board, 1992 - 1997 Editor-in-Chief, 1997 to 2003 Basic and Clinical Science Course Faculty, Refractive Surgery — 2002 to present Committee on Ophthalmic Procedures Assessment Refractive Surgery Panel - Methodologist, 1995 - 2000 Committee on Technology Assessment (OTAC) Corneal Panel - 1996 — present Committee Chair — 2001 — present Self Assessment Panel — Cornea Team Leader Medical Director — TLC Laser Eye Center — Albany, NY Associate Examiner American Board of Ophthalmology, Bala Cynwyd, Pennsylvania American University Professors of Ophthalmology — Fellowship Oversight Committee Vice-Chair — Fellowship Review Committee Medical Director - Albany LCA Laser Vision Center Adjunct Professor of Ophthalmology, University of Ottawa, Ottawa, Ontario, Canada, 1997 Professor of Ophthalmology (with tenure), Albany Medical College, 1996 Case 3:12-cv-01141-SMY-DGW Document 176-34 *SEALED* Filed 12/01/14 Page 20 of 64 Page ID #3159 Case: 16-3334 Document: 55-21 Filed: 02/08/2017 Pages: 64 (820 of 1511) Associate Professor of Ophthalmology, Albany Medical College, 1989 - 1996 Program Director - Department of Ophthalmology, Albany Medical College, 1990 - 1995 State of New York Education Department - Therapeutic Pharmaceutical Agents (TPA) Education Review Committee Eye Bank Association of America - National Advisory Council Meetings & Program Committee - Chairman Accreditation Committee (1994 - 2000) Scientific Program Committee (Chairman) (1992 - 1995) Research Committee (1992 - 1995) Scientific Program Committee (Chairman) ( 2002 to 2004) Board of Directors (2005 to present) Executive Committee Medical Director - Lions Albany Eye Bank, 1990 - present Stratton Veterans Administration Medical Center Employed since 1989 — Current grade (15/10) Chief of Service, Division of Ophthalmology, 1989 - 1990 Assistant Professor of Ophthalmology George Washington University, 1983 - 1989 Assistant Professor of Child Health & Development George Washington University, 1983 - 1989 Assistant Professor of Pediatrics George Washington University, 1989 Cornea and External Disease Consultant, Department of the Navy - Navy Medical Command, National Capital Region, Bethesda, Maryland Medical Director - District of Columbia Lions Eye Bank, 1984-1985 Cornea and External Disease Consultant, Childrens Hospital National Medical Center, Washington, D.C. (1983-9) Tissue Banks International - Washington Eye Bank, Medical Advisory Board (1986-9) Case 3:12-cv-01141-SMY-DGW Document 176-34 *SEALED* Filed 12/01/14 Page 21 of 64 Page ID #3160 Case: 16-3334 Document: 55-21 Filed: 02/08/2017 Pages: 64 (821 of 1511) Editorial Board Asia Pacific Journal of Ophthalmology Editorial Board International Journal of Keratoconus and Ectatic Corneal Diseases Editorial Board Saudi Journal of Ophthalmology COMMITTEES: Dialysis and Transplantation Committee (1984-9) Committee on Human Research (IRB) (1988-9) Committee on Sponsored Research (1987-8) Professional Economics Committee (1987-9) Graduate Medical Education Committee (1990 - current) Alden March Care Governing Council (1990 - 1993) SOCIETIES: American Academy of Ophthalmology - Fellow Senior Honor Award recipient 1998 BCSC Cornea & External Disease Section Chairman 1987-92 Honor Award recipient 1988 Focal Points Module Editor-in-Chief 1997 — 2002 BCSC Refractive Surgery 2002 - 2008 Councilor 2002 to present Secretariat Award 2002 Secretariant Award for International Relations 2009 Lifetime Achievement Award 2009 Royal Australian & New Zealand College of Ophthalmologists (International Member) AAO Representative to Australia & New Zealand Canadian Ophthalmological Society (International Member) Association of University Professors of Ophthalmology (AUPO) Associate Member (1990 - 1995) Fellowship Compliance Committee Vice-Chair Fellowship Review Committee Heed Ophthalmic Foundation (Fellowship Recipient) Cornea Society (formerly Castroviejo Corneal Society) 4 Case 3:12-cv-01141-SMY-DGW Document 176-34 *SEALED* Filed 12/01/14 Page 22 of 64 Page ID #3161 Case: 16-3334 Document: 55-21 Filed: 02/08/2017 Pages: 64 (822 of 1511) Full member with Thesis Board of Directors (2000-4) AAO Councilor 2002 to present President 2006 — 8 Executive Committee 2004 to present Chair International Relations VP for Development 2008 to present American College of Surgeons - Fellow Eye Bank Association of America Chair Scientific Program Committee 1995-98 Chair Scientific Program Committee 2002 — 2004 Accreditation Committee (past) Chair Research Committee Executive Committee House of Delegates I.S.R.K (International Society of Refractive Keratoplasty) A.R.V.O. (Association for Research in Vision and Ophthalmology) Royal Society of Medicine of England - Affiliate member C.L.A.O. (Contact Lens Association of Ophthalmologists) R. Townley Paton Society A.S.C.R.S. (American Society of Cataract and Refractive Surgery) Chairman ASCRS FDA Committee American Medical Association LICENSURE: Arizona # 40790 New York, # 138408 Iowa, # 22961 (Inactive) District of Columbia, # 14075 (Inactive) PUBLICATIONS: Belin MW, Baltch AL, Hay PB: Secondary Syphilitic Uveitis, American Journal of Ophthalmology, 92:210-211, 1981 External Disease and Cornea - Section 7. Ophthalmology Basic 5 Case 3:12-cv-01141-SMY-DGW Document 176-34 *SEALED* Filed 12/01/14 Page 23 of 64 Page ID #3162 Case: 16-3334 Document: 55-21 Filed: 02/08/2017 Pages: 64 (823 of 1511) and Clinical Science Course. American Academy of Ophthalmology, editions - 1980 - present Krachmer JH, Feder RS, Belin MW: Keratoconus and Related Non-inflammatory Corneal Thinning Disorders, Survey of Ophthalmology 28:293-322, 1984 Belin MW, Kersten R: Double Ended Needle Holder for Anterior Segment Surgery, Archives of Ophthalmology 102:1093, 1984 Brownstein S, Belin MW, Krohel GB, Smith RS, Condon G, Codere F: Orbital Dacryops. Ophthalmology 91:1424-1428, 1984 Belin MW, Krachmer JH: Chemical Burns of the Cornea. In External Eye Disease, Easty DL, Smolin G (ed), Kent; Butterworth & Co., LTD, London, pp. 288-309, 1985 Manarino A, Belin MW, Weiner BM: Clinical Fitting Characteristics of Extended Wear Silicone (Silsight) Lenses. CLAO Journal 11:339-342, 1985 Belin MW, Hannush SB: Mucous Membrane Abnormalities. Surgical Intervention in Corneal and External Diseases, Abbott RL (ed),Grune and Stratton, Inc., Orlando, Florida, Chapter 12, pp. 159-176, 1987 Belin MW, Fowler WC, Chambers WA: Keratoconus: Evaluation of Recent Trends in the Surgical and Non-surgical Correction of Keratoconus. Ophthalmology 95:335-338, 1988 Chambers WA, Belin MW, Parenti DM, Simon GL: Corneal Ulcers in House Staff. Are Risk Factors Identifiable? Annals of Ophthalmology 20:172-175, 1988 Bouchard CS, Belin MW: Topical Cyclosporin A: Improved Graft Survival in High Risk Corneal Transplant Patients (abstract). Inv. Ophthalmol Vis Sci(Suppl) 29:450, 1988 Fowler WC, Belin MW, Chambers WA: Contact Lenses in the Visual Correction of Keratoconus. CLAO Journal 14(4):203206,1988 Belin MW, Bouchard CS. Topical Cyclosporin A in High Risk Corneal Transplantation (abstract). Ophthalmology (Suppl) 95:160, 1988 Case 3:12-cv-01141-SMY-DGW Document 176-34 *SEALED* Filed 12/01/14 Page 24 of 64 Page ID #3163 Case: 16-3334 Document: 55-21 Filed: 02/08/2017 Pages: 64 (824 of 1511) Belin MW: Optical and Surgical Correction of Keratoconus - Focal Points: Clinical Module for Ophthalmologists. American Academy of Ophthalmology. Vol VI, Module 11, 1988 Olkowski JD, Belin MW, Bozkir NI, Mannarino AP: Unilateral Graft Rejection in Bilateral Antigen Identical Corneal Transplants. Cornea 8(3):230-232, 1989 Belin MW, Bouchard CS, Frantz S, Chmielinska J: Topical Cyclosporine in High Risk Corneal Transplants. Ophthalmology 96(8):1144-1150, 1989 Bouchard CS, Belin MW: Immunohistologic Findings and Results of Treatment with Cyclosporine in Ligneous Conjunctivitis (Correspondence). American Journal of Ophthalmology 108:210211, 1989 Bouchard CS, Belin MW: The Use of Topical Cyclosporine in High Risk Corneal Transplants. Ophthalmology 97(6):691-694, 1990 Belin MW, Bouchard CS, Phillips TM: Update on Topical Cyclosporin A: Background, Immunology, Pharmacology. Cornea 9(3):184-195, 1990 Litoff D, Belin MW, Winn SS, Smith RS: PAR Technology Corneal Topography System (abstract). Inv. Ophthalmol Vis Sci 32(Suppl):922, 1991 Belin MW, Litoff D, Winn S, Smith RS: The PAR Corneal Topography System. Refractive and Corneal Surgery 8:88-96, 1992 Catalano R, Belin MW (assoc.ed.): Ocular Emergencies, W. B. Saunders Co., Philadelphia, 1991 Belin MW: Non-herpetic Leukoma in Corneal Surgery: Theory, Technique and Tissue ed.2 Brightbill FS (2nd edition.). C.V. Mosby, St. Louis, Missouri, chapter 11, pp. 129-132. Belin MW, Zloty P: Accuracy of the PAR Corneal Topogaphy System with Spatial Misalignment. CLAO Journal 19:64-68, 1993. Belin MW: Intraoperative Raster Photogrammetry - The PAR Corneal Topography System. Journal of Cataract and Case 3:12-cv-01141-SMY-DGW Document 176-34 *SEALED* Filed 12/01/14 Page 25 of 64 Page ID #3164 Case: 16-3334 Document: 55-21 Filed: 02/08/2017 Pages: 64 (825 of 1511) Refractive Surgery 19:188-192, 1993. Zloty P, Belin MW: Pseudomonas Ocular Infections in Pseudomonas Aeruginosa: Infections and Treatment. BaItch AL, Smith RP (ed.). Marcell Dekker Inc., New York, N.Y. 1994: 371-399. Belin MW: Consultation Section. Journal of Cataract & Refractive Surgery 20:202, 1994 Belin MW,Hannush SB, Maloney RK, Riveroll L: Evaluation of Computerized Video-Keratoscopy Decentering and Defocusing Error. Cornea 14:109, 1995. Zobal-Ratner JL, Simon JW, Follett S, Zloty P, Belin MW, Turok D: Serious Ocular Burns from the Wood Ash of Fireplaces and Woodstoves. Trans American Assoc for Ped Ophthalmol and Strab, CRC Press, Boca Raton, 1995, pp 471-73 Wilson SE, Auran JD, Moazami C, Feldman ST, VanMeter WS, Belin MW, et.al.: Hepatitis C Virus (HCV) - Associated Mooren's Corneal Ulcers: Collaborative Study. Cornea 14:109110, 1995. Mozayeni RM, Ditkoff J, Belin MW: Long Term Retrospective Analysis of Corneal Transplants with Molteno Implants. Cornea 14:116, 1995 Belin MW, Ratliff CD, Ditkoff J: Comparison of Color Topometry, Rasterphotogrammetry and Standard Black and White Videokeratography in the Analysis of Severely Distorted Corneas. Cornea 14:117, 1995. Gordon JF, Johnson P, Musch DC, et.al.: Topical Fibronectin Ophthalmic Solution in the Treatment of Persistent Defects of the Corneal Epithelium. Am J Ophthalmol 119:281-287, 1995 Belin MW, Cambier JL, Nabors JR: PAR Corneal Topography System in Corneal Topography: The State of the Art. Slack Inc., Thorofare, N.J., 1995, pp. 105-120. El Hage SG, Salz JJ, Belin MW, Costin JA, Gressel MG.: Corneal Topography as Measured by the EyeMap EH-270 in Corneal Topography: The State of the Art. Slack Inc. Thorofare, N.J., 1995, pp. 37-52. Case 3:12-cv-01141-SMY-DGW Document 176-34 *SEALED* Filed 12/01/14 Page 26 of 64 Page ID #3165 Case: 16-3334 Document: 55-21 Filed: 02/08/2017 Pages: 64 (826 of 1511) Ratliff CD, Belin MW: Ehlers Danlos Syndrome in Diseases of the Eye and Skin. Mannis MJ, Macsai MS, Huntley AC (ed.). Lippincott-Raven Press, New York, N.Y. 1995, pp. 45-53. Belin MW, Cambier JL, Nabors JR, Ratliff CD: PAR Corneal Topography System: The Clinical Application of Close-Range Photogrammetry. Optom and Visual Science, 72:828-837, 1995. . Lee JJ, Belin MW: Comparison of Subjectively Refracted Cylinder, Topographic Cylinder, and Topographic Guided Refractive Cylinder in Normal Patients. CORNEA, 15(2):220, 1996. Aghai M, Mozayeni R, Belin MW: The Effect of Donor Variables in Graft Viability. CORNEA, 15(2):224-5, 1996. Belin MW, Hannush SB: Computerized Corneal Modeling in Recent Advances in Ophthalmology. Kirkness CM, Jay B (ed.). Churchill Livingstone, London, England, 1995, pp. 205-214. Belin MW, Ratliff CD: Evaluating Data Acquisition and Smoothing Functions of Currently Available Videokeratoscopes. J Cataract Refract Surq 22:421-426, 1996. Belin MW: Assessment of Refractive Surgical Procedures. Point of View - International Ophthalmic Journal (Italy), 4:13-16, 1996 Belin MW, Ratliff CD: Anterior Segment Rehabilitation after Trauma: In Krachmer JH, Mannis MJ, Holland EJ (ed.): CORNEA, Mosby Yearbook, St.Louis, 1997, pp. 1947-56. Belin MW, Cambier JL, Nabors JR, Zloty P: Rasterphotogrammetry and the PAR System (PAR CTS) of Corneal Topography In Elander R, Rich L, Robin J (ed.): Principles and Practice of Refractive Surgery, W.B.Saunders Co., Philadelphia, PA, 1997, pp. 525 - 535. Rich LF, MacRae S, Belin MW: Laser Surgeries: Instrumentation In Elander R, Rich LF, Robin J (ed.): Principles and Practice of Refractive Surgery, W. B. Saunders Co., Philadelphia, PA 1997, pp. 321- 326. Simon JW, Miter D, Zobal-Ratner JZ, Hodgetts D, Belin MW: Corneal Edema after Pediatric Cataract Surgery. J AAPOS 1997; 1:102-4. Belin MW, Missry JM: Corneal Topography: Current Systems Case 3:12-cv-01141-SMY-DGW Document 176-34 *SEALED* Filed 12/01/14 Page 27 of 64 Page ID #3166 Case: 16-3334 Document: 55-21 Filed: 02/08/2017 Pages: 64 (827 of 1511) and Emerging Technologies In Wu, Steinert, Clade, Thompson, Hersch (ed.): Refractive Surgery Textbook, Thieme, New York, N.Y. Belin MW: Evaluating Refractive Surgery: What is the Appropriate Baseline. Arch Ophthalmol. 1998; 116:1104-5. The Cornea (book review). Arch Ophthalmol. 1999; 117:551 Corneal Topography: Ophthalmic Procedure Preliminary Assessment. Ophthalmology 1999; 106: 1628-1638 Price FW, Belin MW, Nordan LT, McDonnell PJ, Pop M: Epithelial Haze, Punctate Keratopathy, and Induced Hyperopia after Photorefractive Keratectomy for Myopia. J Refract Surg. 1999; 15(3): 384-7 The Cornea on CD-ROM (book review) Arch Ophthalmol. 1999; 117: 988 Companion Handbook to the Cornea (book review) Arch Ophthalmol. 2000; 118: 1009 Belin MW, Schultze RL: Microkeratomes. International Ophthalmology Clinics 2000; 40 (3): 57-66 Belin MW, et. al. Elevated Intraocular Pressure Induced Interlamellar Stromal Keratitis. Ophthalmology 2002;109:19291933 Belin MW. Evaluation of Emerging Refractive Technologies. International Ophthalmology Clinics Vol 42, #4, Fall 2002 Kaufman SC, Musch DC, Belin MW, et al. Confocal Microscopy OTAC. Ophthalmology 2004; 111:396-406 Cornea Donor Study Group. Baseline Donor Characteristics in the Cornea Donor Study (CDS). Cornea 2005; 24(4):389 — 396 Cornea Donor Study Group. An Evaluation of Image Quality and Accuracy of Eye Bank Measurement of Donor Cornea Endothelial Cell Density in the Specular Microscopy Ancillary Study. Ophthalmology 2005; 112:431-440. Mannis MJ, Holland EJ, Beck RW, Belin MW, Goldberg MA, Gal RL, Kalajian AD, Kenyon KR, Kollman C, Ruedy KJ, Smith P, 10 Case 3:12-cv-01141-SMY-DGW Document 176-34 *SEALED* Filed 12/01/14 Page 28 of 64 Page ID #3167 Case: 16-3334 Document: 55-21 Filed: 02/08/2017 Pages: 64 (828 of 1511) Sugar J, Stark WJ; Cornea Donor Study Group. Clinical profile and early surgical complications in the Cornea Donor Study. Cornea. 2006 Feb;25(2):164-70. Khachikian SS, Morason RT, Belin MW, Mishra G. Thin Head and Single Use Microkeratomes Reduce Epithelial Defects During LASIK" J Refract Surg. 2006;22:482-485 Pentacam Corneal Topography in Wing M (ed): Corneal Topography in the Wavefront Era: A Guide for Clinical Application, Slack Publishing, Thorofare, NJ, 2006 Ciolino J, Belin MW: Changes to the Posterior Cornea after LASIK and PRK. J Cataract & Refract Surg 2006; 32 (9): 1426-31 Zerbe B, Belin MW, Ciolino J: Results from the Multi-Center Boston Keratoprosthesis Type 1 Study Group. Ophthalmology 2006; 113: 1779 - 1784 Belin MW, Khachikian SS: New Devices & Clinical Implications for Measuring Corneal Thickness. Clin & Exp Ophthalmol 2006; 34: 729-731 Belin MW, Khachikian SS: Keratoconus: I know it when I see it.. Amer J Ophthal. Am J Ophthalmol 2007; 1143:500 - 503 Abad JC, Rubinfeld RK, Del Valle M, Belin MW, Kurstin JM. Vertical D: A novel Topograhic Pattern in Keratoconus Suspects. Ophthalmbodv 2007; 114:1020-1026 Belin MW, Khachikian SS. Corneal Diagnosis and Evaluation with the OCULUS Pentacam. Highlights of Ophthalmology 2007; 35 (2):5 - 7, 2007 Ciolino JB, Khachikian SS, Belin MW. Long-Term Stability of the Posterior Cornea after Laser Insitu Keratomileusis, J Cataract Refract Sur. 2007 Aug; 33(8): 1366-70 Belin MW, Khachikian SS. New Developments in Corneal Topograpy. Vision Pan-America, Journal of the Pan-American Association of Ophthalmology Vol 6;3 : 6 — 9, 2007 Belin MW, Khachikian SS. Refractive Surgery & Corneal Disease. GOZDER: Ozel Goz Hastaneleri ve Merkezleri Dernegi Bulteni (Turkey) 11 Case 3:12-cv-01141-SMY-DGW Document 176-34 *SEALED* Filed 12/01/14 Page 29 of 64 Page ID #3168 Case: 16-3334 Document: 55-21 Filed: 02/08/2017 Pages: 64 (829 of 1511) Ciolino JB, Khachikian SS, Belin MW "Comparison of Corneal Thickness Measurements by Ultrasound and Scheimpflug Photography in Eyes that have undergone LASIK" Amer J Ophthal, 2008; 45:75-80 Khachikian SS, Belin MW, Ciiolino JB. Intrasubject Pachymetric Asymmetry Analysis. J Refract Surg, 2008; 24:606-609 Szczotka-Flynn L, Slaughter M, McMahon T, Barr J, Edrington T, Fink B, Lass J, Belin MW, Lyengar S, CLEK Study Group. Disease Severity and Family History of Keratconus. Br J Ophthalmol. 2008 Aug;92(8): 1108-11. Walker RN, Khackikian SS, Belin MW. Scheimpflug Imaging of Pellucid Margainal Degeneration. CORNEA 2008 Sep; 27(8):963-6 Belin MW. Keratoconus and Pre-Operative Screening. Expert Review in Ophthalmology. London (in press) Cornea Donor Study Investigator Group. The effect of donor age on corneal transplantation outcome: results of the cornea donor study. Ophthalmology 2008: Accepted for publication. Cornea Donor Study Investigator Group. Donor age and corneal endothelial cell loss five years after successful cornea transplantation: specular microscopy ancillary study results. Ophthalmology 2008: Accepted for publication. Weiss JS, Moller H. Lisch W, et al. The IC3D Classification of Corneal Dystrophies. CORNEA 2008:27:S1-S42 Khachikian SS, Belin MW. Normal Values for Corneal Elevation using Scheimpflug Topography. (accepted for publication Clinical & Experimental Ophthalmology (CEO)) Hannush SB, Belin MW "Pressure-Induced Interlamellar Stromal Keratitis" in Management of Complications in Refractive Surgery, Springer, Berlin, Germany, 2008. Pp 47 - 49 Elevation Based Topography: Screening for Refractive Surgery. Belin MW, Khachikian SS (Editors). Highlights of Ophthalmology, City of Knowledge, Panama, 2008 Belin MW, Khachikian SS. Comparison of Anterior Chamber diameter measurements made by Scheimpflug photography and OCR, with automated white to white measurements. Clinical & 12 Case 3:12-cv-01141-SMY-DGW Document 176-34 *SEALED* Filed 12/01/14 Page 30 of 64 Page ID #3169 Case: 16-3334 Document: 55-21 Filed: 02/08/2017 Pages: 64 (830 of 1511) Experimental Ophthal 2008; 36 (Suppl 2) A725 Belin MW, Khachikian SS. (ed) Elevation Based Topography. Highlights of Ophthalmology, City of Hope, Panama, 2008 Imaging the Anterior Segment: FOCAL POINTS VolumeXXVII # 11, Dec. 2009, Belin MW (Consultant) Belin MW, Khachikian SS. An Introduction to Understanding Elevation-Based Topography: How Elevation Data are displayed. Clin & Exp Ophthalmol. 2009; 37: 14-29 Khachikian SS, Belin MW. Posterior elevation in keratoconus. Ophthalmology. 2009;116:816 What is the Best Way to Determine the Residual Stromal Bed. Curbside Consults in Refractive Surgery. Slack Publishing (in press) Khachikian SS, Belin MW. Clinical Characteristics of Keratoconus in Wang M, Swartz TS. Keratoconus and Kertatoectasia: Prevention, Diagnosis & Treatment. Slack Inc. 2009, Thorofare, New Jersey pp 43-50. Kwon RO, Price MO, Price FW, Ambrosio R, Belin MW. Pentacam Characterization of Corneas with Fuchs'Dystrophy Treated with Descemet Membrane Endothelial Keratoplasty (DMEK). J Refract Surg 2010; 26(12):972-979. Belin MW. Applications of Anterior Segment Tomography in Corneal Surgery. Highlights of Ophthalmology 2010; 2: 15 — 20. Ciolino JB, Comyn 0, Liu C, Belin MW. Types and Techniqus of Keratoprosthesis in The CORNEA. Krachmer J, Mannis MJ, Holland EJ (ed). In press Belin MW, Ambrosio R. Corneal Ectasia Risk Score System — "Statistical Validity and Clinical Relevance" J Refract Surg 2010; 26(4): 238 — 240 New technology in corneal imaging. Belin MW, Khachikian SS, McGhee CN, Patel D. Int Ophthalmol Clin. 2010 Summer;50(3):177-89. Ambrosio R, Belin MW. Imaging of the Cornea: Topography vs Tomography. J Refract Surg 2010: 26(11): 847 - 849 13 Case 3:12-cv-01141-SMY-DGW Document 176-34 *SEALED* Filed 12/01/14 Page 31 of 64 Page ID #3170 Case: 16-3334 Document: 55-21 Filed: 02/08/2017 Pages: 64 (831 of 1511) Ambrosio R Jr, Dawson DG, Salomao M, Guerra FP, Caiado ALC, Belin MW. Corneal Ectasia after LASIK despite low risk: Evidence of Enhanced Sensitivity based on Tomographic and Biomechanical Findings on the unoperated stable fellow eye. J Refract Surg 2010; 26(11): 906-911 Khachikian SS, Belin MW. Bilateral corneal ectasia after laser in situ keratomileusis in patient with isolated difference in central corneal thickness between eyes. (letter to the Editor) J Cataract Surg 2010; 36(11): 2015 Kim JT, Cortese M, Belin MW, Khachikian SS, Ambrosio R Jr. Tomopgraphic Normal Values for Corneal Elevation and Pachymetry in a Hyperopic Population. J Clinic Experiment Ophthalmol 2011, 2:130 http://dx.doi.org/10.4172/21559570.1000130 Belin MW, Khachikian SS, Ambrosio R Jr. The Use of Intracorneal Rings for Pellucid Marginal Degeneration (letter to the Editor). Am J Ophthalmol 2011; 151(3): 558-559 Ambrosio R Jr., Nogueira LP, Caldas DL, Fontes BM, Luz A, Cazal JO, ALves MR, Belin MW. Evaluation of Corneal Shape and Biomechanics prior to LASIK. International Ophthalmology Clinics 2011; 51:11 — 38 Feng MT, Belin MW, AmbrOsio R, Grewal SPS, Yan W, Shaheen MS, McGhee C, Maeda N, Neuhann TH, Burkhard Dick H, Alageel SA, Steinmueller A, Anterior Chamber Depth in Normal Subjects by Rotating Scheimpflug Imaging, Saudi Journal of Ophthalmology 2011; 25(3): 255-259. doi:http://dx.doi.org/10.1016/j.sjopt.2011.04.005 Todani A, Ciolino JB, Ament JD, Colby KA, Pineda R, Belin MW, Aquavela JV, Chodosh J. Titanium Back Plate for a PMMA Keratoprosthesis Clinical Outcomes. Graefes Arch Clin Exp Ophthalmol (accepted for publication) DOI 10.1007/s00417-0111684-y Belin MW. Syphilitic Retinitis and Uveitis (Correspondence). Clin & Experimental Ophthalmoogy (CEO) 2011; 39(7): 716 Belin MW, Asota IM, Ambrosio R Jr, Khachikian SS. What's in a name: Keratoconus, Pellucid Marginal Degeneration and Related Thinning Disorders. Am J Ophthalmol 2011; 152(2): 157-162 14 Case 3:12-cv-01141-SMY-DGW Document 176-34 *SEALED* Filed 12/01/14 Page 32 of 64 Page ID #3171 Case: 16-3334 Document: 55-21 Filed: 02/08/2017 Pages: 64 (832 of 1511) Feng MT, Belin MW, Ambrosio R, et. al. International Values of Corneal Elevation in Normal Subjects by Rotating Scheimpflug Camera. J Cataract & Refract Surg 2011; 37(10): 1817-1821 Ambrosio R Jr, Caiado AL, Guerra FP, Lousada R, Roy AS, Dupps WJ, Belin MW. Novel Pachymetric Parameters Based on Corneal Tomography for Diagnosing Keratoconus. J Refract Surg 2011; 27(10): 753-758 Stulting RD, Sugar A, Beck R, Belin MW, Dontchev M, et. al. Effect of Donor and Recipient Factors on Corneal Graft Rejection. (Accepted for publication J Cornea) Feng MT, Kim JT, Ambrosio R, Belin MW, et. al. International Values of Central Pachymetry in Normal Subjects by Rotating Scheimpflug Camera. Asia Pac J Ophthalmol 2012; 00-5 Correia FF, Ramos I, Lopes B, Salomao MQ, Luz A, Correa RO, Belin MW, Ambrosio R. Topometric and Tomographic Indies for the Diagnosis of Keratoconus. Int J Kerat Ect Cor Dis 2012; 1(2):92-99 Khachikian SS, Belin MW. Ectatic Diseases of the Cornea: Keratoconus, Pellucid Marginal Degeneration & Keratoglobusl. In Afshari NA, RA Copeland (ed). Jaypee Brothers Medical Publishers (in press) Belin MW, Kim J, Zloty P, Ambrosio R. Simpplified Nomenclature for Describing Keratoconus. International Journal on Keratoconus & Ectatic Disease (in press) Rudnisky CJ, Belin MW, Todani A, Zerbe BJ, Ciolino JB. Risk Factors for the Development of Retroprosthetic Membranes with Boston Keratoprosthesis. Ophthalmology 2012;119: 951-955 Belin MW. Preventing Post-operative Surprises in Refractive Surgery: Use of Scheimpflug Cross-Sectional Imaging & More. in New Tendencies in Modern Ophthalmology. Jaypee-Highlights Medical Publishers (in press) Belin MW, Grant L: Conceitos Basicos para Tomografia de Elevagao da Cornea. In AmbrOsio Jr R, Netto MV, Fontes BM, Chalita MR, Shor P, Chamon W (eds): Wavefront, Topografia e Tomografia de C6rnea e Segmento Anterior, 2nd Ed. Rio de Janeiro. Cultura Medica. 2012. 15 Case 3:12-cv-01141-SMY-DGW Document 176-34 *SEALED* Filed 12/01/14 Page 33 of 64 Page ID #3172 Case: 16-3334 Document: 55-21 Filed: 02/08/2017 Pages: 64 (833 of 1511) Ambrosio R, Ramos I. Luz A, Garia FC, Steinmgilueller A, Krug M, Belin MW, Roberts CJ. Dynamic Ultra High Speed Scheimpflug Imaging for Assessing Cornal Biomechanical Properties. Rev Bras Oftalmol. 2013; 72(2):99-102 Ciolino JB, Belin MW, Todani A, AL-Arfaj K, Rudnisky CJ. Boston Keratoprosthesis Type 1 Retention Rates: Multicenter Study Results. Ophthalmology 2013; 120:1195-1200 Ramos IC, Belin MW, Valbon BF, Luz A, Pimentel LN, Caldas DL, Ambrosio R. Keratoconus Associated with Corneal Guttata. Int J Kerat Ect Cor Dis 2012; 1(3):173-178 Lopos B, Ramos IC, Correia FF, Luz A, Valbon BF, Belin MW, Ambrosio R. Correlation of Topometric and Tomographic Indices with Visual Acuity in Patients with Keratoconus. Int J Kerat Ect Cor Dis 2012; 1(3):167-172 Ramos IC, Correa R, Guerra FP, Trattler W, Belin MW, et. al. Variability of Subjective Classifications of Corneal Topography Maps from LASIK Candidates. J Refract Surg. 2013;29(11):770Zloty P, Villavicencio 0, Belin MW. Aggressive Debridement Improves Outcome of Fungal Keratitis. Asia Pacific Journal of Ophthalmology 2(4):217-220, July/August 20113 DOI: 10.1097/APO.0b013e3182993f4b Belin MW, Ambrosio R Jr. Scheimpflug Imaging for Keratoconus and Ectatic Disease. Indian J Ophthalmol 2013; 61(8): 401 — 406. DOI: 10.4103/0301-4738.116059 Gilani F, Cortese M, Ambrosio RR Jr, Lopes B, Ramos I, Harvey EM, Belin MW. Comprehensive Anterior Segment Normal Values Generated by Rotating Scheimpflug Tomography. J Cat Refract Surg 2013; 39(11):1707-1712 Gao Minghong, Belin MW. Boston Type 1 in Severe Chemical and Therman Burns. Trauma and Critical Care Medicine 2013; 1(1):5456 Belin MW, Hannush SB, Endothelial Keratoplasty: Prospective, Randomized, Maksed Clinical Trial Comparing an Injector with Forceps for Tissue Insertion (correspondence). Am J Ophthalml 2013; 156(12): 1318 16 Case 3:12-cv-01141-SMY-DGW Document 176-34 *SEALED* Filed 12/01/14 Page 34 of 64 Page ID #3173 Case: 16-3334 Document: 55-21 Filed: 02/08/2017 Pages: 64 (834 of 1511) Ambrosio R, Belin MW, et. al. Enhanced Ectasia Screening (EES): the need for advanced and objective data. J Refract Surg. 2014; 30(3): 151-152 Villavicencio 0, Belin MW, Ambrosio R Jr, Steinmueller A. Corneal Pachymetry: New Ways to Look at an Old Measurement. J Cat Refract Surg (accepted for publication) Srikumaran D, Munoz B, Aldave AJ, Aquavella JV, Hannush SB, Schultze R. Belin MW, Akpek EK. Long-term Outcomes of Boston Type 1 Keratoprosthesis Implantation: A Retrospective Multicenter Cohort . Ophthalmology (accepted for publication) Villavicencio OF, Gilani F, Henriquez MA, Izquierdo L Jr, Ambrosio RR Jr, Belin MW. Independent Population Validation of the Belin/Ambrosio Enhanced Ectasia Display: Implications for Keratoconus Studies and Screening. Int J Keratoconus Ectatic Dis 2014;2(2) in press. Yu J, Belin MW, Huang Y, Advances in Keratoprosthesis (submitted for publication) Salomao MQ, Ambrosio R Jr, Khachikian SS, Belin MW. Clinical Study to Determine Best Center for the Exclusion Zone for Calculating the Enhanced Best Fit Surface for Elevation Corneal Tomography (submitted for publication) Ying J, Wang Q, Belin MW, et al. Normative Database for Corneal Elevation in Large Myopic Refractive Surgery Chinese Candidates (submitted for publication) Rudnisky CJ, Belin MW, Ciolino JB. Visual Acuity Outcomes of the Boston Keratoprosthesis Type 1: Multicenter Study Results (submitted for publication) PRESENTATIONS: "Corneal Dystrophies," Ophthalmology Update, Stratton, Vermont, 1982 "Refractive Evaluation of the Triple Procedure: Cornea Transplant, Cataract Extraction, and Intraocular Lens," Ophthalmology Update, Lake Placid, New York, 1983 "Keratoconus - Early Diagnosis and Treatment," Contact Lens Symposium, Crystal City, Virginia, 1994 (invited speaker) "Clinical Fitting Characteristics of Silicone (Silsight) Extended 17 Case 3:12-cv-01141-SMY-DGW Document 176-34 *SEALED* Filed 12/01/14 Page 35 of 64 Page ID #3174 Case: 16-3334 Document: 55-21 Filed: 02/08/2017 Pages: 64 (835 of 1511) Wear Lenses," CLAO Mid-Meeting, San Diego, California, 1985 "Conjunctival Colonization in New House Officers," CLAO MidWinter National Meeting, Las Vegas, Nevada, 1986 "Corneal Edema - Diagnosis and Treatment," and "Scleritis and Episcleritis," American Academy of Ophthalmology Northeast Regional Update Course, Washington, D.C., 1986 (invited speaker) "Slime as a Factor in Bacterial Adherence to Contact Lenses," (Poster Presentation) CLAO Mid-Winter National Meeting, Las Vegas, Nevada, 1987 "Choosing Between Extended Wear and Gas Permeable Contact Lenses," CLAO Mid-Winter National Meeting, Las Vegas, Nevada, 1987 "New Techniques in Penetrating Keratoplasty," American Academy of Ophthalmology Northeast Regional Update Course, Washington, D. C., 1987 (invited speaker) "Anterior Segment Abnormalities," National Children's Eye Care Foundation, Ophthalmic Genetics: Update 1987, National Institute of Health, Bethesda, Maryland, 1987 (invited speaker) "Keratoconus: Evaluation of Recent Trends in the Surgical and Non-Surgical Correction of Keratoconus," American Academy of Ophthalmology Annual Meeting, Dallas, 1987 "Unilateral Graft Rejection in Bilateral Antigen Identical Corneal Transplants," Eye Bank Association of America Scientific Session, Dallas, Texas, 1987 "Medical and Surgical Management of Chemical Corneal Injuries," Walter Reed 12th Biennial Ophthalmology Postgradualte Course and Alumni Meeting, Bethesda, Maryland, 1988 (invited speaker) "Topical Cyclosporine A in High Risk Corneal Transplants," Association for Research in Vision and Ophthalmology (ARVO) (Poster Presentation), Sarasota, Florida, 1988 "Alternative Methods of Contact Lens Fitting in Keratoconus," American Academy of Ophthalmology Annual Meeting, Las 18 Case 3:12-cv-01141-SMY-DGW Document 176-34 *SEALED* Filed 12/01/14 Page 36 of 64 Page ID #3175 Case: 16-3334 Document: 55-21 Filed: 02/08/2017 Pages: 64 (836 of 1511) Vegas, Nevada, 1988 (invited speaker) "Topical Cyclosporin A in High Risk Corneal Allograft Recipients: Long Term Results and Evaluation of Epithelial Toxicity," American Academy of Ophthalmology (Poster Presentation), Las Vegas, Nevada, 1988 "Management of Scleritis and Episcleritis" William Beaumont Hospital, Royal Oak, Michigan, 1989 (invited speaker) "Common Ocular Infections" American Academy of Physician Assistants National Meeting, Washington, D.C., 1989 "Corneal and External Disease Update - Instructional Course" American Academy of Ophthalmology, New Orleans, Louisiana, 1989 "Immunology of Topical Cyclosporine" Immunologic Disorders of the Visual System, University of Dentistry of New Jersey, Atlantic City, New Jersey, 1990 "Corneal Topographical Analysis" and "Ocular Manifestations of Systemic Disease" Rochester Eye Institute Annual Seminar, Rochester, New York, 1990 (invited speaker) "Use of Topical Immunosuppression in High Risk Keratoplasty" and "PAR Corneal Topography System" Moorfields Eye Hospital, London, England, 1990 "Topical Cyclosporine in High Risk Keratoplasty - The American Study" and "Computerized Corneal Modeling" Queen Victoria Hospital, East Grinstead, England, 1990 "The Immunology of Corneal Graft Rejection" Manhattan Eye and Ear Hospital, New York, New York, 1990 (invited speaker) "Postoperative Management of High Risk Keratoplasty" Montifiore Hospital - Albert Einstein Medical Center, New York, New York, 1990 (invited speaker) "The Use of Topical Cyclosporine A in High Risk Keratoplasty" The New York Hospital - Cornell Medical Center, New York, New York, 1990 (invited speaker) "Episcleritis and Scleritis" External Disease and Cornea Course - American Academy of Ophthalmology, Atlanta, Case 3:12-cv-01141-SMY-DGW Document 176-34 *SEALED* Filed 12/01/14 Page 37 of 64 Page ID #3176 Case: 16-3334 Document: 55-21 Filed: 02/08/2017 Pages: 64 (837 of 1511) ..., Georgia, 1990 "New Algorithms for use with the PAR Corneal Topography System" Third International Congress on Laser Surgery of the Cornea, Atlanta, Georgia, 1990 "PAR Technology Corneal Topography System" Association for Research in Vision and Ophthalmology (ARVO), Sarasota, Florida, 1991 "Approach to Contact Lens Fit in Keratoconus", "Topical Cyclosporine and Corneal Inflammatory Disease", and "Cyclosporine in the High-Risk Keratoplasty Patient" Mayo Clinic Ophthalmic Reviews: Update in Corneal and External Disease, Rochester, Minnesota, 1991 (invited speaker) "Advances in Corneal Topography", Lenox Hill Hospital, New York, N.Y., 1991 (invited speaker) "Update on Herpes Simplex", Thousand Islands Corneal & External Disease Symposium, Wellesley Island, New York, 1991 (invited speaker) "PAR - Corneal Topography System Insensitivity to System Defocusing." International Society of Refractive Keratoplasty, Anaheim, CA, 1991 "Clinical Evaluation of Corneal Topography." American Academy of Ophthalmology Course, Anaheim, CA, 1991 "Granulocyte Colony Stimulating Factor in a HIV Patient with Pseudomonas Corneal Ulcer." Ocular Microbiology and Immunology Group Annual Meeting, Anaheim, CA, 1991 (Peter Zloty presenting) "New Immunosuppressives in Ocular Disease," "Review of Corneal Topography." Medical University of South Carolina, Charleston, South Carolina, 1991 (invited speaker) "Topographic Imaging of Freshly Deepithelialized and Keratectomized Corneas - The PAR Corneal Topography System." CLAO Mid-Winter meeting, Las Vegas, Nevada, 1992 "Cyclosporine and the Management of High Risk Keratoplasty" Audio Digest, March, 1992 20 Case 3:12-cv-01141-SMY-DGW Document 176-34 *SEALED* Filed 12/01/14 Page 38 of 64 Page ID #3177 Case: 16-3334 Document: 55-21 Filed: 02/08/2017 Pages: 64 (838 of 1511) "Intraoperative Topographic Analysis of Cadaver Eyes after Erbium:YAG Photoablation" American Society of Cataract and Refractive Surgery Annual Meeting, San Diego, CA, 1992 "Premier Laser Systems Erbium:YAG Photokeratectomy" Industry Symposium on Solid State Refractive Lasers, San Diego, CA, 1992 "Diagnosis and Treatment of the Red Eye" New York State Coalition of Nurse Practitioners Annual Meeting, Lake George, N.Y. 1992 "Atypical Infectious Crystalline Keratopathy" Ocular Microbiology and Immunology Group Meeting, Dallas, TX, 1992 "The Integration of Computerized Topography with Photoablative Laser" International Society of Refractive Keratoplasty Annual Meeting, Dallas, TX, 1992 "Instrumentation Available to Evaluate the Corneal Surface," "Cyclosporine," and "High Risk Keratoplasty" Contact Lens Association of America (CLAO) Annual Meeting, Las Vegas, Nevada, 1993 (invited speaker) "Overview of Corneal Topography and Contact Lens Fitting," University of Alabama School of Optometry Annual Review, Dothan, Alabama, 1993 (invited speaker) "Evaluation of a Low Cost, Hand Held, Direct Reading Microscope for Measuring RK Blade Extension," American Society of Cataract and Refractive Surgery (ASCRS) Annual Meeting, Seattle, WA, 1993 "Corneal Topography: Its Role in Corneal Transplantation," Eye Bank Association of America (EBAA) Annual Meeting, San Diego, CA, 1993 (invited speaker) "Evaluation of Auto-Focus and Pinhole Function of the Visioptic EH-270 Corneal Topography System" International Society of Refractive Surgery Annual Meeting, Chicago, IL., 1993 "Real Time Corneal Topography will Control Refractive Surgical Procedures" American Academy of Ophthalmology Annual Meeting, Chicago, IL., 1993 (invited speaker) 21 Case 3:12-cv-01141-SMY-DGW Document 176-34 *SEALED* Filed 12/01/14 Page 39 of 64 Page ID #3178 Case: 16-3334 Document: 55-21 Filed: 02/08/2017 Pages: 64 (839 of 1511) "Corneal Topography - Indications and Methodologies" American Academy of Ophthalmology Annual Meeting, Chicago, IL., 1993 (invited speaker) "Corneal Topography in Primary Eye Care" Instructional Course, American Academy of Ophthalmology Annual Meeting, Chicago, IL., 1993 "Erbium and Holmium Lasers" New York Eye & Ear Infirmary Corneal and Refractive Surgery 1994: A Preview, New York, N.Y. 1993 (invited speaker) "New Techniques in Corneal Topography" New York Eye & Ear Infirmary - Corneal and Refractive Surgery 1994: A Preview, New York, N.Y. 1993 (invited speaker) "Screening for Keratoconus" CLAO Annual Meeting, Las Vegas, NV., 1994 (invited speaker) "Corneal Topography for the General Ophthalmologist" Instructional Course, CLAO Annual Meeting, Las Vegas, NV., 1994 "Corneal Topography in Incisional Refractive Surgery" Radial and Astigmatic Workshop (CLAO sponsored), Las Vegas, NV., 1994 "Alcon EyeMap EH-270 Corneal Topography Instrument" Royal Hawaiian Eye Meeting, Maui, Hawaii, 1994 "New Antibiotics and Anti-infectives in External Ocular Disease" Visiting Professor Loyola University, Maywood, IL., 1994 "An Evaluation and Comparison of Currently Available Corneal Topographic Equipment" Suffolk Ophthalmology Society, West Islip, N.Y., 1994 (invited speaker) "Serious Ocular Alkali Burns from the Wood Ash of Fireplaces and Woodstoves" (Jitka Zobal-Ratner, M.D. presenting) American Association of Pediatric Ophthalmology and Strabismus Annual Meeting, Vancouver, B.C., 1994 "Corneal Topography in the General Ophthalmic Practice" Current Concepts in Anterior Segment Disorders, Mary Imogene Bassett Hospital, Cooperstown, N.Y., 1994 (invited speaker) 22 Case 3:12-cv-01141-SMY-DGW Document 176-34 *SEALED* Filed 12/01/14 Page 40 of 64 Page ID #3179 Case: 16-3334 Document: 55-21 Filed: 02/08/2017 Pages: 64 (840 of 1511) "Use of Combined Elevation and Curvature Maps in the Detection of Keratoconus" International Society of Refractive Keratoplasty (ISRK), San Francisco, CA., 1994 "A Comparison of Color Topometry, Rasterphotogrammetry, and Standard Black and White Videokeratography in the Analysis of Severely Distorted Corneas" Eye Bank Association of America (EBAA) Annual Scientific Session, San Francisco, CA., 1994 "Evaluation of Computerized Video-Keratoscopy Decentering and Defocusing Error" Castroviejo Corneal Society Annual Scientific Session, San Francisco, CA., 1994 "Long Term Retrospective Analysis of Corneal Transplants with Molteno Implants" Eye Bank Association of America (EBAA) Annual Scientific Session, San Francisco, CA., 1994 "Hepatitis C Virus (HCV) - Associated Mooren's Corneal Ulcers: Collaborative Study" Castroviejo Corneal Society Annual Scientific Session, San Francisco, CA., 1994 "Corneal Topography in Primary Eye Care" Instructional Course, American Academy of Ophthalmology Annual Meeting, San Francisco, CA., 1994 "Comparison of Commercially Available Videokeratoscopes" Contact Lens Association of America (CLAO) Annual Meeting, Las Vegas, NV, 1995 (invited speaker) "Applications of Corneal Topography in Clinical Practice: The Alcon EyeMap" Video Refrattiva 1995, Milan, Italy, 1995 (invited speaker) "Evaluating Point Accuracy of Current Computerized Videokeratoscopes" American Society of Cataract and Refractive Surgery (ASCRS) Annual Meeting, San Diego, CA, 1995 (Best Paper of Session Award) "Evaluation of Data Point Density and Smoothing Functions of Currently Available Computerized Video-keratoscopes. ARVO Annual Meeting, Ft. Lauderdale, FL, 1995 "Measurements Issues in Corneal Topography" & "Use of Elevation Detection Topography in Photo-Refractive Keratectomy" I.S.R.S.- Mid-Summer Symposium, Minneapolis, MN, 1995 (invited speaker) 23 Case 3:12-cv-01141-SMY-DGW Document 176-34 *SEALED* Filed 12/01/14 Page 41 of 64 Page ID #3180 Case: 16-3334 Document: 55-21 Filed: 02/08/2017 Pages: 64 (841 of 1511) "The Effect of Donor Variables in Graft Viability" (Mehrdad Aghai, M.D. presenting). EBBA Scientific Session, Atlanta, GA., 1995 "Beyond the Placido Disc: New Horizons in Corneal Topography" International Society of Refractive Surgery (ISRS) Annual Meeting, Atlanta, GA, 1995 (invited speaker) "Correlation of Topographic & Subjective Astigmatism: Implications to Refractive Surgery" (John J. Lee presenting) ISRS Annual Meeting, Atlanta, GA., 1995 "How Complex Can Contact Lens Fitting Get - Fitting Contacts on PRK & RK" American Academy of Ophthalmology (AAO) Annual Meeting, Atlanta, GA., 1995 (invited speaker) "Comparison of Subjectively Refracted Cylinder, Topographic Cylinder and Topographic Guided Refractive Cylinder in Normal Patients" (John J. Lee presenting) Castroviejo Corneal Society Annual Meeting, Atlanta, GA., 1995 "Regulatory Issues in Refractive Surgery" American Academy of Ophthalmology (AAO) Annual Meeting, Atlanta, GA., 1995 (invited speaker) "State of the Art in Computerized Corneal Topography" New York Eye and Ear Infirmary 175th Anniversary Conference, New York, N.Y., 1995 (invited speaker) "Topographic Application in PRK" Excimer Laser Surgery Course. University of Ottawa Eye Institute, Ottawa, Canada, 1995 (invited speaker) "Understanding Topography in the PRK Patient" Michigan Ophthalmological Society, Southfield, MI, 1996 (invited speaker) "Computerized Topography and PRK" & "FDA Current Status" 1996 CLAO Annual Meeting, Las Vegas, NV (invited speaker) "Current Status of the LaserSight Compak-200 Phase 2a Study" & "Elevation Detection Topography in Evaluating PRK Ablation Depth and Centration" 1996 Pacific Coast Refractive Symposium, Whistler, British Columbia, Canada (invited speaker) "Corneal Topography, Basic Principles, Comparison of Machines" & "Role of Topography in Excimer Surgery" Alcon VISX Excimer 24 Case 3:12-cv-01141-SMY-DGW Document 176-34 *SEALED* Filed 12/01/14 Page 42 of 64 Page ID #3181 Case: 16-3334 Document: 55-21 Filed: 02/08/2017 Pages: 64 (842 of 1511) Laser Course, Cape Girardeau, MO, 1996 (invited speaker) "LaserSight Compak-200 Excimer Initial Phase 2a Results" World Congress on the Cornea IV, Orlando, FL., 1996 "Clinical Experience with PRK: Pre-Op, Surgical, & Post-Op" Primary Care for Optometry Spring Conference, Saratoga Springs, N.Y., 1996 (invited speaker) "Excimer Photorefractive Surgery: Pre-Operative Evaluation" and "Update of Refractive Lasers" State University of New York School of Optometry Meeting, New York, N.Y., 1996 (invited speaker) "Pseudo-Decentration: Anomalous Determination of PRK Centration with Curvature Analysis and Comparison to Elevation Detection Topography" American Society of Cataract and Refractive Surgery Annual Meeting, Seattle, WA., 1996 "Evaluation of Currently Available Video-Keratoscopes" 9th Annual German Ophthalmic Surgeons Meeting, Nuremberg, Germany, 1996 (invited speaker) "Topographic Applications in PRK: Present and Future" Canadian Ophthalmic Society Annual Meeting, Ottawa, Canada, 1996 (invited speaker) "The Comparison of Subjectively Determined Astigmatism and Topographic Astigmatism and its Implications in Refractive Surgery," "The Use of Elevation Detection Topography in the Evaluation of Post-PRK Patients" Canadian External Disease and Corneal Society Annual Meeting, Ottawa, Canada, 1996 "Analysis of Topography as an Input Device for Astigmatic PRK" Ocular Surgery News Symposium on Cataract and Refractive Surgery, New York, N.Y. 1996 (invited speaker) "How to Manage Central Islands" Reshaping the Future: Refractive Surgery, American Academy of Ophthalmology Subspecialty Day, Chicago, IL. 1996 (invited speaker) "Topographical Analysis - The Path to a Better Understanding of Refractive Surgery" American Academy of Ophthalmology Annual Meeting, Chicago, IL. 1996 (invited speaker) "Topographical Analysis in Refractive Surgery" San Diego Naval 25 Case 3:12-cv-01141-SMY-DGW Document 176-34 *SEALED* Filed 12/01/14 Page 43 of 64 Page ID #3182 Case: 16-3334 Document: 55-21 Filed: 02/08/2017 Pages: 64 (843 of 1511) Hospital, San Diego, CA, 1996 "Laser Vision Correction: The use of Lasers to Reshape the Corneal Surface" New York State Section of the American Physical Society, Colgate University, Hamilton, NY, 1997 (invited speaker) "Excimer Laser Calibration ExcaliPar using Topographic Analysis of Ablations on Cross-Linked Collagen" & "Excimer ReTreatment Planning Using Elevation (PAR CTS) Topography" American Society of Cataract and Refractive Surgery Annual Meeting, Boston, MA, 1997 "Clinical Experience with PRK: Updated" Primary Care for Optometry Annual Meeting, Saratoga Springs, NY, 1997 (invited speaker) "Astigmatic Excimer Treatment" & "Corneal Topography and Evaluation Post PRK Patient" 42nd Annual Rochester Ophthalmology Conference, Rochester, NY, 1997 (invited speaker) "Determining the Resolving Power of the Cornea Utilizing Ray Tracing Analysis" 10th Annual German Ophthalmic Surgeons International Symposium, Nurnberg, Germany, 1997. "Understanding Curvature and Elevation Maps" Eye Bank Association of America Annual Meeting, Palm Beach, FL, 1997 (invited speaker) "History, Current Usage and the Future of Topography" Swiss Annual Ophthalmology Society Meeting, Lugano, Switzerland 1997 (invited speaker) "Elevation Based Topography," "Clinical Value of Topography for Refractive Surgeon," "Second and Third Generation Laser Technology," & "The use of Topography in PRK Retreatment Planning" The Sally Letson Symposium - University of Ottawa, Ottawa, Canada, 1997 (invited speaker) "Modern Corneal Topography - Breakfast with the Experts" American Academy of Ophthalmology Annual Meeting, San Francisco, CA, 1997 (invited speaker) "Elevation Based Topography in Refractive Surgery" Visiting Professor Lecture Series, Jules Stein Eye Institute - UCLA, Los 26 Case 3:12-cv-01141-SMY-DGW Document 176-34 *SEALED* Filed 12/01/14 Page 44 of 64 Page ID #3183 Case: 16-3334 Document: 55-21 Filed: 02/08/2017 Pages: 64 (844 of 1511) Angeles, CA, 1998 "VISX Star Hyperopia Optical Analysis Utilizing TechnoMed CScan Ray Tracing and Refractive Power Maps" American Society of Cataract and Refractive Surgery (ASCRS) Annual Meeting 1998, San Diego, CA "Understanding Clinical Topography" & "Clinical Problems in Refraction" Greater New York Ophthalmology Lecture Series, Manhattan Eye & Ear Hospital, New York, N.Y. 1998 "LASIK: A Comparison of Available Microkeratomes" American Academy of Ophthalmology Refractive Surgery Specialty Day 1998, New Orleans, LA "Laser and Incisional Astigmatic Surgery" Instructional Course, American Academy of Ophthalmology Annual Meeting 1998, New Orleans, LA "Treatment of Overcorrected PRK using PTK under Epithelial AutoFluorescence Guidance" American Society of Cataract and Refractive Surgery Annual Meeting, Seattle, WA 1999 "Corneal Complications of LASIK" & "Corneal Topography" Sally Letson Symposium, University of Ottawa Eye Institute, Ottawa, Canada, 1999 "Laser and Incisional Astigmatic Surgery" Instructional Course, American Academy of Ophthalmology Annual Meeting 1999, Orlando, FL "Clinical Problems in Refraction," "Basics of Corneal Topography," "Complications in LASIK Surgery" Visiting Professor, Washington University School of Medicine — Barnes-Jewish Medical Center Department of Ophthalmology, St. Louis, MO, 1999 "Corneal Dystrophies," "Clinical Problems in Refraction" Visiting Professor, Universithy of Ottawa, Ottawa, Ontario, Canada, 2000 "Clinical Experience with the MORIA One Disposable Microkeratome" ASCRS Annual Meeting 2000, Boston MA "New & Emerging Technologies in Refractive Surgery," "LASIK Complications: Diagnosis & Management," "Microkeratomes," "Problem Solving in Optics" Hawaii Ophthalmology Society Mid- 27 Case 3:12-cv-01141-SMY-DGW Document 176-34 *SEALED* Filed 12/01/14 Page 45 of 64 Page ID #3184 Case: 16-3334 Document: 55-21 Filed: 02/08/2017 Pages: 64 (845 of 1511) Winter Meeting, Honolulu, HI, 20001 "Emerging Technologies in Refractive Surgery" 531d Annual Wills Eye Hospital Conference, Philadelphia, PA, 2001 "Epithelial Defects in LASIK: Associations & Risk Factors" ASCRS Annual Meeting, San Diego, CA 2001 (Best Paper of Session) "New & Emerging Technologies in Refractive Surgery" Glens Falls Association for the Blind Primary Eye Care Conference, Queensbury, NY, 2001 "LASIK Complications," "Refractive Surgery Case Presentations" National Medical Center, Taipei, Taiwan, 2001 "Problems in Refraction" EBAA Annual Meeting, Tuscon, AZ, 2001 "New Techniques in Penetrating Keratoplasty" Visiting Professor Wills Eye Hospital, Philadelphia, PA., 2001 "Evalation of the Disposable MORIA Microkeratome" ISRS Annual Meeting, New Orleans, LA., 2001 "DLK Masquerade Syndrome" Castroviejo Corneal Society Annual Meeting, New Orlenas, LA., 2001 "New Techniques in Penetrating Keratoplasty" "Emerging Refractive Technology" "Clinical Problems in Refraction" University of Ottawa (visiting Professor), Ottawa, Ontario, Canada, 2002 "LASIK Complicatons" "Evaluation of Currently Available Microkeratomes" 29th International Congress of Ophthalmology (invited speaker), Sydney, Australia, 2002 "The Effect of Epithelial Disruption on the Long-Term LASIK Enhancement Rate" "New Techniques in Penetrating Keratoplasty" "Diagnosis & Etiology of Diffuse Lamellar Keratitis" American Society of Cataract & Refractive Surgery (ASCRS) Annual Meeting, Philadelphia, PA, 2002 "Long-Term effects of Epithelial Abnormalities during LASIK" Canadian Ophthalmological Society (COS) Annual Meeting, Hull, Quebec, Canada, 2002 "Evaluating of New Techniques in Penetrating Keratoplasty" Eye 28 Case 3:12-cv-01141-SMY-DGW Document 176-34 *SEALED* Filed 12/01/14 Page 46 of 64 Page ID #3185 Case: 16-3334 Document: 55-21 Filed: 02/08/2017 Pages: 64 (846 of 1511) Bank Association of America Annual Meeting 2002, Sawgrass, FL "Conductive Keratoplasty" CORNEA 2002, London, England "New Techniques in Corneal Surgery" Visiting Professor, University of Ottawa, Ottawa General Hospital, Ontario, Canada 2003 "New Techniques in Penetrating Keratoplasty" & "Emerging Technologies in Corneal Transplantation" ASCRS Annual Meeting, San Francisco, CA 2003 "New Techniques in Corneal Surgery," "What's New in Corneal Topography" Royal Australian and New Zealand College of Ophthalmology (RANZCO) Annual Meeting, Auckland, New Zealand, 2003 "Disposable Microkeratomes" Refractive Surgery Interest Group (RSIG) Annual Meeting, Anaheim, CA 2003 "Early Results with the Dohlman-Doane Type 1 Keratoprosthesis" Combined CORNEA Society / EBAA Annual Scientific Session, Anaheim, CA 2003 "Hot Topics Symposium - New Techniques in Penetrating Keratoplasty" "Management of IOUs with Penetrating Keratoplasty" (invited talks) American Society of Cataract & Refractive Surgery (ASCRS) 2004 Annual Meeting, San Diego, CA "Intra and Inter-observer Variability in Central Pachymetry by Rotating Scheimpflug Imaging (Gautam Mishra, M.D. presenting) American Society of Cataract & Refractive Surgery (ASCRS) 2004 Annual Meeting, San Diego, CA "New Technologies for Corneal Replacement" Visiting Professor, University of California at Irvine, Irvine, CA 2004 "Boston Keratoprosthesis — Breakfast with the Experts" American Academy of Ophthalmology Annual Meeting 2004, New Orleans, LA "Thermal Keratoplasty & Presbyopia Correction" BCSC Course, American Academy of Ophthalmology Annual Meeting 2004, New Orleans, LA "Glaucoma Evaluation in Patients with the Boston 29 Case 3:12-cv-01141-SMY-DGW Document 176-34 *SEALED* Filed 12/01/14 Page 47 of 64 Page ID #3186 Case: 16-3334 Document: 55-21 Filed: 02/08/2017 Pages: 64 (847 of 1511) Keratoprosthesis" World Cornea Congress 2005, Washington, DC (presented by Stephen Spitzer) "Initial Results from the Multi-Center Boston K-Pro Study Group" World Cornea Conress 2005, Washington, DC (presented by Brian Zerbe) "Is it Keratoconus or not" World Cornea Congress 2005, Washington, DC "Recent Advances in Keratoplasty — Cornea Transplantation: The Requisites" American Society of Cataract & Refractive Surgery Annual Meeting 2005, Washington, DC "Lunch with the Experts — Boston Keratoprosthesis" American Society of Cataract & Refractive Surgery Annual Meeting 2005, Washington, DC "Analysis of Mutations in the Gene for the Apha 2 Chain of Type VIII Collagen (COL8A2) in Families and Cases with Fuchs' Endothelial Dystrophy" Association of Research & Vision in Ophthalmology (ARVO) Annual Meeting 2005, Ft. Lauderdale, FL (S.K. lyengar presenting) "Initiation of a Multi-Center Study to Map Genes for Fuchs' Endothelial Cornea Dystrophy" (poster) Association of Research & Vision in Ophthalmology (ARVO) Annual Meeting 2005, Ft. Lauderdale, FL (J. H. Lass presenter) "Elevation —Based Scheimpflug Topography" "Preoperative Refractive Surgery Screening for Keratoconus" 2005 ISRS/AAO Meeting — Emerging Trends in Refractive & Cataract Surgery. Hong Kong, China "Evaluation of Post-LASIK Changes on the Posterior Cornea Surface" & "Pre-Operative Screening for Keratoconus" Reractive On-line 2005, Istituto Clinico Humanitas, Milan, Italy "Corneal Topography: Curvature, Elevation and its Understanding" "Pre-Operative Evaluation of Keratoconus" and "Post LASIK Corneal Ectasia Evaluation" Visiting Professor University of Michigan Kellog Eye Center, Ann Arbor, MI, 2005 "Evaluating the Posterior Corneal Surface" International Society of Refractive Surgery Annual Meeting 2005, Chicago, IL 30 Case 3:12-cv-01141-SMY-DGW Document 176-34 *SEALED* Filed 12/01/14 Page 48 of 64 Page ID #3187 Case: 16-3334 Document: 55-21 Filed: 02/08/2017 Pages: 64 (848 of 1511) "Changes to the Corneal Surface after LASIK and PRK" (Joseph Ciolino presenting) Federated Cornea Societies 2005 Annual Meeting, Chicago, IL "Boston Keratoprosthesis" & "Thermal Keratoplasty" & "Presbyopia Surgery" & "Fellowship Certification" & "Multi-Center Study on the Boston Keratoprosthesis" American Academy of Ophthalmology Annual Meeting 2005, Chicago, IL "Multi-Center Update on the Boston Keratoprosthesis" Royal Australian & New Zealand College of Ophthalmology Annual Meeting 2005, Hobart Tasmania "Measurement of Posterior Elevation Changes after LASIK with Scheimpflug Imaging" European Society of Cataract & Refractive Surgeons (ESCRS) Mid-Winter Meeting 2006, Monte Carlo, Monaco "Results of the Multi-Center Study Group on Boston Type 1 Keratoprosthesis," "Keratoprosthesis for High Risk Keratoplasty," "Cornea Topography — What are we Measuring," "Dohlman Dohne Keratoprosthesis" World Ophthalmology Congress / International Congress of Ophthalmology, Sao Paulo, Brazil, 2006 "Evaluation of the Refractive Surgery Patient," "Topographic Case Presentations" CORNEA Day 2006, San Francisco, CA "Interpretation & Use of Scheimpflug Imaging," ":New Techniques in Keratoplasty" American Society of Cataract & Refractive Surgery (ASCRS) Annual Meeting, San Francisco, CA 2006 "Cornea Topography: Truth or Consequences" "Pachymetric Asymmetry" "Fusarium Keratitis" ASCRS Summer Refractive Symposoium 2006, Boston, MA "Improving Outcomes & Reducing Risk in Refractive Surgery" ESCRS Annual Meeting 2006, London, UK "Scheimpflug Corneal Analysis" Refractiva Sympoisum 2006, Istituto Clinico Humanitas, Milan, Italy "Results of Multi-Center Boston Keratoprosthesis Study" EVER Annual Meeting 2006, Faro, Portugal "Understanding Elevation Based Topography" Glasgow, Scotland 2006 31 Case 3:12-cv-01141-SMY-DGW Document 176-34 *SEALED* Filed 12/01/14 Page 49 of 64 Page ID #3188 Case: 16-3334 Document: 55-21 Filed: 02/08/2017 Pages: 64 (849 of 1511) "Ocular Imaging in the 21st Century" "Mitomycin C in Refractive Surgery" Royal Australian & New Zealand College of Ophthalmology Annual Meeting (RANZCO) 2006, Sydney, NSW, Australia "Surgical Correction of Presbyopia" "Technological Advances in the Diagnosis of Ectatic Conditions" "Keratoprosthesis Update" American Academy of Ophthalmology Annual Meeting 2006, Las Vegas, NV "Importance of the Posterior Cornea Surface in the Quest for Quality Vision" Ophthalmologia Belgica 2006, Brussels, Belgium Visiting Professor — John J. Skowron Lecturer "Elevation Based Corneal Analsysis" " Boston Keratoprosthesis" Loyola University, Stritch School of Medicine, Chicago, IL 2006 "Variability in Pre-Op & Operative Parameters with Implications for Refractive Surgery" Mid-Winter ESCRS Annual Meeting, Athens, Greece, 2007 "New Developments in Corneal Topograpy" "Keratoprothesis Update" Visiting Professor University of Ottawa, Ottawa, Ontario, Canada "New Trends in Corneal Replacement" "Risk Assesment for Post LASIK Ectasia" "Modern Topographic Analysis" "Advances in Keratoprosthesis Surgery" Washington Academy of Eye Physicians & Surgeons Annual Meeting, Seattle, WA 2007 Multi-center Boston Keratoprosthesis Study Group Rapid Visual Rehabilitation: 1 Week Post-Operatively J.B. Ciolino, MD; S.S. Khachikian; B.L. Zerbe, MD; M. W. Belin, MD . ARVO Poster Presentation, Fort Lauderdale, FL, 2007 "Elevation Based Topography" "Variability in the Pre-Operative Assessment of the Refractive Surgery Patient" "The Use of Mitomycin (MMC) in Refractive Surgery" University of California at Davis Annual Meeting, Napa, CA 2007 "Pre-Operative Assessment for Keratoconus and Ectasia" Pan American Association of Ophthalmology (PAAO) Annual Meeting, Cancun, Mexico 2007 "Boston KPro Collaborative Study Results" European Associatin 32 Case 3:12-cv-01141-SMY-DGW Document 176-34 *SEALED* Filed 12/01/14 Page 50 of 64 Page ID #3189 Case: 16-3334 Document: 55-21 Filed: 02/08/2017 Pages: 64 (850 of 1511) for Vision and Eye Research (EVER), Portoroz, Slovenia 2007 "Understanding Elevation Based Topography" Turkish National Ophthalmology Meeting, Antalya, Turkey, 2007 "Treatment Options for Patients with Multiple Immunologic Graft Rejections" AAO Cornea Sub-Specialty Day, New Orleans, LA, 2007 "The use of Permanent and Temporary Keratoprosthesis in Traumatized Eyes" American Academy of Ophthalmology Annual Meeting, New Orleans, LA 2007 "Femtosecond vs Mechanical LASIK Flaps: What is the Difference" Royal Australia & New Zealand College of Ophthalmology Annual Meeting, Perth, Australia, 2007 "The Different Uses of Cyclosporine for the Prevention of Rejection in High Risk Keratoplasty" 12th International Cornea Surgery & Diseases Meeting 2008, Barcelona, Spain "Normal Elevation Topography Values in Refractive Surgery Candidates" "Comparison of AC Diameter Measurements Made by Scheimfplug Photography and OCT with Automated White to White Measurements" (Stephen S Khachikian presenting), Winter ESCRS Meeting, Barcelona, Spain 2008 "Treatment of Recurrent Immune Mediated Graft Rejection" Asia Cornea Society 2008, Singapore "Understanding Elevation Based Topography" Singapore National Eye Center Annual Meeting 2008, Singapore "Elevation Topography Pearls" CORNEA Day 2008, Chicago, IL "Boston Keratoprosthesis:Prognostic Indicators" "Basics of Elevation Based Topography" "Belin-Ambrosio Enhanced Ectasia Display" 2008 American Society of Cataract & Refractive Surgery (ASCRS) Annual Meeting, Chicago, IL "Keratoprosthesis in Ocular Surface Disease" IV International Symposium of the Ocular Surface, Bilbao, Spain, 2008 "Keratoconus vs Pellucid Marginal Degeneration" Cornea SubSpecialty Day — American Academy of Ophthalmology 2008, Atlanta, GA 33 Case 3:12-cv-01141-SMY-DGW Document 176-34 *SEALED* Filed 12/01/14 Page 51 of 64 Page ID #3190 Case: 16-3334 Document: 55-21 Filed: 02/08/2017 Pages: 64 (851 of 1511) "Multicenter Boston Keratoprosthesis Study" American Academy of Ophthalmology, Atlanta, GA "Secondary IOL combined with PK" "Medicinal Herbs in Ophthalmology" "Comparison of Technologies for White to White Measurement" Royal Australia & New Zealand College of Ophthalmology Annual Meeting, Melbourne, Australia 2008 "The Boston Keratoprosthesis" "Use of Immunosuppression in High Risk Keratoplasty" "Understanding Elevation Based Topography" "Keratoconus Detection" King Khaled Eye Specialist Hospital Annual Meeting, Riyadh, Saudia Arabia "The Management of High Risk Keratoplasty — Boston Keratoprosthesis" "The Management of High Risk Keratoplasty — Immunosuppression" MEACO 2009, Bahrain "Elevation vs Placido" "Derivation of the Enhanced Reference Surface" "Elevation Topography" American Society of Cataract and Refractive Surgery Annual Meeting 2009, San Francisco, CA "Screening for Ectatic Disease" "The Use of Elevation Based Topography in the Diagnosis of Keratoconus" Keratoconus from A to Z. Levant Hospital, Beirut, Lebanon "Clinical Refraction Case Studies" "Understanding Cornea Topography" Visiting Professor — University of Toronto, Toronto, Canada "Pachymetry: often overlook and misunderstood" "Why is Diagnosing Keratoconus so Difficult (Special APAO Lecture)" "Is it Keratoconus or Not" "Attributes, Benefits & Limitations of Scheimpflug Imaging" 2009 Asia Pacific Association of Ophthalmology (APAO), Bali, Indonesia "Keratoprosthesis as an alternative to Repeat Keratoplasty" "Understanding Scheimpflug Imaging of the Cornea" Israeli Cornea Club Annual Meeting 2009. Hamat Gader Village, Israel "Diagnosing Keratoconus" "LASIK Risk Analysis Scoring System" "Understanding Elevation Based Topography" SOE Annual Meeting 2009, Amsterdam, Netherlands "Understanding Elevation Based Topography" "Screening for Keratoconus" Chinese Ophthalmology Annual Meeting 2009, 34 Case 3:12-cv-01141-SMY-DGW Document 176-34 *SEALED* Filed 12/01/14 Page 52 of 64 Page ID #3191 Case: 16-3334 Document: 55-21 Filed: 02/08/2017 Pages: 64 (852 of 1511) Chongquing, China "Elevation Based Topography" "Keratoprosthesis" "Immunosuppression in High Risk Keratoplasty" "Screening for Keratoconus" Visiting Professor McGill University, Montreal Canada, 2009 "Corneal Tomography" "Essential of Elevation Topography" "Techniques & Instrumentation for Full-Thickness Keratoplasty" European Society of Cataract & Refractive Surgery (ESCRS) Annual Meeting, Barcelona, Spain 2009 "Keratoconus & Ectatic Disorders" "Placido Marginal Degeneration" "Curvature vs Elevation Topography" Refactivo-online, Milan, Italy 2009 "Preoperative Screening for Keratoconus & Ectatic Disorders" "Basics of Elevation Topography" United Kingdom & Ireland Society of Cataract & Refractive Surgery (UKISCRS) Annual Meeting, Leeds, UK 2009 "Component Lamellar Surgery — Where are we at?" Royal Australia & New Zealand College of Ophthalmology (RANZCO) Annual Meeting, Brisbane, Australia 2009 "Understanding Elevation Based Topography" "Refractive Surgical Screening" "Keratoprosthesis Surgery" "Immunosuppression for High Risk Keratoplasty" University of Montreal / McGill Univeristy, Montreal, Canada 2009 "The Early Detection of Keratoconus" The Chinese Ophthalmology Society Annual Meeting (COS) 2009, Chongqing, China "How to Read the Cornea to Avoid Problems" "Instrumentation Required for Full Thickness Transplantation" "Review of Cornea Trephines" European Society of Cataract and Refractive Surgery (ESCRS) Annual Meeting 2009, Barcelona, Spain "Elevation Topography in the Evaluation of the Refractive Surgery Patient" Refractivo On-line 2009, Milan, Italy "Understanding Elevation Based Tomography" "Screening for Keratoconus" United Kingdom & Ireland Cataract and Refractive Surgery Society (UKICRS) Annual Meeting, Leeds, Great Britain, 2009 35 Case 3:12-cv-01141-SMY-DGW Document 176-34 *SEALED* Filed 12/01/14 Page 53 of 64 Page ID #3192 Case: 16-3334 Document: 55-21 Filed: 02/08/2017 Pages: 64 (853 of 1511) "Surgical Instrumentation, Sutures, Needles" Royal Australian & New Zealand College of Ophthalmology Ophthalmic Skills Workshop (East Timor Eye Project), Brisbane, Australia 2009 "Component Lamellar Corneal Surgery" RANZCO Annual Meeting 2009, Brisbane, Australia "Basics of Elevation Based Topography" "Screening for Keratoconus & Ectatic Disease" "LASIK Ectasia Risk Score: A Critique" "Belin/Ambrosio Enhance Ectasia Score" "Mitomycin C in Refractive Surgery: Pros & Cons" Bascom Palmer Cataract & Refractive Surgery Annual Meeting 2010, Miami, FL "Evaluation of the Ectasia Risk Score," "Understanding Elevation Based Tomography" Visiting Professor, Jules Stein Eye Institute UCLA, Los Angeles, CA 2010 "How to diagnosis Form Fruste Keratoconus" World Cornea Congress 2010, Boston, MA "Cornea Tomography & Biomechanics for Enhanced Ectasia Screening" "New Horizons in Cornea Surgery" "Best of World Cornea Congress" American Society of Cataract & Refractive Surgery 2010 Annual Meeting, Boston, MA "Detection of Keratoconus" Royal College of Ophthalmologists Annual Congress 2010, Liverpool, Great Britain "Tomographic Normal Values for Elevation and Pachymetry in a Hyperopic Population" World Ophthalmology Congress 2010, Berlin, Germany "Preoperative Screening for Keratoconus & Ectasia" AUSCRS / APACRS Annual Meeting, Cairns, Australia 2010 "Boston Keratoprosthesis Instructional and Surgical Course" Visiting Professor Liaoning Province Northern Military Hospital, Shenyang, China, 2010 "Elevation Normal Values in a Hyperopic Population" "Understanding Based Topography" "Enhanced Ectasia Screening for Refractive Candidates" "Update in Penetrating and Lamellar Keratoplasty Techniques" European Society of Cataract and Refractive Surgery (ESCRS) Annual Meeting 2010, Paris, France 36 Case 3:12-cv-01141-SMY-DGW Document 176-34 *SEALED* Filed 12/01/14 Page 54 of 64 Page ID #3193 Case: 16-3334 Document: 55-21 Filed: 02/08/2017 Pages: 64 (854 of 1511) "Ectasia Risk Score: Good Science, Bad Practice" "Keratoprosthesis and Glaucoma" "Boston Keratoprosthesis: Techniques & Results" Asia Pacific Academy of Ophthalmology (APAO) Annual Meeting 2010, Beijing, China Corneal Biomechanical Assessment using Dynamic Ultra High Speed Scheimpflug Imaging and Non-Contact Tonometry. Ambrosio R. (presenting), Steinmueller AS, Krug M, Belin MW. ISRS Annual meeting, Chicago, IL 2010 Belin/Ambrosio Display (BAD) Enhanced Sensitivity to detect Mild Abnormalities in Very Asymmetric Keratoconus. Ambrosio R, Pimentel LN, Ramos I, Salomao MQ, Guerra FP, Valbon B, Canedo AL, Belin MW. (poster) ISRS Annual Meeting, Chicago, IL 2010 "Analysis of Ectasia Risk" Royal Australia & New Zealand College of Ophthalmology Annual Meeting 2010, Adelaide, Australia "New Concepts in Corneal Replacement Surgery" Wenzhou Medical College, Wenzhou, China 2010 "Refractive Applications of Scheimpflug Imaging" Hangzhou, China 2010 "Boston Keratoprosthesis as an Alternative to Penetrating Keratoplasty" "Scheimplfug Imaging of the Cornea & Anterior Segment" 2nd Annual Asia Cornea Society Meeting (2010), Kyoto, Japan "My Surgical Approach to DSEK" "Ectasia Risk Score: Is it Applicabale" Asia Pacific Academy of Ophthalmology Annual Meeting 2011, Sydney, Australia "Understanding Elevation Tomography" "Customized Normal Elevation Values — International Data Base"SICSSO / Refractive online (Society of Italian Ocular Surface Disease) Grosetto, Italy 2011 "3D Cornea tomography in Corneal Disease" "Boston Type 1 in the Developing World: Challenges" EuCORNEA 2011, Vienna, Austria "Advance Optics Gullstrand: Tomography vs Topography" "Geographic Variation of Corneal Elevation Values by Scheimpflug Imaging" "Understanding Elevation Based Tomogrpahy" "Cornea 37 Case 3:12-cv-01141-SMY-DGW Document 176-34 *SEALED* Filed 12/01/14 Page 55 of 64 Page ID #3194 Case: 16-3334 Document: 55-21 Filed: 02/08/2017 Pages: 64 (855 of 1511) Transplant Surgical Course" "Concepts for Tomographic Corneal Elevation" ESCRS Annual Meeting 2011, Vienna, Austria "Role of Tomogrpahy & Biomechanics for Diagnosis, Prognosis & Treatment Planning of Ectatic Diseases" EuKeratoconus 2011, Bordeaux, France "Scheimpflug vs Placido" invited paper, ISRS Refractive Subday Annual Meeting, Orlando, FL 2011 "Normal Astigmatism vs Keratoectasia" invited paper, American Academy of Ophthalmology Annual Meeting 2011, Orlando, FL "Ectasis Risk Analysis" "Understanding Elevation Tomography" XII International Congress Modern Technologies in Cataract and Refractive Surgery 2011, Moscow, Russia "Techniques & Instrumentation for DS(A)EK" "Analysis of Ectasia Risk" "Elevation Based Corneal Tomography" 62n° Annual PostGraduate Review Course Upstate Medical Center 2011, Syracuse, New York "Boston Keratoprosthesis Surgical Training Course" "Keratoprosthesis for Limbal Stem Cell Failure" Pan American Regional Course 2012, Cartagena, Columbia "How not to diagnose Keratoconus" "Understanding Elevation Based Tomography" "Keratoprosthesis, Indications, Update & Outcomes" World Ophthalmology Congress 2012, Abu Dhabi, U.A.E. "How to select and follow refractive surgery patients with Tomography" Refractive.Online/SICSSO annual meeting, Rome, Italy, 2012 "Clinical Applications of Advanced Corneal Imaging" EuCornea Annual Meeting, Milan, Italy, 2012 "Understanding Elevation Based Topography" "Basics of Corneal Transplanation: Instrumentation & Trephines" "Elevation Tomography: How to Interpret Results" ESCRS Annual Meeting, Milan, Italy 2012 "DSEK Instrumentation & Techniques" "Analysis of Post LASIK Ectasia Risk" 16th Annual University of Colorado Ophthalmology Symposium, Denver, Colorado, 2012 38 Case 3:12-cv-01141-SMY-DGW Document 176-34 *SEALED* Filed 12/01/14 Page 56 of 64 Page ID #3195 Case: 16-3334 Document: 55-21 Filed: 02/08/2017 Pages: 64 (856 of 1511) "History of Corneal Imaging: 130 Years of Advancement Since Antonio Placido" "Basics of Understanding Elevation Based Corneal Tomography" "Measuring Corneal Thickness: Are our Method Incorrect?" "Post LASIK Ectasia Risk Analysis: Is the ERSS still Relevant?" 38th Seminar on Imaging in Ophthalmology, King Saud University Department of Ophthalmology, Riyadh, Kingdom of Saudi Arabia, 2012 "Boston Keratoprosthesis Surgical Training Course" "Basics of Elevation Based Corneal Tomography" "Post LASIK Ectasia Risk Analysis" Ophthalmological Society of Taiwan Annual Meeting, Taipei, Taiwan 2012 "Scheimpflug Imaging" "When all else fails: the role of keratoprosthesis" 44th Annual Scientific Congress Royal Australian and New Zealand College of Ophthalmologists (RANZCO), Melbourne, Australia 2012 "Diagnosing Keratoconus, Pellucid Marginal Degeneration and Post LASIK Ectasia" 3rd Annual Asia Cornea Society Meeting, Manila, Philippines, 2012 "Topography vs Tomography: Ectasia Sensitivity" "Keratoconus: When to Intervene" "Workup of the Refractive Surgery Patient:Topography" 28th Asia-Pacific Academy of Ophthalmology 2013, Hyderabad, India "Aggressive Surgical Debridement for Fusarium Keratitits Improves Outcomes" "Early Ectatic Changes in Keratoconus" "Different Insertion Techniques / Equipment for DSEK" "Evolution of Tomographic Diagnosis of Ectatic Disease" Society of Italian Corneal Transplant Surgeons (S.I.Tra.C) Bari, Italy, 2013 "Permanent Keratoprosthesis" "Pachymetry: New Methods to Look at Corneal Thickness" 56th Annual Postgraduate Symposium in Ophthalmology: Advances in Corneal Disease. Ohio State University, Columbus, Ohio 2013 "Urge to Rub: Is there a Link between Eye Rubbing, Atopy and Keratoconus. 10th Annual ISOPT Conference, Paris, France 2013 "Understanding Scheimpflug Imaging of the Cornea" SHIOL Annual Meeting (Hungarian Society of Ophthalmology), Budapest, Hungary 2013 "When not to use a Toric IOL" 2013 Cornea Day, San Francisco, 39 Case 3:12-cv-01141-SMY-DGW Document 176-34 *SEALED* Filed 12/01/14 Page 57 of 64 Page ID #3196 Case: 16-3334 Document: 55-21 Filed: 02/08/2017 Pages: 64 (857 of 1511) CA "What we don't have & Why we don't have it: ASCRS/FDA symposium" "Basics of Elevation Based Tomograpy/New Thoughts on Corneal Pachymetry" 2013 ASCRS Annual Meeting, San Francisco, CA "Corneal Examination Techniques: Pachymetry, Topo/Tomography, OCT, Confocal, Wavefront" European University Postgraduate Course (EUPO) 2013, Copenhagen, Denmark "Keratoconus Classification: Time for a change" "Corneal Tomography" European Society of Ophthalmology Annual Meeting (SOE) 2013, Copenhagen, Denmark. "Evolution of the Belin/Ambrosio Display" "Keratoconus Case Presentation: Surgical Treatment of Hydrops in Pellucid Marginal Degeneration" "DSEK: Instrumentation & Insertion Techniques" SICSSO, Refractive online annual meeting 2013, Sienna, Italy "When Not to use a Premium 10L" "Update on Diagnosis of Keratoconus in the Refractive Patient", Asia Pacific Society of Cataract & Refractive Surgery (APSCRS) 2013, Singapore "Boston KPRO for World Blindness" "Ultimate Strategies for Diagnosing & Evaluating Keratoconus" "Boston KPRO Training Course" Pan American Association of Ophthalmology (PAAO) Annual Meeting 2013, Rio de Janerio, Brazil "DSEK Insertion Techniques and Instrumentation" "Corneal Pachymetry: New way to look at an old measurement" "Understanding Elevation Based tomography: From basics to refractive screening" " Ectasia Risk Score: Is it applicable" Southern African Society of Cataract & Refractive Surgery (SASCRS) Annual Meeting 2013, Livingstone, Zambia "Diagnosis an Stage-Related Therapy of Keratoconus & Ectati Diseases" "Bostin Keratoprosthesis" DOG (German Ophthalmological Society) Annual Meeting 2013, Berlin Germany "Corneal Imaging: Scheimpflug" EuCornea Annual Meeting 2013, Amsterdam, Netherlands "Update on Penetrating Keratoplasty" "Basics of Corneal Topography:Understanding what you are seeing" " Enhanced Ectasia Screening" ESCRS Annual Meeting 2013, Amsterdam, 40 Case 3:12-cv-01141-SMY-DGW Document 176-34 *SEALED* Filed 12/01/14 Page 58 of 64 Page ID #3197 Case: 16-3334 Document: 55-21 Filed: 02/08/2017 Pages: 64 (858 of 1511) Netherlands "Keratoprosthesis Surgery in China: Keynote Address" " Aggressive Debridement aids Treatment of Fungal Keratitis" 9th International Symposium of Ophthalmology, Guangzhou, China "Understanding the Basics of Corneal Tomography" Bombay Ophthalmologists Association & P.D. Hinduja National Hospital, Mumbai, India, December 2013 "DSEK Training Course" "Tomography Mastercourse" "Current Methods of Diagnosing & Monitoring Corneal Ectasia" "Donor Insertion Techniques in Endoethlial Keratoplasty" KERACON 2013 — National Meeting of the Cornea Society of India, Goa, India 2013 "Overview on Keratoprosthesis" "Novel ways to look at Corneal Thickness: Pan American Regional Meeting (PAAO), Panama City, Panama "Posterior Corneal Curvature conforms to Anterior Cornea Curvature in Astigmatic Tohono O'odham Native American Schoolchildren" (ARVO Poster). Miller JM, Harvey EM, Twelker JD, Belin MW, Sherrill D. 2014, Orlando, Fl "Screening vs Diagnosing Ectatic Disease: Whats the Difference" Keynote address — VISTA dinner / Cornea Society Young Physicians Dinner, 2014, Orlando, FL. CONSULTING & GRANTS: KeraVision Incorporated, Feemont, CA — Consultant STTR # AF96T004 (F30602-96-C-0322) Rasterstereographic Corneal Topography $247,000.00, Phoenix Systems & Technologies, New Hartford, N.Y. VISX Incorporated, Santa Clara, CA - Consultant and Physician Trainer Excimer laser Hyperopia Principal Investigator Hyperopia with Astigmatism Principal Investigator LaserSight Technologies, Orlando, FL. - Consultant and Investigator Excimer laser Chiron Vision, Claremont, CA - Consultant Topography and Excimer laser 41 Case 3:12-cv-01141-SMY-DGW Document 176-34 *SEALED* Filed 12/01/14 Page 59 of 64 Page ID #3198 Case: 16-3334 Document: 55-21 Filed: 02/08/2017 Pages: 64 (859 of 1511) PAR Microsystems Corporation, New Hartford, N.Y., Consultant and Investigator - PAR Corneal Topography System Allergan Pharmaceuticals, Irvine, CA., Consultant and Investigator Sandoz Pharmaceuticals, East Hanover, N.J., Investigator Topical Cyclosporine Premier Laser Systems, Irvine, CA., Consultant and Investigator - Erbium:YAG Corneal Photoablation Fisons Corporation, Investigator Telor Pharmaceuticals, Woburn, MA. - Consultant Case 3:12-cv-01141-SMY-DGW Document 176-34 *SEALED* Filed 12/01/14 Page 60 of 64 Page ID #3199 Case: 16-3334 Document: 55-21 Filed: 02/08/2017 Pages: 64 (860 of 1511) List of Materials Reviewed by Michael W. Belin, M.D. Eike, et al. v. Allergan, Inc., et al. A. PLEADINGS 1. First Amended Complaint B. REPORTS 1. Exert Report of Alan Robin, M.D., May 30, 2014 C. DEPOSITION TESTIMONY 1. Plaintiff Charlene Eike, March 7, 2014 2. Plaintiff Shirley Fisher, February 24, 2014 3. Plaintiff Jordan Pitler, February 10, 2014 4. Plaintiff Alan Raymond, February 27, 2014 5. Alan Robin, M.D., August 6, 2014 D. LITERATURE 1. Aptel F, Masset H, Bunion C, Robin A, Denis P. The influence of quality of eye drop administration in patients with glaucoma or ocular hypertension. British J of Ophthalmol. 2009; 93: 700-701 2. Byrne, Jennifer - "Combination drugs for glaucoma: convenience alone is not enough," Primary Care Optometry News, April 2005 3. Center for Drug Evaluation and Research, Application Number: 22-184, Summary Review, July 13, 2010, at 1, n. 1 4. Chrai SS, Makoid MC, Eriksen SP, Robinson JR. Drop Size and Initial Dosing Frequency Problems of Topically Applied Ophthalmic Drugs. J. Pharm Sci. 1974; 63:333-338 5. Chrai SS, Patton TF, Mehta A, Robinson JR. Lacrimal and Instilled Fluid Dynamics in Rabbit Eyes, J Pharmaceutical Sciences. 1973; 62(7): 1112-1121 at 1112 6. Charap A, Shin D, Petursson G, et al. Effect of Varying Drop Size on the Efficacy and Safety of a Topical Beta Blocker. Ann Ophthalmol. 1989; 21: 351-357 7. CLINICAL STUDY REPORT: A Multicenter, Double-Masked, Randomized, Parallel, Vehicle-Controlled, Two Week Study of the Safety, Tolerability, and Efficacy of Once-Daily Bimatoprost 0.03% Ophthalmic solution Administered in Microdrop Volumes of f-11,, 10 iaL, Compared with the Marketed Volume (30µL) in 151.4.1-, and 20 EXHIBIT B Case 3:12-cv-01141-SMY-DGW Document 176-34 *SEALED* Filed 12/01/14 Page 61 of 64 Page ID #3200 Case: 16-3334 Document: 55-21 Filed: 02/08/2017 Pages: 64 (861 of 1511) Patients with Glaucoma or Glaucoma Suspects. Study Number: 192024-023 8. Fiscella R., Wilensky J.T., Chiang T.H., & Walt JG. Efficiency of instillation methods for prostaglandin medications. J of Ocular Pharm. and Ther. 2006; 22(6): 477-482 9. Geyer et. al. Microbial Contamination of Medications Used to Treat Glaucoma. Br J Ophthalmol. 1995; 79:376-379 10. Ghate D & Edelhauser HF. Barriers to Glaucoma Drug Delivery. Journal of Glaucoma. 2008; 17(2): 147-156 11. Gupta, R, Patil, B, Shah, BM, Bali, SJ, Mishra, SK, Dada, Evaluating Eye Drop Instillation Technique in Glaucoma Patients Journal of Glaucoma March 2012, Vol. 21, Issue 3 12. Hennessy, et. al., Eyedrop Instillation in Low-Vision Glaucoma Patients, 17 Ophthalmol. Number 12 (2010) 13. Hennessy AL, Katz J, Covert D, Protzko C, Robin AL. Videotaped Evaluation of Eyedrop Instillation in Glaucoma Patients with Visual Impairment of Moderate to Severe Visual Field Loss. Ophthalmol. 2010; 117(12): 2345-2352. 14. Hennessy AL, Katz J, Covert D, et al. A Video Study of Drop Instillation in Both Glaucoma and Retina Patients with Visual Impairment. Am. J. Ophthalmol. 2011; 152(6):982-988 15. H-Kauffmann Jokl D. Bacterial contamination of ophthalmic solutions used in an extended care facility. BrJ Ophthalmol. 2007; 91:1308-1310 16. Kass MA, Hodapp E, Gordon M, Kolker AE, Goldberg I, "Part I. Patient Administration of Eyedrops: Interview. Annals of Ophthalmology August 1982, 775-779 17. Kass MA, Hodapp E, Gordon M, Kolker AE, Goldberg I, "Patient Administration of Eyedrops: Observation. Annals of Ophthalmology September 1982, 14(9):889-893 18. Kelly JA, Molyneux PD, Smith SA, and Smith SE. Relative bioavailability of pilocarpine from a novel ophthalmic delivery system and conventional eyedrop formulations. British Journal of Ophthalmol. 1989; 73(5):360-362 19. Lederer, et. al., Drop Size of Glaucoma Medication, Am. J. of Opthalmology 1986; 101:691-694 20. Livingstone DJ, Hanlon GW, Dyke S. Evaluation of an extended period of use of preserved eye drops in hospital practice. BrJ Ophthalmol. 1998; 82:473-475 21. Lynch MG, Brown RH, Goode SM, Schoenwald RD, Chien DS. Reduction of Phenylephrine Drop Size in Infants Achieves Equal Dilation with Decreased Systemic Absorption. Arch Ophthalmology. 1987; 105: 1364-1365 22. Nentwich MM et al. Microbial contamination of multi-use ophthalmic solutions. Br J Ophthalmol. 2007; 91:1265-1268 2 Case 3:12-cv-01141-SMY-DGW Document 176-34 *SEALED* Filed 12/01/14 Page 62 of 64 Page ID #3201 Case: 16-3334 Document: 55-21 Filed: 02/08/2017 Pages: 64 (862 of 1511) 23. Petursson G, Cole R, Hanna C. Treatment of Glaucoma Using Minidrops of Clonidine, Arch Ophthalmol. 1984; 102: 1180-1181 24. Porges Y et al. Sterility of Glaucoma Medications Among Chronic Users in the Community. J Ocular Pharm. 2004; 20:123-128 25. Rahrnan et al. Microbial contamination of preservative-free eye drops in multiple application containers. Br J Ophthalmol. 2006; 90:139-141 26. Schacknow PN, Samples JR, eds. The Glaucoma Book: A Practical, Evidence-Based Approach to Patient Care. New York, NY. Springer; 2010; at 970. 27. Sleath B, Blalock SJ, Stone JL, Skinner AC, Covert D, Muir K, Robin AL. Validation of a Short Version of the Glaucoma Medication Self-Efficacy Questionnaire. Brit J Ophthalmol. 2012; 96:258-262 28. Stone JL, Robin AL, Novack GD, Covert DW, Cagle GD. An Objective Evaluation of Eyedrop Instillation in Patients with Glaucoma. Arch Ophthalmology. 2009; 127(6): 732-736. 29. Van Santvliet L and Ludwig A. Influence of the Dropper Tip Design on the Size of Eyedrops. 2001; Pharm Ind. 2001; 63(4): 402-409 30. Van Santvliet L & Ludwig A. Determinants of Eye Drop Size. Sug Ophthalmology. 2004; 49(2): 197-213 31. Ventura MP, Saheb NE, Solari HP, Saraiva VS, Vianna NG, Burnier MN. Cost considerations of the new fixed combinations for glaucoma medical therapy. J of Clin Pharm and Then 2005; 30: 251-254 32. Vocci M, Rohin A, Wahl J, et al. Reformulation and drop size of apraclonidine hydrochloride. Am J Ophthalmol. 1992. 113:154-60 33. "CAls may offer benefit as adjunct to prostaglandin therapy," Ocular Surgery News, May 15, 2007 34. http://www.glaucomaexpert.com/glaucoma_treatment.htm (last visited September 12, 2014). E. PLAINTIFFS' PHARMACY AND MEDICAL RECORDS 1. Plaintiff Charlene Eike CE 000001-000048 2. Plaintiff Shirley Fisher SF 000001-000051 3. Plaintiff Jordan Pitler JP 000001-000136 4. Plaintiff Alan Raymond AR 000001-000033 3 Case 3:12-cv-01141-SMY-DGW Document 176-34 *SEALED* Filed 12/01/14 Page 63 of 64 Page ID #3202 Case: 16-3334 Document: 55-21 Filed: 02/08/2017 Pages: 64 (863 of 1511) F. OTHER MATERIALS 1. February 27, 2012 FDA Ophthalmic Drug Advisory Committee Meeting Minutes 2. February 27, 2012 FDA Ophthalmic Drug Advisory Committee Meeting PowerPoint 3. February 27, 2012 FDA Ophthalmic Drug Advisory Committee Pre-Meeting Briefing G. DEFENDANTS' PRODUCTION 1. ARGN_0002428 — 0002461 2. ARGN0002642 — 0002693 3. ARGN0003774 — 0003779 4. ARGNLUM03 0005877 — 0005994 5. ADDORZOLAMIDE_EIKE 000603 — 000604 6. ADDORZOLAMIDEEIKE 000605 — 000616 7. AD_DORZOLAMIDE_EIKE 000617 8. AD_DORZOLAMIDE_EIKE 000618 9. ADDORZOLAMIDE_EIKE 000619 — 000626 10. AD DORZ-TIM EIKE 001214 — 001221 11. ADEIKE 0001167 — 0001171 12. ADEIKE 001200 — 001249 13. ADEIKE 001281 — 001282 14. ADEIKE 001283 — 001294 15. ADEIKE 001312 — 001316 16. ADLATANOPROSTEIKE 000121 — 000128 17. AD_VIGAMOX_EIKE 016359 — 016372 18. BHLB BRIM 0000900 — 0000906 19. BHLB BRIM 0001052 — 0001055 20. PFIZER_XALATAN 00001531 — 00001546 Case 3:12-cv-01141-SMY-DGW Document 176-34 *SEALED* Filed 12/01/14 Page 64 of 64 Page ID #3203 Case: 16-3334 Document: 55-21 Filed: 02/08/2017 Pages: 64 (864 of 1511) 21. PFIZER_XALATAN 00001547 - 00001600 22. PFIZER_XALATAN 00024279 - 00024280 23. NDA_Merck_Prasco 00010382 - 00010433 Case 3:12-cv-01141-SMY-DGW Document 176-9 *SEALED* Filed 12/01/14 Page 1 of 24 Page ID #2418 Case: 16-3334 Document: 55-22 Filed: 02/08/2017 Pages: 24 (865 of 1511) May 4, 2007 Mr. Gary Buehler Director Office of Generic Drugs Center for Drug Evaluation and Research Food and Drug Administration Document Control Room Metro Park North II 7500 Standish Place Rockville, MD 20855-2773 Re: 6201 SOUTH FREEWAY FORT WORTH, TEXAS 76134-2099 (817) 293-0450 Original Submission Abbreviated New Drug Application Dorzolamide Hydrochloride Ophthalmic Solution, 2% Dear Mr. BuelJer: Alcon, Inc submits today an original abbreviated new drug application (ANDA) seeking approval to market Dorzolamide Hydrochloride Ophthalmic Solution, 2% which is pharmaceutica ly equivalent to the listed drug, Trusopt Ophthalmic Solution, manufactured >y Merck & Co., Inc. Alcon Research Ltd. is the U.S. representative for Alcon, Inc. This application is submitted pursuant to 5050) of the Federal Food, Drug and Cosmetic Act and complies with the requirements of Section 314.92 through 314.99 of Title 21 of the Code of Federal Regulations. Dorzolamide Hydrochloride Ophthalmic Solution, 2% is a sterile pro-duct in a semi-permeable container which is indicated in the treatment of elevated intrao cular pressure in patients with ocular hypertension or open-angle glaucoma. ICt Q1A, section 2.2.7.3 recommends that stability evaluations for an aqueous-based product in semi-permeable containers (e.g. LDPE bottle) should be under conditions of lo>w humidity (i.e. 40°C ± 2°C/ not more than 25% RH). Alcon has included accele::rated stability data which is in compliance with these Q1A criteria. This ANDA &insists of eight volumes. Alcon is providing the documents listed below for this appliedion: Archival copy (blue binders) in the CTD format At the front of Module 1 please find: > Original signed Form 356h > Original signed field copy certifications > Original signed debarment certifications > Original signed patent certification > Original signed exclusivity certification > Original signed environmental impact analysis statement > Original signed GMP certification CONFIDENTIAL PURSUANT TO THE PROTECTIVE ORDER AD DORZOLAMIDE EIKE000603 Case 3:12-cv-01141-SMY-DGW Document 176-9 *SEALED* Filed 12/01/14 Page 2 of 24 Page ID #2419 Case: 16-3334 Document: 55-22 Filed: 02/08/2017 Pages: 24 (866 of 1511) Page 2 > > > > > Original signed reprocessing statement 1 CD containing PDF copies of the labeling 1 CD containing SPL labeling 1 CD containing an electronic copy of the package insert in MS Word 1 CD containing copy of Module 2, Section 2.3 in PDF and MS Word formats • Chemistry review copy (red binders) which contains all of the information required in the archive copy. • Microbiology review copy (white binders) which contains all of the information required in the archive copy. This additional copy is provided to assist the reviewer since this is a sterile product. • 3 separately bound copies of the Methods Validation information (Section 3.2.R.3.P) are included for each copy of the application (archive, chemistry review and micro review). These are identified as "3.2.R.P.3 Methods Validation Package." Alcon commits to the resolution of any issues identified in the methods validation process after approval. • Field copy of the submission (burgundy binders) A true copy of the technical sections of the ANDA was also sent to the Dallas District Office since the U.S. Agent for Alcon, Inc. is Alcon Research, Ltd, located in Fort Worth, Texas. This additional "field copy" includes a copy of the FDA From 356h and a certification that the contents are a true copy of the technical sections filed with the Office of Generic Drugs. We appreciate the Agency's time and consideration spent in the review of this application. As appropriate, communications maybe sent via facsimile to (817) 551­ 4630. If there are any questions, regarding the content or format of this application, do not hesitate to contact the undersigned directly at (817) 551-4517. Sincerely, Sarah J. Cantrell, MS Assistant Director, Regulatory Affairs Enclosures CONFIDENTIAL PURSUANT TO THE PROTECTIVE ORDER AD DORZOLAMIDE EIKE000604 Case 3:12-cv-01141-SMY-DGW Document 176-9 *SEALED* Filed 12/01/14 Page 3 of 24 Page ID #2420 Case: 16-3334 Document: 55-22 Filed: 02/08/2017 Pages: 24 (867 of 1511) H to £3 B C S
  • CONFIDENTIAL PURSUANT TO THE PROTECTIVE ORDER AD DORZOLAMIDE EIKE000605 Case 3:12-cv-01141-SMY-DGW DocumentSolution 176-9 AND *SEALED* Filed 12/01/14 Page 4 of 24 Dorzolamide Hydrochloride Ophthalmic A Page ID #2421 Case: 16-3334 Document: 55-22 Filed: 02/08/2017 Pages: 24 (868 of 1511) Module 1 Table of Contents Volume - Module Tab Identifier 1.1 Form 356h Vol. , Module 1 1.2 Comprehensive Table of Contents Vol. , Module 1 1.3 Administrative Information Vol. , Module 1 1.3.1 Contact/Sponsor/Applicant Information. Vol. , Module 1 1.3.2 Field Copy Certification Vol. , Module 1 1.3.3 Debarment Certification Vol. , Module 1 1.3.4 Financial Certification and Disclosure.... Vol. , Module 1 1.3.5 Patent and Exclusivity Vol. 1.3.5.1 Patent Information Vol. , Module 1 1.3.5.2 Patent Certification Vol. , Module 1 1.3.5.3 Exclusivity Request Vol. , Module 1 1.4 , Module 1 References Vol. , Module 1 1.4.1 Letters of Authorization Vol. , Module 1 1.4.2 Statement of Right of Reference Vol. , Module 1 1.4.3 Cross Reference to Other Applications.. Vol. , Module 1 1.5 Application Status (Not Applicable) 1.6 Meetings (Not Applicable) 1.7 Fast Track (Not Applicable) 1.8 Special Protocol Assessment Request (Not Applicable) 1.9 Pediatric Administrative Information (Not Applicable) 1.10 Dispute Resolution (Not Applicable) 1.11 Information Amendment (Not Applicable) 1.2 Comprehensive Table of Contents, Page 1 CONFIDENTIAL PURSUANT TO THE PROTECTIVE ORDER AD DORZOLAMIDE EIKE000606 Case 3:12-cv-01141-SMY-DGW DocumentSolution 176-9 ANDA *SEALED* Filed 12/01/14 Page 5 of 24 Dorzolamide Hydrochloride Ophthalmic Page ID #2422 Case: 16-3334 Document: 55-22 Filed: 02/08/2017 Pages: 24 (869 of 1511) Module 1 - Table of Contents - Continued Tab Identifier Volume - Module 1.12 Other Correspondence Vol. 1 , Module 1 1.12.10 Generic Drug Enforcement Act Statement 1.12.11 Basis for Submission Statement 1.12.12 Comparison of Generic Drug and Reference Listed Drug 1.12.13 Request for Waiver for in vivo Studies 1.12.14 Environmental Analysis 1.12.15 Request for Waiver of in vivo Bioavailability Studies Vol. 1 , Module 1 Vol. 1 , Module 1 Vol. 1, Module 1 Vol. 1 , Module 1 Vol. 1 , Module 1 Vol. 1 , Module 1 1.13 Annual Report (Not Applicable) 1.14 Labeling Vol. 1 , Module 1 1.14.1 Draft Labeling • Vol. 1 , Module 1 1.14.1.1 Draft carton and container labels 1.14.1.2 Side by Side Labeling of Containers and Carton 1.14.1.3 Electronic Labeling 1.14.3 Listed Drug Labeling Vol. 1 , Module 1 Vol. 1 , Module 1 Vol. 1 , Module 1 Vol. 1 , Module 1 1.14.3.1 Annotated comparison with listed drug 1.14.3.2 Approved Labeling Text for Listed Drug 1.14.3.3 Labeling Text for Reference Listed Drug Vol. 1 , Module 1 Vol. 1 , Module 1 Vol. 1 , Module 1 1.15 Promotional Material (Not Applicable) 1.16 Risk Management Plans (Not Applicable) 1.2 Comprehensive Table of Contents, Page 2 CONFIDENTIAL PURSUANT TO THE PROTECTIVE ORDER AD DORZOLAMIDE EIKE000607 Case 3:12-cv-01141-SMY-DGW DocumentSolution 176-9 *SEALED* Filed 12/01/14 Page 6 of 24 Dorzolamide Hydrochloride Ophthalmic ANDA Page ID #2423 Case: 16-3334 Document: 55-22 Filed: 02/08/2017 Pages: 24 (870 of 1511) Module 1- Table of Contents - Continued Tab Identifier Volume - Module MODULE 2 - Introductions, Overview and Summary 2.3 Table of Contents Vol. , Module 2 Introduction Vol. , Module 2 Quality Overall Summary Vol. , Module 2 2.3.S Drug Substance Vol. , Module 2 2.3.S.1 General Information Vol. , Module 2 2.3.S.2 Manufacture Vol. , Module 2 2.3.S.3 Characterization Vol. , Module 2 2.3.S.4 Control of Drug Substance Vol. , Module 2 2.3.S.5 Reference Standards or Materials Vol. , Module 2 2.3.S.6 Container Closure System Vol. , Module 2 2.3.S.7 Stability Vol. , Module 2 2.3.P Vol. , Module 2 Drug Product 2.3.P.1 Description and Composition of the Drug Product Vol. , Module 2 2.3.P.2 Product Development Vol. , Module 2 2.3.P.3 Manufacture Vol. , Module 2 2.3.P.4 Control of Excipients Vol. , Module 2 2.3.P.5 Control of Drug Product Vol. , Module 2 2.3.P.6 Reference Standards or Materials Vol. , Module 2 2.3.P.7 Container Closure System Vol. , Module 2 2.3.P.8 Stability Vol. , Module 2 2.3.A Appendices Vol. , Module 2 2.3.R Regional Information Vol. , Module 2 2.4 Nonclinical Overview (Not Applicable) 2.5 Clinical Overview (Not Applicable) 2.6 Nonclinical Written and Tabulated Summaries (Not Applicable) 2.7 Clinical Summary (Not Applicable) 1.2 Comprehensive Table of Contents, Page 3 CONFIDENTIAL PURSUANT TO THE PROTECTIVE ORDER AD DORZOLAMIDE EIKE000608 Case 3:12-cv-01141-SMY-DGW DocumentSolution 176-9 ANDA *SEALED* Filed 12/01/14 Page 7 of 24 Dorzolamide Hydrochloride Ophthalmic Page ID #2424 Case: 16-3334 Document: 55-22 Filed: 02/08/2017 Pages: 24 (871 of 1511) Module 1 - Table of Contents - Continued Tab Identifier Volume - Module MODULE 3 - (CMC) Quality 3.1 Table of Contents Vol. 1 , Module 3 3.2 Body of Data Vol. 1 , Module 3 3.2.S Vol. 1 , Module 3 Drug Substance (Dorzolamide HCL, TEVA) 3.2.S.1 General Information (Dorzolamide HCL, TEVA) 3.2.5.1.1 3.2.5.1.2 3.2.S.1.3 3.2.S.2 Nomenclature (Dorzolamide HC1, TEVA) Structure (Dorzolamide HC1, TEVA) General Properties (Dorzolamide HC1, TEVA) Manufacture (Dorzolamide hydrochloride, TEVA) 3.2.5.2.1 3.2.5.2.2 3.2.S.2.3 3.2.5.2.4 3.2.5.2.5 3.2.5.2.6 Manufacturer(s) (Dorzolamide Hydrochloride, TEVA) Description of Manufacturing Process and Process Controls (Dorzolamide Hydrochloride, TEVA) Control of Materials (Dorzolamide Hydrochloride, TEVA) Controls of Critical Steps and Intermediates (Dorzolamide Hydrochloride, TEVA) Process Validation and/or Evaluation (Dorzolamide Hydrochloride, TEVA) Manufacturing Process Development (Dorzolamide Hydrochloride, TEVA) Vol. 1 , Module 3 Vol. 1, Module 3 Vol. 1 , Module 3 Vol. 1 , Module 3 Vol. 1 , Module 3 Vol. 1 , Module 3 Vol. 1 , Module 3 Vol. 1 , Module 3 Vol. 1, Module 3 Vol. 1 , Module 3 Vol. 1, Module 3 1.2 Comprehensive Table of Contents, Page 4 CONFIDENTIAL PURSUANT TO THE PROTECTIVE ORDER AD DORZOLAMIDE EIKE000609 Case 3:12-cv-01141-SMY-DGW DocumentSolution 176-9 *SEALED* Filed 12/01/14 Page 8 of 24 Dorzolamide Hydrochloride Ophthalmic ANDA Page ID #2425 Case: 16-3334 Document: 55-22 Filed: 02/08/2017 Pages: 24 (872 of 1511) Module 1 - Table of Contents - Continued Tab Identifier 3.2.5.3 Characterization (Dorzolamide Hydrochloride, TEVA) 3.2.5.3.1 3.2.5.3.2 3.2.5.4 3.2.5.4.2 3.2.5.4.3 3.2.5.4.4 3.2.5.4.5 3.2.5.6 3.2.5.7 Elucidation of Structure and Other Characteristics (Dorzolamide Hydrochloride, TEVA).... Impurities (Dorzolamide Hydrochloride, TEVA)..... Control of Drug Substance (Dorzolamide Hydrochloride, TEVA) 3.2.5.4.1 3.2.5.5 Volume - Module Specification (Dorzolamide Hydrochloride, TEVA).... Analytical Procedures (Dorzolamide Hydrochloride, TEVA)...., Validation of Analytical Procedures (Dorzolamide Hydrochloride, TEVA) Batch Analyses (Dorzolamide Hydrochloride, TEVA).... Justification of Specifications (Dorzolamide Hydrochloride, TEVA).r.. Reference Standards or Materials (Dorzolamide Hydrochloride, TEVA) Container Closure System (Dorzolamide Hydrochloride, TEVA) Stability (Dorzolamide Hydrochloride, TEVA) 3.2.S.7.1 Stability Summary and Conclusions (Dorzolamide Hydrochloride, TEVA).... Vol. 1 , Module 3 Vol. 1, Module 3 Vol. 1 , Module 3 Vol. 1, Module 3 Vol. 1, Module 3 Vol. 1 , Module 3 Vol. 1 , Module 3 Vol. 1, Module 3 Vol. 1, Module 3 Vol. 1, Module 3 Vol. 1, Module 3 Vol. 1 , Module 3 Vol. 1, Module 3 1.2 Comprehensive Table of Contents, Page 5 CONFIDENTIAL PURSUANT TO THE PROTECTIVE ORDER AD DORZOLAMIDE EIKE000610 Case 3:12-cv-01141-SMY-DGW DocumentSolution 176-9 ANDA *SEALED* Filed 12/01/14 Page 9 of 24 Dorzolamide Hydrochloride Ophthalmic Page ID #2426 Case: 16-3334 Document: 55-22 Filed: 02/08/2017 Pages: 24 (873 of 1511) Module 1 - Table of Contents - Continued Tab Identifier 3.2.5.7.2 3.2.5.7.3 3.2.P Volume - Module Post-approval Stability Protocol and Stability Commitment (Dorzolamide Hydrochloride, TEVA) Stability Data (Dorzolamide Hydrochloride, TEVA) Drug Product [Dorzolamide Hydrochloride Ophthalmic Solution, 2%] 3.2.P.1 3.2.P.2 Vol. 1, Module 3 Vol. 1 , Module 3 Vol. 1 , Module 3 Description and Composition of the Drug Product [Dorzolamide Hydrochloride Ophthalmic Solution, 2%] Vol. 1, Module 3 Pharmaceutical Development [Dorzolamide Hydrochloride Ophthalmic Solution, 2%] Vol. 1, Module 3 3.2.P.2.1 3.2.P.2.2 3.2.P.2.3 3.2.P.2.4 3.2.P.2.5 Components of the Drug Product [Dorzolamide Hydrochloride Ophthalmic Solution, 2%] Drug Product [Dorzolamide Hydrochloride Ophthalmic Solution, 2%] Manufacturing Process Development [Dorzolamide Hydrochloride Ophthalmic Solution, 2%] Container Closure System [Dorzolamide Hydrochloride Ophthalmic Solution, 2%] Microbiological Attributes [Dorzolamide Hydrochloride Ophthalmic Solution, 2%] Vol. 1, Module 3 Vol. 1 , Module 3 Vol. 1 , Module 3 Vol. 1 , Module 3 Vol. 2 , Module 3 1.2 Comprehensive Table of Contents, Page 6 CONFIDENTIAL PURSUANT TO THE PROTECTIVE ORDER AD DORZOLAMIDE EIKE000611 Case 3:12-cv-01141-SMY-DGW Document Solution 176-9 *SEALED* Filed 12/01/14 Page 10 of 24 Dorzolamide Hydrochloride Ophthalmic ANDA Page ID #2427 Case: 16-3334 Document: 55-22 Filed: 02/08/2017 Pages: 24 (874 of 1511) Module 1 - Table of Contents - Continued Tab Identifier 3.2.P.2.6 3.2.P.3 Volume - Module Compatibility [Dorzolamide Hydrochloride Ophthalmic Solution, 2%] Manufacture [Dorzolamide Hydrochloride Ophthalmic Solution, 2%] 3.2.P.3.1 3.2.P.3.2 . 3.2.P.3.3 3.2.P.3.4 3.2.P.3.5 Manufacturers) [Dorzolamide Hydrochloride Ophthalmic Solution, 2%] Batch Formula [Dorzolamide Hydrochloride Ophthalmic Solution, 2%] Description of Manufacturing Process and Process Controls [Dorzolamide Hydrochloride Ophthalmic Solution, 2%] Controls of Critical Steps and Intermediates [Dorzolamide Hydrocholoride Ophthalmic Solution, 2%] Process Validation and/or Evaluation [Dorzolamide Hydrochloride Ophthalmic Solution, 2%] Vol. 2 , Module 3 Vol. 2 , Module 3 Vol. 2 , Module 3 Vol. 2 , Module 3 Vol. 2 , Module 3 Vol. 2 , Module 3 Vol. 2 , Module 3 1.2 Comprehensive Table of Contents, Page 7 CONFIDENTIAL PURSUANT TO THE PROTECTIVE ORDER AD DORZOLAMIDE EIKE000612 Case 3:12-cv-01141-SMY-DGW 176-9 *SEALED* Filed 12/01/14 Page 11 of 24 Dorzolamide Hydrochloride Document Ophthalmic Solution ANDA Page ID #2428 Case: 16-3334 Document: 55-22 Filed: 02/08/2017 Pages: 24 (875 of 1511) Module 1 - Table of Contents - Continued Tab Identifier 3.2.P.4 Control of Excipients [Dorzolamide Hydrochloride Ophthalmic Solution, 2%] 3.2.P.4.1 3.2.P.4.2 3.2.P.4.3 3.2.P.4.4 3.2.P.4.5 3.2.P.4.6 3.2.P.5 Volume - Module Specifications [Dorzolamide Hydrochloride Ophthalmic Solution, 2%] Analytical Procedures [Dorzolamide Hydrochloride Ophthalmic Solution, 2%] Validation of Analytical Procedures [Dorzolamide Hydrochloride Ophthalmic Solution, 2%] Justification of Specifications [Dorzolamide Hydrochloride Ophthalmic Solution, 2%] Excipients of Human or Animal Origin [Dorzolamide Hydrochloride Ophthalmic Solution, 2%] Novel Excipients [Dorzolamide Hydrochloride Ophthalmic Solution, 2%] Control of Drug Product [Dorzolamide Hydrochloride Ophthalmic Solution, 2%] 3.2.P.5.1 Specification^) [Dorzolamide Hydrochloride Ophthalmic Solution, 2%] Vol. 3 , Module 3 Vol. 3 , Module 3 Vol. 3 , Module 3 Vol. 3 , Module 3 Vol. 3 , Module 3 Vol. 3 , Module 3 Vol. 3 , Module 3 Vol. 3 , Module 3 Vol. 3 , Module 3 1.2 Comprehensive Table of Contents, Page 8 CONFIDENTIAL PURSUANT TO THE PROTECTIVE ORDER AD DORZOLAMIDE EIKE000613 Case 3:12-cv-01141-SMY-DGW 176-9 *SEALED* Filed 12/01/14 Page 12 of 24 Dorzolamide Hydrochloride Document Ophthalmic Solution ANDA Page ID #2429 Case: 16-3334 Document: 55-22 Filed: 02/08/2017 Pages: 24 (876 of 1511) Module 1 - Table of Contents - Continued Tab Identifier 3.2.P.5.2 3.2.P.5.3 3.2.P.5.4 3.2.P.5.5 3.2.P.5.6 3.2.P.6 3.2.P.7 Volume - Module Analytical Procedures [Dorzolamide Hydrochloride Ophthalmic Solution, 2%] Validation of Analytical Procedures [Dorzolamide Hydrochloride Ophthalmic Solution, 2%] Batch Analyses [Dorzolamide Hydrochloride Ophthalmic Solution, 2%] Characterization of Impurities [Dorzolamide Hydrochloride Ophthalmic Solution, 2%] Justification of Specification(s) [Ofloxacin Otic Solution, 0.3%] Reference Standards or Materials [Dorzolamide Hydrochloride Ophthalmic Solution, 2%] Container Closure System [Dorzolamide Hydrochloride Ophthalmic Solution, 2%] Vol. 3 , Module 3 Vol. 3 , Module 3 Vol. 3 , Module 3 Vol. 3 , Module 3 Vol. 3 , Module 3 Vol. 3 , Module 3 Vol. 3 , Module 3 Tab 1 Packaging DMF Letters Vol. 3 , Module 3 Tab 2 Pkg Component Certificates.... Vol. 3 , Module 3 Tab 3 FWMDOC-02925 Vol. 3 , Module 3 Tab 4 FWMDOC-00825 Vol. 3 , Module 3 1.2 Comprehensive Table of Contents, Page 9 CONFIDENTIAL PURSUANT TO THE PROTECTIVE ORDER AD DORZOLAMIDE EIKE000614 Case 3:12-cv-01141-SMY-DGW Document Solution 176-9 *SEALED* Filed 12/01/14 Page 13 of 24 Dorzolamide Hydrochloride Ophthalmic ANDA Page ID #2430 Case: 16-3334 Document: 55-22 Filed: 02/08/2017 Pages: 24 (877 of 1511) Module 1 - Table of Contents - Continued Tab Identifier 3.2.P.8 Stability [Dorzolamide Hydrochloride Ophthalmic Solution, 2%\ 3.2.P.8.1 3.2.P.8.2 3.2.P.8.3 3.2.A 3.2.R Volume - Module Stability Summary and Conclusion [Dorzolamide Hydrochloride Ophthalmic Solution, 2%] Post-approval Stability Protocol and Stability Commitment [Dorzolamide Hydrochloride Ophthalmic Solution, 2%] Stability Data [Dorzolamide Hydrochloride Ophthalmic Solution, 2%] Vol. 4 , Module 3 Vol. 4 , Module 3 Vol. 4 , Module 3 Vol. 4 , Module 3 Appendices Vol. 4 , Module 3 3.2.A.1 3.2.A.2 Facilities and Equipment Adventitious Agents Safety Evaluation Vol. 4 , Module 3 3.2.A.3 Novel Excipients Vol. 4 , Module 3 Vol. 4 , Module 3 Regional Information Vol. 4 , Module 3 3.2.R.1.S Executed Batch Record - Drug Substance Vol. 4 , Module 3 3.2.R.2.S Comparability Protocols Vol. 4, Module 3 3.2.R.3.S Methods Validation Package 3.2.R.1.P.1 Executed Batch Record - Drug Product Vol. 4, Module 3 Vol. 4, Module 3 3.2.R.1.P.2 Information on Components Vol. 4, Module 3 3.2.R.2.P Comparability Protocols Vol. 4 , Module 3 3.2.R.3.P Methods Validation Package Vol. 4, Module 3 Tab 1 Executed Batch Record Vol. 4, Module 3 Tab 2 Methods Validation Package Vol. 6 , Module 3 1.2 Comprehensive Table of Contents, Page 10 CONFIDENTIAL PURSUANT TO THE PROTECTIVE ORDER AD DORZOLAMIDE EIKE000615 Case 3:12-cv-01141-SMY-DGW DocumentSolution 176-9 *SEALED* Filed 12/01/14 Page 14 of 24 Dorzolamide Hydrochloride Ophthalmic ANDA Page ID #2431 Case: 16-3334 Document: 55-22 Filed: 02/08/2017 Pages: 24 (878 of 1511) Module 1 - Table of Contents - Continued Tab Identifier 3.3 Literature References. Volume - Module Vol. 6 , Module 3 MODULE 4 (Not Applicable) MODULE 5 (Not Applicable) 1.2 Comprehensive Table of Contents, Page 11 CONFIDENTIAL PURSUANT TO THE PROTECTIVE ORDER AD DORZOLAMIDE EIKE000616 Case 3:12-cv-01141-SMY-DGW Document 176-9 *SEALED* Filed 12/01/14 Page 15 of 24 PageSolution ID #2432 Case: 16-3334 Document: 55-22 Filed: 02/08/2017 Pages: 24 (879 of 1511) Dor/olamide Hydrochloride Ophthalmic ANDA #!tl.Biil»SESilT i ««»« i»M 1, iitli lilt#. -«»TOT, *11a« iMTJiU, 2, COW »fl» • m mIT UfftiBlTti*meT *BWtiS, Si«« m cauH mmmmm. i. mmtmm-mmm tmm m mmmummmm. • r»ii»¥ I fi§SW V;L t&ftmk mm 4, 3UIT mm - MB TIXT »B CHUBHU.5MD i. PHWHIlii i. :< tasits*. : ! msjsw. MH msaer WW«0Htt GRAPHICR wnnrnivs rnp tvr A006S6AA 61 ifIfiftii rli Rs My •1st 6y: FWXQN PHARMACEUTICALS, LTD Fort Worth, Texas 76134USA Mfgfiy ALCON MAMWMTffiffl&lTD, Fort ifcift, Texas 76134 USA ©2C07F3iar<" ~w xjt ltd. AAA719-0207 : container, nstojct uivaierrt to 2u ma dorzolarrtide AFFHIAU i ALCON water toriniffiiai rusv REBSON FOR CHANGE DATE Mout IHBw 02/06/06 a Hayes A Text Revisions omm J. Gil! s Twtftevtslons 02/20/8? 1 ARTIST PILE MAMB: AAA719-0S07 OORZ SmL C,«l ARTIST mmmmowm,: J. Yonkman. PREPRESS t£CH CORP-OOOI07 Dorzolamtde 5 ml Carton Label, Page1 CONFIDENTIAL PURSUANT TO THE PROTECTIVE ORDER AD DORZOLAMIDE EIKE000617 Case 3:12-cv-01141-SMY-DGW Document 176-9 *SEALED* Filed 12/01/14 Page 16 of 24 Page ID #2433 Case: 16-3334 Document: 55-22 Filed: 02/08/2017 Pages: 24 (880 of 1511) s? riiiitiiiiivtit n 1 % 2% PcndafflidB Eqwatent mmn S ESrl"LU itWtT AK Hi Profectferofegli' l»l««kElis*(l»wte. art**: imbue! Is Mid festewte •plwteit (S»III« toariwtto If# arfiw efcrtsctifdsfe stai hptiril> H 1 'i r I I OCl CM CO - tgrnamm Maintenance of Sterility The microbiological attributes of the packaging system for Dorzolamide Hydrochloride Ophthalmic Solution, 2% are described in Module 3, Section 3.2.P.2.5. 3.2.P.2.4. Container Closure System [Dorzolamide Hydrochloride Ophthalmic Solution, 2%], Page 5 CONFIDENTIAL PURSUANT TO THE PROTECTIVE ORDER AD_DORZOLAMIDE_EIKE000624 Case 3:12-cv-01141-SMY-DGW Document 176-9 *SEALED* Filed 12/01/14 Page 23 of 24 Dorzolamide Hydrochloride Ophthalmic Solution ANDFiled: A Page ID #2440 Case: 16-3334 Document: 55-22 02/08/2017 Pages: 24 (887 of 1511) Appendix to Section 3.2.P.2.4 Contents Item Tab Alcon Technical Report 125:38560:1094 Evaluation of Owens Brockway,Low Density Polyethylene, Gamma Sterilized, 30mL Bottles, Lot X-0118-G, According to USP XXH, Physico-chemical Tests - Plastics 1 Alcon Technical Report 056:33700:1086 Evaluation of the EtO Sterilized Low Density Polyethylene Bottles (Alathon 20-PE6064, White; 1-369) Using USP XXI Physico-chemical Tests - Plastics Alcon Technical Report 004:38520:0195 Agar Diffusion Test With Gamma Sterilized Dupont 20-6064 LDPE White DROP-TAINERs . Alcon Technical Report 005:38520:0195 Elution Test with Gamma Sterilized Dupont 20-6064 LDPE White DROP-TAINERs Alcon Technical Report 006:38520:0195 Acute Systemic Toxicity in Mice with Extracts of Gamma Sterilized Dupont 20-6064 LDPE White DROP-TAINERs Alcon Technical Report 007:38520:0195 Intracutaneous Reactivity Test in Albino Rabbits with Extracts of Gamma Sterilized Dupont 20-6064 LDPE White DROP-TAINERs Alcon Technical Report 037:38520:0595 Intracutaneous Reactivity Test in Albino Rabbits with Extracts of EtO Sterilized 15 mm Polyethylene White DROP-TAINERs Alcon Technical Report 048:38520:0595 Agar Diffusion Test of EtO Sterilized 15 mm Polyethylene White DROP-TAINERs Alcon Technical Report 049:38520:0595 Elution Test of EtO Sterilized 15 mm Polyethylene White DROP-TAINERs Alcon Technical Report 050:38520:0595 Acute Systemic Toxicity in Mice with Extracts of EtO Sterilized Polyethylene White DROP-TAINERs 10 Alcon Technical Report 052:38520:0595 Primary Ocular Irritation in Rabbits with Extracts of EtO Sterilized 15 mm Polyethylene White DROP-TAINERs 11 Alcon Technical Report 095:38560:1090 Evaluation of Dupont 20-6064, Gamma Irradiated, Low Density Polyethylene, 10 mL Natural DROP-TAINERs According USP XXII, Physico-chemical Tests- Plastics 12 3.2.P.2.4. Container Closure System [Dorzolamide Hydrochloride Ophthalmic Solution, 2%], Page 6 CONFIDENTIAL PURSUANT TO THE PROTECTIVE ORDER AD_DORZOLAMIDE_EIKE000625 Case 3:12-cv-01141-SMY-DGW Document 176-9 *SEALED* Filed 12/01/14 Page 24 of 24 Dorzolamide Hydrochloride Ophthalmic Solation ANDA Page ID #2441 Case: 16-3334 Document: 55-22 Filed: 02/08/2017 Pages: 24 (888 of 1511) + Appendix to Section 3.2.P.2.4 (continued) Contents Item Tab Alcon Technical Report 039:38520:0495 Agar Diffusion Test with Gamma Sterilized Dupont 20-6064 LDPE Natural DROP-TAINERs 13 Alcon Technical Report 040:38520:0495 Elution Test with Gamma Sterilized Dupont 20-6064 LDPE Natural DROP-TAINERs 14 Alcon Technical Report 041:38520:0495 Acute Systemic Toxicity in Mice with Extracts of Gamma Sterilized Dupont 20-6064 LDPE Natural DROP-TAINERs 15 Alcon Technical Report 042:38520:0495 Intracutaneous Reactivity Test in Albino Rabbits with Extracts of Gamma Sterilized Dupont 20-6064 LDPE Natural DROP-TAINERs 16 Alcon Technical Report 043:38520:0495 Primary Ocular Irritation in Rabbits with Extracts of Gamma Sterilized Dupont 20-6064 LDPE Natural DROP-TAINERs 17 Alcon Technical Report 025:38560:0294 Evaluation of Gamma Sterilized WIMCO Polypropylene 15 MM Orange Closures, Lot MD-2081-G, by USP XXII Physico-chemical Tests - Plastics 18 Alcon Technical Report 061:38520:0694 Agar Diffusion Test with Gamma Sterilized Himont Orange Polypropylene Closures 19 Alcon Technical Report 062:38520:0694 Elution Test with Gamma Sterilized Himont Orange Polypropylene Closures 20 Alcon Technical Report 063:38520:0694 Acute Systemic Toxicity in Mice with Extracts of Gamma Sterilized Himont Orange Polypropylene Closures 21 Alcon Technical Report 064:38520:0694 Intracutaneous Reactivity Test in Albino Rabbits with Extracts of Gamma Sterilized Himont Orange Polypropylene Closures 22 Alcon Technical Report TDOC-0006015 Package Leaching Study for Dorzolamide, 2% Ophthalmic Solution FID 109937 23 3.2.P.2.4. Contaioer Closnre System [Dorzolamide Hydrochloride Ophthalmic Solation, 2%], Page 7 CONFIDENTIAL PURSUANT TO THE PROTECTIVE ORDER AD DORZOLAMIDE EIKE000626 Case 3:12-cv-01141-SMY-DGW Document 176-35 *SEALED* Filed 12/01/14 Page 1 of 31 Page ID #3204 Case: 16-3334 Document: 55-23 Filed: 02/08/2017 Pages: 31 (889 of 1511) UNITED STATES DISTRICT COURT SOUTHERN DISTRICT OF ILLINOIS EAST ST. LOUIS DIVISION CHARLENE EIKE, SHIRLEY FISHER JORDAN PITLER and ALAN RAYMOND, on behalf of themselves and all others similarly situated, Plaintiffs, v. ALLERGAN, INC., et al., Defendants. ) ) ) ) ) ) ) ) ) ) ) ) No. 3:12-cv-01141-SMY-DGW EXPERT REPORT OF DR. DAVID LIN Case 3:12-cv-01141-SMY-DGW Document 176-35 *SEALED* Filed 12/01/14 Page 2 of 31 Page ID #3205 Case: 16-3334 Document: 55-23 Filed: 02/08/2017 Pages: 31 (890 of 1511) EXPERT REPORT OF DR. DAVID LIN I have prepared the following report at the request of counsel for the Defendants. I have been asked to provide my opinions regarding the United States Food and Drug Administration (“FDA”) regulations, guidance and practices governing changes in container closure systems for ophthalmic drug products that result in a decrease in their drop volume. This report sets forth my opinions and the basis for those opinions. I. SUMMARY OF CREDENTIALS AND EXPERIENCE 1. Since January 2005, I have been employed as a Senior Consultant at Biologics Consulting Group, Inc. (“BCG”), a team of consultants who provide national and international regulatory and product development advice on the development and commercial production of small molecular weight synthetic drug, biotechnological and biological products. 2. Before joining BCG, I held various positions with the FDA. From 1997-2001, I was a Chemistry Reviewer in the Division of Reproductive and Urologic Drug Products, Center for Drug Evaluation and Research (“CDER”). In 2001, I became the Team Leader in the same Division and served in that role until 2003, when I was promoted to the position of acting Deputy Division Director in the Division of New Drug Chemistry III, Office of New Drug Chemistry (currently referred to as Office of New Drug Quality Assessment). In 2004, I was promoted to the position of acting Division Director. 3. As a Chemistry Reviewer at CDER, I was responsible for the comprehensive review of Chemistry, Manufacturing and Controls (“CMC”) data for drugs being investigated during Phase 1, 2, and 3 clinical studies. I was also responsible for the review of CMC data in Investigational New Drug Applications (“INDs”), New Drug Applications (“NDAs”), and NDA post-approval Supplements, and provided regulatory input to CMC reviewers responsible for Case 3:12-cv-01141-SMY-DGW Document 176-35 *SEALED* Filed 12/01/14 Page 3 of 31 Page ID #3206 Case: 16-3334 Document: 55-23 Filed: 02/08/2017 Pages: 31 (891 of 1511) review of Abbreviated New Drug Applications (“ANDAs”). This included providing scientific and regulatory guidance during development of small molecular weight drugs and biotechnological/biological drugs across a wide variety of dosage forms. 4. As the acting Deputy Division Director and acting Division Director of the Office of New Drug Chemistry, I directly managed and supervised chemists with review responsibilities in the following six medical-reviewing divisions: (1) anti-inflammatory/analgesic/ ophthalmologic, (2) dermatologic/dental, (3) anti-viral, (4) anti-infective, (5) special pathogen/immunologic, and (6) over-the-counter drugs. 5. I have reviewed CMC data submitted with respect to over 100 INDs and NDAs (original and supplemental) as a chemistry reviewer, contributed to decisions regarding the approval of drugs, made presentations before scientific and regulatory conferences and participated in a variety of special FDA projects and committees, including serving as the coChair of the CMC Good Review Practices Committee. 6. As both a chemistry reviewer and acting Division Director I became experienced with FDA’s expectations and requirements for approval of the CMC section of NDAs, and in particular as it relates to ophthalmic products. As described further below, the CMC review of new ophthalmic products includes information on the container closure system to dispense the drug product, and in some instances includes information on drop volume as well. 7. As Team Leader, acting Deputy Division Director and acting Division Director in the Office of New Drug Chemistry, I was actively involved in directing the content of FDA guidances that pertained to CMC topics. As acting Deputy Division Director and Division Director, I was directly involved in discussions regarding the content of the 2003 FDA draft guidance on Drug Product-Chemistry, Manufacturing, and Controls Information, with the 2 Case 3:12-cv-01141-SMY-DGW Document 176-35 *SEALED* Filed 12/01/14 Page 4 of 31 Page ID #3207 Case: 16-3334 Document: 55-23 Filed: 02/08/2017 Pages: 31 (892 of 1511) committee responsible for writing this guidance. I had signatory authority for this draft guidance prior to public issuance by FDA. As acting Deputy Division Director and Division Director, I was involved in regular meetings with the supervisory staff in the Office of Generic Drugs to discuss regulatory and review policy issues that are common to both NDAs and ANDAs, including ensuring consistency of review for new drug and generics. 8. I consider myself an expert in the fields of FDA practice and procedure as applicable to the review of INDs, NDAs and ANDAs. 9. Before joining FDA I was a staff scientist at General Electric Company’s Biological Sciences Laboratory from 1989 to 1994, and a research assistant in the Department of Chemistry/Biochemistry at the University of Maryland from 1984-1989. 10. I received my B.A. in Biochemistry from the University of Pennsylvania in 1984, my Ph.D. in Organic Chemistry from the University of Maryland in 1989 and my M.B.A. from the University of Maryland’s RH Smith School of Business in 2002. Attached hereto as Appendix A is my curriculum vitae, including a list of my publications for the past ten years. 11. I have provided expert testimony by trial or deposition in three cases in the past four years. Attached hereto as Appendix B is a listing of those cases. My hourly fee for work in this case is $350 per hour. II. SUMMARY OF OPINIONS 12. I disagree with the plaintiffs’ assertion, set forth in their First Amended Class Action Complaint for Damages, Punitive Damages, and Injunctive Relief (the “Complaint”), that “Defendants are not constrained by any legal or regulatory constriction of the FDA from changing the sizes of their eye drops.” In order to obtain approval for a new drug, Defendants had to submit comprehensive applications to the FDA about their drugs, including the dosing regimen, labeling, volume, and packaging. Based upon my review of Defendants’ submissions, 3 Case 3:12-cv-01141-SMY-DGW Document 176-35 *SEALED* Filed 12/01/14 Page 5 of 31 Page ID #3208 Case: 16-3334 Document: 55-23 Filed: 02/08/2017 Pages: 31 (893 of 1511) they included information on the container closure systems and a number included specific information on drop volume dispensed by the container closure systems. Each of the drugs at issue was approved by FDA following its review of those submissions. Defendants would not be allowed to make changes to the container closure systems in order to reduce the drop volume of their medications to no greater than 15-16 µl without first seeking and obtaining FDA’s prior approval, because such a change would be considered a “major change” by FDA. 13. In addition, because the nearly 60 different prescription eye drop medications listed in the Complaint have different characteristics and properties, FDA could not simply do a one-size-fits-all review to determine that a 15-16 µL drop size for all “eye drop medications” would be safe and effective. Rather, based upon my experience at CDER and my review of FDA guidance documents, FDA would have to conduct an individualized review of each proposed container closure system and into studies and testing for each ophthalmic drug product, to determine on a drug-by-drug basis whether the quality, safety and effectiveness of each product would be changed as a result of the redesign of the container closure system and the resulting reduced drop volume, and therefore whether each proposed redesigned product could be approved. 1 This review would need to include a determination of whether each drug could be delivered at a drop volume of 15-16 µL at all, whether each drug could reliably be delivered at such a reduced volume safely and effectively, and whether reducing the drop volume to 15-16 µL might require changes to the formulation or concentration of each drug. I cannot predict with 1 See FDA Guidance for Industry: Container Closure Systems for Packaging Human Drugs and Biologics, May 1999, at 5 (“CDER and CBER approve a container closure system to be used in the packaging of a human drug or biologic as part of the application (NDA, ANDA or BLA) for the drug or biologic. A packaging system found acceptable for one drug product is not automatically assumed to be appropriate for another. Each application should contain enough information to show that each proposed container closure system and its components are suitable for its intended use.”). 4 Case 3:12-cv-01141-SMY-DGW Document 176-35 *SEALED* Filed 12/01/14 Page 6 of 31 Page ID #3209 Case: 16-3334 Document: 55-23 Filed: 02/08/2017 Pages: 31 (894 of 1511) any degree of certainty whether such approval would actually be granted by FDA as to any particular drug product or any particular dropper tip design. 14. I further disagree with the Plaintiffs’ assertion, set forth in the Complaint, that “Generic eye drops are not limited to being marketed at the same size as their brand-name equivalents.” An ANDA must contain information to show that the conditions of use prescribed, recommended, or suggested in the labeling proposed for the generic drug have been previously approved for the reference listed drug, that the generic drug shares the same route of administration, dosage form, and strength as its reference listed drug, and that the generic drug is bioequivalent to the reference listed drug. For this reason, a generic manufacturer or distributor cannot market its eye drops in different drop volumes from their brand-name equivalents. The drop volume of the generic eye drop must remain equivalent to the drop volume of the brandname equivalent or reference listed drug. Causing the generic eye drops to deviate from their brand-name equivalents would again require prior FDA approval, with individualized review of each proposed container closure system and individualized inquiry into separate studies and testing for each generic drug to demonstrate on a drug-by-drug basis its continuing equivalence to its reference listed drug. III. MATERIALS CONSIDERED 15. In support of my opinions, I have considered and relied on materials set forth in Appendix C, my knowledge and understanding of applicable FDA regulations, guidances, and practices, and my knowledge and experience with ophthalmic products over the course of my education and career. 5 Case 3:12-cv-01141-SMY-DGW Document 176-35 *SEALED* Filed 12/01/14 Page 7 of 31 Page ID #3210 Case: 16-3334 Document: 55-23 Filed: 02/08/2017 Pages: 31 (895 of 1511) IV. OVERVIEW OF OPHTHALMIC PRODUCT REGULATIONS AND FDA CONSIDERATION OF CONTAINER CLOSURE SYSTEMS AND DROP VOLUME DATA 16. FDA is a federal agency responsible for, among other duties, ensuring that a drug marketed in the United States is safe and effective for use as prescribed in the labeling of the drug, and can be adequately manufactured, processed and packaged to preserve the drug’s identity, strength, quality and purity. 2 There are additional rules, regulations and guidances that further delineate the requirements necessary to satisfy these statutory requirements. 17. Prescription ophthalmic products are closely scrutinized and regulated by FDA. Based on my more than 19 years of pharmaceutical regulatory experience, I am intimately familiar with the regulations, guidances, practices governing prescription ophthalmic products. 18. An original NDA, including for an ophthalmic drug, requires comprehensive technical information concerning the drug, “including its physical and chemical characteristics”, and “all components used in the manufacturer of the drug product,” among other things. 3,4 19. An NDA requires submission of the full reports of the investigations used to show that the drug is safe for use and is effective in use, the component and composition of the drug, the methods used in and the facilities and controls used for the manufacturing, processing and packing of the drug, and the labeling for the drug. 5 20. In order to determine whether a new ophthalmic drug product is safe and effective and can be brought to market, FDA requires pharmaceutical companies to conduct various 2 21 USC § 355 (d). 3 21 C.F.R. § 314.50(d)(1)(i). 4 21 C.F.R. § 314.50(d)(1)(ii)(a). 5 21 USC § 355 (1). 6 Case 3:12-cv-01141-SMY-DGW Document 176-35 *SEALED* Filed 12/01/14 Page 8 of 31 Page ID #3211 Case: 16-3334 Document: 55-23 Filed: 02/08/2017 Pages: 31 (896 of 1511) scientific studies in addition to preclinical animal studies and clinical trials in humans. All drug products possess critical quality attributes that are necessary to ensure the safe and efficacious use of the product by patients. These quality attributes are assessed during the scientific studies through the use of drug product manufactured with specified performance characteristics. Critical characteristics identified for ophthalmic products that may affect the safety and effectiveness of the drugs, include, but are not limited to, some or all of the following: the level of impurities, source of impurities (from drug substances, excipients, container closure components), foreign particulate matter, color, amount of active ingredients and breakdown products, sterility, amount of drug (assay), and drop volume. 6 21. FDA evaluates not only the reports of the clinical investigations, but also the nonclinical pharmacology and toxicology studies conducted in animals, human pharmacokinetic and bioavailability studies, and chemistry, manufacturing and controls information. 7 It is this complete package of information and data that allows FDA to determine the safety and effectiveness of the drug, and the ability of the manufacturer to produce a consistent and quality product. 22. The statutory provisions and regulations do not provide specific details on the information FDA requires in an NDA with respect to the container closure system used to package the drug product. However, FDA has issued guidance on the information and data recommended for inclusion in the NDA for an ophthalmic drug product container closure 6 Proposed revisions to USP General Chapter <771> Ophthalmic Ointments. Volume of each drop is called “drop size”. The compendial requirements in the proposed revision to USP <771> reflect actual FDA practices that have been in place for ophthalmic products at least since my tenure at CDER/FDA began in 1997. 7 21 C.F.R. § 314.50. 7 Case 3:12-cv-01141-SMY-DGW Document 176-35 *SEALED* Filed 12/01/14 Page 9 of 31 Page ID #3212 Case: 16-3334 Document: 55-23 Filed: 02/08/2017 Pages: 31 (897 of 1511) system. 8 This information includes a description of the container closure, the suitability of the container closure, quality control of the container closure components, stability of the drug product in the container closure, and “functionality and/or drug delivery.” 23. Suitability refers to the capability of the container closure to protect the drug product, the safety of the components used to manufacture the container closure, the compatibility of the container closure with the drug product and the performance of the container closure. Performance refers to the ability of the container closure to function in the manner for which it was designed. Performance can be evaluated by considering container closure functionality and drug delivery. Functionality is a design characteristic that is focused on patient needs. Drug delivery refers to the ability of the packaging system to deliver the dosage form in the amount or at the rate described in the package insert. 9 24. For an ophthalmic drug product, drug delivery is sometimes measured by drop volume and/or drop rate. Because drug delivery of an eye drop medication is controlled by the container closure system (i.e., the dropper tip), some NDAs contain specific data regarding drop volume in the container closure sections of the NDA. Drop volume also can be relevant to the container closure used in the clinical studies, stability data for the drug product used in the clinical studies, and quality control data for the clinical drug product, so this information may be located in many other sections of these NDAs. I have reviewed numerous excerpts of NDAs submitted in connection with the ophthalmic drug products at issue in this litigation. All contained information on the container closure systems, and some contained specific information 8 Guidance for Industry: Container Closure Systems for Packaging Human Drugs and Biologics – Chemistry, Manufacturing, and Controls Documentation, May 1999. 9 Guidance for Industry: Container Closure Systems for Packaging Human Drugs and Biologics – Chemistry, Manufacturing, and Controls Documentation, May 1999. 8 Case 3:12-cv-01141-SMY-DGW Document 176-35 *SEALED* Filed 12/01/14 Page 10 of 31 Page ID #3213 Case: 16-3334 Document: 55-23 Filed: 02/08/2017 Pages: 31 (898 of 1511) on drop volume data and drop volume studies submitted by Defendants to FDA as part of the approval process. FDA also may exercise, and has exercised, its authority to request drop volume information for an approved drug if drop volume may be relevant to post-approval changes to the drug or container closure system. 25. One example is an Alcon NDA product, Travatan Z (travopost ophthalmic solution), 0.004%. In the NDA, Alcon provided data on the performance of the container closure system through the evaluation of the drop volume. 10 “The drop volume data indicate an overall drop volume of 28.7 microliters (28.8 mg) with a standard deviation of ± 3.2 microliters.” A similar study was conducted and provided in the NDA of Alcon’s Vigamox (moxifloxacin hydrochloride ophthalmic solution), 0.5% product. 11 V. CHANGES TO THE CONTAINER CLOSURE SYSTEM AND/OR DROP VOLUME ARE MAJOR CHANGES REQUIRING PRIOR FDA APPROVAL OF A SUPPLEMENTAL NEW DRUG APPLICATION FOR EACH DRUG 26. Plaintiffs’ expert, Dr. Alan Robin, opines that the drop volume for Defendants’ ophthalmic products should be decreased by an average of more than 50% to 16 µl. On page 8 of his expert report Dr. Robin provides a picture of a dropper tip, which has never been commercially available, but which Plaintiffs allege could dispense drops of approximately 16 µl. 12 27. Plaintiffs assert in the Complaint that “Defendants are not constrained by any legal or regulatory constriction from changing the size for the eye drop.” I disagree. The changes proposed by Plaintiffs and Dr. Robin (redesigning Defendants’ container closure 10 AD_Travatan_Eike041118. 11 AD_Vigamox_Eike016364. 12 Alan L. Robin, MD expert report, May 30, 2014. 9 Case 3:12-cv-01141-SMY-DGW Document 176-35 *SEALED* Filed 12/01/14 Page 11 of 31 Page ID #3214 Case: 16-3334 Document: 55-23 Filed: 02/08/2017 Pages: 31 (899 of 1511) systems so that they all dispense drops of 15-16 µl) would be considered major changes that would require Defendants to file, and FDA to approve, a supplemental new drug application for each medication before Defendants could distribute the new drug products with the redesigned dropper tips. 28. Under 21 C.F.R. § 314.70(b), a change in the container closure system that results in a change in drop volume or amount delivered would be classified as a “major change” requiring FDA approval, for several separate reasons. First, the regulations provide that “[c]hanges in a drug product container closure system that controls the drug product delivered to a patient” are classified as “major changes.” 13 An eye dropper controls the amount of drug delivered to a patient based on the dimensions of the dropper tip, as compared to, for example, a bottle of tablets, where the amount of drug delivered is controlled by the patient independent of the packaging. Second, eye drop medications are sterile products. 14 As FDA’s guidance on “Changes to an Approved NDA or ANDA” 15 states, a change to the shape and size of the container closure for a sterile drug product would be considered a “major change” and thus require a Prior Approval Supplement. 16 Third, a reduction in drop volume would (unless the drug was reformulated) result in a reduction of the amount of active ingredient in each dose 13 21 C.F.R. §314.70 (b)(2)(vi). 14 21 C.F.R. § 200.50(a)(1). 15 Guidance for Industry: Changes to an Approved NDA or ANDA, April 2004. 16 See also 69 Fed. Reg. 18,728-01, 18,745 (Apr. 8, 2004) (“Changes in the container closure system, even if minimal, may affect the sterility assurance of the drug product and are a major change.”). 10 Case 3:12-cv-01141-SMY-DGW Document 176-35 *SEALED* Filed 12/01/14 Page 12 of 31 Page ID #3215 Case: 16-3334 Document: 55-23 Filed: 02/08/2017 Pages: 31 (900 of 1511) delivered to the patient, which would be considered a reduction in “dosage strength.” 17 Because such a reduction would have to be supported by study data to demonstrate equivalence, 18 it would be considered a major change for that reason as well. 19 Fourth, to the extent Defendants’ approved product labels state the amount of drug delivered in each drop, the reduction in the amount of drug delivered per drop would also therefore require a labeling change. Such a change also requires a Prior Approval Supplement. 20 29. Thus, for a variety of reasons, a change to the container closure dropper tip for an ophthalmic drug product is considered a major change, requiring FDA approval prior to implementing the change. As set forth above, this conclusion is based on FDA guidance. 21 30. The changes that some of the Defendants have made to their container closure systems under the current regulations support this opinion. For example, I reviewed a change to an alternative dropper tip design for Pfizer’s Xalatan product, which required submission of a Prior Approval Supplement to FDA. 22 The drop volume and drop rate data provided in the NDA Supplement demonstrated that the alternative dropper tips were comparable to the container closure dropper tip in the approved product. 23,24 To support the change to an alternative dropper 17 Drugs@FDA Glossary of Terms, available at http://www.fda.gov/Drugs/InformationOnDrugs/ucm079436.htm (“strength” refers to “how much of the active ingredient is present in each dosage”). 18 21 C.F.R. § 320.21 (c)(1). 19 21 C.F.R. § 314.70(b)(2)(ii). 20 21 C.F.R. § 314.70(b)(2)(v). 21 Guidance for Industry: Changes to an Approved NDA or ANDA, April 2004. 22 Pfizer_XALATAN_00000001. 23 Pfizer_XALATAN_00000038-00000040. 24 Pfizer_XALATAN_00000157-00000159. 11 Case 3:12-cv-01141-SMY-DGW Document 176-35 *SEALED* Filed 12/01/14 Page 13 of 31 Page ID #3216 Case: 16-3334 Document: 55-23 Filed: 02/08/2017 Pages: 31 (901 of 1511) tip, data were provided to demonstrate sterility assurance, a requirement for an ophthalmic drug product. 31. As another example, I reviewed a change to an alternative dropper design for Merck’s Cosopt product, which required submission of a Prior Approval Supplement to FDA. 25 Again, to support the change to an alternative dropper design, data were provided to demonstrate sterility assurance. 32. For these reasons, it is my opinion, based on FDA regulations and guidance, and contrary to Plaintiffs’ assertions, that Defendants cannot change the container closure system or the sizes of their eye drops, as the Plaintiffs and their expert, Dr. Robin, propose, without first seeking and obtaining FDA approval. FDA would need to consider each supplemental application separately, on a drug-by-drug basis, as the ability to change the drop volume and/or container closure system and maintain safety and efficacy would be highly dependent on the properties of the individual product and their container closure system, and the individualized results observed with respect to safety and efficacy of each product at smaller drop volumes. VI. GENERIC EYE DROPS MUST REMAIN EQUIVALENT TO THEIR REFERENCE LISTED DRUG 33. Plaintiffs further assert in their Complaint that, “Generic eye drops are not limited to being marketed at the same size as their brand-name equivalents.” I disagree with this statement as well. 34. Under 21 U.S.C. § 355(d), an ANDA must contain information to show that the conditions of use prescribed, recommended, or suggested in the labeling proposed for the generic drug have been previously approved for the reference listed drug. 25 NDA_Merck_Prasco0009182-0009655. 12 Case 3:12-cv-01141-SMY-DGW Document 176-35 *SEALED* Filed 12/01/14 Page 14 of 31 Page ID #3217 Case: 16-3334 Document: 55-23 Filed: 02/08/2017 Pages: 31 (902 of 1511) 35. Likewise, under 21 U.S.C. § 355(j)(2)(A)(iii), an ANDA must contain “information to show that the route of administration, the dosage form, and the strength of the new drug are the same as those of the listed drug referred.” 36. The generic drug must also be “bioequivalent” to the reference listed drug under 21 U.S.C. § 355(j)(2)(A)(iv). 37. In FDA’s publication, “Approved Drug Products with Therapeutic Equivalence Evaluations 26” (commonly known as the Orange Book), therapeutic equivalents are defined as drug products that are pharmaceutical equivalents, bioequivalent, and approved as safe and effective. Pharmaceutical equivalents (also defined in paragraph 36) contain identical amounts of the same active drug ingredient in the same dosage form and route of administration. Therefore, if a generic drug product is not both pharmaceutically equivalent and bioequivalent to the reference listed drug, then is it not therapeutically equivalent. 38. One example is provided in Alcon’s ANDA for Dorzolamide Hydrochloride- Timolol Maleate Ophthalmic Solution. The performance of the container closure system was assessed through the evaluation of the drop volume and compared to the drop volume of the reference listed drug, Cosopt. The drop volume data for the generic indicated an average drop volume of 44.5 mg with a standard deviation of ± 3.6 mg. These data demonstrate equivalency to the reference Cosopt product with an average drop volume of 46 mg and a standard deviation of ± 6.4 mg. 27 26 Referenced in 21 C.F.R. 314.3. 27 AD_DORZOLAMIDE_EIKE000274-000275. 13 Case 3:12-cv-01141-SMY-DGW Document 176-35 *SEALED* Filed 12/01/14 Page 15 of 31 Page ID #3218 Case: 16-3334 Document: 55-23 Filed: 02/08/2017 Pages: 31 (903 of 1511) 39. Changing the drop volume of a generic eye drop to deviate materially from its brand-name equivalent or reference listed drug would violate the requirement that the generic drug conform in pharmaceutical equivalence and bioequivalence to the reference listed drug. 40. Under applicable FDA regulations, the “strength” of a drug is “[t]he concentration of the drug substance (for example, weight/weight, weight/volume, or unit dose/volume basis)” and/or “[t]he potency, that is, the therapeutic activity of the drug product as indicated by appropriate laboratory test or by adequately developed and controlled clinical data.” 21 C.F.R. §210.3. A more concise definition as presented in FDA’s “Glossary of Terms” 28 is “[t]he strength of a drug product tells how much of the active ingredient is present in each dosage.” 41. A change to a generic eye drop is contingent on a change being made to the brand-name equivalent or reference listed drug. Plaintiffs’ proposal to reduce drop volume to 15 or 16 µl would reduce the amount of the active and inactive ingredients in each dose of the generic product. This would deviate from the strength of the reference listed drug and also change the quantitative formulation. FDA regulations also require prior FDA approval for “changes in the qualitative or quantitative formulation of the drug product, including inactive ingredients[.]” 21 C.F.R. § 314.70 (b)(2). “Quantitative formulation” includes “both active and inactive ingredients.” 21 C.F.R. § 314.200(e)(2). These changes would require, on a drug-bydrug basis, data to demonstrate both pharmaceutical equivalence and bioequivalence to the reference listed drug. 28 See http://www.fda.gov/drugs/informationondrugs/ucm079436.htm#S (accessed on 9/7/14). 14 Case 3:12-cv-01141-SMY-DGW Document 176-35 *SEALED* Filed 12/01/14 Page 16 of 31 Page ID #3219 Case: 16-3334 Document: 55-23 Filed: 02/08/2017 Pages: 31 (904 of 1511) 42. Additionally, as discussed above and as stated in FDA’s guidance on “Changes to an Approved NDA or ANDA,” 29 a change to the shape and size of the container closure for a sterile drug product in an approved ANDA would be considered a “major change” and thus require a Prior Approval Supplement. 43. For these reasons, it is my opinion, based on FDA regulations and guidance, contrary to Plaintiffs’ assertion, that generic eye drops are limited to the same size as their brandname equivalents. 30 29 Guidance for Industry: Changes to an Approved NDA or ANDA, April 2004. 30 21 C.F.R. § 314.54. 15 Case 3:12-cv-01141-SMY-DGW Document 176-35 *SEALED* Filed 12/01/14 Page 17 of 31 Page ID #3220 Case: 16-3334 Document: 55-23 Filed: 02/08/2017 Pages: 31 (905 of 1511) I declare under penalty of perjury that the foregoing is true and correct. Executed on this 12th day of September, 2014. YlJ47~·- David T. Lin, Ph.D. 16 Case 3:12-cv-01141-SMY-DGW Document 176-35 *SEALED* Filed 12/01/14 Page 18 of 31 Page ID #3221 Case: 16-3334 Document: 55-23 Filed: 02/08/2017 Pages: 31 (906 of 1511) Appendix A David T. Lin CV 17 Case 3:12-cv-01141-SMY-DGW Document 176-35 *SEALED* Filed 12/01/14 Page 19 of 31 Page ID #3222 Case: 16-3334 Document: 55-23 Filed: 02/08/2017 Pages: 31 (907 of 1511) EXPERTISE            19+ years pharmaceutical regulatory experience. o 7+ years regulatory chemistry, manufacturing and controls (CMC) experience at CDER/FDA on small molecular-weight drugs, botanical drugs, peptide drugs, and protein drugs formulated in a broad range of sterile and non-sterile dosage forms. o 3+ years research/regulatory experience at CBER/FDA (vaccines, therapeutic proteins). o 9+ years experience as regulatory CMC consultant (therapeutic proteins, monoclonal antibodies, synthetic small molecules, peptides, botanicals). Unique combination of biologic/biotechnological and small molecular-weight drug regulatory experience, including device/drug and device/biologics combination products. Understanding of FDA regulatory requirements and expectations for drug development and marketing approval. Performed primary CMC review and assessment of drug products for treatment of reproductive and urologic disorders and diseases. Supervised CMC review activities in 7 CDER medical reviewing divisions including Reproductive/Urologic, Anti-viral, Dermatologic/Dental, Anti-inflammatory/ Analgesic/Ophthalmologic, Anti-infective, Special Pathogen/Immunologic, and Over-theCounter drug products. Understanding of drug substance and drug product analytical method development and validation. Understanding of drug substance and drug product stability protocol development and stability data analysis. Understanding of current Good Manufacturing Practices (cGMPs) Experienced in chemical synthesis, small-scale and pilot-scale fermentation, biologics/ biotechnology, and protein chemistry. Experienced working in cross-functional teams (i.e., Pharmacology/toxicology, Clinical, Biostatistics, Biopharmaceutics, and Analytical). Ph.D. in Organic Chemistry; M.B.A. degree and training for managers. EXPERIENCE BIOLOGICS CONSULTING GROUP, INC. Alexandria, VA January 2005 – Present Senior Consultant  Evaluate and provide advice on client CMC scientific and regulatory strategies for a wide range of therapeutic drug products (biologic and non-biologic) in dosage forms that include tablets, topicals, injectables, transdermals, implants, sprays, and inhalation, at all stages of product development, from pre-IND through post-NDA/BLA approval.  Evaluate and provide advice on client CMC scientific and regulatory strategies for drug/device and biologic/device combination products, at all stages of product development, from IDE through post-PMA approval.  Review and provide advice on IND, NDA/BLA and ANDA submissions for suitability relative to FDA expectations for CMC data.  Perform gap analysis audits for deficiencies relative to FDA expectations.  Conduct regulatory and scientific due diligence audits for business acquisitions and licensing partnerships. Provide assessment of strengths and deficiencies.  Represent clients in interactions with FDA.  Prepare and write submissions to FDA, with focus on CMC sections.  Represent client as FDA regulatory expert in legal proceedings. 18 Case 3:12-cv-01141-SMY-DGW Document 176-35 *SEALED* Filed 12/01/14 Page 20 of 31 Page ID #3223 Case: 16-3334 Document: 55-23 Filed: 02/08/2017 Pages: 31 (908 of 1511)     Advise clients on manufacturing contractor and vendor evaluation and selection. Provide management and technical oversight of contract manufacturing organizations (CMOs). Involved in business development to increase client base. Provide scientific and regulatory training and presentations at pharmaceutical/biopharmaceutical conferences. FOOD & DRUG ADMINISTRATION, CENTER FOR DRUG EVALUATION AND RESEARCH, OFFICE OF NEW DRUG CHEMISTRY, DIVISION OF NEW DRUG CHEMISTRY III. Rockville, MD July 2003 – December 2004 Division Director (acting) March 2004 – December 2004 Deputy Division Director (acting) July 2003 – March 2004  Supervised 34 employees in 9 therapeutic product classes, includes 6 Team Leaders, review chemists and administrative staff. Responsible for employee work performance review and career development.  Planned and set long-range plans and schedules for Division work. Directed and coordinated workload, and assured implementation of Division policies, goals and objectives.  Evaluated budget and fiscal controls to manage Division functions.  Made critical decisions and provided expert advice concerning regulatory, scientific and compliance approaches and options consistent with Office policies and objectives.  Represented FDA in dealing and negotiating with the regulated industry, and professional and industry organizations.  Interacted with the Office of Generic Drugs to discuss regulatory CMC issues that pertained to both New Drugs and Generic Drugs.  Interacted with CDRH to discuss CMC issues that pertained to combination products.  Interacted with CBER and CVM to discuss CMC issues that cut across these Centers.  Participated as invited speaker at regulatory and scientific conferences on behalf of FDA.  Served as the Chair of the Stability Guidance Technical Committee, Co-chair of the Conjugated Estrogens Working Group and Co-chair of the Good Review Practices Working Group. FOOD & DRUG ADMINISTRATION, CENTER FOR DRUG EVALUATION AND RESEARCH, DIVISION OF REPRODUCTIVE AND UROLOGIC DRUG PRODUCTS. Rockville, MD October 2001-July 2003 Lead Chemist (Team Leader)  Managed a team of 4 review chemists in 2 therapeutic product classes.  Responsible for secondary review, consistency of CMC reviews and adherence to FDA/ONDC policies and guidances.  Coordinated reviewers’ workload of IND and NDA submissions to ensure that reviews were conducted in timely manner.  Interacted extensively with the regulated industry to provide regulatory direction during IND drug development and NDA post-approval activities.  Active in the development of FDA guidances for industry and internal good review practices. Served as the Chair of the Stability Guidance Technical Committee, Co-chair of the Conjugated Estrogens Working Group and Co-chair of the Good Review Practices Working Group. 19 Case 3:12-cv-01141-SMY-DGW Document 176-35 *SEALED* Filed 12/01/14 Page 21 of 31 Page ID #3224 Case: 16-3334 Document: 55-23 Filed: 02/08/2017 Pages: 31 (909 of 1511) FOOD & DRUG ADMINISTRATION, CENTER FOR DRUG EVALUATION AND RESEARCH, DIVISION OF REPRODUCTIVE AND UROLOGIC DRUG PRODUCTS. Rockville, MD April 1997-October 2001 Chemistry Reviewer       Evaluated the quality of new drug products submitted to the FDA for approval. Integral part of a cross-functional review team responsible for evaluating the quality and effectiveness of reproductive and urologic drug products being investigated in clinical studies. Major contributor to committees responsible for establishing drug product quality standards and publishing guidances for pharmaceutical companies. Provided regulatory guidance to pharmaceutical company representatives during drug development. Mentored new reviewers. Served as computer focal point to facilitate and troubleshoot computer issues. FOOD & DRUG ADMINISTRATION, CENTER FOR BIOLOGICS EVALUATION AND RESEARCH, LABORATORY OF PARASITIC BIOLOGY AND BIOCHEMISTRY. Bethesda, MD February 1994-April 1997 National Research Council Fellow  Investigated the biological role of specific proteins in the sexual differentiation of the malaria parasite. Published three research papers in peer-reviewed journals.  Presented research data at three separate scientific conferences.  CMC assessment of INDs.  Supervised the research projects of college students.  Responsible for the coordination of instrument repairs and the ordering of laboratory supplies. GENERAL ELECTRIC CO., CORPORATE RESEARCH & DEVELOPMENT, BIOLOGICAL SCIENCES LABORATORY. Schenectady, NY July 1989-January 1994 Staff Scientist  Developed recombinant biphenyl-metabolizing microorganisms capable of degrading environmental contaminants. Marketed this technology to the GE business units and government agencies responsible for environmental clean-up.  Investigated the factors affecting aerobic biodegradation of indigenous PCBs in Hudson River sediment by various bacterial strains.  Isolated and conducted mechanistic studies of the dioxygenase enzymes involved in biodegradation.  Investigated the scientific and economic feasibility of biologically synthesizing aromatic monomers for use as a feedstock to produce biodegradable polymers.  Supervised research projects of summer interns.  Published research in peer-reviewed journals.  Recruited at major East Coast universities. Interviewed and screened graduating science Ph.D. students for second round interviews at the Research Center. 20 Case 3:12-cv-01141-SMY-DGW Document 176-35 *SEALED* Filed 12/01/14 Page 22 of 31 Page ID #3225 Case: 16-3334 Document: 55-23 Filed: 02/08/2017 Pages: 31 (910 of 1511) UNIVERSITY OF MARYLAND, Dept. of Chemistry/Biochemistry. College Park, MD May 1985-May 1989 Research Assistant  Investigated mechanism of action of two bacterial enzymes, mandelate racemase and Damino acid oxidase.  Synthesized and tested novel halogenated aromatic hydroxy- and amino- acid analogs as potential irreversible inhibitors.  Published research in peer-reviewed journals and co-authored one chapter in a biotechnology book. In addition, the research data was presented at two national scientific conferences.  Served as the computer expert for the laboratory group. EDUCATION Robert H. Smith School of Business. College Park, MD University of Maryland Master of Business Administration (MBA), 2002 Concentration: Finance UNIVERSITY OF MARYLAND. College Park, MD Department of Chemistry and Biochemistry Ph. D. -- Organic Chemistry, 1989 Research Advisor -- Dr. John W. Kozarich UNIVERSITY OF PENNSYLVANIA. Philadelphia, PA Bachelor of Arts with Honors – Biochemistry, 1984 Dean's List, Phi Lambda Upsilon Chemical Honor Society TRAINING         Facilitation Skills, CDER/FDA (Fall 2002) Six Sigma Strategy and Methods, Univ. of MD (Summer 2002) Group Decision-Making Techniques, CDER/FDA (Feb. 2002) Managing Written Communications for Team Leaders, CDER/FDA (Spring 2002) Organizational Behavior and Human Resources, Univ. of MD (Fall 1999) Management of Human Resources, Univ. of MD (Fall 1999) Introduction to Drug Law and Regulation, CDER/FDA (Nov. 1998) Basic Statistical Methods, CDER/FDA (Fall 1998) HONORS/AWARDS         CDER’s Team Excellence Award (Nov 2004) FDA’s Group Recognition Award (May 2004) CDER’s Special Recognition Award (Nov 2002) CDER’s Team Excellence Award (Nov 2002) OPS/ONDC Special Recognition Award (Dec 2001) CDER’s Team Excellence Award (Nov 2000) OPS/ONDC Special Recognition Award (Jun 2000) CDER’s Excellence in Mentoring Award (Nov 1999) 21 Case 3:12-cv-01141-SMY-DGW Document 176-35 *SEALED* Filed 12/01/14 Page 23 of 31 Page ID #3226 Case: 16-3334 Document: 55-23 Filed: 02/08/2017 Pages: 31 (911 of 1511) PRESENTATIONS                       BIO 2014 The Tenth Annual Biotechnology Entrepreneurship Boot Camp, “Regulatory Planning and the Implications for Strategy and Financing”, San Diego, CA (Jun 2014). 6th DIA China Annual Meeting, “Principles for Successful GxP Inspections: A Hands-on Interactive Approach Based on FDA, WHO and Industry Experiences”, Shanghai, China (May 2014). 6th DIA China Annual Meeting, “Drug-Device Combination Products in US”, Shanghai, China (May 2014). IBC’s 6th Annual AsiaTIDES, “FDA Requirements for the Investigational Use of Peptide Products”, Tokyo, Japan (Feb 2014). 5th DIA China Annual Meeting, “Regulatory Challenges in Developing Botanical Drug Products in the United States”, Beijing, China (May 2013). Conducting Effective & Compliant Stability Programs for Pharmaceuticals & Biologics, “Stability Studies During Development”, “Stability of Biopharmaceuticals”, “Development of Specifications for Biopharmaceuticals”, and “Extractables, Leachables, and Particulates – Safety Concern for Biotechnology Products”, Dubai, UAE (Sep 2012). 4th DIA China Annual Meeting, “ICH Guidelines Q1D, Bracketing and Matrixing Designs for Stability Testing of New Drug Substances and Products”, and “Q1E, Evaluation of Stability Data”, Shanghai, China (May 2012). IPA’s Current Trends and Practices in Stability Testing, “Stability Testing Requirements for Biopharmaceutical Products”, Montreal, Canada (Oct 2011) IPA’s Current Trends and Practices in Stability Testing, “Stability Program for Combination Products”, Montreal, Canada (Oct 2011) 3rd DIA China Annual Meeting, “Thinking About Comparability for Biosimilar Proteins”, Beijing, China (May 2011). IPA’s Current Trends and Practices in Stability Testing, “Stability Challenges for Combination Products”, Boston, MA (May 2011). IPA’s Current Trends and Practices in Stability Testing, “Country Specific Stability Requirements”, Boston, MA (May 2011). Stability Programs Forum, “Stability Testing for Biotechnology/Biologic Products”, Philadelphia, PA (Dec 2010). 11th Annual EuroTIDES/EuroPEPTIDES Conference, “Stability Considerations and Testing for Peptide-and Oligo-Based Therapeutics”, Barcelona, Spain (Nov 2010). International Summit of China Pharmaceutical Industry, “FDA Requirements for Peptide Product Development: Considerations from Small Molecule and Biological Products”, Hangzhou, China (Oct 2010). 7th Annual Method Validation Conference, “Ensure Method Validation Compliance through a Review of FDA Warning Letters”, San Francisco, CA (Jul 2010). 6th Annual BioProcess International European Conference, “Extractables, Leachables and Particulates – Safety Concern for Biotechnology Products,” Vienna, Austria (May 2010) ISPE-CSAC Meeting, “Biotechnological Drug Development and Interactions with CDER,” Raleigh, NC (Oct 2009). Seminar on China International Bio-medicine Outsourcing Service, “Product Quality Issues with GLPs and GCPs,” Hangzhou, China (Sep 2009). Informa Stability Testing for Biologics Conference, “Understanding Product Expiry and ShelfLife,” Prague, Czech Republic (Sep 2009). Informa Stability Testing for Biologics Conference Workshop, “Stability Testing Performed Over a Product Lifecycle,” Prague, Czech Republic (Sep 2009). IVT Lab Compliance Conference, “Implement a Comprehensive and Compliant Stability Program,” Philadelphia, PA (Aug 2009). 22 Case 3:12-cv-01141-SMY-DGW Document 176-35 *SEALED* Filed 12/01/14 Page 24 of 31 Page ID #3227 Case: 16-3334 Document: 55-23 Filed: 02/08/2017 Pages: 31 (912 of 1511)                       OKBio ACCELERATE Workshop, “Product Development – Regulatory CMC Considerations,” Oklahoma City, OK (Jun 2009). IVT Method Validation Conference, “Challenges in Understanding Impurities and Degradants for Biological/Biotechnological Products,” San Francisco, CA (Oct 2008). IVT Method Validation Conference, “Strategies for Setting Biological Product Specifications,” San Francisco, CA (Oct 2008). CBI 3rd Annual Stability Programs Conference, “Complex Stability Programs for Biologics,” Philadelphia, PA (Jun 2008). IVT Lab Compliance Conference, “Stability Testing Fundamentals and Considerations in the Current Regulatory Environment,” Baltimore, MD (Apr 2008). R&D Direction’s 5th Annual Drug Development Summit, “Looking Forward in 2008: Regulatory Priorities and Considerations,” Amelia Island, FL (Feb 2008). 2007 AAPS Annual Meeting, “Critical Stability Evaluation of Biopharmaceuticals During Clinical Development Stages,” San Diego, CA (Nov 2007). 2007 DIA Annual Meeting, “The Impact of FDA’s Quality by Design Initiative on Biologics Development,” Atlanta, GA (Jun 2007). Institute for International Research: Formulation and Forced Degradation Strategies for Biomolecules, “Regulatory Requirements for Successful Product Development,” San Diego, CA (Mar 2007). International Pharmaceutical Academy: Effective Management of Stability Programs, “Stability Design Considerations for Global Regulatory Filings,” Toronto, Canada (Feb 2007). Cambridge Healthtech Institute’s PepTalk: Optimizing Protein and Antibody Therapeutics, “Regulatory Considerations for the Development of Protein Therapeutic Products,” San Diego, CA (Jan 2007). 2006 AAPS Annual Meeting, “The Impact of FDA Initiatives on the Development of Biological Products,” San Antonio, TX (Nov 2006). SWE Enterprises: Stability Testing for the FDA Regulated Industry, “In-Use Testing of Biotechnological and Biologic Products,” Boston, MA (Oct 2006). SWE Enterprises: Stability Testing for the FDA Regulated Industry, “Cost Efficient Design of Stability Studies,” Boston, MA (Oct 2006). Institute for International Research: Chemistry Manufacturing & Controls, “Clarifying and Understanding ICH Guidance to Help Meet International Requirements for Submissions,” Philadelphia, PA (July 2006). IVT Stability Testing: Implementing Effective Processes for Stability Program Development, "Cost Efficient Design of Stability Studies,” San Diego, CA (June 2006). IVT Stability Testing: Implementing Effective Processes for Stability Program Development, "Stability Requirements for Global Regulatory Filings," San Diego, CA (June 2006). CBI Stability Programs: New Approaches to Test, Analyze and Document Data for Improved Program Design and Global Compliance, "In Use Testing of Biotechnological and Biological Products," Princeton, NJ (June 2006). IBC/TIDES: Oligonucleotide and Peptide Technology and Product Development, “Stability Considerations and Testing for Oligo- and Peptide-Based Therapeutics,” Carlsbad, CA (May 2006). IBC Biopharm Manufacturing and Distribution Summit: Logistics for Biopharmaceutics, “Stability Studies to Support the Chain of Custody of Biotechnology Products,” Reston, VA (Dec 2005). 2005 AAPS Annual Meeting: AAPS Short Course on Degradation and Stability in Small Molecule Active Pharmaceutical Ingredients/Stability Testing for Global Filings, “Stability Requirements for Global Regulatory Filings,” Nashville, TN (Nov 2005). Therapeutic Strategies Against Neurodegenerative Conditions, “The Regulatory Product Development Process,” Burlington, MA (Oct 2005). 23 Case 3:12-cv-01141-SMY-DGW Document 176-35 *SEALED* Filed 12/01/14 Page 25 of 31 Page ID #3228 Case: 16-3334 Document: 55-23 Filed: 02/08/2017 Pages: 31 (913 of 1511)            International Pharmaceutical Federation (FIP) Workshop: Harmonizing Clinical Trial GMP and Quality Requirements Across the EU and Beyond, “The US Investigational New Drug (IND) System,” Noordwijk Zee, The Netherlands (Mar 2005). 2004 AAPS Annual Meeting, “Phase 2 and 3 IND CMC Guidance: FDA Perspective,” Baltimore, MD (Nov 2004). 64th Annual World FIP Congress, “Clinical Trial Application Process – CMC: US FDA Perspective,” New Orleans, LA (Sep 2004). AAPS Pharmaceutical Technologies 3rd Summer Conference: Optimizing the Global Clinical Trial Process, “IND Applications – FDA Perspective,” Cherry Hill, NJ (Aug 2004). 2004 DIA Annual Meeting, “FDA Stability Guidance Update,” Washington, DC (Jun 2004). DIA Meeting on CM&C/Regulatory and Technical Strategies, “Challenges and Opportunities in CMC Requirements for Phase 2-3,” Bethesda, MD (Mar 2004). 2003 PDA Annual Meeting, “Draft FDA Stability Guidance,” Atlanta, GA (Nov 2003). 2003 DIA Annual Meeting, “Product Quality of Non-clinical and Clinical Trial Materials,” San Antonio, TX (Jun 2003). PARCS Meeting, “Managing CMC Requirements during IND,” Irvine, CA (Apr 2003). PARCS Meeting, “Use of SUPAC Guidances during IND Development,” Irvine, CA (Apr 2003). DIA Meeting on Global Chemistry, Manufacturing and Controls: Pre IND/CTX and IND/CTX Development Challenges, “FDA Perspective on Stability Testing during IND Development,” Philadelphia, PA (Feb 2003). PUBLICATIONS       C. Syin, D. Parzy, F. Traincard, I. Boccaccio, M.G. Joshi, D.T. Lin, X.-M. Yang, K. Assemat, C. Doerig, and G. Langeley, “The H89 cAMP-dependent protein kinase inhibitor blocks Plasmodium falciparum development in infected erythrocytes,” Eur. J. Biochem. 268, 4842 (2001). J.P. McDaniel, C. Syin, D.T. Lin, M.B. Joshi, S. Li, and N.D. Goldman, “Expression and characterization of a Plasmodium falciparum protein containing domains homologous to sarcalumenin and a tyrosine kinase substrate, eps15,” Int. J. Parasitol. 29, 723 (1999). D.T. Lin, N.D. Goldman, and C. Syin, "Stage specific expression of a Plasmodium falciparum protein related to the eukaryotic mitogen-activated protein kinase," Mol. Biochem. Parasitol. 78, 67 (1995). M.R. Harkness, J.B. McDermott, D.A. Abramowicz, J.J. Salvo, W.P. Flanagan, M.L. Stephens, F.J. Mondello, R.J. May, J.H. Lobos, K.M. Carroll, M.J.Brennan, A.A. Bracco, K.M. Fish, G.L. Warner, P.R. Wilson, D.K. Dietrich, D.T. Lin, C.B. Morgan, and W.L. Gately, "In situ stimulation of aerobic PCB biodegradation in Hudson River sediments," Science 259, 503 (1993). D.T. Lin, V.M. Powers, L.J. Reynolds, C.P. Whitman, G.L. Kenyon and J.W. Kozarich, "Evidence for the generation of α-carboxy-α-hydroxy-p-xylylene from p(bromomethyl)mandelate by mandelate racemase," J. Am. Chem. Soc. 110, 323 (1988). M.S. Lakshmikumaran, E. D'Ambrosio, L.A. Laimins, D.T. Lin and A.V. Furano, "Long interspersed repeat DNA(LINE) causes polymorphism at the rat insulin 1 locus," Mol. Cell. Biol. 5, 2197 (1985). BOOK CHAPTER  N.R. Schmuff and D.T. Lin, “Contents of Module 3 for an Electronic Common Technical Document Investigational New Drug Application,” in Preparation and Maintenance of the 24 Case 3:12-cv-01141-SMY-DGW Document 176-35 *SEALED* Filed 12/01/14 Page 26 of 31 Page ID #3229 Case: 16-3334 Document: 55-23 Filed: 02/08/2017 Pages: 31 (914 of 1511)   IND Application in eCTD Format, W.K. Sietsema (ed.), FDAnews, Falls Church, VA, 117134 (2008). N.R. Schmuff and D.T. Lin, “Chemistry, Manufacturing and Controls (CMC),” in Wiley Encyclopedia of Clinical Trials, (2008). J.A. Gerlt, G.L. Kenyon, J.W. Kozarich, D.T. Lin, D.C. Neidhart, G.A. Petsko, V.M. Powers, S.C. Ransom and A.Y. Tsou, "Structure-function relationships in mandelate racemase and muconate lactonizing enzyme," in Chemical Aspects of Enzyme Biotechnology, T.O. Baldwin, F.M. Raushel and A.I. Scott (eds.), Plenum, New York, NY, 9-21 (1990). PROCEEDINGS OF MEETINGS      D.T. Lin, N.D. Goldman, and C. Syin, "Plasmodium falciparum mitogen-activated protein kinase homologue contains an unusually large carboxyl terminal domain which is highly charged and homologous to merozoite surface antigens," Molecular Parasitology Meeting, Woods Hole, MA (1995). C. Syin, D. Lin, B. Krzyzanowska, and N.D. Goldman, "Plasmodium cGMP-dependent protein kinase," FDA Science Forum on Regulatory Sciences, Washington, D.C. (1994). J. H. Lobos, M. J. Brennan, J. T. Jackman and D. T. Lin, "In situ stimulation of PCB biodegradation in Hudson River sediment: III. enumeration and characterization of aerobic bacteria," ASM Meeting, New Orleans (1992). G.L. Kenyon, D.T. Lin, V.M. Powers, L.J. Reynolds, C.P. Whitman and J.W. Kozarich, "Generation of α-carboxy-α-hydroxy-p-xylylene from p-bromomethyl-mandelate by mandelate racemase-- further evidence for a carbanion mechanism," FASEB J. 2, 1329 (1988). D.T. Lin, V.M. Powers, L.J. Reynolds, C.P. Whitman, G.L. Kenyon and J.W. Kozarich, "Formation of p-xylylene species in the mandelate racemase catalyzed reaction of p(bromomethyl)mandelate," Fed. Proc. 46, 2042 (1987) 25 Case 3:12-cv-01141-SMY-DGW Document 176-35 *SEALED* Filed 12/01/14 Page 27 of 31 Page ID #3230 Case: 16-3334 Document: 55-23 Filed: 02/08/2017 Pages: 31 (915 of 1511) Appendix B Expert Testimony Cases 1. September 12, 2013 Omeprazole Patent Litigation Civil Action No. 01-CIV-9351 (DLC) United States District Court Southern District of New York Deposition and Trial 2. May 16, 2012 Carter v. B. Braun Medical Inc. Case No. CV-10-02573-PHX-ROS United States District Court for the District of Arizona Expert Report 3. September 16, 2011 Wellbutrin XL Antitrust Litigation Case No. 2:08-cv-2431 (direct) United States District Court For the Eastern District of Pennsylvania Deposition 26 Case 3:12-cv-01141-SMY-DGW Document 176-35 *SEALED* Filed 12/01/14 Page 28 of 31 Page ID #3231 Case: 16-3334 Document: 55-23 Filed: 02/08/2017 Pages: 31 (916 of 1511) Appendix C Materials Reviewed 1. Materials cited as footnotes in the expert report. 2. PLEADINGS • First Amended Class Action Complaint • Protective Order 3. DEPOSITIONS • Deposition of Lisa Blackwell (Alcon), including exhibits • Deposition of Gary Charbonneau (Allergan), including exhibits • Deposition of Scott Grossman (Merck), including exhibits • Deposition of Diane Rocco (Pfizer), including exhibits • Deposition of Greg Seitz (Sandoz), including exhibits • Deposition of Brad Wooldridge (Alcon), including exhibits • Deposition of Alan Robin, M.D., including exhibits 4. EXPERT REPORTS • Expert report of Alan Robin, M.D., 05/30/2014 • Supplemental Expert report of Alan Robin, M.D., 06/09/2014 • Expert report of Brian Kriegler, Ph.D., 05/30/2014 5. DOCUMENTS PRODUCED BY DEFENDANTS • AD_AZOPT_EIKE000001 – 012195 • AD_AZOPT_EIKE012597 – 012606 • AD_AZOPT_EIKE 012196 - 012596 • Medical Review, 8/5/97 [AD_AZOPT_EIKE012207-012335] • Chemistry Review, 5/28/97 [AD_AZOPT_EIKE012336-012345] • Pharmacology Review, 5/31/97 [AD_AZOPT_EIKE012374-012452] • Statistical Review, 5/28/97 [AD_AZOPT_EIKE012453-012490] • Microbiology Review, 6/3/97 [AD_AZOPT_EIKE012491-012493] • Pharmacology Biopharmaceutics Review, 1/28/97 [AD_AZOPT_EIKE012494-012515] • Azopt label, 1998 [AD_AZOPT_EIKE009895] • Azopt label, 04/01/1998 [AD_AZOPT_EIKE 012201-012206] • Azopt label, 2009 [AD_AZOPT_EIKE009896] • Azopt label, 2011 [AD_AZOPT_EIKE009897] • Azopt label, 03/08/2011 [AD_AZOPT_EIKE012592-012596] • Azopt label, 2012 [AD_AZOPT_EIKE009898] • Azopt approval letter, 04/01/1998 [AD_AZOPT_EIKE012199-01200] • Azopt approval letter, 07/22/2003 [AD_AZOPT_EIKE012580-012581] • Azopt approval letter, 09/08/2011 [AD_AZOPT_EIKE012588-012591] • AD_DORZOLAMIDE_EIKE000001 - 000626 • AD_DORZ-TIM_EIKE00001 – 001231 27 Case 3:12-cv-01141-SMY-DGW Document 176-35 *SEALED* Filed 12/01/14 Page 29 of 31 Page ID #3232 Case: 16-3334 Document: 55-23 Filed: 02/08/2017 Pages: 31 (917 of 1511) • • • • • • • • • • • • • • • • • • • • • • • • • • • • • • • • • • • • • • • • • • AD_DORZ-TIM_EIKE001317 - 002770 AD_DORZ-TIM_EIKE001232 - 001316 Dorzolamide-Timolol label, 2010 [AD_DORZ-TIM_EIKE000349-000350] Dorzolamide-Timolol label, 2010 [AD_DORZ-TIM_EIKE000351] Dorzolamide-Timolol label, 2011 [AD_DORZ-TIM_EIKE000787-000812] Dorzolamide-Timolol label, 2012 [AD_DORZ-TIM_EIKE000352-000353] Dorzolamide-Timolol label, 2012 [AD_DORZ-TIM_EIKE000354] Dorzolamide-Timolol approval letter, 11/18/2009 [AD_DORZ-TIM_EIKE001310001316] AD_LATANOPROST_ EIKE000001-000076 AD_LATANOPROST_ EIKE000081-000362 Latanoprost label, 2011 [AD_LATANOPROST_ EIKE000077-000078] Latanoprost label, 2012 [AD_LATANOPROST_ EIKE000079-000080] Latanoprost label, Undated [AD_LATANOPROST_EIKE000010-000017] Latanoprost approval letter, 03/22/2011 [AD_LATANOPROST_ EIKE000349-000356] AD_TIMOLOL_EIKE000001-000774 Timolol label, 04/28/1995 [AD_TIMOLOL_EIKE000320] Timolol label, 2004 [AD_TIMOLOL_EIKE000174-000175] Timolol label, 2004 [AD_TIMOLOL_EIKE000176] Timolol label, Undated [AD_TIMOLOL_EIKE000206-000222] Timolol approval letter, 04/28/0995 [AD_TIMOLOL_EIKE000318-000319] AD_TIMOLOL-GFS_EIKE000001-009678 Medical Review, 8/13/98 [AD_TIMOLOL-GFS_EIKE009530-009572] Chemistry Review, 9/2/98 [AD_TIMOLOL-GFS_EIKE009573-009577] Pharmacology Review, 7/15/98 [AD_TIMOLOL-GFS_EIKE009578-009601] Microbiology Review, 3/31/98 [AD_TIMOLOL-GFS_EIKE009602-009608] Pharmacology Biopharmaceutics Review, 2/18/98 [AD_TIMOLOL-GFS_EIKE009609009613] Timolol GFS label, 10/21/1998 [AD_TIMOLOL-GFS_EIKE009513-009529] Timolol GFS label, 07/02/2003 [AD_TIMOLOL-GFS_EIKE009667-009668] Timolol GFS label, 2007 [AD_TIMOLOL-GFS_EIKE003777-003780] Timolol GFS label, 06/08/2007 [AD_TIMOLOL-GFS_EIKE009672-009678] Timolol GFS label, 2008 [AD_TIMOLOL-GFS_EIKE003781-003782] Timolol GFS label, 2010 [AD_TIMOLOL-GFS_EIKE003783-003784] Timolol GFS approval letter, 10/21/1998 [AD_TIMOLOL-GFS_EIKE009511-009512] Timolol GFS approval letter, 07/02/2003 [AD_TIMOLOL-GFS_EIKE009664-009666] Timolol GFS approval letter, 06/08/2007 [AD_TIMOLOL-GFS_EIKE009669-009671] AD_TRAVATAN_EIKE00001-041604 Chemistry Review, 11/9/00 [AD_TRAVATAN_EIKE041329-041333] Clinical Pharmacology Review, 7/7/00 [AD_TRAVATAN_EIKE041334-041351] Medical Review, 10/30/00 [AD_TRAVATAN_EIKE041369-041534] Microbiology Review, 8/7/00 [AD_TRAVATAN_EIKE041534-041537] Pharmacology Review, 10/31/00 [AD_TRAVATAN_EIKE041538-041604] Travatan label, 2001 [AD_TRAVATAN_EIKE041271-041277] 28 Case 3:12-cv-01141-SMY-DGW Document 176-35 *SEALED* Filed 12/01/14 Page 30 of 31 Page ID #3233 Case: 16-3334 Document: 55-23 Filed: 02/08/2017 Pages: 31 (918 of 1511) • • • • • • • • • • • • • • • • • • • • • • • • • • • • • • • • • • • • • • • • • • • Travatan label, 2003 [AD_TRAVATAN_EIKE041278-041283] Travatan carton label, 2004 [AD_TRAVATAN_EIKE041261-041267] Travatan carton label, 2004 [AD_TRAVATAN_EIKE041251-041257] Travatan label, 2010 [AD_TRAVATAN_EIKE041290-041294] Travatan label, 2011 [AD_TRAVATAN_EIKE041299-041306] Travatan approval letter, 06/16/2001 [AD_TRAVATAN_EIKE041288-041289] Travatan approval letter, 09/07/2001 [AD_TRAVATAN_EIKE041307-041309] AD_VIGAMOX_EIKE00001-016615 Medical Review, 4/11/03 [AD_VIGAMOX_EIKE046382-016441] Pharmacology Review, 2/10/03 [AD_VIGAMOX_EIKE016442-016474] Microbiology Review, 3/12/03 [AD_VIGAMOX_EIKE016475-016497] Pharmacology Biopharmaceutics Review, 12/13/02 [AD_VIGAMOX_EIKE016498016532] Vigamox label, 04/15/2003 [AD_VIGAMOX_EIKE016376-016381] Vigamox Carton label, 10/03/2003 [AD_VIGAMOX_EIKE016584] Vigamox label, 04/12/2004 [AD_VIGAMOX_EIKE016588-016593] Vigamox label, 06/25/2004 [AD_VIGAMOX_EIKE016597-016599] Vigamox label, 2006 [AD_VIGAMOX_EIKE012740] Vigamox label, 10/07/2011 [AD_VIGAMOX_EIKE016603-016608] Vigamox label, 2012 [AD_VIGAMOX_EIKE012741] Vigamox approval letter, 04/15/2003 [AD_VIGAMOX_EIKE016373-016375] Vigamox approval letter, 10/03/2003 [AD_VIGAMOX_EIKE016581-016583] Vigamox approval letter, 04/12/2004 [AD_VIGAMOX_EIKE016585-016587] Vigamox approval letter, 06/25/2004 [AD_VIGAMOX_EIKE016594-016596] Vigamox approval letter, 10/07/2011 [AD_VIGAMOX_EIKE016600-016602] AD_EIKE000001-001199 AD_EIKE001250 - 001335 ARGN_ALP1_00000015 - 0000019 ARGN_LUM01_0000001 - 0000013 ARGN_LUM01_0009674 – 0009682 Merck_Prasco0009138-009699 Merck_Prasco0010376-0010420 PFIZER_XALATAN_00000001 - 00000107 PFIZER_XALATAN_00000131 - 00000135 PFIZER_XALATAN_00000140 - 00000161 PFIZER_XALATAN_00000165 - 00000183 PFIZER_XALATAN_00000188 - 00000198 PFIZER_XALATAN_00000226 - 00000324 PFIZER_XALATAN_00000374 - 0000512 PFIZER_XALATAN_00000885 - 00000897 PFIZER_XALATAN_00001262 - 00001288 PFIZER_XALATAN_00001329 - 00001367 PFIZER_XALATAN_00001484 - 00001488 PFIZER_XALATAN_00001525 - 00001527 29 Case 3:12-cv-01141-SMY-DGW Document 176-35 *SEALED* Filed 12/01/14 Page 31 of 31 Page ID #3234 Case: 16-3334 Document: 55-23 Filed: 02/08/2017 Pages: 31 (919 of 1511) • • • • • • • • • • • • • • • • • PFIZER_XALATAN_00001547 - 00001615 PFIZER_XALATAN_00001621 - 00001628 PFIZER_XALATAN_00001637 - 00002071 PFIZER_XALATAN_00002075 - 00002093 PFIZER_XALATAN_00002098 PFIZER_XALATAN_00002126 - 00002140 PFIZER_XALATAN_00002144 - 00002145 PFIZER_XALATAN_00002152 - 00002169 PFIZER_XALATAN_00002429 - 00002434 PFIZER_XALATAN_00004755 - 00005195 PFIZER_XALATAN_00023605 - 00023607 PFIZER_XALATAN_00023656 - 00023664 PFIZER_XALATAN_00023686 - 00023690 PFIZER_XALATAN_00024111 - 00024120 PFIZER_XALATAN_00024636 - 00024645 PFIZER_XALATAN_00024650 - 00024654 PFIZER_XALATAN_00024688 – 00024694 30 3.2.P.2.4. Container Case 3:12-cv-01141-SMY-DGW Document 176-10 *SEALED* Filed 12/01/14 Page 1 of 14 Closure System Page ID #2442 Case: 16-3334 Document: 55-24 Filed: 02/08/2017 Pages: 14 CONFIDENTIAL PURSUANT TO THE PROTECTIVE ORDER (920 of 1511) AD_VIGAMOX_EIKE016359 Case 3:12-cv-01141-SMY-DGW Document 176-10 *SEALED* Filed 12/01/14 NDA Page 2 of 14 Moxifloxacin Ophthalmic Solution, 0.5% 21-458 Page ID #2443 Case: 16-3334 Document: 55-24 Filed: 02/08/2017 Pages: 14 (921 of 1511) 3.2.P.2.4. Container Closure System There will be two packaging presentations for Moxifloxacin Ophthalmic Solution, 0.5%. The trade size and sample size will be addressed separately. Trade Size Alcon's oval DROP-TAINER® package system was selected for the trade size of Moxifloxacin Ophthalmic Solution, 0.5% (see Figure 3.2.P.2.4-1). This system consists of a low density polyethylene (LDPE) bottle and dispensing plug and a polypropylene (PP) closure as described in Table 3.2.P.2.4-1. Each bottle will be labeled with a pressure sensitive label and provide tamper evidence through the use of a shrink band around the neck and closure area of the bottle. The fill volume for the trade size is 3 mL. Figure 3.2.P.2.4-1 Moxifloxacin Ophthalmic Solution Trade Size Package 7 3.2.P.2.4. Container Closure System, Page 1 CONFIDENTIAL PURSUANT TO THE PROTECTIVE ORDER AD_VIGAMOX_EIKE016360 Case 3:12-cv-01141-SMY-DGW Document 176-10 *SEALED* Filed 12/01/14 NDA Page 3 of 14 Moxifloxacin Ophthalmic Solution, 0.5% 21-458 Page ID #2444 Case: 16-3334 Document: 55-24 Filed: 02/08/2017 Pages: 14 (922 of 1511) Choice of Materials This package system was selected as it is appropriately sized for the desired label claim and is easy to squeeze due to its oval shape and resin characteristics. The resins used for the construction of the bottle, plug and closure (as described in Table 3.2.P.2.4-1) have been approved for use with other U.S. ophthalmic productsa and have been subjected to USP testing. A natural DROP-TAINER was selected based on stability studies demonstrating that the drug product is sufficiently stable in the presence of light to preclude the need for an opaque container (see Section 3.2.P.8). The packaging components are compatible with the chosen method of sterilization, gamma irradiation. Table 3.2.P.2.4-1 Trade Size Packaging System for Moxifloxacin Ophthalmic Solution, 0.5% a b Component Material Natural Oval Bottle Dupont 20-6064 LDPEa Natural Dispensing Plug Dupont 20-6064 LDPE Tan or White Closureb Base11 Profax PF511 PPc Pressure Sensitive Label Primax Label with Fasson S1000 Adhesive LDPE = low density polyethylene The white closure is for international distribution. PP = polypropylene Since the moisture vapor transmission rate of this packaging configuration and designated fill size was not well defined, stability studies were conducted on both overwrapped and nonoverwrapped samples. Results presented in Section 3.2.P.8 demonstrate that a foil overwrap is not required to maintain the stability of the product. a The resins used for the construction of the bottle, plug and closure have been approved for use with numerous other U.S. ophthalmic products including BETAXONTM (levobetaxolol hydrochloride ophthalmic suspension) 0.5%, NDA 21-114, approved 2/23/00; PATANOL® (olopatadine hydrochloride ophthalmic solution) 0.1%, NDA 20-688, approved 12/18/96; Timolol GFS (timolol maleate ophthalmic gel forming solution) 0.25% and 0.5%, NDA 20-963, approved 10/21/98; AZOPT® (brinzolamide ophthalmic suspension) 1%, NDA 20-816, approved 4/1/98; and EMADINETM(emedastine difumarate ophthalmic solution) 0.05%, NDA 20-706, approved 12/29/97. 3.2.P.2.4. Container Closure System, Page 2 CONFIDENTIAL PURSUANT TO THE PROTECTIVE ORDER AD_VIGAMOX_EIKE016361 Case 3:12-cv-01141-SMY-DGW Document 176-10 *SEALED* Filed 12/01/14 NDA Page 4 of 14 Moxifloxacin Ophthalmic Solution, 0.5% 21-458 Page ID #2445 Case: 16-3334 Document: 55-24 Filed: 02/08/2017 Pages: 14 (923 of 1511) Safety of Materials - USP Testing Safety (physicochemical and toxicological) testing has been completed according to USP General Chapter <661> using packaging components sterilized by gamma irradiation. All results were acceptable and the reports containing the specific information are tabulated in Table 3.2.P.2.4-2. Table 3.2.P.2.4-2 USP Testing of Packaging Components/Resins for Moxifloxacin Ophthalmic Solution, 0.5% Material Testing Report Number' Dupont 20-6064 LDPE — Natural Physicochemical LIMS I.D. 100006261 Dupont 20-6064 LDPE — Natural Toxicology 039:38520:0495 Dupont 20-6064 LDPE — Natural Toxicology 040:38520:0495 Dupont 20-6064 LDPE — Natural Toxicology 041:38520:0495 Dupont 20-6064 LDPE — Natural Toxicology 042:38520:0495 Dupont 20-6064 LDPE — Natural Toxicology 043:38520:0495 Base11 Profax PF 511 PP — Tan Physicochemical 005:38560:0191 Base11 Profax PF 511 PP — Tan Toxicology 010:38520:0291 Base11 Profax PF 511 PP — Tan Toxicology 012:38520:0291 Base11 Profax PF 511 PP — White Physicochemical 038:38560:0589 Base11 Profax PF 511 PP — White Toxicology 043:38520:0689 Base11 Profax PF 511 PP — White Toxicology 044:38520:0690 a Copies can be found in the Appendix to Section 3.2.P.2.4 as Tabs 1 through 12. 3.2.P.2.4. Container Closure System, Page 3 CONFIDENTIAL PURSUANT TO THE PROTECTIVE ORDER AD_VIGAMOX_EIKE016362 Case 3:12-cv-01141-SMY-DGW Document 176-10 *SEALED* Filed 12/01/14 NDA Page 5 of 14 Moxifloxacin Ophthalmic Solution, 0.5% 21-458 Page ID #2446 Case: 16-3334 Document: 55-24 Filed: 02/08/2017 Pages: 14 (924 of 1511) Packaging Compatibility Studies Extractables Alcon has used the LDPE DROP-TAINER as a package for numerous ophthalmic solution products and, historically, this material does not produce significant levels of leachables. Alcon Technical Report 045:38560:0494 (Appendix, Tab 13) describes an extractable study that has been done on a gamma-sterilized natural DROP-TAINER made from the Dupont 20-6064 LDPE resin. The container was extracted (60°C/7 days) with pH 3 and pH 9 buffered saline solutions and the extracts were analyzed using HPLC, non-polar GC and polar GC methods. No extractables were observed to originate from this package above the 1 ppm level. Leachables In addition, a leachables study was conducted using drug product solution filled into the assembled package [gamma sterilized bottles (with affixed labels), plugs and closures]. The study is described in Alcon Technical Report 016:60:0202 (see Appendix to Section 3.2.P.2.4, Tab 14). The package was extracted for 24 hours at 70°C and the extracts were analyzed using HPLC, non-polar GC and polar GC methods. No leachables were observed to originate from this package above the 1 ppm level. Acrylates An impurity, identified as an acrylate reaction product, was observed during stability studies on the trade size of Moxifloxacin Ophthalmic Solution, 0.5%. Its formation was due to reaction of moxifloxacin with low levels of acrylate from the packaging labels. Therefore, three stability lots of the trade size of Moxifloxacin Ophthalmic Solution, 0.5% were screened for residual acrylic acid by HPLC. The lots had been stored for 60 weeks at both 25°C and 40°C. The results are summarized in Table 3.2.P.2.4-3 and in Alcon Technical Report 011:60:0202 (see Appendix to Section 3.2.P.2.4, Tab 15). In all of the lots tested, the acrylic acid levels were found to be below 0.5 ppm, the limit of quantitation. The acrylate reaction product is controlled by the drug product specification and the levels observed in stability studies are reported in Section 3.2.P.8. 3.2.P.2.4. Container Closure System, Page 4 CONFIDENTIAL PURSUANT TO THE PROTECTIVE ORDER AD_VIGAMOX_EIKE016363 Case 3:12-cv-01141-SMY-DGW Document 176-10 *SEALED* Filed 12/01/14 NDA Page 6 of 14 21-458 Moxifloxacin Ophthalmic Solution, 0.5% Page ID #2447 Case: 16-3334 Document: 55-24 Filed: 02/08/2017 Pages: 14 (925 of 1511) In summary, results of these studies demonstrate that there are no significant extractable or leachate impurities from the packaging components. Consequently, no additional • compatibility studies were warranted, including monitoring of these substances on stability. Table 3.2.P.2.4-3 Acrylic Acid Results for Trade Size Lots of Moxifloxacin Ophthalmic Solution, 0.5% 16878-01 Acrylic Acid (60 weeks at 25°C) < 0.5 ppm Acrylic Acid (60 weeks at 40°C) < 0.5 ppm 16879-01 < 0.5 ppm < 0.5 ppm 16882-01 < 0.5 ppm < 0.5 ppm Stability Lot Number Performance Drop Size Evaluation The oval LDPE bottle is easy to squeeze due to its geometry and choice of resin material. A drop size study to simulate patient use of the product was conducted for Moxifloxacin Ophthalmic Solution, 0.5%. The drop size data indicates an average drop size of 38 microliters with a standard deviation of ± 3 microliters (see Figure 3.2.P.2.4-2). Drop Weight (mg) Figure 3.2.P.2.4-2 Drop Size Evaluation of Trade Size of Moxifloxacin Ophthalmic Solution, 0.5% • 45 40 • • • • • • • • • • • • 35 • • 30 25 20 15 10 — 5— p • • • • • •• • • • • • • • • • 4.- 111111 •-- n O I., CO 0, 04 10 CO •-- N <-4 r.-> r"-. O M M , 1 CO 0, N Lf") oo tr) LI) CO CO c0 c=, M c0 01 Dose Maintenance of Sterility The microbiological attributes of the trade size package for Moxifloxacin Ophthalmic Solution, 0.5% are described in Section 3.2.P.2.5. 3.2.P.2.4. Container Closure System, Page 5 CONFIDENTIAL PURSUANT TO THE PROTECTIVE ORDER AD_VIGAMOX_EIKE016364 Case 3:12-cv-01141-SMY-DGW Document 176-10 *SEALED* Filed 12/01/14 NDA Page 7 of 14 Moxifloxacin Ophthalmic Solution, 0.5% 21-458 Page ID #2448 Case: 16-3334 Document: 55-24 Filed: 02/08/2017 Pages: 14 (926 of 1511) Environmental Stress Crack Resistance Testing Environmental stress crack resistance testing was completed to challenge the packaging system. The results of this study are summarized in Alcon Technical Report 006:89:0502 (see Tab 16 in the Appendix to Section 3.2.P.2.4). There was no leakage due to stress cracking. Additional Testing Since the resins used for the construction of the bottle, plug and closure have been approved for use with other US ophthalmic products, no additional performance testing is warranted. 3.2.P.2.4. Container Closure System, Page 6 CONFIDENTIAL PURSUANT TO THE PROTECTIVE ORDER AD_VIGAMOX_EIKE016365 Case 3:12-cv-01141-SMY-DGW Document 176-10 *SEALED* Filed 12/01/14 NDA Page 8 of 14 21-458 Moxifloxacin Ophthalmic Solution, 0.5% Page ID #2449 Case: 16-3334 Document: 55-24 Filed: 02/08/2017 Pages: 14 (927 of 1511) Sample Size A unit-dose LDPE vial, produced by the blow/fill/seal (B/F/S) process, was selected for the sample size of Moxifloxacin Ophthalmic Solution, 0.5% (see Figure 3.2.P.2.4-3). This package consists of three segments: the bell-shaped top, the vial containing the fluid and the label tab where the product information will be embossed. This package is opened by twisting the top of the vial until it breaks loose.a The filled units will be sealed into a foil laminate overwrap suitably sized to hold one vial. The foil laminate overwrap provides a barrier to prevent moisture loss. Figure 3.2.P.2.4-3 Moxifloxacin Ophthalmic Solution, 0.5% Sample Size Package a There are two possibilities for top design with the proposed vial. The first type is similar to a flat disk while the second is bell shaped. Alcon does not intend to pursue the flat disk shaped top even though we have generated primary stability data with this design. The small difference in design does not impact the opening characteristics or the stability of the product. However, a bridging stability study with the bell shaped configuration in compliance with FDA's request has been conducted and is reported in Section 3.2.P.8. The actual opening surface of either top design is the same. 3.2.P.2.4. Container Closure System, Page 7 CONFIDENTIAL PURSUANT TO THE PROTECTIVE ORDER AD_VIGAMOX_EIKE016366 Case 3:12-cv-01141-SMY-DGW Document 176-10 *SEALED* Filed 12/01/14 NDA Page 9 of 14 Moxifloxacin Ophthalmic Solution, 0.5% 21-458 Page ID #2450 Case: 16-3334 Document: 55-24 Filed: 02/08/2017 Pages: 14 (928 of 1511) Choice of Materials This package system (see Table 3.2.P.2.4-4) was selected as it is appropriately sized for the desired label claim (0.25 mL) and is easy to squeeze due to its shape and resin characteristics. The stability of the finished package will be further enhanced with the addition of the foil laminate overwrap since it improves the overall moisture barrier of the package system. The resin used for the construction of the vial is currently used for other Alcon unit-dose products including BION® TEARS and has been subjected to USP testing. Table 3.2.P.2.4-4 Sample Size Packaging System for Moxifloxacin Ophthalmic Solution, 0.5% Component Material Natural Unit Dose Vial BASF Lupolena 3020D LDPEb Foil Laminate Overwrap PEr/Aluminum Foil/LDPE a Basell, through a joint venture with BASF, is licensing this low density polyethylene resin. The b designation is not changing. LDPE = low density polyethylene PET = polyethylene terephthalate Safety of Materials - USP Testing Safety testing has been completed according to USP General Chapter <661> using the blow/fill/seal vial proposed for the Moxifloxacin Ophthalmic Solution, 0.5% sample size. All results were acceptable and the reports containing the specific information are tabulated in Table 3.2.P.2.4-5. Table 3.2.P.2.4-5 USP Testing of Packaging Components/Resins for Moxifloxacin Ophthalmic Solution, 0.5% Material Testing Report Numbera BASF Lupolen 3020D LDPE - Natural Physicochemical LIMS ID 100003472 BASF Lupolen 3020D LDPE - Natural Toxicology 059:38520:1093 BASF Lupolen 3020D LDPE - Natural Toxicology 060:38520:1093 BASF Lupolen 3020D LDPE - Natural Toxicology 061:38520:1093 BASF Lupolen 3020D LDPE - Natural Toxicology 062:38520:1093 a Copies can be found in the Appendix to Section 3.2.P.2.4 as Tabs 17 through 21. 3.2.P.2.4. Container Closure System, Page 8 CONFIDENTIAL PURSUANT TO THE PROTECTIVE ORDER AD_VIGAMOX_EIKE016367 Case 3:12-cv-01141-SMY-DGW Document 176-10 *SEALED* Filed 12/01/14 NDA Page21-458 10 of 14 Moxifloxacin Ophthalmic Solution, 0.5% Page ID #2451 Case: 16-3334 Document: 55-24 Filed: 02/08/2017 Pages: 14 (929 of 1511) Packaging Compatibility Studies Leachables A leachables study was conducted using drug product solution and B/F/S vials made from the BASF Lupolen 3020D LDPE resin. The study is described in Alcon Technical Report 016:60:0202 (see Appendix to Section 3.2.P.2.4, Tab 14). The shredded vials were submerged in the drug product solution and extracted for 24 hours at 70°C. The extracts were analyzed using HPLC, non-polar GC and polar GC methods. No leachables were observed to originate from this package above the 1 ppm level. Residual Solvents Three primary stability lots of sample size Moxifloxacin Ophthalmic Solution, 0.5% were screened for the presence of 24 residual solvents by GC/MS. These results are summarized in Alcon Technical Report 012:60:0202 (see Appendix to Section 3.2.P.2.4, Tab 22) and in Table 3.2.P.2.4-6. The stability lots had been stored at both the 25°C/40% RH and 40°C/15%RH for 28 weeks. Trace levels of two Class 3 solvents were detected in the lots, methyl ethyl ketone and ethyl acetate. The source of these solvents is the foil laminate overwrap. Not more than 4 ppm of either of these solvents was found in the lots. These levels are well below the ICH Q3C Guideline limit of 5000 ppm for Class 3 solvents. Table 3.2.P.2.4-6 Residual Solvent Results for Sample Size Lots of Moxifloxacin Ophthalmic Solution, 0.5% Stability Lot Number 16985-01 16985-02 16985-03 28 weeks at 25°C/40%RH Methyl Ethyl Ketone (ppm) 2.11 / 1.94 Ethyl Acetate (ppm) 0.59 / 0.66 28 weeks at 40°C/15%RH 0.23 / 0.29 ND / ND 28 weeks at 25°C/40%RH 0.18 / 0.20 0.05 / 0.05 28 weeks at 40°C/15%RH 0.14 / 0.10 ND / ND 28 weeks at 25°C/40%RH 1.17 / 2.48 ND / 1.24 28 weeks at 40°C/15%RH 3.21 / 0.99 0.91 / 0.47 Storage ND = not detected; detection limit is 0.05 ppm. 3.2.P.2.4. Container Closure System, Page 9 CONFIDENTIAL PURSUANT TO THE PROTECTIVE ORDER AD_VIGAMOX_EIKE016368 Case 3:12-cv-01141-SMY-DGW Document 176-10 *SEALED* Filed 12/01/14 NDA Page21-458 11 of 14 Moxifloxacin Ophthalmic Solution, 0.5% Page ID #2452 Case: 16-3334 Document: 55-24 Filed: 02/08/2017 Pages: 14 (930 of 1511) Acrylates The acrylate reaction product is an impurity that has been detected in trade size stability samples of Moxifloxacin Ophthalmic Solution, 0.5% due to reaction of moxifloxacin with low levels of acrylate from the packaging label. However, in the sample size packaging configuration, the label is affixed to the outside of a foil laminate overwrap and does not come into direct contact with the LDPE vial. For this reason, neither residual acrylic acid nor the acrylate reaction product is expected to be observed in sample size stability samples of Moxifloxacin Ophthalmic Solution, 0.5%. To confirm this, three primary stability lots of sample size Moxifloxacin Ophthalmic Solution, 0.5% were screened for acrylic acid using an HPLC method. The stability lots had been stored for 28 weeks at both 25°C and 40°C. These results are summarized in Alcon Technical Report 011:60:0202 (see Appendix to Section 3.2.P.2.4, Tab 15) and in Table 3.2.P.2.4-7. In all of the lots tested acrylic acid was not detected above the limit of quantitation of 0.5 ppm. The acrylate reaction product is controlled by the drug product specification and the levels observed in stability studies are reported in Section 3.2.P.8. Table 3.2.P.2.4-7 Acrylic Acid Results for Sample Size Lots of Moxifloxacin Ophthalmic Solution, 0.5% Acrylic Acid Acrylic Acid (28 weeks at 25°C) < 0.5 ppm < 0.5 ppm < 0.5 ppm (28 weeks at 40°C) < 0.5 ppm < 0.5 ppm < 0.5 ppm Stability Lot Number 16985-01 16985-02 16985-03 3.2.P.2.4. Container Closure System, Page 10 CONFIDENTIAL PURSUANT TO THE PROTECTIVE ORDER AD_VIGAMOX_EIKE016369 Case 3:12-cv-01141-SMY-DGW Document 176-10 *SEALED* Filed 12/01/14 NDA Page21-458 12 of 14 Moxifloxacin Ophthalmic Solution, 0.5% Page ID #2453 Case: 16-3334 Document: 55-24 Filed: 02/08/2017 Pages: 14 (931 of 1511) Performance Drop Size Evaluation This B/F/S vial is easy to squeeze due to its geometry and choice of resin material. A drop size study was conducted using product produced from a stability production lot by dispensing drops from each of ten samples until the vial was emptied. The drop size data indicates an average drop size of 58 microliters with a standard deviation of ± 8 microliters (see Figure 3.2.P.2.4-4). Figure 3.2.P.2.4-4 Drop Size Evaluation of Sample Size of Moxifloxacin Ophthalmic Solution, 0.5% ...... 70.0 60.0 N 50.0 ' 40 0 a • ..': 30.0 ?.: 20.0 4 10.0 0.0 • avg 1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18 19 20 Sample Number Maintenance of Sterility The microbiological attributes of the professional sample size package for Moxifloxacin Ophthalmic Solution, 0.5% are described in Section 3.2.P.2.5. Additional Testing Since the resin used for the construction of B/F/S vial has been subjected to USP Safety Testing and Compatibility Testing, no additional performance testing is warranted. 3.2.P.2.4. Container Closure System, Page 11 CONFIDENTIAL PURSUANT TO THE PROTECTIVE ORDER AD_VIGAMOX_EIKE016370 Case 3:12-cv-01141-SMY-DGW Document 176-10 *SEALED* Filed 12/01/14 NDA Page21-458 13 of 14 Moxilloxacin Ophthalmic Solution, 0.5% Page ID #2454 Case: 16-3334 Document: 55-24 Filed: 02/08/2017 Pages: 14 (932 of 1511) Appendix to Section 3.2.P.2.4 Contents Tab Item Alcon LIMS I.D. 100006261 1 Alcon Technical Report 039:38520:0495 Agar Diffusion Test with Gamma Sterilized DuPont 20-6064 LDPE Natural DROP-TAINERs 2 Alcon Technical Report 040:38520:0495 Elution Test with Gamma Sterilized DuPont 20-6064 LDPE Natural DROP-TAINERs 3 Alcon Technical Report 041:38520:0495 Acute Systemic Toxicity in Mice with Extracts of Gamma Sterilized DuPont 20-6064 LDPE Natural DROP-TAINERs 4 Alcon Technical Report 042:38520:0495 Intracutaneous Reactivity Test in Albino Rabbits with Extracts of Gamma Sterilized DuPont 20-6064 LDPE Natural DROP-TAINERs 5 Alcon Technical Report 043:38520:0495 Primary Ocular Irritation in Rabbits with Extracts of Gamma Sterilized DuPont 20-6064 LDPE Natural DROP-TAINERs 6 Alcon Technical Report 005:38560:0191 Evaluation of Gamma Irradiated Eastman 984A (MD-1953) and Himont PF511 (MD-1954) Polypropylene Closures for use with Ciprofloxacin Ophthalmic Solution (CILOXAN) 7 Alcon Technical Report 010:38520:0291 Agar Overlay of Gamma Irradiated Himont PF-511 Tan Polypropylene Closures 8 Alcon Technical Report 012:38520:0291 Acute Systemic Toxicity in Mice with Extracts of Gamma Sterilized DuPont 20-6064 LDPE Natural DROP-TAINERs 9 Alcon Technical Report 038:38560:0589 Evaluation of Gamma Irradiated Himont PF511 and Eastman 984A 9 Polypropylene Closures 10 3.2.P.2.4. Container Closure System, Page 12 CONFIDENTIAL PURSUANT TO THE PROTECTIVE ORDER AD_VIGAMOX_EIKE016371 Case 3:12-cv-01141-SMY-DGW Document 176-10 *SEALED* Filed 12/01/14 NDA Page21-458 14 of 14 Moxifloxacin Ophthalmic Solution, 0.5% Page ID #2455 Case: 16-3334 Document: 55-24 Filed: 02/08/2017 Pages: 14 (933 of 1511) Alcon Technical Report 043:38520:0689 Acute Systemic Toxicity in Mice and Primary Ocular Irritation in Rabbits of Extracts of Gamma Irradiated 15 mm Polypropylene Himont PF511 (red, blue, green and white) Closures Manufactured by Wheaton Injection Molding 11 Alcon Technical Report 044:38520:0690 Agar Overlay of Gamma Irradiated Himont Red, Blue, Green and White Polypropylene Closures 12 Alcon Technical Report 045:38560:0494 Analysis of Owens Brockway Gamma Sterilized Dupont 20-6064 LDPE 5 mL Natural DROP-TAINER Lot 5-93-06, for Materials Extracted into pH 3 and pH 9 Buffered Saline Solutions 13 Alcon Technical Report 016:60:0202 Evaluation of Packaging Components For Leachables Into Moxifloxacin Drug Product Solutions 14 Alcon Technical Report 011:60:0202 Screening For Acrylic Acid in Stability Lots of Moxifloxacin Drug Product By HPLC 15 Alcon Technical Report 006:89:0502 Stress Crack Evaluation of LDPE Oval Package System 16 Alcon LIMS I.D. 100003472 17 Alcon Technical Report 059:38520:1093 Agar Diffusion Test with Lupolen 3020D LDPE Natural FFS Containers 18 Alcon Technical Report 060:38520:1093 Elution Test with Lupolen 3020D Natural FFS Containers 19 Alcon Technical Report 061:38520:1093 Acute Systemic Toxicity in Mice and Primary Ocular Irritation in Rabbits of Extracts of Lupolen 3020D LD PE Natural FFS Containers 20 Alcon Technical Report 062:38520:1093 FitzGerald G. Intracutaneous Reactivity Test in Albino Rabbits with Extracts of Lupolen 3020D LDPE Natural FFS Containers 21 Alcon Technical Report 012:60:0202 Screening For Residual Solvents In Sample Size Stability Lots of Moxifloxacin Drug Product By GC/MS 22 3.2.P.2.4. Container Closure System, Page 13 CONFIDENTIAL PURSUANT TO THE PROTECTIVE ORDER AD_VIGAMOX_EIKE016372 Case 3:12-cv-01141-SMY-DGW Document 176-36 *SEALED* Filed 12/01/14 Page 1 of 42 Page ID #3235 Case: 16-3334 Document: 55-25 Filed: 02/08/2017 Pages: 42 (934 of 1511) Expert Report of Steven N. Wiggins Submitted in the matter of: CHARLENE EIKE, SHIRLEY FISHER, JORDAN PITLER AND ALAN RAYMOND, on behalf of themselves and all others similarly situated, Plaintiff, v. ALLERGAN, INC.; ALLERGAN USA, INC.; ALLERGAN SALES, LLC; ALCON LABORATORIES, INC.; ALCON RESEARCH, LTD.; FALCON PHARMACEUTICALS, Ltd.; SANDOZ, INC.; BAUSCH AND LOMB INCORPORATED; PFIZER INC., MERCK & CO., INC.; MERCK, SHARP & DOHME CORP., and PRASCO, LLC Defendants. Submitted by: Steven N. Wiggins Senior Consultant Charles River Associates 1716 Briarcrest Drive, Suite 600 Bryan, Texas 77802 Date: 09/12/2014 Highly Confidential-Attorneys’ Eyes Only Case 3:12-cv-01141-SMY-DGW Document 176-36 *SEALED* Filed 12/01/14 Page 2 of 42 Page ID #3236 Case: 16-3334 Document: 55-25 Filed: 02/08/2017 Pages: 42 (935 of 1511) September 12, 2014 CONFIDENTIAL — SUBJECT TO PROTECTIVE ORDER I. Background and Experience 1. My name is Steven N. Wiggins. I am a Professor of Economics at Texas A&M University. I received my B.A. from Oklahoma State University in 1975 and my Ph.D. in Economics from the Massachusetts Institute of Technology in 1979. I have taught at Texas A&M since that time. My fields of specialization include Industrial Organization and Econometrics. My Curriculum Vitae is attached as Exhibit A. 2. I have conducted research in the pharmaceutical industry for more than thirty years, beginning with my Ph.D. dissertation at MIT. My pharmaceutical research has covered a wide array of topics, including the drug development process, United States Food & Drug Administration ("FDA") regulation and the drug approval process, price competition, rates of return to pharmaceuticals and the quality of new drugs. 3. My research in this industry has been funded by various entities, including the National Science Foundation, the Sloan Foundation and the Office of Technology Assessment. My pharmaceutical research has been published in leading economics journals such as the Review of Economics and Statistics and Economic Inquiry. I have presented the results of my research at leading universities throughout the United States and at national and international symposia. I have also refereed pharmaceutical research papers for leading economics journals and for the National Science Foundation, advising editors of leading journals and funding agencies regarding the merits of particular works and the soundness of their methodologies. 1 Case 3:12-cv-01141-SMY-DGW Document 176-36 *SEALED* Filed 12/01/14 Page 3 of 42 Page ID #3237 Case: 16-3334 Document: 55-25 Filed: 02/08/2017 Pages: 42 (936 of 1511) September 12, 2014 CONFIDENTIAL — SUBJECT TO PROTECTIVE ORDER 4. I also provide consulting and expert services to companies in varied circumstances. My consulting work has included assignments dealing with damages, damage methodologies, class certification, intellectual property, antitrust and contractual issues. As an economic expert, I have rendered opinions related to Industrial Organization, which is the study of markets, including competition, pricing, advertising, research and development, and regulation, as well as the internal organization of business firms. I have opined on a wide variety of Industrial Organization issues involving the health care industry including pharmaceuticals, hospitals and managed care. I have also testified in numerous matters involving the pharmaceutical industry. A list of the cases in which I have provided deposition or trial testimony in the past four years is included in my Curriculum Vitae. II. Introduction 5. I have reviewed Plaintiffs' First Amended Class Action Complaint for Damages, Punitive Damages, and Injunctive Relief ("Complaint"). I understand Plaintiffs allege that "all persons" who have "purchased prescription eye drops . . . sold in multi-dose dispensers" suffered "actual damages measured by the allocated purchase price for the portion of their eye drops in excess of 15 .iL" because any excess volume is allegedly not absorbed by the human eye.' 6. Counsel for Defendants asked me to review Plaintiffs' claims in this matter as they relate to alleged damages associated with Defendants' alleged violations of the Illinois Consumer Fraud Statute ("ICFA") and Missouri Merchandising Practices Act ' Complaint, pp. 29-31. 7 Case 3:12-cv-01141-SMY-DGW Document 176-36 *SEALED* Filed 12/01/14 Page 4 of 42 Page ID #3238 Case: 16-3334 Document: 55-25 Filed: 02/08/2017 Pages: 42 (937 of 1511) September 12, 2014 CONFIDENTIAL — SUBJECT TO PROTECTIVE ORDER ("MMPA"). Defendants also asked me to review the report, opinions, and testimony of Plaintiffs' expert Dr. Brian Kriegler, Ph.D. 7. I have reviewed numerous documents and various data in reaching my conclusions, including legal pleadings, deposition testimony, and other documents. A complete list of the documents I reviewed in connection with this matter is provided in Exhibit B. 8. I have reviewed Dr. Kriegler's "Estimation of Alleged Class-wide Losses."2 Dr. Kriegler's methodology incorrectly calculates class damages as the percentage of each drug's total sales directly proportional to the drug's average eye drop volume in excess of 16 tiL.3 Therefore, according to Dr. Kriegler, if a drug's average eye drop volume is 32 4, class damages equal fifty percent of the drug's total sales. Dr. Kriegler proposes calculating an "average drop size" for each product identified in the Complaint from data Defendants generated.4 As explained below, this estimation and methodology is fundamentally flawed because it does not account for drop size variability, or patient variability and error when instilling eye drops. The proposed methodology is also inconsistent with the basic economics of prescription drugs in that it erroneously assumes that prices are linearly proportional to the cost of materials. I disagree with Dr. Kriegler's opinions. 2 Expert Report of Dr. Brian Kriegler, May 30, 2014, p. 24. 3 Expert Report of Dr. Brian Kriegler, May 30, 2014, p. 24. 4 Expert Report of Dr. Brian Kriegler, May 30, 2014, pp. 24-25 and Exhibit E. 3 Case 3:12-cv-01141-SMY-DGW Document 176-36 *SEALED* Filed 12/01/14 Page 5 of 42 Page ID #3239 Case: 16-3334 Document: 55-25 Filed: 02/08/2017 Pages: 42 (938 of 1511) September 12, 2014 CONFIDENTIAL — SUBJECT TO PROTECTIVE ORDER III. Dr. Kriegler's Proposed Methodology: Overview 9. A summary of Dr. Kriegler's proposed methodology for calculating class damages is as follows. Dr. Kriegler: a. Relies on Dr. Robin's opinion that "drops be no larger than 16 RL on average."5 b. Purports to calculate the mean drop size for each of the Defendants' drugs at issue and measure the difference between his calculated mean and Dr. Robin's benchmark of 16 4. The difference between the mean drop size and 16 4, he alleges, is "wasted" product.6 c. Relies on what he claims are Defendants' laboratory drop size studies as a measure of actual patient dosing practices for the Plaintiffs in the class. d. Transforms physical "waste" into monetary damages by assuming that a reduction in the amount of product in a bottle would result in a proportionate reduction in price. e. Calculates class-wide damages for each drug by multiplying the price of each unit sold by the proportion of each bottle allegedly "wasted." 10. Each of these steps contains substantial errors as discussed further below. 5 Expert Report of Dr. Brian Kriegler, May 30, 2014, p. 4. 6 Dr. Kriegler states that his model "is designed to calculate the percentage of waste per drop...really per average drop." Deposition of Brian Kriegler, August 20, 2014, p. 128. 4 Case 3:12-cv-01141-SMY-DGW Document 176-36 *SEALED* Filed 12/01/14 Page 6 of 42 Page ID #3240 Case: 16-3334 Document: 55-25 Filed: 02/08/2017 Pages: 42 (939 of 1511) September 12, 2014 CONFIDENTIAL — SUBJECT TO PROTECTIVE ORDER IV. Drop Size Economics 11. A central economic issue regarding damages in this case regards the medically and economically appropriate size of the drops dosed from Defendants products. Defendants face an economic imperative to make sure that each and every dose dispensed from their products is of sufficient size to ensure proper dosing. 12. The most important underpinning of this imperative is patient health and well-being. Defendants sell their products with a claim that the product is effective for its intended uses per federal law and FDA guidelines. To be effective, these products require regular, adequate dosing consistent with the label instructions and clinical trials that have been carried out to achieve regulatory approval for sale. If some doses are inadequate, the effectiveness of the product becomes an open issue, and the manufacturer cannot sell products that are not proven effective. 13. It is my understanding that the products at issue have effectiveness claims that require the patient to receive adequate dosing consistent with the label of the product. This requirement means that all administered doses must be at least as large as the size needed to ensure proper dosing. This conclusion implies that the range of eye drops emitted by a dropper must uniformly equal or exceed the size necessary for sufficient dosing. 14. Another fundamental element of the economics of drop size is the fact that drops vary in size in ways that are difficult to predict or determine. Dr. Kriegler acknowledges in his report that there are a number of "factors that can affect the magnitude of drop sizes."7 He notes that testimony in this case indicates that "drop size is a function of where and s Case 3:12-cv-01141-SMY-DGW Document 176-36 *SEALED* Filed 12/01/14 Page 7 of 42 Page ID #3241 Case: 16-3334 Document: 55-25 Filed: 02/08/2017 Pages: 42 (940 of 1511) September 12, 2014 CONFIDENTIAL — SUBJECT TO PROTECTIVE ORDER how a patient squeezes the bottle, where the patient holds the bottle, how long the patient squeezes the bottle . . . temperature, and bottle angle."8 Deposition testimony of the named plaintiffs illustrates the variation in patient dosing techniques.9 Deposition testimony of Dr. Robin also acknowledges that drop size varies based on patientcontrolled factors.1° Dr. Kriegler also acknowledges that he is unable to measure the differences in drop size resulting from variation in patient technique. He states that he is "unaware of any studies that quantify differences in terms of temperature or patient technique."' I 15. The facts show that drop sizes vary. Such variation in drop size means that if a manufacturer were to make a dropper that provided average drop sizes equal to the capacity of the human eye, then that dropper would also commonly provide doses that were inadequate for effective dosing. For example, if the average is equal to the size needed for adequate dosing, and large and small drops were equally common, then fully half the doses administered would be too small. Such an outcome would be unacceptable because it would mean that patients were commonly receiving inadequate doses. 16. The need to ensure adequate dosing carries over into the conduct of clinical trials. Manufacturers spend hundreds of millions of dollars developing their products. The success of those development efforts hinges on the successful completion of clinical trials 7 Expert Report of Dr. Brian Kriegler, May 30, 2014, p. 16. 8 Expert Report of Dr. Brian Kriegler, May 30, 2014, pp. 16-17. See Deposition of Charlene Eike, March 7, 2014, pp. 38-39, 55, Deposition of Shirley Mae Fisher, February 24, 2014, pp. 60-64, Deposition of Jordan Pitler, February 10, 2014, pp. 28-29, 159-160, and Deposition of Alan Raymond, February 27, 2014, pp. 35-37, 47. 9 1" Deposition of Alan Robin, M.D., August 6, 2014, pp. 73-74. 11 Expert Report of Dr. Brian Kriegler, May 30, 2014, p.17. 6 Case 3:12-cv-01141-SMY-DGW Document 176-36 *SEALED* Filed 12/01/14 Page 8 of 42 Page ID #3242 Case: 16-3334 Document: 55-25 Filed: 02/08/2017 Pages: 42 (941 of 1511) September 12, 2014 CONFIDENTIAL — SUBJECT TO PROTECTIVE ORDER to establish effectiveness. Manufacturers preparing to conduct clinical trials face an economic imperative to ensure that droppers uniformly emit drop sizes sufficient for fully effective dosing. Such dosing is necessary to maximize effective treatment and the likelihood of a successful clinical trial.[' Clinical trials themselves are very costly, but a failure of a clinical trial has consequences even larger than the cost of the study itself. The failure of a clinical trial could compromise an entire development effort and potentially hundreds of millions of dollars in development costs." Success rates in clinical trials for new drugs are often low and the direct cost and opportunity cost of trials are very large.I4 Hence ophthalmic drug manufacturers have large incentives to make sure that all patients in clinical trials receive adequate dosing. 17. In contrast, the cost of making a drop that is larger than the bare minimum required for adequate dosing is minimal. The reason is that manufacturing costs constitute a small portion of the overall cost of ophthalmic and other drugs. Importantly, manufacturing costs are very low relative to the large potential cost of poor clinical trial results.I5 Hence ophthalmic drug manufacturers have strong incentive to ensure that drop sizes are adequate so that the full range of drop sizes uniformly exceeds the minimum amounts 12 Success rates in clinical trials for new drugs are very low. 71 percent of new drugs survive to phase II trials, but only 31.4 percent survive to phase III, and only 21.5 percent complete phase III trials. "Research and Development in the Pharmaceutical Industry", Congressional Budget Office, October 2006, p. 23. 13 The failure of a clinical trial may also compromise future development projects as revenue from approved drugs generate large cash flows that are subsequently invested in new research and development. "Research and Development in the Pharmaceutical Industry", Congressional Budget Office, October 2006, p. 23. 14 Clinical trials take on average 7.5 years and result in $282 million in direct costs, with an estimated additional $185 million opportunity cost. "Research and Development in the Pharmaceutical Industry", Congressional Budget Office, October 2006, p. 23. 15 Berndt, Ernst R., Thomas McGuire, and Joseph P. Newhouse (2011), "A Primer on the Economics of Prescription Pharmaceutical Pricing in Health Insurance Markets", Forum for Health Economics & Policy, 14(2):3, Article 10. 7 Case 3:12-cv-01141-SMY-DGW Document 176-36 *SEALED* Filed 12/01/14 Page 9 of 42 Page ID #3243 Case: 16-3334 Document: 55-25 Filed: 02/08/2017 Pages: 42 (942 of 1511) September 12, 2014 CONFIDENTIAL — SUBJECT TO PROTECTIVE ORDER required for fully effective dosing. This ensures adequate dosing both in use and in the clinical trials. 18. Defendants, therefore, have both medical and economic reasons to develop and use droppers that emit average drop sizes that are larger than the bare minimum drop size that may be required for effective dosing. Only by doing so can a manufacturer guarantee a range of doses that uniformly equals or exceeds adequate dosing. 19. Once droppers have been approved following Phase III clinical trials it would be costly to both patients and firms to change the drop size. It is my understanding that such changes require regulatory approval and would include new multi-million dollar studies. (Expert Report of Janet Arrowsmith, September 12, 2014, p. 3). Companies who conduct such studies would be economically incentivized to price their products to recover those costs. Given the low cost of materials it is quite possible that the net price to patients would rise since the manufacturing cost savings would be small. 20. Plaintiffs' proposed damages model fails to account for the need for all doses to equal or exceed minimum dosing requirements. As a result, their proposed model cannot be used to develop a reliable damages estimate. V. Dr. Kriegler's Methodology Fails To Properly Account For Drop Size Variability 21. Turning to Plaintiffs' proposed damages methodology, Dr. Kriegler defines "waste" as the difference between average drop size and 16 vL, where the latter represents a putative "conservative" estimate of the capacity of the human eye. According to this argument, a dropper should provide a mean drop size of 16 4. Dr. Kriegler then defines the s Case 3:12-cv-01141-SMY-DGW Document 176-36 *SEALED* Filed 12/01/14 Page 10 of 42 Page ID #3244 Case: 16-3334 Document: 55-25 Filed: 02/08/2017 Pages: 42 (943 of 1511) September 12, 2014 CONFIDENTIAL — SUBJECT TO PROTECTIVE ORDER difference between the actual average drop size of a dropper and 16 tL as "waste," and seeks damages associated with those amounts. This logic implies that the only way a manufacturer could have zero damages is to provide an average drop size of 16 4. Such a conclusion is clearly incorrect because drop sizes vary. If larger and smaller drop sizes are equally likely, then an average drop size of 16 tL implies that patients will be underdosed half of the time they administer drops. 22. To address this issue, a proper economic methodology would account for the need to ensure that the minimum, not the average, drop size is at least as large as the minimum required for full dosing. Dr. Kriegler has not reported any calculations regarding the range of drop sizes, which means that his calculations of allegedly "wasted" product ignore drop size variability and potential under-dosing for those numerous drops below the mean. 23. Dr. Kriegler's proposed model begins with Dr. Robin's opinion that "drops be no larger than 16 tL on average."I6 However, Dr. Robin's opinion regarding the appropriate mean drop size does not account for those drops that are smaller than the mean. Dr. Robin states that "larger drops are no more effective than drops of 15 I.LL or even smaller."I7 Dr. Robin does not state, however, that drops smaller than 15 iiI_. are uniformly effective.1 8 Moreover, I am unaware of any evidence that would support such a conclusion. If average drop size were equal to 15 tiL (or 16 [IL) then the evidence implies that patients would consistently receive doses below proven effective levels. 16 Expert Report of Dr. Brian Kriegler, May 30, 2014, p. 4. 17 Expert Report of Alan Robin, M.D., May 30, 2014, p. 5. 18 I understand that Dr. Robin stated in his deposition that his ideal drop size of 16 uL can be plus or minus ten percent, between 14.4 uL and 17.6 pL. Deposition of Alan Robin, August 6, 2014, p. 162. 9 Case 3:12-cv-01141-SMY-DGW Document 176-36 *SEALED* Filed 12/01/14 Page 11 of 42 Page ID #3245 Case: 16-3334 Document: 55-25 Filed: 02/08/2017 Pages: 42 (944 of 1511) September 12, 2014 CONFIDENTIAL — SUBJECT TO PROTECTIVE ORDER Hence, the damages model proposed assumes that it is proper to regularly dose patients at levels below Dr. Robin's 164 cut-off. Such a model is clearly unreliable. 24. Dr. Kriegler also errs by failing to provide a range of real-world drop sizes. This range is essential because proper dosing requires that the smallest drops be at least large enough to achieve therapeutic dosing. While Dr. Kriegler offers some opinions in this area, his methodology is flawed. Dr. Kriegler uses Defendants' drop size studies regarding drop size variability. He calculates a mean and a standard deviation and he then uses these results incorrectly to calculate a probability that individual drops would be less than 16 4.19 Dr. Kriegler's methodology is not correct and is unreliable for this purpose. His calculations require that individual drops are normally distributed (commonly called "bell-shaped"). This assumption is highly speculative and it would be improper for companies to make such assumptions about drop sizes without underlying scientific support. As a result, it is improper for Dr. Kriegler to make such an assumption in calculating damages. Further, Dr. Kriegler provides no analysis or other evidence to support his speculative assumption. 25. Dr. Kriegler further errs significantly by using Defendants' drop size studies [in controlled laboratory settings] as a measure of drop size variation in actual patient settings. He asserts that the drop size studies that he relies on "emulate patient usage," particularly patients who are "members of each subclass."20 The literature, studies, and testimony in this case, however, show patients vary widely in their abilities to self- 19 Dr. Kriegler's Exhibits C, D-1, and D-2 report standard deviations from his relied upon drop size studies and purport to calculate probabilities "that Any One Drop Size Is <= 16 µL." 20 Expert Report of Dr. Brian Kriegler, May 30, 2014, pp. 6-7. 10 Case 3:12-cv-01141-SMY-DGW Document 176-36 *SEALED* Filed 12/01/14 Page 12 of 42 Page ID #3246 Case: 16-3334 Document: 55-25 Filed: 02/08/2017 Pages: 42 (945 of 1511) September 12, 2014 CONFIDENTIAL — SUBJECT TO PROTECTIVE ORDER administer eye drops. (See 919128-29) To accurately calculate the average drop size for each drug identified in the Amended Complaint, Dr. Kriegler would need to rely on patient-use studies that accurately depict to a degree of statistical reliability the range of variable drop volumes or weights members of the class actually emit in the real world. I am unaware of any such data and Dr. Kriegler has not used such data. 26. Dr. Kriegler's proposed methodology will also improperly measure damages associated with his calculations of alleged "wasted" product. He errs by proposing to calculate damages proportional to the amount by which the average drop size exceeds the 16 vL size he assumes is the optimal drop size that would provide for full dosing and no "waste." Dr. Kriegler described his proposed model as a model "designed to calculate the percentage of waste...per average drop."2' This is an error because it does not reflect the economic imperative manufacturers face to ensure that each drop is of sufficient size for full dosing. A proper economic methodology would account for the need to ensure that the minimum, not the average, drop size is at least as large as the minimum drop size for full dosing. 27. Dr. Kriegler's proposed methodology will substantially overstate damages because it subtracts his benchmark drop size of 16 tL from the defendants' average drop size instead of the minimum (lower) drop size. His estimate of alleged "waste" will always be overstated because the average drop size will always exceed the minimum (or lower end of the range) as a result of drop size variability. Further, data which would allow one to compare the range and distribution of actual drop sizes to Dr. Robin's benchmark of 16 21 Deposition of Brian Kriegler, August 20, 2014, p. 128. 11 Case 3:12-cv-01141-SMY-DGW Document 176-36 *SEALED* Filed 12/01/14 Page 13 of 42 Page ID #3247 Case: 16-3334 Document: 55-25 Filed: 02/08/2017 Pages: 42 (946 of 1511) September 12, 2014 CONFIDENTIAL — SUBJECT TO PROTECTIVE ORDER v1_, are not available.22 Dr. Kriegler acknowledged that he has no such data and is not aware of any data of this type. 73 Hence Dr. Kriegler's proposed methodology is unreliable for calculating damages. VI. Dr. Kriegler's Methodology Fails to Account for Patient Variability 28. Dr. Kriegler's proposed methodology also fails to account for the drop size variation that results from the substantial variability in how patients administer their prescription eye drops. (See ¶91 14-15). The literature shows that patients vary widely in how they administer their eye drops. Some patients touch the bottle or dropper to the globe of the eye, some pull the lower lid down and instill drops to the cul-de-sac, others hold the dropper at a distance from the eye and drop medication into the cul-de-sac, and yet others place drops on the orbital rim and rotate their head so that the drop runs into the eye.24 Additionally, patients vary in whether they administer drops standing, sitting, or laying down and whether they use a mirror when instilling the drops.25 Dr. Kriegler only uses Defendants' drop size testing data, which does not reflect individual patient variability. 29. Deposition testimony by the named plaintiffs in this case illustrates this variation in patient methods for administering eye drops. Charlene Eike testified that she is right handed, stands next to the sink in the bathroom, pulls down the lower lid with her left 22 This likewise applies to Dr. Robin's clarified ideal drop size of 16 !AL plus or minus ten percent. 23 Deposition of Brian Kriegler, August 20, 2014, p. 154. Kass, Michael A., Elizabeth Hodapp, Mae Gordon, Allen E. Kolker, and Ivan Goldberg (1982), "Patient Administration of Eyedrops: Observation Part II", Annals of Ophthalmology, 14(9):889-893, September 1982. 24 Kass, Michael A., Elizabeth Hodapp, Mae Gordon, Allen E. Kolker, and Ivan Goldberg (1982), "Patient Administration of Eyedrops: Observation Part II", Annals of Ophthalmology, 14(9):889-893, September 1982. 25 12 Case 3:12-cv-01141-SMY-DGW Document 176-36 *SEALED* Filed 12/01/14 Page 14 of 42 Page ID #3248 Case: 16-3334 Document: 55-25 Filed: 02/08/2017 Pages: 42 (947 of 1511) September 12, 2014 CONFIDENTIAL — SUBJECT TO PROTECTIVE ORDER hand, and instills the drops with her right hand, aiming for the center of the eye.26 She also testified that she sometimes smokes prior to instilling the drops.27 Shirley Fisher testified that she is right handed, sits down, tilts her head back, pulls the lower eyelid down with her left hand and instills the drops with her right hand, aiming for the center of the eye.28 Jordan Pitler testified that he is left handed, sits down, tilts his head back putting a finger from his left hand on his forehead and instills drops into the corner of his eye nearest his nose with his left hand.29 Additionally, Alan Raymond testified that he stands, tilts his head back facing the ceiling, uses his left hand to open the upper and lower lid and instills drops to his eye using his right hand, aiming for the center of the eye.30 30. The Defendants' drop size studies relied upon by Dr. Kriegler do not account for this type of real-world variation in patient usage and the resulting variance in real-world drop sizes. The dosing data used by Dr. Kriegler does not account for this type of variation across patients. Dr. Robin agreed in his deposition that research studies relying on research personnel to administer drops do not emulate real-world use.3I Dr. Robin also acknowledged in his deposition testimony that even his own studies based on videotaped patient use may not have simulated real-world use.32 To accurately calculate the average and ranges of drop size for each drug identified in the Amended Complaint, Dr. Kriegler 26 Deposition of Charlene Eike, March 7, 2014, pp. 38-39, 55. 27 Deposition of Charlene Eike, March 7, 2014, pp. 38-39, 55. 28 Deposition of Shirley Mae Fisher, February 24, 2014, pp. 60-64. 29 Deposition of Jordan Pitler, February 10, 2014, pp. 28-29, 159-160. 30 Deposition of Alan Raymond, February 27, 2014, pp. 35-37, 47. 31 Deposition 32 of Alan Robin, M.D., August 6, 2014, p. 308. Deposition of Alan Robin, M.D., August 6, 2014, pp. 402-403. 13 Case 3:12-cv-01141-SMY-DGW Document 176-36 *SEALED* Filed 12/01/14 Page 15 of 42 Page ID #3249 Case: 16-3334 Document: 55-25 Filed: 02/08/2017 Pages: 42 (948 of 1511) September 12, 2014 CONFIDENTIAL — SUBJECT TO PROTECTIVE ORDER would need to rely on patient-use studies for each drug. Only with such data can one reliably measure the range of and average drop volume glaucoma patients actually experience in the real world. Neither Dr. Kriegler, nor Dr. Robin, have identified any such studies.33 31. Additionally, Dr. Kriegler's proposed methodology does not account for other types of individualized wasted medication such as spills, leaks, tip occlusion, and product contamination. Because Dr. Kriegler's proposed valuation of damages relies on the assumption that drug pricing is directly proportional to the quantity of material in the bottle, he must account for amounts that are "wasted" due to patient error and other reasons unrelated to the allegations in this case. Dr. Kriegler does not propose any methodology for calculating such "waste." 32. Wasted drops resulting from patient usage appears to be commonplace. One study estimated that "[o]ver 37% of patients instill two or more drops per eye treatment, and over 20% of patients instill three or more drops per eye treatment" despite the finding that "83% of patients indicate [on a survey] that they put one drop of medication in each eye per treatment."34 The same study concluded that patients wasted an average of 1.4 drops per treatment.35 Another study of glaucoma patients found that the mean number of drops per instillation was 1.8 (with a range of 1 to 8 drops), 31 percent of patients missed the eye (with drops falling on eyelids or cheek), and 76 percent of patients 33 Deposition of Alan Robin, M.D., August 6, 2014, pp. 403-404. Kass, Michael A., Elizabeth Hodapp, Mae Gordon, Allen E. Kolker, and Ivan Goldberg (1982), "Patient Administration of Eyedrops: Observation Part II", Annals of Ophthalmology, 14(9):889-893, September 1982. 34 Kass, Michael A., Elizabeth Hodapp, Mae Gordon, Allen E. Kolker, and Ivan Goldberg (1982), "Patient Administration of Eyedrops: Observation Part II", Annals of Ophthalmology, 14(9):889-893, September 1982. 35 14 Case 3:12-cv-01141-SMY-DGW Document 176-36 *SEALED* Filed 12/01/14 Page 16 of 42 Page ID #3250 Case: 16-3334 Document: 55-25 Filed: 02/08/2017 Pages: 42 (949 of 1511) September 12, 2014 CONFIDENTIAL — SUBJECT TO PROTECTIVE ORDER incorrectly touched the tip of the bottle to the globe of the eye.36 This study concluded that nearly "9 of 10 glaucoma patients were unable to instill eye drops correctly."37 Dr. Robin's own research has produced similar results. Dr. Robin's videotaped study of 204 glaucoma patients concluded that the subjects instilled an average of 1.4 drops per instillation, 25 percent of subjects instilled more than one drop, 32 percent of subjects incorrectly touched the bottle to the surface of the eye and only 16 percent used a mirror to assist in application.38 Another videotaped study of 139 glaucoma patients by Dr. Robin determined that patients "performed relatively poorly when instilling a single eyedrop into the eye without touching the bottle tip to the eye."39 The study found that less than one quarter of the patients successfully instilled a single drop into their eye without touching their eye.4° 33. Finally, Dr. Kriegler's proposed methodology does not account for medication fillvolume overage that class members may instill into their eyes. Defendants fill many of their prescription eye drop containers in excess of the label claim. For example, a 10 mL 36 Gupta, Raghav, Bharat Patil, Bhavin Shah, Shveta Jindal Bali, Sanjay K. Mishra, and Tanuj Dada (2012), "Evaluating Eye Drop Instillation Technique in Glaucoma Patients", Journal of Glaucoma, 21(3): 189-192, March 2012. 37 Gupta, Raghav, Bharat Patil, Bhavin Shah, Shveta Jindal Bali, Sanjay K. Mishra, and Tanuj Dada (2012), "Evaluating Eye Drop Instillation Technique in Glaucoma Patients", Journal of Glaucoma, 21(3): 189-192, March 2012. Hennessy, Amy L., Joanne Katz, David Covert, Colleen Protzko, and Alan L. Robin (2010), "Videotaped Evaluation of Eyedrop Instillation in Glaucoma Patients with Visual Impairment or Moderate to Severe Visual Field Loss", Ophthalmology, 117(12): 2345-2352, December 2010. 38 Stone, Jennifer L., Alan L. Robin, Gary D. Novak, David W. Covert, and Gerald D. Cagle (2009), "An Objective Evaluation of Eyedrop Instillation in Patients with Glaucoma", Archives of Ophthalmology, 127(6):732-736, June 2009. 39 4° Stone, Jennifer L., Alan L. Robin, Gary D. Novak, David W. Covert, and Gerald D. Cagle (2009), "An Objective Evaluation of Eyedrop Instillation in Patients with Glaucoma", Archives of Ophthalmology, 127(6):732-736, June 2009. 15 Case 3:12-cv-01141-SMY-DGW Document 176-36 *SEALED* Filed 12/01/14 Page 17 of 42 Page ID #3251 Case: 16-3334 Document: 55-25 Filed: 02/08/2017 Pages: 42 (950 of 1511) September 12, 2014 CONFIDENTIAL — SUBJECT TO PROTECTIVE ORDER bottle of Cosopt has a target fill volume between 10.86 mL and 12.34 mL.41 The amount of overage varies from product to product. Each named plaintiff testified they get all of the medication out of their bottles. This means, for each product identified in the Complaint that is overfilled, class plaintiffs instill varying amounts of medications for which they did not bargain. Overfill amounts also vary among the products identified in the Amended Complaint. And all class plaintiffs may not get all the medication out of each of the bottles. Dr. Kriegler's estimation ignores these individual issues and does not account for the varying overage amounts individual class plaintiffs obtain from their prescription eye drops. Dr. Kriegler testified at deposition that he did not know bottles were filled in excess of their label claim.42 Hence Dr. Kriegler's proposed methodology is flawed and cannot correctly calculate damages. VII. Dr. Kriegler's Methodology Wrongly Assumes Prescription Eye Drop Cost is Linear to Volume 34. Dr. Kriegler's methodology also rests on the erroneous assumption of a direct linear relationship between the cost of prescription eye drops and their volume. Prescription pharmaceutical drug price determinants are unique from other markets. Those determinants include: insurance coverage of product, the prescription-only status of products, the determination by FDA of product quality prior to marketing and continued FDA monitoring, FDA review and approval of labeling and marketing materials, the participation of physicians, patients, and pharmacists in purchase decisions, the limitations of payor formularies and copayment structures, and the rigid structure of 41 NDA_Merck_Prasco_00009667. 42 Deposition of Brian Kriegler, August 20, 2014, p. 125. 16 Case 3:12-cv-01141-SMY-DGW Document 176-36 *SEALED* Filed 12/01/14 Page 18 of 42 Page ID #3252 Case: 16-3334 Document: 55-25 Filed: 02/08/2017 Pages: 42 (951 of 1511) September 12, 2014 CONFIDENTIAL — SUBJECT TO PROTECTIVE ORDER the competitive landscape including product categories and approvals for particular conditions.43 These market factors, together with basic economic theory, establish that Dr. Kriegler's proposed methodology for calculating class-wide damages is inconsistent with the basic economics of prescription pharmaceuticals. 35. First, the methodology wrongly assumes that prescription drug cost is linear to dosing— i.e., that decreasing the dosing volume of eye drops by a certain percentage would result in a proportional cost savings to plaintiffs. There is no requirement that eye drop manufacturers price their products in exact proportion to the size of the drop or volume in the bottle, and manufacturers of drugs, in pricing their products, are allowed to take account of all of the expenditures that go into bringing their products to market. For example, the prescription drug industry is characterized by very large R&D and regulatory expenditures with relatively low or modest manufacturing costs. Recent economic studies have estimated that the fully capitalized cost to bring a new drug to market is approximately $800 million." The relationship between prescription drug prices and the marginal cost of production is further distorted by the presence of indirect consumer demand and third-party payors.45 Because drug prices are not driven solely by the volume of the product, Dr. Kriegler's belief that reducing eye drop volume by half would have an equal impact on drug cost is incorrect. Prescription pharmaceutical 43 "Research and Development in the Pharmaceutical Industry", Congressional Budget Office, October 2006, p. 1. This amount is approximately 50 percent out of pocket costs for R&D and clinical trials and 50 percent capitalized opportunity cost. DiMasi, Joseph A., Ronald W. Hansen, and Henry G. Grabowski (2003), "The Price of Innovation: New Estimates of Drug Development Costs", Journal of Health Economics, 22:151-185. In addition, drug manufacturers incur substantial up-front regulatory costs. "Research and Development in the Pharmaceutical Industry", Congressional Budget Office, October 2006, p. 4. 44 Lakdawalla, Darius and Neeraj Sood (2009) "Innovation and the Welfare Effects of Public Drug Insurance," Journal of Public Economics 93:541-548. 45 17 Case 3:12-cv-01141-SMY-DGW Document 176-36 *SEALED* Filed 12/01/14 Page 19 of 42 Page ID #3253 Case: 16-3334 Document: 55-25 Filed: 02/08/2017 Pages: 42 (952 of 1511) September 12, 2014 CONFIDENTIAL — SUBJECT TO PROTECTIVE ORDER pricing results from numerous price determinants that make this assumption incorrect, including: • Research and developments costs; • Research and development costs related to abandoned drugs; • Drug innovation capital allotment and risk; • Regulatory compliance costs including post-approval regulation; • Indirect consumer demand facilitated through doctors, health insurers, and payor formularies and copay structures; • Market competition. 36. Dr. Kriegler's proposed methodology does not account for price variation resulting from any of the above factors. Dr. Kriegler acknowledged in his deposition that his proposed model and implicit theory of pricing does not account in any way for the amount of money spent on research and development.46 Dr. Kriegler also acknowledged that his proposed methodology does not account for differences in branded and generic drug prices.47 37. Second, the methodology does not account for the cost of the Phase III clinical trials Defendants would have to conduct for each drug listed in the Complaint to obtain regulatory approval for medications with a 16 tL drop volume. Phase III trials are very costly. New drug manufacturers can incur direct costs in the tens of millions of dollars for Phase III trials. The trials can span several years and involve testing on thousands of 46 Deposition of Brian Kriegler, August 20, 2014, pp. 92-93. 47 Deposition of Brian Kriegler, August 20, 2014, p. 114. 18 Case 3:12-cv-01141-SMY-DGW Document 176-36 *SEALED* Filed 12/01/14 Page 20 of 42 Page ID #3254 Case: 16-3334 Document: 55-25 Filed: 02/08/2017 Pages: 42 (953 of 1511) September 12, 2014 CONFIDENTIAL — SUBJECT TO PROTECTIVE ORDER individuals." To even submit Phase III clinical trials to FDA as a supplemental NDA, Defendants would have to pay a $1,084,550 fee for each drug per the 2014 Prescription Drug User Fee Amendments." Manufacturers of generic drugs would also incur significant additional regulatory costs to obtain regulatory approval of the modified generic drugs listed in the First Amended Complaint. As stated above, research and development and regulatory compliance costs can all be considered in prescription pharmaceutical pricing. Defendants' costs to redesign the drug and dropper tip, conduct Phase III clinical trials, and obtain regulatory approval from FDA would likely not result in lower prescription prices, even if there was a potential reduction in material costs from using smaller droppers. 38. Finally, Dr. Kriegler's proposed methodology does not accurately calculate the price class members actually paid for the prescription eye drops. Dr. Kriegler's proposed model uses the "total amount of sales of eye drops during the proposed class period."5° The total sales amount includes payments made by multiple sources other than putative class members for prescription eye drops dispensed in Missouri and Illinois, including the following: insurers, Medicare, Medicaid, and potentially purchasers of prescription eye drops that are not Missouri or Illinois residents. 39. The cost any patient pays for a prescription drug is a highly variable and individualized determination that depends on individual factors, including third-party payor coverages, 48 Phase III trials have been estimated to cost approximately $86 million and last 30 months on average. DiMasi, Joseph A., Ronald W. Hansen, and Henry G. Grabowski (2003), "The Price of Innovation: New Estimates of Drug Development Costs", Journal of Health Economics, 22:151-185. FDA, CDER/CBER, Guidance for Industry, Submitting Separate Marketing Applications and Clinical Data for Purposes of Assessing User Fees, (December 2004). 49 3" Expert Report of Dr. Brian Kriegler, May 30, 2014, p. 24. 19 Case 3:12-cv-01141-SMY-DGW Document 176-36 *SEALED* Filed 12/01/14 Page 21 of 42 Page ID #3255 Case: 16-3334 Document: 55-25 Filed: 02/08/2017 Pages: 42 (954 of 1511) September 12, 2014 CONFIDENTIAL — SUBJECT TO PROTECTIVE ORDER government payor coverages, and pharmacies, among other things. Individualized inquiry to each class member would be necessary to ascertain each class member's expenditure. 311 Case 3:12-cv-01141-SMY-DGW Document 176-36 *SEALED* Filed 12/01/14 Page 22 of 42 Page ID #3256 Case: 16-3334 Document: 55-25 Filed: 02/08/2017 September Pages: 42 (955 of 1511) 12, 2014 CONFIDENTIAL — SUBJECT TO PROTECTIVE ORDER Steven N. Wiggins Case 3:12-cv-01141-SMY-DGW Document 176-36 *SEALED* Filed 12/01/14 Page 23 of 42 Page ID #3257 Case: 16-3334 Document: 55-25 Filed: 02/08/2017 Pages: 42 (956 of 1511) STEVEN N. WIGGINS ADDRESS: Department of Economics Texas A&M University TAMU 4228 College Station, TX 77843-4228 Telephone: (979) 845-7383 swiggins@tamu.edu EDUCATION: Massachusetts Institute of Technology, Ph.D., 1979 Oklahoma State University, B.A., 1975 PROFESSIONAL EXPERIENCE: Senior Consultant, Charles River Associates, 2000 - present Senior Consultant, LECG, 1996 - 2000 Professor of Economics, Texas A&M University, 1991 - present Associate Professor of Economics, Texas A&M University, 1984 - 1991 Assistant Professor of Economics, Texas A&M University, 1979 - 1984 HONORS AND AWARDS: Thunderbird Award, Business Association of Latin American Studies, Barcelona, Spain, 2010. George and Mary Jordan Professor of Economics and Public Policy, Texas A&M University, 1993 - 1998. Rex B. Grey Professor, Private Enterprise Research Center, Texas A&M University, 1986 - 1989. Visiting Distinguished Lecturer on American Economic Institutions, Johann Wolfgang Goethe University, Frankfurt am Main, May - July, 1988. University Teacher/Scholar, Texas A&M Honors Program, 1986-87. Visiting Distinguished Lecturer on Economic Institutions Professor, University of the Saarlands, Saarbrucken, West Germany, May - August 1984. DISSERTATION TITLE: Product Quality Regulation and Innovation in the Pharmaceutical Industry RESEARCH INTERESTS: Industrial Organization, Regulation, and Antitrust Steven N. Wiggins June 2014 Page 1 Case 3:12-cv-01141-SMY-DGW Document 176-36 *SEALED* Filed 12/01/14 Page 24 of 42 Page ID #3258 Case: 16-3334 Document: 55-25 Filed: 02/08/2017 Pages: 42 (957 of 1511) LAST FOUR YEARS OF DEPOSITION AND TRIAL TESTIMONY: 2011 Shelia Adams and James Adams, et al. v. Pilgrim’s Pride Corporation, Civil No. 2:09CV-397 (TJW-CE), in the United States District Court for the Eastern District of Texas, Marshall Division Deposition and Trial Testimony 2011 Jean Smith and Loria Ivie, on behalf of themselves and others similarly situated v. Barry Collinsworth, Thomas Pugh, United American Insurance Company, Heartland Alliance of America Association, Farm & Ranch Healthcare, Inc. and John Does 1-20, Civil Action No. CV2004-72-2, In the Circuit Court of Saline County, Arkansas Deposition People’s Electric Cooperative v. Western Farmers Electric Cooperative, CIV-09-1129HE, In the United States District Court for the Western District of Oklahoma Deposition 2011 2011 Canadian Valley Electric Cooperative, Inc. v. Western Farmers Electric Cooperative, In the District Court of the 22nd Judicial District Sitting in and for Seminole County, Seminole Division, State of Oklahoma Deposition 2012 Mary Plubell and Ted Ivey, on behalf of themselves and all others similarly situated vs. Merck, & Co., Inc., Case No. 04CV235817, In the Circuit Court of Jackson County, Missouri at Independence Deposition 2012 City of Clinton, Arkansas, vs. Pilgrim's Pride Corporation, and Shelia Adams and James Adams, et al., vs. Pilgrim's Pride Corporation, Action No. 4:09-CV-386-Y (Consolidated With 4:09-CV-387-Y) Trial Testimony 2012 April Krueger, Individually and on Behalf of All Others Similarly Situated vs. Wyeth, Inc. F/K/A American Home Products, A Pennsylvania Corporation; Wyeth Pharmaceuticals F/K/A Wyeth Ayerst Pharmaceuticals, A Pennsylvania Corporation; And Does 1 Through 100, Inclusive, Case No 03:03-CV-02496JAH-AJB, United States District Court Southern District Of California Deposition 2013/2014 MM Steel, LP vs. Reliance Steel & Aluminum Co., Chapel Steel Corp., American Alloy Steel, Inc., Arthur J. Moore, JSW Steel (USA) Inc., Nucor Corp. & SSAB Enterprises, LLC D/B/A SSAB Americas, Case No. 4:12-cv-01227, United States District Court for the Southern District of Texas, Houston Division Deposition and Trial Testimony OTHER SELECTED CONSULTING EXPERIENCE: State of Louisiana, ex rel. James D. Caldwell, Jr., Attorney General v. Merck & Co., Inc., MDL No. 1657, United States District Court, Eastern District of Louisiana Steven N. Wiggins June 2014 Page 2 Case 3:12-cv-01141-SMY-DGW Document 176-36 *SEALED* Filed 12/01/14 Page 25 of 42 Page ID #3259 Case: 16-3334 Document: 55-25 Filed: 02/08/2017 Pages: 42 (958 of 1511) Michael H. Kirsch, D.D.S., individually and on behalf of all others similarly situated vs. Horizon Blue Cross Blue Shield of New Jersey, Inc., Superior Court of New Jersey Law Division – Essex County Alcoa Inc., vs. Luminant Generation Company LLC, Luminant Mining Company LLC, Sandow Power Company LLC, Luminant Energy Company LLC, and Energy Future Holdings Corp., In the District Court of Milam County, Texas, 20th Judicial District, No. 32,540 In Re: Pilgrim’s Pride Corporation, et al., Case No. 08-45664 (DML), In the United States Bankruptcy Court for the Northern District of Texas, Fort Worth Division Frank’s Casing Crew and Rental Tools, Inc. and Frank’s International, Inc. v. Tesco Corporation and Tesco Corporation (US), Civil Action No. 2:07-cv-15, In the United States District Court for the Eastern District of Texas, Marshall Division Logan Farms v. Smithfield, et al; Case No. 05-0766. In the United States District Court for the Southern District of Texas, Houston Division Alfred T. Giuliano, Trustee on Behalf of Debtors’ Estate of Graham-Field Health Products v. Ernst & Young LLP; AAA Case No. 18 199 10398 02 - American Arbitration Association Professional Accounting and Related Services Arbitration Tribunal The State of Texas v. Merck & Co., Inc., Cause No. GV 503021, In the District Court, Travis County, Texas, 345th Judicial District Board of Regents, The University of Texas System, on behalf of The University of Texas at Austin and Hydro-Québec v. Nippon Telephone and Telegraph Corporation, Cause No. A 01 CA 47, In the Western District of Texas, Austin Division ReedHycalog UK, Ltd., ReedHycalog, LP, and Grant PrideCo, Inc. vs. Baker Hughes Oilfield Operations, Halliburton Energy Services, Inc., US Synthetic Corporation, In the U.S. District Court for the Eastern District of Texas, Tyler Division; Civil Action No. 6:06-CV-222(LED) Champagne Metals, an Oklahoma Limited Liability Company vs. Ken-Mac, Inc., an Ohio corporation; Samuel, Son & Co., Limited, an Ontario, Canada corporation, Samuel Specialty Metals, Inc., a New Jersey corporation, Metal West, L.L.C., an Alabama limited liability company, Integris Metals, Inc., a New York corporation, Earle M. Jorgensen Company, a Delaware corporation, and Ryerson Tull, Inc., an Illinois corporation; in the U.S. Dist. Court for the Western District of Oklahoma; No. CIV-02-528C. Rick Love, M.D., et al., vs. Blue Cross and Blue Shield of Arizona, Inc., et al., in the U.S. District Court, Southern District of Florida, Miami Division; Case No. 03-21296-CIV-Moreno. Century Martial Art Supply, Inc. v. Martial Arts Enterprises, Inc.; No. 03-1711-T; USDC WD Oklahoma; Arbitration Number 71 181 J 00407 05 Brazos River Authority v. Ionics, Incorporated; Civil Action No. W 03 CA 324, in the U.S. District Court of Texas, Waco Division Parkade Center, Inc. v. Simon Property Group (Texas), L.P. and Simon Property Group (Delaware), Inc.; Cause No. C-2584-06-1, in the 398th Judicial District of Hidalgo County, Texas Steven N. Wiggins June 2014 Page 3 Case 3:12-cv-01141-SMY-DGW Document 176-36 *SEALED* Filed 12/01/14 Page 26 of 42 Page ID #3260 Case: 16-3334 Document: 55-25 Filed: 02/08/2017 Pages: 42 (959 of 1511) Natalie M. Grider, M.D., et al. v. Keystone Health Plan Central, Inc., et al.; In the U.S. District Court for the Eastern District of Pennsylvania Milissa Boisseau v. 7-Eleven, Inc.; Cause No. 04-05250; In the 68th Judicial District Court, Dallas County, Texas John Ivan Sutter, M.D., P.A. on behalf of himself and all others similarly situated vs. Horizon Blue Cross Blue Shield of New Jersey, Inc., Superior Court of New Jersey, Law Division Essex County, Docket No. ESX-L-3685-02 EEMSO, Inc. v. Compex Technologies, Inc. f/k/a Rehabilicare, Inc. and Iomed, Inc.; Civil Action No. 3:CV-05-0897-P; In the United States District Court, Northern District of Texas, Dallas Division Scruggs Management Services, Inc. d/b/a Scruggs Consulting v. Panasonic Communications & Systems Co., et al.; No. 01-0151; In the Supreme Court of Texas Gary Shapiro and Rich Fitzgerald, individually and on behalf of all others similarly situated v. International Business Machines Corporation, Docket No. MID-L-007413-02; Superior Court of New Jersey Law Division: Middlesex County Crest Foods of Edmund, LLC v. Wal-Mart Stores, Inc., Cause No. CIV-00-1659-F; In the U.S. District Court,Western District of Oklahoma Andrew Daugherity, et al., v. International Business Machines Corporation, Cause No. 23,162; In the District Court of Burleson County, Texas, 21st/335th Judicial District Logan Farms, Inc. and James P. Logan, Jr. v. Honeybaked Ham, L.P., Mi., et al., Cause No. H-01-1611; In the U.S. District Court for the Southern District of Texas, Houston Division Park Cities Hotel, L.P. v. Meristar Management Company, L.L.C. Cause No. 01-08447; In the District Court, Dallas County, Texas, B-44th Judicial District Marion Crane, et al., v. International Paper Company and Canal Wood, LLC; Civil Action No.: 3-023352-17; In the United States District Court for the District of South Carolina, Columbia Division Richard A. Lippe, et al. v. Bairnco Coporation, et al. Case No. 96-CV-7600, United States District Court For the Southern District of New York Alcatel USA, Inc. v. Cisco Systems, Inc. Case No. 4:00cv199, United States District Court for the Eastern District of Texas Sherman Division IMODCO Inc. v. FMC Corporation and SOFEC, Inc., Cause No. H-99-2174, United States District Court, Southern District of Texas, Houston Division American Permanent Ware Company v. Emerson Electric Co., d/b/a Chromolax, Don Shuhart Company, and Maytag Corp. d/b/a Heatube, Maytag Clarence Component Parts, Cause No. 00-07351; In the 298th Judicial District, Dallas County, Texas Palacio del Rio, Ltd. v. Hilton Hotels Corporation, et al., Cause No. 2000-CI-13691; In the 407th Judicial District Court, Bexar County, Texas Steven N. Wiggins June 2014 Page 4 Case 3:12-cv-01141-SMY-DGW Document 176-36 *SEALED* Filed 12/01/14 Page 27 of 42 Page ID #3261 Case: 16-3334 Document: 55-25 Filed: 02/08/2017 Pages: 42 (960 of 1511) Gilbert Moreno Enterprises, Inc. d/b/a La Monita, et al., v. Gruma Corporation, Individually and d/b/a Mission Foods Corporation, et al., Cause No. G-0-546; In the U.S. District Court for the Southern District of Texas, Galveston District United States of America v. Moore Supply Co. et al., CR-H-94-17, United States District Court, Southern District of Texas, Houston Division Brand Name Prescription Drug Antitrust Litigation, 94 C 897, MDL 997, United States District Court, Northern District Manuel Arechiga, Sr. v. Chevron U.S.A., Inc. and G.E. Darby, No. C-93-00844-D1, District Court of Webb County, Texas 49th Judicial District Acme Plumbing & Heating Co., Inc. and Bruce Brooks v. Morrison Supply Company, Inc., et al., No. 80534-B, District Court of Potter County, Texas 181st District Court Todd E. Samuelson, M.D. and Todd E. Samuelson, M.D., P.A., Individually and On Behalf of All Other Persons Similarly Situated, Appellants V. United Healthcare of Texas, Inc. and United Healthcare Insurance Company, Appellees, No. 2-01-407-CV, Court of Appeals of Texas, Second District, Fort Worth Humco Holding Group, Inc. v. The Dow Chemical Company; CV No.: 5:04-CV-287 (TJW); United States District Court for the Eastern District of Texas, Texarkana Division Schlotzsky's, Ltd. v. Sterling Purchasing & National Distribution Co. and Commissary Operations, Inc. and The Sygma Network, Inc.; Civil Action No. A05CA195 SS, United States District Court for the Western District of Texas, Austin Division Star Fuel Marts, LLC v. Murphy Oil USA, Inc., et al.; No. CIV-02-0202-F; United States District Court, Western District, Oklahoma Bolick Distributors Corporation v. Armstrong Holdings, Inc., Armstrong Wood Products, Inc., Robbins Hardwood Floorings, Inc., Hartco Flooring Company; Civil Action No.: 3-03-CV-1386-N; In the U.S. District Court for the Northern District of Texas, Dallas Division Port of Houston Authority v. GB Biosciences Corporation, GB Biosciences Holdings, Inc., ISK Magnetics, Inc., Occidental Chemical Corporation, John Stansbury, William Hutton, Zeneca Holdings, Inc., Zeneca Inc., Zeneca AG Products, Inc., Syngenta AG, Syngenta Corporation, Syngenta Crop Protection, Inc.; Cause No. 2001-07795, In the District Court of Harris County, Texas, 151st Judicial District Biovail Pharmaceuticals, Inc. v. Eli Lilly Company; United States District Court, for the Eastern District of North Carolina, Western Division, Case No. 5 :01CV352-BO(3) Ruhrpumpen, Inc. v. Flowserve Corporation et al, Civil Action No. 3:02-CV-01931, USDC, North District of Texas, Dallas Division Esther Kiobel et al v. Royal Dutch Petroleum Company; Shell Transport and Trading Company, p.l.c.; Civil Action No. 02 CV 7618 (KMW), USDC Southern District of New York BSA Enterprises, Inc. d/b/a BSA Provider Network v. Healthsmart Preferred Care II, L.P.; No. 91253-E In the 108th District Court, Potter County, Texas Steven N. Wiggins June 2014 Page 5 Case 3:12-cv-01141-SMY-DGW Document 176-36 *SEALED* Filed 12/01/14 Page 28 of 42 Page ID #3262 Case: 16-3334 Document: 55-25 Filed: 02/08/2017 Pages: 42 (961 of 1511) HomeTeam Pest Defense LLC v. Curtis Warren and OnDuty Security Systems, Inc.; Cause No. C-200432777; In the District Court, Harris County, Texas; 189th Judicial District KCI Licensing, Inc., KCI USA, Inc., and Wake Forest University Health Sciences v. Bluesky Medical Corporation, Medela AG, Medela, Inc., and Patient Care Systems, Inc., In the United States District Court for the Western District of Texas, San Antonio Division; Civil Action No. SA-03-CA-0832RF; Kinetic Concepts, Inc. VAE Nortrak North America, Inc., Meridian Track Products Corp., and Meridian Rail Information Systems Corp. v. Progress Rail Services Corporation; Civil Action No. 03 CV 1480; In the United States District Court for the Northern District of Alabama, Middle Division Brazos River Authority v. Ionics, Incorporated; Civil Action No. W 03 CA 324, in the U.S. District Court of Texas, Waco Division In the Matter of the Arbitration Ordinance (Chapter 341 of the Laws of Hong Kong) and In the Matter of An Arbitration Between Brunswick Bowling & Billiard Corporation and Shanghai Zhonglu Industrial Company Limited and Chen Rong PUBLICATIONS: “Nonlinear Pricing Strategies and Competitive Conditions in the Airline Industry,” with Manuel A. Hernandez, Economic Inquiry, Vol. 52, No. 2, April 2014, 539–561. “Airline Pricing, Price Dispersion, and Ticket Characteristics On and Off the Internet,” with Anirban Sengupta, American Economic Journal: Economic Policy, 2014, vol. 6, issue 1, pages 272-307. “The Impacts of Breakthrough Drug Classes on Total Healthcare Expenditures,” with Zeynal Karaca, Journal of Health Economics and Outcomes Research, 2013;1(3):276-95. “The Evolving Modern Theory of the Firm,” with Rob Maness, in Handbook of Managerial Economics, Oxford University Press, July 2013. “Comparing Price Dispersion On and Off the Internet Using Airline Transaction Data,” with Anirban Sengupta, Review of Network Economics, Vol. 11, Issue 1, March 2012, pages 1-38. “Examining the effect of low cost carriers on nonlinear pricing strategies of legacy airlines”, with Manuel A. Hernandez and Anirban Sengupta, in Pricing Behavior and Non-Price Characteristics in the Airlines Industry, James Peoples, Editor, 2011. "Identifying Market Power through Accounting Profits and Margins”, Market Power in Antitrust Law, Philip Nelson, editor, American Bar Association, 2004. "Price Competition in Pharmaceuticals: The Case of Anti-infectives," with Robert Maness, Economic Inquiry, vol. 42, no. 2, April 2004, 247-263. "Demand Systems and the "True" Subindex of the Cost-of-Living for Pharmaceuticals," with Michael R. Baye and Robert Maness, Applied Economics, 1997, 29, 1179-1189. Steven N. Wiggins June 2014 Page 6 Case 3:12-cv-01141-SMY-DGW Document 176-36 *SEALED* Filed 12/01/14 Page 29 of 42 Page ID #3263 Case: 16-3334 Document: 55-25 Filed: 02/08/2017 Pages: 42 (962 of 1511) "Competition or Compensation: Supplier Incentives under the American and Japanese Subcontracting System," with Curtis Taylor, American Economic Review, September, 1997. "Intangible Capital, Hedonic Pricing and International Transfer Pricing," with David Raboy, Public Finance Review, Vol. 25, No. 4, July, 1997, pp. 347-365. "Price Premia to Name-Brands: An Empirical Analysis," with David Raboy, Journal of Industrial Economics, Vol. XLIV, NO. 4, December 1996, pp. 377-388. "Entrepreneurial Enterprises, Endogenous Ownership, and the Limits to Firm Size," Economic Inquiry, Vol. XXXIII, No. 1, January 1995, pp. 54-69. "Institutional Control and Large-Scale, Long-Term Hazards," with Al H. Ringleb, Government and Risk Bearing, Mark Sniderman, ed., Federal Reserve Bank, Cleveland, 1993. "Adverse Selection, Liability, and Long Term Hazards," with Al Ringleb, Journal of Legal Studies, Vol. XXI, No. 1, January 1992, pp. 189-215. "Takeover Raids: Managerial Incompetence or Managerial Shirking," with James Griffin, Economic Inquiry, Vol. XXX, No. 2, April 1992, pp. 355-370. "The Economics of Contracts and Firms: A Selective Survey," Journal of Institutional and Theoretical Economics, Vol. 147, No. 4, December 1991, pp. 603-661. "The Comparative Advantage of Long Term Contracts and Firms," Journal of Law, Economics, and Organization, Vol. 6(1), Spring 1990, pp. 155-170. Reprint in The Theory of the Firm, Mark Casson, Editor, Edward Elgar Publishing Limited, Cheltenham, United Kingdom, Winter of 1997. "Liability and Large-Scale, Long Term Hazards," with Al Ringleb, Journal of Political Economy, 1990, Vol. 98(3), pp. 574-595. Reprint in Economics and Liability for Environmental Problems, Kathleen Segerson, Editor, Burlington, VT: Ashgate, 2002. "Social Control and Labor Relations in the American South Before 1950: Comment,"Journal of Institutional and Theoretical Economics, 1988, Vol. 145(1), pp. 158-161. "Firm Heterogeneities and Cartelization Efforts in Domestic Crude Oil," with G. Libecap, Journal of Law, Economics and Organization, Vol. 3(1). Spring 1987, pp. 1-25. "Organizational Theory, Information Processing, and Short Run Dynamics: Theory and Empirical Tests," Journal of Institutional and Theoretical Economics, Vol. 143(1), March 1987, pp. 204-21. The Cost of Developing a New Drug, Pharmaceutical Manufacturers' Association, Washington, D.C., 1987, 28 pp. "Innovation, Market Structure, and Market Dynamics: Comment," Journal of Institutional and Theoretical Economics, March 1986, pp. 200-203. "The Influence of Private Contractual Failure on Regulation: The Case of Oil Field Unitization," with G. Libecap, Journal of Political Economy, Vol. 93, No. 4, August 1985, pp. 690-714. Steven N. Wiggins June 2014 Page 7 Case 3:12-cv-01141-SMY-DGW Document 176-36 *SEALED* Filed 12/01/14 Page 30 of 42 Page ID #3264 Case: 16-3334 Document: 55-25 Filed: 02/08/2017 Pages: 42 (963 of 1511) Reprinted in The International Library of the New Institutional Economics, Claude Ménard, Editor, Edward Elgar Publishing Limited, Cheltenham, United Kingdom. "Oil Field Unitization: Contractual Failure in the Presence of Imperfect Information," with G. Libecap, American Economic Review, Vol. 75, No.3, June 1985, pp. 368-85. Reprint in Institutional Law and Economics, Pablo T. Spiller, Editor, Economic Approaches to Law series, Francesco Parisi and Richard Posner, Series Editors, Edward Elgar Publishing Limited, Cheltenham, United Kingdom, 2010. "Contractual Responses to the Common Pool: Prorationing of Crude Oil Production," with G. Libecap, American Economic Review, Vol. 74, No. 1, March 1984, pp. 87-98. Reprint in The Foundations of Regulatory Economics, Robert B. Ekelund, Jr., Edward H. Lowder and Catherine L. Lowder, Editors, Edward Elgar Publishing Limited, Cheltenham, United Kingdom. Reprint in Corporate Reorganization and Bankruptcy: Legal and Financial Materials, Mark J. Roe, Editor, Foundation Press, 2000. "Plant Closings, Worker Reallocation Costs, and Efficiency Gains to Labor Representation on Boards of Directors," with E. Furubotn, Journal of Institutional and Theoretical Economics, Vol. 140, No.1, March 1984, pp. 176-92. "The Effect of U.S. Pharmaceutical Regulation on New Introductions," Pharmaceutical Economics, Bjorn Lindgren, editor, 1984, pp. 191-206. "Is Regulation Really Necessary When Product Quality is Unknown?" in A. Shapiro, ed., Management and Regulation, The Basis for a Corporate Policy, Stevens Institute of Technology, 1984. "Quality Uncertainty, Search, and Advertising," with W.J. Lane, American Economic Review, Vol. 73, No. 5, December 1983, pp. 881-94. "The Impact of Regulation on Pharmaceutical Research Expenditures: A Dynamic Approach," Economic Inquiry, Vol. XXI, January 1983, pp. 115-28. "Product Quality Regulation and New Drug Introductions: Some New Evidence From the 1970s," Review of Economics and Statistics, Vol. LXIII, No. 4, November 1981, pp. 615-19. "A Theoretical Analysis of Conglomerate Mergers," in The Conglomerate Corporation, R.D. Blair and R.F. Lanzillotti, editors, Cambridge, Massachusetts, 1981, pp. 53-70. "The Pharmaceutical Research and Development Decision Process," in Drugs and Health: Economic Issues and Policy Objectives, R. Helms, editor, American Enterprise Institute for Public Policy Research, 1981, pp. 55-83. "Economic Factors Affecting Investment in Planned Birth Technologies," Congressional Office of Technology Assessment, 1980. Steven N. Wiggins June 2014 Page 8 Case 3:12-cv-01141-SMY-DGW Document 176-36 *SEALED* Filed 12/01/14 Page 31 of 42 Page ID #3265 Case: 16-3334 Document: 55-25 Filed: 02/08/2017 Pages: 42 (964 of 1511) PAPERS IN PROGRESS: “Testing Theories of Price Dispersion and Scarcity Pricing in the Airline Industry,” with Steven L. Puller and Anirban Sengupta. “Pyramidal Ownership in Ecuadorian Business Groups,” with Maria L. Granda. REVIEW RESPONSIBILITIES: Editorial Board Member: Journal of Regulatory Economics: 1989-1993 Journal of Corporate Finance: 1994-2000. Referee for: American Economic Review Applied Economics Bulletin of Economic Research Economic Inquiry Economic Journal International Economic Review Journal of Corporate Finance Journal of Economic Behavior and Organization Journal of Economics and Management Strategy Journal of Environmental Economics and Management Journal of Finance Journal of Health Economics Journal of Industrial Economics Journal of Institutional and Theoretical Economics Journal of Law and Economics Journal of Law, Economics, and Organization Journal of Political Economy Journal of Regulatory Economics Journal of the Japanese and International Economies Managerial and Decision Economics National Science Foundation Quarterly Review of Economics and Business RAND Journal of Economics Review of Economics and Statistics Southern Economic Journal Ph.D. STUDENTS (YEAR OF COMPLETION) DISSERTATION TITLE: Steve Hackett (1989), Essays on the Economics of Contracting and Institutional Choice Andreas Ortmann (1991), Essays on Quality Uncertainty, Information, and Institutional Choice Robert Maness (1992), Essays on Organization, Form, and Pricing Behavior Hanne Meihuizen (1994), Three Essays on Contracts Steven N. Wiggins June 2014 Page 9 Case 3:12-cv-01141-SMY-DGW Document 176-36 *SEALED* Filed 12/01/14 Page 32 of 42 Page ID #3266 Case: 16-3334 Document: 55-25 Filed: 02/08/2017 Pages: 42 (965 of 1511) Wenjie Shi (1997), An Integrated Approach To The Choice Between Firms, Joint Ventures And Entrepreneurial Enterprises Jennifer Vanderhart (2000), Quality Signals, Word-of-Mouth, and Star Power: The Determinants of Motion Picture Success Jun Byoung Oh (2002), Southwest Airlines and Competition in the Airline Industry Ahmed Alwaked (2005), Estimating Fare and Expenditure Elasticities of Demand for Air Travel in the U.S. Domestic Market Jong Ho Kim (2006), Price Dispersion in The Airline Industry: The Effect Of Industry Elasticity And Cross-Price Elasticity Ivan Tasic (2006), Impact Of Retailers Promotional Activities on Customer Traffic Zeynal Karaca (2007) The Impacts of Break-Through Drug Classes on Total Health Expenditures: Empirical Evidence from the 1996-2001 Medical Expenditure Panel Survey Anirban Sengupta (2007) Airline Pricing, Price Dispersion, and Ticket CharacteristicsOn and Off the Internet Maria Granda Kuffo (2009) Pyramidal Ownership in Ecuadorian Business Groups Manuel Hernandez (2009) Nonlinear Pricing Strategies and Market Concentration in the Airline Industry Sung Ick Cho (Current) Jinkook Lee (Current) Fan Ji (Current) CONFERENCE PRESENTATIONS: 2010 “Pyramidal Ownership in Ecuadorian Business Firms,” Business Association of Latin American Studies, Barcelona, Spain. 1997 The Brookings Institution, Conference on Human Capital and the Theory of the Firm, Washington, D.C. 1996 National Bureau of Economic Research, Summer Institute, sessions on New Approaches to Supply and Demand Analysis and Aging, Health Care and Productivity, Cambridge, MA. Steven N. Wiggins June 2014 Page 10 Case 3:12-cv-01141-SMY-DGW Document 176-36 *SEALED* Filed 12/01/14 Page 33 of 42 Page ID #3267 Case: 16-3334 Document: 55-25 Filed: 02/08/2017 Pages: 42 (966 of 1511) University of Chicago, ELO Workshop, “Information Cascades and Contractual Incompleteness in Natural Gas Contracting, Chicago, IL University of Wisconsin-Madison, IO Workshop, “Information Cascades and Contractual Incompleteness in Natural Gas Contracting, Madison, WI 1995 National Bureau of Economic Research, Spring IO meetings, "Price Competition in Pharmaceutical Markets," Boston, MA. 1994 American Economic Association, "The Price of Pharmaceuticals," Boston, MA. Southern Economic Association, "Pricing and Promotion of Pharmaceuticals," New Orleans, LA. 1993 National Bureau of Economic Research, "Cooperation, Coordination, and Collusion Among Firms," Boston, MA. Harvard Conference on the Pharmaceutical Industry, Boston, MA. 1992 Tenth Annual Seminar on the New Institutional Economics, Wallerfangen, Germany. Future of the Pharmaceutical Industry: Developments in Market Structure and Technology, MIT. Editors Conference for the Journal of Regulatory Economics, October 1992. 1991 Annual Meetings of the Pharmaceutical Manufacturers' Association, Session on Models of Pharmaceutical Competition. Annual Meetings of Southern Economic Association, Session on the Pharmaceutical Industry. 1990 Annual Meetings of the American Economic Association, Session on Experimental Economics Unitization. Eighth Annual Seminar on the New Institutional Economics, Wallerfangen, Germany. Steven N. Wiggins June 2014 Page 11 Case 3:12-cv-01141-SMY-DGW Document 176-36 *SEALED* Filed 12/01/14 Page 34 of 42 Page ID #3268 Case: 16-3334 Document: 55-25 Filed: 02/08/2017 Pages: 42 (967 of 1511) 1989 "Improving the Translation of Research Findings into Clinical Practice: The Changing Economics of Technological Innovation in Medicine" Sponsored by National Academy of Sciences, Washington, DC. Carnegie-Mellon Conference on Political Economy. Seventh Annual Conference on the New Institutional Economics in Saarbrucken, West Germany. Econometric Society Summer Meetings, Ann Arbor, Michigan. 1988 Annual Meetings of the American Economic Association, Session on Endogenous Institutional Choice. Annual Meetings of the Economic Science Association (Experimental), San Francisco, Sessions on Public Goods Experiments and Experiments on Institutional Choice. Sixth Annual Conference on the New Institutional Economics, Saarbrucken, Germany Second Annual Hayek Symposium on Knowledge, Information, and Competition, Freiburg, Germany. 1987 Fifth Annual Conference on the New Institutional Economics, Saarbrucken, Germany. First Annual Hayek Symposium on Knowledge, Information, and Competition, Freiberg, Germany. American Economic Association Meetings, Session on Regulation and Long Term Contracts, Chicago. 1986 Econometric Society Meetings, Winter Meetings, New Orleans, Session on Long Term Contracts. NBER Summer Institute, Cambridge, MA. Fourth Annual Conference on the New Institutional Economics, Saarbrucken, Germany. Thirteenth Annual Interlaken Conference, Interlaken, Switzerland. 1985 American Economic Association, Session on Monopoly and Competition, New York. Third Annual Conference on the New Institutional Economics, Saarbrucken, Germany. Twelfth Annual Interlaken Conference, Interlaken, Switzerland. Steven N. Wiggins June 2014 Page 12 Case 3:12-cv-01141-SMY-DGW Document 176-36 *SEALED* Filed 12/01/14 Page 35 of 42 Page ID #3269 Case: 16-3334 Document: 55-25 Filed: 02/08/2017 Pages: 42 (968 of 1511) 1984 Conference on Management and Regulation: The Basis of a Corporate Policy, sponsored by Stevens Institute of Technology, Hoboken, New Jersey. Conference on Economics and Philosophy, sponsored by Civitas, Munich. Second Annual Conference on the New Institutional Economics, sponsored by the Saarlands, Mettlach, Germany. Eleventh Annual Interlaken Conference, sponsored by the Universities of Bern and Rochester, Interlaken, Switzerland. 1983 Econometric Society Winter Meetings, Billboard Session. First Annual Conference on the New Institutional Economics, sponsored by the University of the Saarlands, Mettlach, Germany. 1982 Arne Ryde Symposium on Pharmaceutical Economics, Helsingborg, Sweden. Session on Problems of Industrial Policy, American Economic Association Annual Meeting, December. 1981 Western Economic Association Meetings, Session on Strategic Planning Models, Association 1980 Conference on The Conglomerate Corporation, sponsored by the University of Florida, Gainesville. 1979 Conference on Drugs and Health: Economic Issues and Policy Objectives, American Enterprise Institute, Washington, D.C. WORKSHOP PRESENTATIONS: 2010 University of Washington, University of Texas at Arlington 1996 University of Wisconsin, University of Chicago, Rice University Steven N. Wiggins June 2014 Page 13 Case 3:12-cv-01141-SMY-DGW Document 176-36 *SEALED* Filed 12/01/14 Page 36 of 42 Page ID #3270 Case: 16-3334 Document: 55-25 Filed: 02/08/2017 Pages: 42 (969 of 1511) 1995 Rice University 1994 University of Chicago, UCLA 1993 Penn State, University of Houston, Louisiana State University 1992 Oklahoma State University, University of Pennsylvania 1991 Northwestern University, University of Chicago, Rice University 1990 University of Pennsylvania, Brown University 1989 Harvard, State University of New York-Albany, Massachusetts Institute of Technology, University of Chicago, University of Michigan, Boston University, Columbia University, Northwestern University, University of Indiana, Ohio State, UCLA 1988 University of Chicago, Stanford University, University of California-San Diego, University of Illinois, Washington University, University of Bonn, University of the Saarlands, University of Wurzburg, University of Washington 1987 Virginia Commonwealth University, University of New Orleans, University of Arizona, UCLA, Federal Trade Commission, George Mason University, University of Houston, University of Texas, University of Zurich 1986 Northwestern University, Carnegie Mellon, University of Rochester, Penn State, University of Michigan, University of California-San Diego 1985 Federal Reserve Bank of Dallas, Washington University-St. Louis, Yale University, University of Houston 1984 University of British Columbia, University of Washington, Northwestern University, University of Michigan, Duke University, Yale University Steven N. Wiggins June 2014 Page 14 Case 3:12-cv-01141-SMY-DGW Document 176-36 *SEALED* Filed 12/01/14 Page 37 of 42 Page ID #3271 Case: 16-3334 Document: 55-25 Filed: 02/08/2017 Pages: 42 (970 of 1511) 1983 University of Houston, University of Texas 1982 MIT 1981 Federal Trade Commission Steven N. Wiggins June 2014 Page 15 Case 3:12-cv-01141-SMY-DGW Document 176-36 *SEALED* Filed 12/01/14 Page 38 of 42 Page ID #3272 Case: 16-3334 Document: 55-25 Filed: 02/08/2017 Pages: 42 (971 of 1511) CONFIDENTIAL – SUBJECT TO PROTECTIVE ORDER September 12, 2014 EXHIBIT B Documents Reviewed: Document Affidavit of Steven N. Wiggins, Ph.D., Plubell & Ivey v. Merck & Co., Inc., Case No. 04CV235817, Exhibit 10 Summary of Opinions of Steven N. Wiggins, Plubell & Ivey v. Merck & Co., Inc., Case No. 04CV235817, Exhibit 6 Expert Report of Alan Robin, M.D., May 30, 2014 First Amended Class Action Complaint for Damages, Punitive Damages, and Injunctive Relief Summary of Opinions of Steven N. Wiggins, Plubell & Ivey v. Merck & Co., Inc., Case No. 04CV235817 First Amended Class Action Complaint for Damages, Punitive Damages, and Injunctive Relief, Filed 2/22/13 Expert Report of Brian Kriegler, PhD, May 30, 2014 Deposition of Charlene Eike, Vol. 1, March 7, 2014 Deposition of Shirley Mae Fisher, February 24, 2014 Deposition of Jordan S. Pitler, February 10, 2014 Deposition of Alan Raymond, February 27, 2014 DiMasi, JA, Hansen, RW, Grabowski, HG, “The Price of Innovation: New Estimates of Drug Development Costs,” Journal of Health Economics, vol. 22, no. 2 (March 2003) Congressional Budget Office Study, October 2006, Research and Development in the Pharmaceutical Industry. Gupta, R, Patil, B, Shah, BM, Bali, SJ, Mishra, SK, Dada, T (2012) Evaluating Eye Drop Instillation Technique in Glaucoma Patients Journal of Glaucoma March 2012, Vol. 21, Issue 3 Kass MA, Hodapp E, Gordon M, Kolker AE, Goldberg I, “Part I. Patient Administration of Eyedrops: Interview. Annals of Ophthalmology August 1982, 775-779. Kass MA, Hodapp E, Gordon M, Kolker AE, Goldberg I, “Patient Administration of Eyedrops: Observation. Annals of Ophthalmology September 1982, 889-893. Hennessy AL, Katz J, Covert D, Protzko C, Robin AL. Videotaped Evaluation of Eyedrop Instillation in Glaucoma Patients with Visual Impairment of Moderate to Severe Visual Field Loss. Ophthalmology. 2010; 117(12): 2345-2352. Stone JL, Robin AL, Novack GD, Covert DW, Cagle GD. An Objective Evaluation of Eyedrop Instillation in Patients with Glaucoma. Arch Ophthalmology. 2009; 127(6): 732-736. Hennessy AL, Katz J, Covert D, et al. A Video Study of Drop Instillation in Both Glaucoma and Retina Patients with Visual Impairment. Am. J. Ophthalmology 2011; 152(6): 982-988 Van Santvliet, L, Ludwig, A (1998) The influence of penetration enhancers on the volume instilled of eye drops, European Journal of Pharmaceutics and Biopharmaceutics 45, 1998, 189-198 Pharmacy Records: Charlene Eike Pharmacy Records: Shirley Mae Fisher Pharmacy Records: Jordan Pitler Pharmacy Records: Alan Raymond Generic Cosopt Label Bates Nos. CE000036-0000048 SF000029-000051 JP-000120-000136 AR-000016-000033 Prasco 000001-000007 1 Case 3:12-cv-01141-SMY-DGW Document 176-36 *SEALED* Filed 12/01/14 Page 39 of 42 Page ID #3273 Case: 16-3334 Document: 55-25 Filed: 02/08/2017 Pages: 42 (972 of 1511) CONFIDENTIAL – SUBJECT TO PROTECTIVE ORDER EXHIBIT B Documents Reviewed: Document Letter from Cantrell to Buehler RE: Original Submission, Abbreviated New Drug Application, Dorzolamide Hydrochloride Ophthalmic Solution, 2%, May 4, 2007 Comprehensive Table of Contents, Dorzolamide Hydrochloride Ophthalmic Solution ANDA Dorzolamide Hydrochloride Ophthalmic Solution ANDA Label, Dorzolamide 5 ml Carton Label, Page 1 Dorzolamide Hydrochloride Ophthalmic Solution ANDA Label, Dorzolamide Generic to RLD Carton Labeling, Page 1 Container Closure System, Dorzolamide Hydrochloride Ophthalmic Solution ANDA Container Closure System, Dorzolamide HCl - Timolol Maleate Ophthalmic Solution Introduction to the Quality Overall Summary, Dorzolamide HCl and Timolol Maleate Ophthalmic Solution Comparison of Drop Size Drop Size Test Results Alcon Standard Test Method for Evaluation of Drop Size by Weight of Solutions and Suspensions, 2/15/13 Package Development, November 15, 2001 Package Development, March 27, 2007 Package Development, March 27, 2007 Package Development, September 26, 2007 Package Development, April 15, 1997 Package Development, March 27, 2007 Package Development, April 1, 1997 Package Development, April 1, 1997 Package Development, July 7, 2005 Drop Size Test Travatan, Project #22-5202 Package Development, December 3, 2003 Package Development, September 19, 2001 Alcon - Test Panel Assessment of Drop Size for Selected Alcon Products and Packages, March 2, 2009 Alcon Measurement of Drop Size and Doses per Container During an InUse Simulation of Ophthalmic Products, 2/6/02 Dorzolamide HCl and Timolol Maleate Ophthalmic Solution, Batch Formula Alcon Comparison of Control Tip Solution Plugs, 0.006" Orifice vs 0.10" Orifice, 2/21/01 Package Development, February 5, 2008 Package Development Package Development, September 19, 2001 Package Development, October 15, 2001 Package Development, March 27, 2007 Package Development, August 23, 2001 Drop Data Summary for Travatan Z, Comparing Current and Proposed 13 mm Dispensing Plug Drop Size - Travatan Package Development, October 24, 2007 September 12, 2014 Bates Nos. AD_DORZOLAMIDE_EIKE000603-000604 AD_DORZOLAMIDE_EIKE000605-000616 AD_DORZOLAMIDE_EIKE000617 AD_DORZOLAMIDE_EIKE000618 AD_DORZOLAMIDE_EIKE000619-000626 AD_DORZ-TIM_EIKE001214-001221 AD_DORZ-TIM_EIKE001234-001235 AD_EIKE0001167-0001171 AD_EIKE0001172-0001190 AD_EIKE001012-001029 AD_EIKE001065-001066 AD_EIKE001067-001068 AD_EIKE001069-001070 AD_EIKE001074-001075 AD_EIKE001076-001077 AD_EIKE001078-001080 AD_EIKE001081-001082 AD_EIKE001083-001084 AD_EIKE001085-001086 AD_EIKE001250-001252 AD_EIKE001253-001255 AD_EIKE001256-001257 AD_EIKE001258-001267 AD_EIKE001281-001282 AD_EIKE001283-001294 AD_EIKE001295-001299 AD_EIKE001300-001301 AD_EIKE001302-001303 AD_EIKE001304-001305 AD_EIKE001306-001307 AD_EIKE001308-001309 AD_EIKE001310-001311 AD_EIKE001312-001316 AD_EIKE001317 AD_EIKE001321-001322 2 Case 3:12-cv-01141-SMY-DGW Document 176-36 *SEALED* Filed 12/01/14 Page 40 of 42 Page ID #3274 Case: 16-3334 Document: 55-25 Filed: 02/08/2017 Pages: 42 (973 of 1511) CONFIDENTIAL – SUBJECT TO PROTECTIVE ORDER EXHIBIT B Documents Reviewed: Document Package Development, March 27, 2007 Package Development, September 19, 2001 Package Development, June 30, 2004 Package Development, August 11, 2004 Package Development, January 18, 2008 Package Development, February 5, 2008 Latanoprost ANDA Container Closure System Completed Primary Packaging Approval Form, Travatan Alcon Clinical Study Report, Travoprost Three Month Study Email from Wiernas to Puglisi Re: E-Assist Delivery Aid, February 24, 2004 Alcon Risk Assessment Report Approval, Travatan Dosing Aid Container Closure System, Travatan BAC-free Container Closure System, Moxifloxacin Ophthalmic Solution, 0.5% Allergan, Lumigan Drop Size Study Allergan, Drop Weight Test Allergan, Drop Weight Test Allergan, Drop Size Study Allergan Regulatory Affairs Binder, BMT 320N, Lumigan, NDA 21-275/S007, Amendment to Supplement for New Container Closure System, November 7, 2002 Packaging Development Information R&D Materials R&D Materials Allergan Non-Clinical-EZ, Technical Report Allergan 3-Month Clinical Study Report Allergan, NDA 21-398 Allergan, Clinical Study Report 190342-023T Allergan, NDA-21-398, Safety Evaluation Allergan Clinical Study Report, NDA 21-398 Allergan Clinical Study Report 190342-024T, A Multi-Center Randomized, Double-Masked, Parallel-Group Study to Evaluate the Safety of BID Administration of 0.2% Brimonidine Allergan Clinical Study Report, Study Number: 190342T-012T NDA 21398 Qualification Report PDD-R-01-175 Drop Study FDSD 2003-003 Bausch & Lomb Pharmaceuticals, Report Number: FD-2003-003, Assessment of Drop Uniformity of Alphagan P and Brimonidine Tartrate Ophthalmic Solution 0.2% Study Design Number: FDSD-2000-024, Assessment of Drop Uniformity of Alphagan 0.2% Overview on the Container-Closure Selection for Brimonidine Tartrate Ophthalmic Solution 0.2% Email from Herber to Validation Memo to File #V51-U-00 Re: Drop Size Technical Assessment Report for Approved ANDA/NDA Ophthalmic Drug Products, March 17, 2002 September 12, 2014 Bates Nos. AD_EIKE001323-001324 AD_EIKE001325-001326 AD_EIKE001327-001328 AD_EIKE001329-001330 AD_EIKE001331-001333 AD_EIKE001334-001335 AD_LATANOPROST_EIKE000121-000128 AD_TRAVATAN_EIKE000011-000015 AD_TRAVATAN_EIKE037870-038351 AD_TRAVATAN_EIKE039914-039920 AD_TRAVATAN_EIKE040560-040581 AD_TRAVATAN_EIKE041118-041123 AD_VIGAMOX_EIKE016359-016372 ARGN_00009444-0001075 ARGN_0001093-0001099 ARGN_0002352-0002389 ARGN_0002428-002461 ARGN_0002642-0002693 ARGN_0002745-0002857 ARGN_0002858-002962 ARGN_0003197-0003313 ARGN_0003774-0003779 ARGN-ALP1_0001412-0004133 ARGN_COMB_0005644-0006222 ARGN_COMB_0010322-0010328 ARGN_COMB_0010396 ARGN_COMB_0020527-0022362 ARGN_COMB_0022363-0029025 ARGN_COMB_0029026-0029033 ARGN_LUM03_0005644-0006222 BHLB_BRIM_0000858-0000860 BHLB_BRIM_0000900-0000906 BHLB_BRIM_0001052-0001055 BHLB_BRIM_0001070-0001074 BHLB_BRIM_0001076-0001134 3 Case 3:12-cv-01141-SMY-DGW Document 176-36 *SEALED* Filed 12/01/14 Page 41 of 42 Page ID #3275 Case: 16-3334 Document: 55-25 Filed: 02/08/2017 Pages: 42 (974 of 1511) CONFIDENTIAL – SUBJECT TO PROTECTIVE ORDER EXHIBIT B September 12, 2014 Documents Reviewed: Document Bates Nos. Dorzolamide Hydrochloride and Timolol Maleate Ophthalmic Solution NDA_MERCK_Prasco_00000328-0000353 Chemical and Pharmaceutical Manufacturing and Control Documentation Merck, Cosopt, Proposed Labeling Text NDA_MERCK_Prasco_00009185-00009196 Merck, Cosopt, Proposed Labeling Text NDA_MERCK_Prasco_00009214-00009232 Cosopt Supplemental Drug Application Documents NDA_MERCK_Prasco_00009675-00009696 Letter from Soriano to Cornfeld, May 22, 2014 Transmitting documents produced in response to document requests after company witness depositions Dorzolamide Hydrochloride-Timolol Maleate Ophthalmic Solution Packaging and Insert; Merck & Prasco Supply and Distribution Agreement Xalatan Quality Overall Summary Latanoprost Ophthalmic Solution, 0.005%, Response to 10-November2010 FDA Query 4 Latanoprost Ophthalmic Solution, 0.005%, Response to 10-November2010 FDA Query 5 Xalatan, Sterile Ophthalmic Solution, NDA 20-597, Amendment to Application, November 2, 1995 Letter from Shawaryn to Chambers Re: Xalatan, Transmitting References cited in the Drug Information Letter, September 21, 1998 Letter from Gremban to FDA Re: Xalatan, Changes Being Effected Supplement, Dropper Tip Modification, January 25, 2002 Letter from Rocco to Soreth Re: NDA 20-597 XALAT AN® (latanoprost ophthalmic solution) Prior Approval Supplement- Chemistry, Manufacturing and Controls eCTD Sequence No. 0004, May 7, 2008 Pfizer Certification of Compliance, Xalatan, 5/7/2008 Pfizer, Application to Market a New Drug, Biologic, or an Antibiotic Drug for Human Use, Xalatan, 5/7/2008 Letter from Verbestel to FDA Re: Letter of Authorization, Drug Master File Holder Name: Pfizer Manufacturing Belgium NV, Drug Master File (Type V) #7105, June 21, 2007 Letter from Jones to Deneve Re: EIR for the Puurs, Belgium facility, August 24, 2007 Xalatan Quality Overall Summary, May 6, 2008 Xalatan Quality Overall Summary, October 212 Xalatan NDA 20-597, Clinical Pharmacia Determination of Xalatan Drop Volume using Xal-Ease, 5/3/2002 Xalatan Drop Study Document Allergan Confidential, LUMIGAN® (bimatoprost ophthalmic solution) 0.01%, 3.2.P.3.5 Process Validation and/or Evaluation Deposition of Brian R. Kriegler, August 20, 2014 Deposition of Alan Robin, August 6, 2014 NDA_MERCK_Prasco_00010382-00010433 Prasco 000001-000094 PFIZER_XALATAN_00000038-00000040 PFIZER_XALATAN_00000093-00000096 PFIZER_XALATAN_00000097-00000106 PFIZER_XALATAN_00000378-00000512 PFIZER_XALATAN_00001531-00001546 PFIZER_XALATAN_00001547-00001600 PFIZER_XALATAN_00002144-00002145 PFIZER_XALATAN_00002146 PFIZER_XALATAN_00002147-00002148 PFIZER_XALATAN_00002149 PFIZER_XALATAN_00002150-00002151 PFIZER_XALATAN_00002152-00002169 PFIZER_XALATAN_00002495-00002512 PFIZER_XALATAN_00010314-00010741 PFIZER_XALATAN_00023573-00023577 PFIZER_XALATAN_00024279-00024280 ARGN_LUM01_0000014-0000061 4 Case 3:12-cv-01141-SMY-DGW Document 176-36 *SEALED* Filed 12/01/14 Page 42 of 42 Page ID #3276 Case: 16-3334 Document: 55-25 Filed: 02/08/2017 Pages: 42 (975 of 1511) CONFIDENTIAL – SUBJECT TO PROTECTIVE ORDER EXHIBIT B September 12, 2014 Documents Reviewed: Document Bates Nos. Berndt, Ernst R., Thomas McGuire, and Joseph P. Newhouse (2011), “A Primer on the Economics of Prescription Pharmaceutical Pricing in Health Insurance Markets”, Forum for Health Economics & Policy, 14(2):3, Article 10. NDA_Merck_Prasco_00009667 Lakdawalla, Darius and Neeraj Sood (2009) “Innovation and the Welfare Effects of Public Drug Insurance,” Journal of Public Economics 93:541548 FDA, CDER/CBER, Guidance for Industry, Submitting Separate Marketing Applications and Clinical Data for Purposes of Assessing User Fees, (December 2004). 5 Case 3:12-cv-01141-SMY-DGW 176-11 *SEALED* Dorzolamide HC1 and TimololDocument Maleate Ophthalmic Solution Filed 12/01/14 Page 1 of 8 Case: 16-3334 Document:Page 55-26ID #2456 Filed: 02/08/2017 Pages: 8 (976 of 1511) 3.2.P.2.4. Container Closure System [Dorzolamide-Timolol Ophthalmic Solution] Choi ce of Materi al s The package system selected is appropriately sized for the desired label claim and is easy to squeeze due to its shape and resin characteristics. Dorzolamide-Timolol Ophthalmic Solution will be packaged in Al con's standard DROP-TAINER® packaging system (see Table 3.2.P.2.4-1 and Figure 3.2.P.2.4-1). This system consists of a low density polyethylene (LDPE) bottle and dispensing plug and a polypropylene (PP) closure. A white DROPTAINER with blue closure was selected to resemble the container of the innovator product, COSOPT, marketed by Merck. Consistent with the COSOPT labeling, the opaque (white) bottle also provides protection from light. The bottle and plug are sterilized by either ethylene oxide or gamma irradiation, and the closure by gamma irradiation. Each bottle will be labeled with a pressure sensitive label. Tamper evidence is provided through the use of a shrink band around the neck and closure area of the bottle. The product will be packaged with labeled fill volumes of 5 mL in 8 mL bottles and 10 mL in 10 mL bottles. Table 3.2.P.2.4-1 Packaging System for Dorzolamide-Timolol Ophthalmic Solution Component Materiala 8 mL and 10 mL White Bottles b Dupont 20-6064 LDPE0 Natural Dispensing Plug Dupont 20-6064 LDPE Blue Closureb Pressure Sensitive Label Basell Profax PF-511 PPd Paper Label with Greenbay P508 Adhesive a These materials are currently used in a number of currently approved Alcon ophthalmic products (including ANDA 78-031 for Diclofenac Ophthalmic Solution, ANDA 76-254 for Brimonidine Tartrate Ophthalmic Solution and ANDA 76-231 for Ofloxacin Ophthalmic Solution). b The bottle color will be white and the closure color will be blue to resemble the container of the imiovator product, COSOPT, marketed by Merck. c Low density polyethylene d Polypropylene 3.2.P.2.4 Container Closure System [Dorzolamide-Timolol Ophthalmic Solution], Page 1 CONFIDENTIAL PURSUANT TO THE PROTECTIVE ORDER AD DORZ-TIM EIKE001214 Case 3:12-cv-01141-SMY-DGW 176-11 *SEALED* Dorzolamide HC1 and TimololDocument Maleate Ophthalmic Solution Filed 12/01/14 Page 2 of 8 Case: 16-3334 Document:Page 55-26ID #2457 Filed: 02/08/2017 Pages: 8 (977 of 1511) Figure 3.2.P.2.4-1 Packaging System for Dorzolamide-Timolol Ophthalmic Solution • Safety of Materials - USP Testing The resins used in the packaging components for Dorzolamide-Timolol Ophthalmic Solution have been previously approved for use in numerous ophthalmic products marketed by Alcon and have been subjected to USP physicochemical and toxicological testing in accordance with the USP. All results are acceptable and the reports containing the specific information are tabulated in Table 3.2.P.2.4-2. Testing was conducted using sterilized packaging components. The resins for the bottle, plug and closure are identical for all fabricators of packaging components. In addition, Alcon verifies that no processing aids are employed by stating this criteria on the specification sheet provided to the fabricator. 3.2.P.2.4 Container Closure System [Dorzolamide-Timolol Ophthalmic Solution], Page 2 CONFIDENTIAL PURSUANT TO THE PROTECTIVE ORDER AD DORZ-TIM EIKE001215 Case 3:12-cv-01141-SMY-DGW Document 176-11 *SEALED* Dorzolamide HC1 and Timolol Maleate Ophthalmic Solution Filed 12/01/14 Page 3 of 8 Case: 16-3334 Document:Page 55-26ID #2458 Filed: 02/08/2017 Pages: 8 (978 of 1511) Table 3.2.P.2.4-2 USP Testing of Packaging Components for Dorzolamide-Timolol Ophthalmic Solution Material Testing Report Number" White Dupont 20-6064 LDPEb - EtO Physicochemical 056:33700:1086 White Dupont 20-6064 LDPE - Gamma Physicochemical 125:38560:1094 White Dupont 20-6064 LDPE - EtO Toxicology 037:38520:0595 White Dupont 20-6064 LDPE - Gamma Toxicology 004:38520:0195 White Dupont 20-6064 LDPE - EtO Toxicology 048:38520:0595 White Dupont 20-6064 LDPE - Gamma Toxicology 005:38520:0195 White Dupont 20-6064 LDPE - EtO Toxicology 049:38520:0595 White Dupont 20-6064 LDPE - Gamma Toxicology 006:38520:0195 White Dupont 20-6064 LDPE - EtO Toxicology 050:38520:0595 White Dupont 20-6064 LDPE - Gamma Toxicology 007:38520:0195 White Dupont 20-6064 LDPE - EtO Toxicology 052:38520:0595 Natural Dupont 20-6064 LDPE - EtO Physicochemical 009:97:0402 Natural Dupont 20-6064 LDPE - Gamma Physicochemical 095:38560:1090 Natural Dupont 20-6064 LDPE - Gamma Toxicology 039:38520:0495 Natural Dupont 20-6064 LDPE - EtO Toxicology 058:38520:0595 Natural Dupont 20-6064 LDPE - Gamma Toxicology 040:38520:0495 Natural Dupont 20-6064 LDPE - EtO Toxicology 059:38520:0595 Natural Dupont 20-6064 LDPE - Gamma Toxicology 041:38520:0495 Natural Dupont 20-6064 LDPE - EtO Toxicology 060:38520:0595 Natural Dupont 20-6064 LDPE - Gamma Toxicology 042:38520:0495 Natural Dupont 20-6064 LDPE - EtO Toxicology 061:38520:0595 Natural Dupont 20-6064 LDPE - Gamma Toxicology 043:38520:0495 Natural Dupont 20-6064 LDPE - EtO Toxicology 062:38520:0595 Blue Basell Profax PF511 PP° - Gamma Physicochemical 019:38560:0390 Blue Basell Profax PF511 PP - Gamma Toxicology 044:38520:0690 Blue Basell Profax PF511 PP - Gamma Toxicology 045:38520:0690 aCopies can be found in the Appendix to Section 3.2.P.2.4 as Tabs 1 through 26. = low density polyethylene °PP = polypropylene bLDPE 3.2.P.2.4 Container Closure System [Dorzolamide-Timolol Ophthalmic Solution], Page 3 CONFIDENTIAL PURSUANT TO THE PROTECTIVE ORDER AD DORZ-TIM EIKE001216 Case 3:12-cv-01141-SMY-DGW 176-11 *SEALED* Dorzolamide HC1 and TimololDocument Maleate Ophthalmic Solution Filed 12/01/14 Page 4 of 8 Case: 16-3334 Document:Page 55-26ID #2459 Filed: 02/08/2017 Pages: 8 (979 of 1511) • Compatibility Testing Alcon has used the LDPE DROP-TAINER as a package for numerous ophthalmic solution products and, historically, this material does not produce significant levels of leachables. Leachables/Extractables Studies A study was conducted to evaluate leachables/extractables from the proposed packaging system (white 8 mL and 10 mL DROP-TAINERs) into Dorzolamide-Timolol Ophthalmic Solution as reported in Alcon Technical Report TDOC-0007485 (Appendix to Section 3.2.P.2.4, Tab 27). The product was heated within the complete primary packaging system then analyzed versus a negative control of the same solution heated in a glass ampoule and a positive control of normal saline solution exposed to the same packaging. Analyses were conducted using gas chromatography (GC) and high performance liquid chromatography (HPLC) to search for potential leachables from the packaging components. Solutions were tested using the complete primary packaging system including bottle, plug, closure and adhesive label. No leaching from the package components into Dorzolamide-Timolol Ophthalmic Solution above 2 ppm was observed in the study. • Performance Drop Size Evaluation The LDPE bottle is easy to squeeze due to its geometry and choice of resin material. A drop size study to simulate patient use of the product was conducted for Dorzolamide-Timolol Ophthalmic Solution. The drop size data indicate an average drop size of 44.5 mg with a standard deviation of ± 3.6 mg. This is equivalent to COSOPT delivering a drop size of 46 mg with a standard deviation of ± 6.4 mg. (see Figure 3.2.P.2.4-2). 3.2.P.2.4 Container Closure System [Dorzolamide-Timolol Ophthalmic Solution], Page 4 CONFIDENTIAL PURSUANT TO THE PROTECTIVE ORDER AD DORZ-TIM EIKE001217 Case 3:12-cv-01141-SMY-DGW 176-11 *SEALED* Dorzolamide HC1 and TimololDocument Maleate Ophthalmic Solution Filed 12/01/14 Page 5 of 8 Case: 16-3334 Document:Page 55-26ID #2460 Filed: 02/08/2017 Pages: 8 (980 of 1511) Figure 3.2.P.2.4-2 Drop Size Evaluation of Dorzolamide-Timolol Ophthalmic Solution • Cosopt -iw-i'DoffiSlorWeNW Ti(fiol )f ftifele^te: 55 50 • • ' * . • * " * 45 ' • :1 * : ' ># '-•'I >+:* ' * * • • M §TJiTj i '' i': N <75 §" 35 a \ 30 25 20 4 \ ] <3 j i- i \& \ i i s : ; • : :- - j Drop Number (bN <& <£> i s : ; 12 3.2.P.2.4 Container Closure System [Dorzolamide-Timolol Ophthalmic Solution], Page 6 CONFIDENTIAL PURSUANT TO THE PROTECTIVE ORDER AD DORZ-TIM EIKE001219 Case 3:12-cv-01141-SMY-DGW 176-11 *SEALED* Dorzolamide HC1 and TimololDocument Maleate Ophthalmic Solution Filed 12/01/14 Page 7 of 8 Case: 16-3334 Document:Page 55-26ID #2462 Filed: 02/08/2017 Pages: 8 (982 of 1511) Contents Item Tab Alcon Technical Report 095:38560:1090 Evaluation of Dupont 20-6064, Gamma Irradiated, Low Density Polyethylene, 10 mL Natural DROP-TAINERS® According USP XXII, Physicochemical Tests-Plastics 13 Alcon Technical Report 039:38520:0495 Agar Diffusion test with Gamma Sterilized Dupont 20-6064 LDPE Natural DROPTAINERS 14 Alcon Technical Report 058:38520:0595 Agar Diffusion Test with EtO Sterilized Natural Polyethylene Plugs 15 Alcon Technical Report 040:38520:0495 Elution Test with Gamma Sterilized Dupont 20-6064 LDPE Natural DROP-TAINERS 16 Alcon Technical Report 059:38520:0595 Elution Test with EtO Sterilized Natural Polyethylene Plugs 17 Alcon Technical Report 041:38520:0495 Acute Systemic Toxicity in Mice with Extracts of Gamma Sterilized Dupont 20-6064 LDPE Natural DROP-TAINERS 18 Alcon Technical Report 060:38520:0595 Acute Systemic Toxicity in Mice with Extracts of EtO Sterilized Natural Polyethylene Plugs 19 Alcon Technical Report 042:38520:0495 Intracutaneous Reactivity Test in Albino Rabbits with Extracts of Gamma Sterilized Dupont 20-6064 LDPE Natural DROP-TAINERS 20 Alcon Technical Report 061:38520:0595 21 Intracutaneous Reactivity Test in Albino Rabbits with Extracts of EtO Sterilized Natural Sterilized Natural Polyethylene Plugs Alcon Technical Report 043:38520:0495 22 Primary Ocular Irritaition in Rabbits with Extracts of Gamma Setrilized Dupont 20-6064 LDPE Natural DROP-TAINERS. Alcon Technical Report 062:38520:0595 23 Primary Ocular Irritation in Rabbits with Extracts of EtO Sterilized Natural Polyethylene Plugs Alcon Technical Report 019:38560:0390 Evaluation of Gamma Irradiated Himont PF511 and Eastman 984A Blue Polypropylene Closures for use with Betoptic DROP-TAINERS 24 3.2.P.2.4 Container Closure System [Dorzolamide-Timolol Ophthalmic Solution], Page 7 CONFIDENTIAL PURSUANT TO THE PROTECTIVE ORDER AD DORZ-TIM EIKE001220 Case 3:12-cv-01141-SMY-DGW 176-11 *SEALED* Dorzolamide HC1 and TimololDocument Maleate Ophthalmic Solution Filed 12/01/14 Page 8 of 8 Case: 16-3334 Document:Page 55-26ID #2463 Filed: 02/08/2017 Pages: 8 (983 of 1511) Contents Item Tab Alcon Technical Report 044:38520:0690 Agar Overlay Test of Gamma Irradiated Himont Red, Blue, Green and White Polypropylene Closures 25 Alcon Technical Report 045:38520:0690 Agar Overlay Test of Gamma Irradiated Eastman Red, Blue, Green and White Polypropylene Closures 26 Alcon Technical Report TDOC-0007485 Package Leaching Study for Dorzolamide/Timolol Ophthalmic Solution FID 111894 27 3.2.P.2.4 Container Closure System [Dorzolamide-Timolol Ophthalmic Solution], Page 8 CONFIDENTIAL PURSUANT TO THE PROTECTIVE ORDER AD DORZ-TIM EIKE001221 Case 3:12-cv-01141-SMY-DGW Document 176-37 *SEALED* Filed 12/01/14 Page 1 of 2 Case: 16-3334 Document:Page 55-27ID #3277 Filed: 02/08/2017 Pages: 2 (984 of 1511) Case 3:12-cv-01141-SMY-DGW Document 176-37 *SEALED* Filed 12/01/14 Page 2 of 2 Case: 16-3334 Document:Page 55-27ID #3278 Filed: 02/08/2017 Pages: 2 (985 of 1511) Case 3:12-cv-01141-SMY-DGW Document 176-12 *SEALED* Filed 12/01/14 Page 1 of 22 Page ID #2464 Case: 16-3334 Document: 55-28 Filed: 02/08/2017 Pages: 22 (986 of 1511) o "-G o k) -i O C A C\ 5 ZA a 3 3 sr o —1 CONFIDENTIAL PURSUANT TO THE PROTECTIVE ORDER AD LATANOPROST EIKE000121 Case 3:12-cv-01141-SMY-DGW Document 176-12 *SEALED* Filed 12/01/14 Page 2 of 22 Latanoprost ANDA Page ID #2465 Case: 16-3334 Document: 55-28 Filed: 02/08/2017 Pages: 22 (987 of 1511) 3.2.P.2.4. Container Closure System [Latanoprost Ophthalmic Solution] Choice of Materials The package system selected is appropriately sized for the desired label claim and is easy to squeeze due to its shape and resin characteristics. Latanoprost Ophthalmic Solution will be packaged in Alcon's standard DROP-TAINER® packaging system (see Table 3.2.P.2.4-1 and Figure 3.2.P.2.4-1). This system consists of a low density polyethylene (LDPE) bottle and dispensing plug and a polypropylene (PP) closure. A natural DROP-TAINER with turquoise closure was selected to resemble the container of the innovator product, Xalatan, marketed by Pharmacia and Upjohn Company. The bottle and plug are sterilized by ethylene oxide, and the closure by gamma irradiation. Each bottle will be labeled with a pressure sensitive label. Tamper evidence is provided through the use of a shrink band around the neck and closure area of the bottle. The product will be packaged with a labeled fill volume of 2.5 mL in 4 mL bottles. Table 3.2.P.2.4-1 Packaging System for Latanoprost Ophthalmic Solution Component Materiala 4 mL Natural Bottlesb Dupont 20-6064 LDPE c I Natural Dispensing Plug Dupont 20-6064 LDPE I Turquoise Closure" I Pressure Sensitive Label a These Basell Profax PF-511 PPd Paper Label with Greenbay P508 Adhesive materials are currently used in a number of currently approved Alcon ophthalmic products (including ANDA 78-031 for Diclofenac Ophthalmic Solution, ANDA 78-222 for Ofloxacin Otic Solution and ANDA 76-231 for Ofloxacin Ophthalmic Solution). b The bottle color will be natural and the closure color will be turquoise to resemble the container of the innovator product, Xalatan, marketed by Pharmacia and Upjohn Company. c Low density polyethylene d Polypropylene 3.2.P.2.4. Container Closure System [Latanoprost Ophthalmic Solution], Page 1 CONFIDENTIAL PURSUANT TO THE PROTECTIVE ORDER AD LATANOPROST EIKE000122 Case 3:12-cv-01141-SMY-DGW Document 176-12 *SEALED* Filed 12/01/14 Page 3 of 22 Latanoprost AN DA Page ID #2466 Case: 16-3334 Document: 55-28 Filed: 02/08/2017 Pages: 22 (988 of 1511) Figure 3.2.P.2.4-1 Packaging System for Latanoprost Ophthalmic Solution I 1 ?—S • Safety of Materials - USP Testing The resins used in the packaging components for Latanoprost Ophthalmic Solution have been previously approved for use in numerous ophthalmic products marketed by Alcon and have been subjected to USP physicochemical and toxicological testing in accordance with the USP. All results are acceptable and the reports containing the specific information are tabulated in Table 3.2.P.2.4-2. Testing was conducted using sterilized packaging components. The resins for the bottle, plug and closure are identical for all fabricators of packaging components. In addition, Alcon verifies that no processing aids are employed by stating this criteria on the specification sheet provided to the fabricator. 3.2.P.2.4. Container Closure System [Latanoprost Ophthalmic Solution], Page 2 CONFIDENTIAL PURSUANT TO THE PROTECTIVE ORDER AD LATANOPROST EIKE000123 Case 3:12-cv-01141-SMY-DGW Document 176-12 *SEALED* Filed 12/01/14 Page 4 of 22 Latanoprost ANDA Page ID #2467 Case: 16-3334 Document: 55-28 Filed: 02/08/2017 Pages: 22 (989 of 1511) Table 3.2.P.2.4-2 USP Testing of Packaging Components for Latanoprost Ophthalmic Solution Material Testing Report Number® Natural Dupont 20-6064 LDPEb - EtO Physicochemical 009:97:0402 Natural Dupont 20-6064 LDPE - EtO Toxicology 058:38520:0595 Natural Dupont 20-6064 LDPE - EtO Toxicology 059:38520:0595 Natural Dupont 20-6064 LDPE - EtO Toxicology 060:38520:0595 Natural Dupont 20-6064 LDPE - EtO Toxicology 061:38520:0595 Natural Dupont 20-6064 LDPE - EtO Toxicology 062:38520:0595 Turquoise Basell Profax PF511 PPC - Gamma Physicochemical TDOC-0009409 Turquoise Basell Profax PF511 PP - Gamma Toxicology TDOC-0009446 Turquoise Basell Profax PF511 PP - Gamma Toxicology TDOC-0009447 Turquoise Basell Profax PF511 PP - Gamma Toxicology TDOC-OOQ9449 Turquoise Basell Profax PF511 PP - Gamma Toxicology TDOC-0009450 Turquoise Basell Profax PF511 PP - Gamma Toxicology TDOC-0009451 "Copies can be found in the Appendix to Section 3.2.P.2.4 as Tabs 1 through 12. h LDPE = low density polyethylene c PP = polypropylene • Compatibility Testing Alcon has used the LDPE DROP-TAINER as a package for numerous ophthalmic solution products and, historically, this material does not produce significant levels of leachables. Leachables/Extractables Studies A study was conducted to evaluate leachables/extractables from the proposed packaging system (natural 4 mL DROP-TAESEERs) into Latanoprost Ophthalmic Solution as reported in Alcon Technical Report TDOC-0009331 (Appendix to Section 3.2.P.2.4, Tab 13). The product was heated within the complete primary packaging system then analyzed versus a negative control of the same solution heated in a glass container and positive controls of normal saline solution exposed to the same packaging. Analyses were conducted using gas chromatography (GC) and high performance liquid chromatography (HPLC) to search for potential leachates from the packaging components. Solutions were tested using the complete 3.2.P.2.4. Container Closure System [Latanoprost Ophthalmic Solution], Page 3 CONFIDENTIAL PURSUANT TO THE PROTECTIVE ORDER AD LATANOPROST EIKE000124 Case 3:12-cv-01141-SMY-DGW Document 176-12 *SEALED* Filed 12/01/14 Page 5 of 22 Latanoprost ANDA Page ID #2468 Case: 16-3334 Document: 55-28 Filed: 02/08/2017 Pages: 22 (990 of 1511) primary packaging system including bottle, plug, closure and adhesive label. No significant leaching from the package components into the Latanoprost Ophthalmic Solution was observed using HPLC, polar or non-polar GC. • Performance Drop Size Evaluation The LDPE bottle is easy to squeeze due to its geometry and choice of resin material. A drop size study to simulate patient use of the product was conducted for Latanoprost Ophthalmic Solution. The drop size data indicate an average drop size of 28.4 mg with a standard deviation of ± 2.2 mg. This is equivalent to Xalatan delivering a drop size of 31.8 mg with a standard deviation of ± 2.9 mg (see Figure 3.2.P.2.4-2). Figure 3.2.P.2.4-2 Drop Size Evaluation of Latanoprost Ophthalmic Solution : 3.2.P.2.4. Container Closure System [Latanoprost Ophthalmic Solution], Page 4 CONFIDENTIAL PURSUANT TO THE PROTECTIVE ORDER AD LATANOPROST EIKE000125 Case 3:12-cv-01141-SMY-DGW Document 176-12 *SEALED* Filed 12/01/14 Page 6 of 22 Latanoprost ANDA Page ID #2469 Case: 16-3334 Document: 55-28 Filed: 02/08/2017 Pages: 22 (991 of 1511) Maintenance of Sterility The microbiological attributes of the packaging system for Latanoprost Ophthalmic Solution are described in Module 3, Section 3.2.P.2.5. 3.2.P.2.4. Container Closure System [Latanoprost Ophthalmic Solution], Page 5 CONFIDENTIAL PURSUANT TO THE PROTECTIVE ORDER AD_LATANOPROST_EIKE000126 Case 3:12-cv-01141-SMY-DGW Document 176-12 *SEALED* Filed 12/01/14 Page 7 of 22 Latanoprost ANDA Page ID #2470 Case: 16-3334 Document: 55-28 Filed: 02/08/2017 Pages: 22 (992 of 1511) Appendix to Section 3.2.P.2.4 Contents Item Tab Alcon Technical Report 009:97:0402 Physiocochemical Testing of EtO Sterilized 15 mm Natural LDPE Plugs, Part No. 279087, Using USP 25 <661> 1 Alcon Technical Report 058:38520:0595 Agar Diffusion Test with EtO Sterilized Natural Polyethylene Plugs 2 Alcon Technical Report 059:38520:0595 Elution Test with EtO Sterilized Natural Polyethylene Plugs 3 Alcon Technical Report 060:38520:0595 Acute Systemic Toxicity in Mice with Extracts of EtO Sterilized Natural Polyethylene Plugs 4 Alcon Technical Report 061:38520:0595 5 Intracutaneous Reactivity Test in Albino Rabbits with Extracts of EtO Sterilized Natural Sterilized Natural Polyethylene Plugs Alcon Technical Report 062:38520:0595 6 Primary Ocular Irritation in Rabbits with Extracts of EtO Sterilized Natural Polyethylene Plugs Alcon Technical Report TDOC-0009409 Evaluation of Gamma Sterilized Turquoise 15 mm Polypropylene Closures Lot IF38003G According to USP <661> Physicochemical Tests - Plastics 7 Alcon Technical Report TDOC-0009446 Agar Diffusion Cytotoxicity Test with Closure: Basell Profax PF511 PP, Turquoise PolyOne CC00001476 (P/N X-6483) [gamma sterilized] 8 Alcon Technical Report TDOC-0009447 9 L929 MEM Elution Cytotoxicity Test with Closure: Basell Profax PF511 PP, Turquoise PolyOne CC00001476 (P/N X-6483) [gamma sterilized] Alcon Technical Report TDOC-0009449 Acute Systemic Toxicity Test (Systemic Injection) with Extracts of Closure: Basell Profax PF511 PP, Turquoise PolyOne CC00001476 (P/N X-6483) [gamma sterilized] 10 Alcon Technical Report TDOC-0009450 11 Intracutaneous Irritation Test (Intracutaneous Injection) with Extracts of Closure: Basell Profax PF511 PP, Turquoise PolyOne CC00001476 (P/N X-6483) [gamma sterilized] 3.2.P.2.4. Container Closure System [Latanoprost Ophthalmic Solution], Page 6 CONFIDENTIAL PURSUANT TO THE PROTECTIVE ORDER AD LATANOPROST EIKE000127 Case 3:12-cv-01141-SMY-DGW Document 176-12 *SEALED* Filed 12/01/14 Page 8 of 22 Latanoprost ANDA Page ID #2471 Case: 16-3334 Document: 55-28 Filed: 02/08/2017 Pages: 22 (993 of 1511) Appendix to Section 3.2.P.2.4 (continued) Contents Item Tab Alcon Technical Report TDOC-0009451 Primary Ocular Irritation Test with Extracts of Closure: Basell Profax PF511 PP, Turquoise PolyOne CC00001476 (P/N X-6483) [gamma sterilized] 12 Alcon Technical Report TDOC-0009331 Package Leaching Study for Latanoprost Ophthalmic Solution, 0.005%, FID 101547 13 3.2.P.2.4. Container Closure System [Latanoprost Ophthalmic Solution], Page 7 CONFIDENTIAL PURSUANT TO THE PROTECTIVE ORDER AD LATANOPROST EIKE000128 Case 3:12-cv-01141-SMY-DGW Document 176-12 *SEALED* Filed 12/01/14 Page 9 of 22 ANDA Latanoprost Page ID #2472 Case: 16-3334 Document: 55-28 Filed: 02/08/2017 Pages: 22 (994 of 1511) Module 3 Table of Contents Volume - Module Tab Identifier 3.1 Table of Contents Vol. 1, Module 3 3.2 Body of Data Vol. 1, Module 3 3.2.S Drug Substances (Latanoprost) Vol. 1, Module 3 3.2.S Drug Substance (Latanoprost, Chirogate) Vol. 1, Module 3 3.2.5.1 General Information (Latanoprost, Chirogate) Vol. 1, Module 3 3.2.5.1.1 Nomenclature (Latanoprost, Chirogate) 3.2.5.1.2 Structure (Latanoprost, Chirogate) 3.2.5.1.3 General Properties (Latanoprost) Vol. 1, Module 3 Vol. 1, Module 3 Vol. 1, Module 3 3.2.5.2 Manufacture (Latanoprost, Chirogate) • Vol. 1, Module 3 3.2.S.2.1 Manufacturers) (Latanoprost, Chirogate) 3.2.5.2.2 Description of Manufacturing Process and Process Controls (Latanoprost, Chirogate) Tab 1 Chirogate Latanoprost Synthesis Scheme 3.2.S.3.1 Elucidation of Structure and Other Characteristics (Latanoprost, Chirogate) Tab 1 TDOC-0009438 Vol. 1, Module 3 Vol. 1, Module 3 3.2.5.2.3 Control of Materials (Latanoprost, Chirogate) 3.2.5.2.4 Controls of Critical Steps and Intermediates (Latanoprost, Chirogate) 3.2.5.2.5 Process Validation and/or Evaluation (Latanoprost, Chirogate) 3.2.5.2.6 Manufacturing Process Development (Latanoprost, Chirogate) 3.2.5.3 Characterization (Latanoprost, Chirogate) Vol. 1, Module 3 Vol. 1, Module 3 Vol. 1, Module 3 Vol. 1, Module 3 Vol. 1, Module 3 Vol. 1, Module 3 Vol. 1, Module 3 Vol. 1, Module 3 3.1 Table of Contents, Page 1 CONFIDENTIAL PURSUANT TO THE PROTECTIVE ORDER AD LATANOPROST EIKE000129 Case 3:12-cv-01141-SMY-DGW Document 176-12 *SEALED* Filed 12/01/14 Page 10 of 22 Latanoprost Page ID #2473 ANDA Case: 16-3334 Document: 55-28 Filed: 02/08/2017 Pages: 22 (995 of 1511) Module 3- Table of Contents - Continued Tab Identifier Volume - Module Vol. 1, Module 3 3.2.S.3.2 Impurities (Latanoprost, Chirogate) Vol. 1, Module 3 Tab 1 PROC-0004011 3.2.5.4 Control of Drug Substance (Latanoprost, Chirogate) Vol. 1, Module 3 3.2.5.4.1 Specification (Latanoprost, Chirogate) Vol. 1, Module 3 Vol. 1, Module 3 Tab 1 PROC-0001745 3.2.5.4.2 Analytical Procedures (Latanoprost, Chirogate) Vol. 1, Module 3 Vol. 1, Module 3 Vol. 1, Module 3 Tab 1 PROC-0001744 Tab 2 PROC-0004799 • 3.2.5.4.3 Validation of Analytical Procedures (Latanoprost, Chirogate) 3.2.5.4.4 Batch Analyses (Latanoprost, Chirogate) Tab 1 Chirogate Lantanoprost Certificates Tab 2 Alcon Latanoprost Certificates... 3.2.5.4.5 Justification of Specifications (Latanoprost, Chirogate) 3.2.5.5 Reference Standards or Materials (Latanoprost, Chirogate) Tab 1 TDOC-0008158 3.2.5.6 Container Closure System (Latanoprost, Chirogate) 3.2.5.7 Stability (Latanoprost, Chirogate) 3.2.5.7.1 Stability Summary and Conclusions (Latanoprost, Chirogate) 3.2.5.7.2 Post-approval Stability Protocol and Stability Commitment (Latanoprost, Chirogate) 3.2.5.7.3 Stability Data (Latanoprost, Chirogate) Vol. 1, Module 3 Vol. 1, Module 3 Vol. 1, Module 3 Vol. 1, Module 3 Vol. 1, Module 3 Vol. 1, Module 3 Vol. 1, Module 3 Vol. 1, Module 3 Vol. 1, Module 3 Vol. 1, Module 3 Vol. 1, Module 3 Vol. 1, Module 3 3.1 Table of Contents, Page 2 CONFIDENTIAL PURSUANT TO THE PROTECTIVE ORDER AD LATANOPROST EIKE000130 Case 3:12-cv-01141-SMY-DGW Document 176-12 *SEALED* Filed 12/01/14 Page 11 of 22 ANDA Latanoprost Page ID #2474 Case: 16-3334 Document: 55-28 Filed: 02/08/2017 Pages: 22 (996 of 1511) Module 3- Table of Contents - Continued Tab Identifier Volume - Module Vol.2 Module 3 3.2.P Drug Product [Latanoprost Ophthalmic Solution] 3.2.P.1 Description and Composition of the Drug Product [Latanoprost Ophthalmic Solution] 3.2.P.2 Pharmaceutical Development [Latanoprost Ophthalmic Solution] Vol.2 Module 3 Vol.2 Module 3 3.2.P.2.1 Components of the Drug Product [Latanoprost Ophthalmic Solution] 3.2.P.2.2 Drug Product [Latanoprost Ophthalmic Solution] Vol.2 Module 3 Vol.2 Module 3 Tab 1 TDOC-0008877 3.2.P.2.3 Manufacturing Process Development [Latanoprost Ophthalmic Solution] 3.2.P.2.4 Container Closure System [Latanoprost Ophthalmic Solution] Tab 1 009:97:0402 Tab 2 058:38520:0595 Tab 3 059:38520:0595 Tab 4 060:38520:0595 Tab 5 061:38520:0595 Tab 6 062:38520:0595 Tab 7 TDOC-0009409 Tab 8 TDOC-0009446 Tab 9 TDOC-0009447 Tab 10 TDOC-0009449 Tab 11 TDOC-0009450 Tab 12 TDOC-0009451 Tab 13 TDOC-0009331 3.2.P.2.5 Microbiological Attributes [Latanoprost Ophthalmic Solution] Tab 1 TDOC-0007660 Tab 2 TDOC-0009429 Tab 3 TDOC-0009389 Tab 4 TDOC-0007147 Tab 5 TDOC-0009469 Vol.2 Module 3 Vol.2 Module 3 Vol.2 Module 3 Vol.2 Vol.2 Vol. 2 Vol.2 Vol.2 Vol.2 Vol.2 Vol.2 Vol.2 Vol. 2 Vol.2 Vol.2 Vol. Module 3 Module 3 Module 3 Module 3 Module 3 Module 3 Module 3 Module 3 Module 3 Module 3 Module 3 Module 3 Module 3 Vol.2 Module 3 Vol.2 Vol.2 Vol.2 Vol.2 Vol.2 Module 3 Module 3 Module 3 Module 3 Module 3 3.1 Table of Contents, Page 3 CONFIDENTIAL PURSUANT TO THE PROTECTIVE ORDER AD_LATANOPROST_EIKEOOQ131 Case 3:12-cv-01141-SMY-DGW Document 176-12 *SEALED* Filed 12/01/14 Page 12 of 22 Page ID #2475 Latanoprost ANDA Case: 16-3334 Document: 55-28 Filed: 02/08/2017 Pages: 22 (997 of 1511) Module 3 - Table of Contents - Continued Tab Identifier Volume - Module 3.2.P.2.6 Compatibility [Latanoprost Ophthalmic Solution] Vol. 3, Module 3 3.2.P.3 Manufacture [Latanoprost Ophthalmic Solution] 3.2.P.3.1 Manufacturers) [Latanoprost Ophthalmic Solution] 3.2.P.3.2 Batch Formula [Latanoprost Ophthalmic Solution] 3.2.P.3.3 Description of Manufacturing Process and Process Controls [Latanoprost Ophthalmic Solution] Vol. 3, Module 3 Vol. 3, Module 3 Vol. 3, Module 3 Vol. 3, Module 3 Vol. 3, Module 3 Tab 1 Blank Batch Record 3.2.P.3.4 Controls of Critical Steps and Intermediates [Latanoprost Ophthalmic Solution] 3.2.P.3.5 Process Validation and/or Evaluation [Latanoprost Ophthalmic Solution]..... Vol. 3, Module 3 Vol. 3, Module 3 3.2.P.4 Control of Excipients [Latanoprost Ophthalmic Solution] Vol. 3, Module 3 3.2.P.4.1 Specifications [Latanoprost Ophthalmic Solution] Vol. 3, Module 3 Tab 1 Supplier Excipient CertificatesTab 2 Residual Solvents (BAC) Tab 3 Residual Solvents (Dibasic Sod Phosphate) Tab 4 Residual Solvents (Monobasic Sod Phosphate) Tab 5 Residual Solvents (Sodium Chloride) 3.2.P.4.2 Analytical Procedures 3.2.P.4.3 Validation of Analytical Procedures 3.2.P.4.4 Justification of Specifications Tab 1 Alcon Excipient Certificates 3.2.P.4.5 Excipients of Human or Animal Origin [Latanoprost Ophthalmic Solution] Novel Excipients [Latanoprost 3.2.P.4.6 Solution] Vol. 3, Module 3 Vol. 3, Module 3 Vol. 3, Module 3 Vol. 3, Module 3 Vol. 3, Module 3 Vol. 3, Module 3 Vol. 3, Module 3 Vol. 3, Module 3 Vol. 3, Module 3 Vol. 3, Module 3 Vol. 3, Module 3 3.1 Table of Contents, Page 4 CONFIDENTIAL PURSUANT TO THE PROTECTIVE ORDER AD_LATANOPROST_EIKEOOQ132 Case 3:12-cv-01141-SMY-DGW Document 176-12 *SEALED* Filed 12/01/14 Page 13 of 22 Page ID #2476 AN DA Latanoprost Case: 16-3334 Document: 55-28 Filed: 02/08/2017 Pages: 22 (998 of 1511) Module 3 - Table of Contents - Continued Tab Identifier Volume - Module 3.2.P.5 Control of Drug Product [Latanoprost Ophthalmic Solution] Vol. 3, Module 3 3.2.P.5.1 Specification(s) [Latanoprost Ophthalmic Solution] 3.2.P.5.2 Analytical Procedures [Latanoprost Ophthalmic Solution] - Vol. 3, Module 3 Vol. 4, Module 3 Tab 1 FWMDOC-12477 Tab 2 PROC-0004456 Tab 3 FWMDOC-04847 Tab 4 PROC-0001746 Tab 5 FWMDOC-02848 Tab 6 PROC-0000447 Tab 7 FWMDOC-02850 Tab 8 PROC-0000448 Tab 9 FWMDOC-02868 Tab 10 PROC-0001329 Tab 11 FWMDOC-02869 Tab 12 PROC-0000580 Tab 13 PROC-0000436 Tab 14 FWMDOC-00792 Tab 15 PROC-0000883 Tab 16 FWMDOC-00392 Tab 17 PROC-0001124 Tab 18 FWMDOC-O1692 Vol. 4, Module 3 Vol. 4, Module 3 Vol. 4, Module 3 Vol. 4, Module 3 Vol. 4, Module 3 Vol. 4, Module 3 Vol. 4, Module 3 Vol. 4, Module 3 Vol. 4, Module 3 Vol. 4, Module 3 Vol. 4, Module 3 Vol. 4, Module 3 Vol. 4, Module 3 Vol. 4, Module 3 Vol. 4, Module 3 Vol. 4, Module 3 Vol. 4, Module 3 Vol. 4, Module 3 3.2.P.5.3 Validation of Analytical Procedures [Latanoprost Ophthalmic Solution].. Vol. 4, Module 3 Tab 1 TDOC-0007590 Tab 2 TDOC-0006825 3.2.P.5.4 Batch Analyses [Latanoprost Ophthalmic Solution] Tab 1 Alcon Drug Product Certificates Vol. 4, Module 3 Vol. 4, Module 3 Vol. 4, Module 3 Vol. 4, Module 3 3.1 Table of Contents, Page 5 CONFIDENTIAL PURSUANT TO THE PROTECTIVE ORDER AD LATANOPROST EIKE000133 Case 3:12-cv-01141-SMY-DGW Document 176-12 *SEALED* Filed 12/01/14 Page 14 of 22 Page ID #2477 Latanoprost ANDA Case: 16-3334 Document: 55-28 Filed: 02/08/2017 Pages: 22 (999 of 1511) Module 3 - Table of Contents - Continued Tab Identifier Volume - Module 3.2.P.5.5 Characterization of Impurities [Latanoprost Ophthalmic Solution]... Vol. 4, Module 3 Tab 1 TDOC-0009463 3.2.P.5.6 Justification of Specification(s) [Latanoprost Ophthalmic Solution]... 3.2.P.6 Reference Standards or Materials [Latanoprost Ophthalmic Solution] 3.2.P.7 Container Closure System [Latanoprost Ophthalmic Solution] Tab 1 Packaging DMF Letters Tab 2 Packaging Component Certificates Tab 3 FWMDOC-02925 Tab 4 FWMDOC-00825 3.2.P.8 Stability [Latanoprost Ophthalmic Solution] 3.2.P.8.1 Stability Summary and Conclusion [Latanoprost Ophthalmic Solution] Tab 1 PROC-0001316 Tab 2 PROC-OOOl 137 3.2.P.8.2 Post-approval Stability Protocol and Stability Commitment [Latanoprost Ophthalmic Solution] 3.2.P.8.3 Stability Data [Latanoprost Ophthalmic Solution] Tab 1 TDOC-0009276 Tab 2 Exhibit Batch Stability Data Tab 3 Xalatan Stability Data Vol. 4, Module 3 Vol. 4, Module 3 Vol. 4, Module 3 Vol. 4, Module 3 Vol. 4, Module 3 Vol. 4, Module 3 Vol. 4, Module 3 Vol. 5, Module 3 Vol. 5, Module 3 Vol. 5, Module 3 Vol. 5, Module 3 Vol. 5, Module 3 Vol. 5, Module 3 Vol. 5, Module 3 Vol. 5, Module 3 Vol. 5, Module 3 Vol. 5, Module 3 3.2.A Appendices 3.2.A.1 Facilities and Equipment 3.2.A.2 Adventitious Agents Safety Evaluation 3.2.A.3 Novel Excipients 3.2.R Regional Information 3.2.R.1.S 3.2.R.2.S Vol. 4, Module 3 Executed Batch Record - Drug Substance Comparability Protocols Vol. 5, Module 3 Vol. 5, Module 3 Vol. 5, Module 3 Vol. 5, Module 3 Vol. 5, Module 3 Vol. 5, Module 3 3.1 Table of Contents , Page 6 CONFIDENTIAL PURSUANT TO THE PROTECTIVE ORDER AD LATANOPROST EIKE000134 Case 3:12-cv-01141-SMY-DGW Document 176-12 *SEALED* Filed 12/01/14 Page 15 of 22 Latanoprost ANDA Page ID #2478 Case: 16-3334 Document: 55-28 Filed: 02/08/2017 Pages: 22 (1000 of 1511) Module 3 - Table of Contents - Continued Tab Identifier 3.2.R.3.S Volume - Module Methods Validation Package Vol. 5, Module 3 Tab 1 Drug Substance Validation Package.... Vol. 5, Module 3 3.2.R.1.P.1 Executed Batch Record - Drag Product Tab 1 Executed Batch Record Vol. 5, Module 3 Vol. 5, Module 3 3.2.R.1.P.2 Information on Components Vol. 6, Module 3 3.2.R.2.P 3.2.R.3.P Comparability Protocols Methods Validation Package Vol. 6, Module 3 Vol. 6, Module 3 Tab 1 Drug Product Validation Package Vol. 6, Module 3 3.3 Literature References Vol. 6, Module 3 3.1 Table of Contents, Page 7 CONFIDENTIAL PURSUANT TO THE PROTECTIVE ORDER AD LATANOPROST EIKE000135 Case 3:12-cv-01141-SMY-DGW Document 176-12 *SEALED* Filed 12/01/14 Page 16 of 22 AM) A Latanoprost Page ID #2479 Case: 16-3334 Document: 55-28 Filed: 02/08/2017 Pages: 22 (1001 of 1511) Module 3 Table of Contents Tab Identifier Volume - Module 3.1 Table of Contents Vol. 1, Module 3 3.2 Body of Data Vol. 1, Module 3 3.2.S Drug Substances (Latanoprost) Vol. 1, Module 3 3.2.S Drag Substance (Latanoprost, Chirogate) Vol. 1, Module 3 3.2.S.1 General Information (Latanoprost, Chirogate) 3.2.S.1.1 Nomenclature (Latanoprost, Chirogate) 3.2.S.1.2 Structure (Latanoprost, Chirogate) 3.2.S.1.3 General Properties (Latanoprost) Vol. 1, Module 3 3.2.5.2 Manufacture (Latanoprost, Chirogate) Vol. 1, Module 3 Vol. 1, Module 3 Vol. 1, Module 3 Vol. 1, Module 3 3.2.5.2.1 Manufacturers) (Latanoprost, Chirogate) 3.2.5.2.2 Description of Manufacturing Process and Process Controls (Latanoprost, Chirogate) Tab 1 Chirogate Latanoprost Synthesis Scheme Vol. 1, Module 3 Vol. 1, Module 3 3.2.5.2.3 Control of Materials (Latanoprost, Chirogate) 3.2.5.2.4 Controls of Critical Steps and Intermediates (Latanoprost, Chirogate) 3.2.5.2.5 Process Validation and/or Evaluation (Latanoprost, Chirogate) 3.2.5.2.6 Manufacturing Process Development (Latanoprost, Chirogate) 3.2.5.3 Characterization (Latanoprost, Chirogate) Vol. 1, Module 3 Vol. 1, Module 3 Vol. 1, Module 3 Vol. 1, Module 3 Vol. 1, Module 3 Vol. 1, Module 3 3.2.S.3.1 Elucidation of Structure and Other Characteristics (Latanoprost, Chirogate) Vol. 1, Module 3 Tab 1 TDOC-0009438 Vol. 1, Module 3 3.1 Table of Contents, Page 1 CONFIDENTIAL PURSUANT TO THE PROTECTIVE ORDER AD LATANOPROST EIKE000136 Case 3:12-cv-01141-SMY-DGW Document 176-12 *SEALED* Filed 12/01/14 Page 17 of 22 Page ID #2480 Latanoprost AN DA Case: 16-3334 Document: 55-28 Filed: 02/08/2017 Pages: 22 (1002 of 1511) Module 3 - Table of Contents - Continued Tab Identifier Volume - Module 3.2.S.3.2 Impurities (Latanoprost, Chirogate) Vol. 1, Module 3 Tab 1 PROC-0004011 Vol. 1, Module 3 3.2.5.4 Control of Drug Substance (Latanoprost, Chirogate) Vol. 1, Module 3 3.2.5.4.1 Specification (Latanoprost, Chirogate) Vol. 1, Module 3 Tab 1 PROC-OOO1745 Vol. 1, Module 3 3.2.5.4.2 Analytical Procedures (Latanoprost, Chirogate) Vol. 1, Module 3 Tab 1 PROC-OOO1744 Tab 2 PROC-0004799 Vol. 1, Module 3 Vol. 1, Module 3 3.2.5.4.3 Validation of Analytical Procedures (Latanoprost, Chirogate) 3.2.5.4.4 Batch Analyses (Latanoprost, Chirogate) Jjfc Vol. 1, Module 3 Vol. 1, Module 3 Tab 1 Chirogate Lantanoprost Certificates Tab 2 Alcon Latanoprost Certificates... • Vol. 1, Module 3 Vol. 1, Module 3 3.2.5.4.5 Justification of Specifications (Latanoprost, Chirogate) Vol. 1, Module 3 3.2.5.5 Reference Standards or Materials (Latanoprost, Chirogate) Vol. 1, Module 3 Tab 1 TDOC-OOO8158 3.2.5.6 Container Closure System (Latanoprost, Chirogate) 3.2.5.7 Stability (Latanoprost, Chirogate) 3.2.5.7.1 Stability Summary and Conclusions (Latanoprost, Chirogate) 3.2.5.7.2 Post-approval Stability Protocol and Stability Commitment (Latanoprost, Chirogate) 3.2.5.7.3 Stability Data (Latanoprost, Chirogate) Vol. 1, Module 3 Vol. 1, Module 3 Vol. 1, Module 3 Vol. 1, Module 3 Vol. 1, Module 3 Vol. 1, Module 3 • 3.1 Table of Contents, Page 2 CONFIDENTIAL PURSUANT TO THE PROTECTIVE ORDER AD LATANOPROST EIKE000137 Case 3:12-cv-01141-SMY-DGW Document 176-12 *SEALED* Filed 12/01/14 Page 18 of 22 Page ID #2481 Latanoprost ANDA Case: 16-3334 Document: 55-28 Filed: 02/08/2017 Pages: 22 (1003 of 1511) Module 3- Table of Contents - Continued Tab Identifier Volume - Module Vol.2 Module 3 3.2.P Drug Product [Latanoprost Ophthalmic Solution] 3.2.P.1 Description and Composition of the Drug Product [Latanoprost Ophthalmic Solution] 3.2.P.2 Pharmaceutical Development [Latanoprost Ophthalmic Solution] Vol.2 Module 3 Vol.2 Module 3 3.2.P.2.1 Components of the Drug Product [Latanoprost Ophthalmic Solution] 3.2.P.2.2 Drag Product [Latanoprost Ophthalmic Solution] Vol.2 Module 3 Vol.2 Module 3 Vol.2 Module 3 Tab 1 TDOC-0008877 3.2.P.2.3 Manufacturing Process Development [Latanoprost Ophthalmic Solution] 3.2.P.2.4 Container Closure System [Latanoprost Ophthalmic Solution] Tab 1 009:97:0402 Tab 2 058:38520:0595 Tab 3 059:38520:0595 Tab 4 060:38520:0595 Tab 5 061:38520:0595 Tab 6 062:38520:0595 Tab 7 TDOC-0009409 Tab 8 TDOC-0009446 Tab 9 TDOC-0009447 Tab 10 TDOC-0009449 Tab 11 TDOC-0009450 Tab 12 TDOC-0009451 Tab 13 TDOC-0009331 3.2.P.2.5 Microbiological Attributes [Latanoprost Ophthalmic Solution] Tab 1 TDOC-0007660 Tab 2 TDOC-0009429 Tab 3 TDOC-0009389 Tab 4 TDOC-0007147 Tab 5 TDOC-0009469 Vol.2 Module 3 Vol.2 Module 3 Vol.2 Vol.2 Vol.2 Vol.2 Vol.2 Vol.2 Vol.2 Vol.2 Vol.2 Vol.2 Vol.2 Vol.2 Vol.2 Module 3 Module 3 Module 3 Module 3 Module 3 Module 3 Module 3 Module 3 Module 3 Module 3 Module 3 Module 3 Module 3 Vol.2 Module 3 Vol.2 Vol.2 Vol.2 Vol.2 Vol.2 Module 3 Module 3 Module 3 Module 3 Module 3 3.1 Table of Contents, Page 3 CONFIDENTIAL PURSUANT TO THE PROTECTIVE ORDER AD LATANOPROST EIKE000138 Case 3:12-cv-01141-SMY-DGW Document 176-12 *SEALED* Filed 12/01/14 Page 19 of 22 Page ID #2482 Latanoprost ANDA Case: 16-3334 Document: 55-28 Filed: 02/08/2017 Pages: 22 (1004 of 1511) Module 3 - Table of Contents - Continued Tab Identifier Volume - Module 3.2.P.2.6 Compatibility [Latanoprost Ophthalmic Solution] Vol.3 Module 3 3.2.P.3 Manufacture [Latanoprost Ophthalmic Solution] 3.2.P.3.1 Manufacturers) [Latanoprost Ophthalmic Solution] 3.2.P.3.2 Batch Formula [Latanoprost Ophthalmic Solution] 3.2.P.3.3 Description of Manufacturing Process and Process Controls [Latanoprost Ophthalmic Solution] Tab 1 Blank Batch Record 3.2.P.3.4 Controls of Critical Steps and Intermediates [Latanoprost Ophthalmic Solution] 3.2.P.3.5 Process Validation and/or Evaluation [Latanoprost Ophthalmic Solution] Vol.3 Module 3 Vol.3 Module 3 Vol.3 Module 3 Vol.3 Module 3 Vol.3 Module 3 Vol.3 Module 3 Vol.3 Module 3 3.2.P.4 Control of Excipients [Latanoprost Ophthalmic Solution] Vol.3 Module 3 3.2.P.4.1 Specifications [Latanoprost Ophthalmic Solution] Vol.3 Module 3 Tab 1 Supplier Excipient Certificates... Tab 2 Residual Solvents (BAC) Tab 3 Residual Solvents (Dibasic Sod Phosphate) Tab 4 Residual Solvents (Monobasic Sod Phosphate) Tab 5 Residual Solvents (Sodium Chloride) Vol.3 Module 3 Vol.3 Module 3 Vol.3 Module 3 Vol.3 Module 3 Vol.3 Module 3 3.2.P.4.2 Analytical Procedures 3.2.P.4.3 Validation of Analytical Procedures 3.2.P.4.4 Justification of Specifications Vol.3 Module 3 Vol.3 Module 3 Vol.3 Module 3 Tab 1 Alcon Excipient Certificates 3.2.P.4.5 Excipients of Human or Animal Origin [Latanoprost Ophthalmic Solution] 3.2.P.4.6 Novel Excipients [Latanoprost Solution] Vol.3 Module 3 Vol.3 Module 3 Vol.3 Module 3 3.1 Table of Contents, Page 4 CONFIDENTIAL PURSUANT TO THE PROTECTIVE ORDER AD LATANOPROST EIKE000139 Case 3:12-cv-01141-SMY-DGW Document 176-12 *SEALED* Filed 12/01/14 Page 20 of 22 Page ID #2483 Latanoprost ANDA Case: 16-3334 Document: 55-28 Filed: 02/08/2017 Pages: 22 (1005 of 1511) Module 3 - Table of Contents - Continued Tab Identifier 3.2.P.5 Control of Drug Product [Latanoprost Ophthalmic Solution] 3.2.P.5.1 Specification(s) [Latanoprost Ophthalmic Solution] Analytical Procedures [Latanoprost Ophthalmic Solution] Volume - Module Vol. 3, Module 3 Vol. 3, Module 3 Vol. 4, Module 3 Tab 1 FWMDOC-12477 Tab 2 PROC-0004456 Tab 3 FWMDOC-04847 Tab 4 PROC-0001746 Tab 5 FWMDOC-02848 Tab 6 PROC-0000447 Tab 7 FWMDOC-02850 Tab 8 PROC-0000448 Tab 9 FWMDOC-02868 Tab 10 PROC-0001329 Tab 11 FWMDOC-02869 Tab 12 PROC-0000580 Tab 13 PROC-0000436 Tab 14 FWMDOC-00792 Tab 15 PROC-0000883 Tab 16 FWMDOC-00392 Tab 17 PROC-OOOH24 Tab 18 FWMDOC-01692 Vol. 4, Module 3 Vol. 4, Module 3 Vol. 4, Module 3 Vol. 4, Module 3 Vol. 4, Module 3 Vol. 4, Module 3 Vol. 4, Module 3 Vol. 4, Module 3 Vol. 4, Module 3 Vol. 4, Module 3 Vol. 4, Module 3 Vol. 4, Module 3 Vol. 4, Module 3 Vol. 4, Module 3 Vol. 4, Module 3 Vol. 4, Module 3 Vol. 4, Module 3 Vol. 4, Module 3 Validation of Analytical Procedures [Latanoprost Ophthalmic Solution] Vol. 4, Module 3 Tab 1 TDOC-0007590 Tab 2 TDOC-0006825 3.2.P.5.4 Batch Analyses [Latanoprost Ophthalmic Solution] Tab 1 Alcon Drug Product Certificates Vol. 4, Module 3 Vol. 4, Module 3 Vol. 4, Module 3 Vol. 4, Module 3 3.1 Table of Contents, Page 5 CONFIDENTIAL PURSUANT TO THE PROTECTIVE ORDER AD LATANOPROST EIKE000140 Case 3:12-cv-01141-SMY-DGW Document 176-12 *SEALED* Filed 12/01/14 Page 21 of 22 Page ID #2484 Latanoprost ANDA Case: 16-3334 Document: 55-28 Filed: 02/08/2017 Pages: 22 (1006 of 1511) Module 3 - Table of Contents - Continued Tab Identifier 3.2.P.5.5 Characterization of Impurities [Latanoprost Ophthalmic Solution] Tab 1 TDOC-0009463 3.2.P.5.6 Justification of Specification(s) [Latanoprost Ophthalmic Solution] 3.2.P.6 Reference Standards or Materials [Latanoprost Ophthalmic Solution] 3.2.P.7 Container Closure System [Latanoprost Ophthalmic Solution] Tab 1 Packaging DMF Letters Tab 2 Packaging Component Certificates Tab 3 FWMDOC-02925 Tab 4 FWMDOC-00825 3.2.P.8 Stability [Latanoprost Ophthalmic Solution] 3.2.P.8.1 Stability Summary and Conclusion [Latanoprost Ophthalmic Solution] Tab 1 PROC-0001316 Tab 2 PROC-OOOl 137 3.2.P.8.2 Post-approval Stability Protocol and Stability Commitment [Latanoprost Ophthalmic Solution] 3.2.P.8.3 Stability Data [Latanoprost Ophthalmic Solution] Tab 1 TDOC-0009276 Tab 2 Exhibit Batch Stability Data Tab 3 Xalatan Stability Data Vol.4 Module Vol.4 Module Vol.4 Module Vol.4 Module Vol.4 Module Vol.4 Vol.4 Vol.4 Vol.4 Module Module Module Module Vol.5 Module Vol.5 Module Vol.5 Module Vol. 5 Module Vol.5 Module Vol.5 Module Vol.5 Module Vol.5 Module Vol.5 Module Vol.5 Module 3.2.A Appendices 3.2.A.1 Facilities and Equipment 3.2.A.2 Adventitious Agents Safety Evaluation 3.2.A.3 Novel Excipients 3.2.R Regional Information 3.2.R.1.S 3.2.R.2.S Volume - Module Executed Batch Record - Drug Substance Comparability Protocols Vol.5 Module Vol.5 Module Vol.5 Module Vol.5 Module Vol. 5 Module Vol.5 Module 3.1 Table of Contents, Page 6 CONFIDENTIAL PURSUANT TO THE PROTECTIVE ORDER AD LATANOPROST EIKE000141 Case 3:12-cv-01141-SMY-DGW Document 176-12 *SEALED* Filed 12/01/14 Page 22 of 22 Page ID #2485 ANDA Latanoprost Case: 16-3334 Document: 55-28 Filed: 02/08/2017 Pages: 22 (1007 of 1511) Module 3 - Table of Contents - Continued Tab Identifier 3.2.R.3.S Volume - Module Methods Validation Package Vol. 5, Module 3 Tab 1 Drug Substance Validation Package.... Vol. 5, Module 3 3.2.R.1.P.1 Executed Batch Record - Drug Product Tab 1 Executed Batch Record Vol. 5, Module 3 Vol. 5, Module 3 3.2.R.1.P.2 Information on Components Vol. 6, Module 3 3.2.R.2.P 3.2.R.3.P Comparability Protocols Methods Validation Package Vol. 6, Module 3 Vol. 6, Module 3 Tab 1 Drug Product Validation Package Vol. 6, Module 3 3.3 Literature References Vol. 6, Module 3 3.1 Table of Contents, Page 7 CONFIDENTIAL PURSUANT TO THE PROTECTIVE ORDER AD_LATANOPROST_EIKE000142 Case 3:12-cv-01141-SMY-DGW Document 176-38 *SEALED* Filed 12/01/14 Page 1 of 2 Case: 16-3334 Document:Page 55-29ID #3279 Filed: 02/08/2017 Pages: 2 (1008 of 1511) Case 3:12-cv-01141-SMY-DGW Document 176-38 *SEALED* Filed 12/01/14 Page 2 of 2 Case: 16-3334 Document:Page 55-29ID #3280 Filed: 02/08/2017 Pages: 2 (1009 of 1511) Case 3:12-cv-01141-SMY-DGW Document 176-13 *SEALED* Filed 12/01/14 Page 1 of 2 Case: 16-3334 Document:Page 55-30ID #2486 Filed: 02/08/2017 Pages: 2 (1010 of 1511) TECHNICAL REPORT ALCON RESEARCH LIMITED 6201 SOUTH FREEWAY FORT WORTH, TEXAS 76134 UNIT: TECHNICAL REPORT NO.: Package Development 004:89:0102 TITLE: REVISION NO.: Measurement of Drop Size and Doses per Container During an In-Use Simulation of Ophthalmic Products PAGE: 1 OF 2 PROTOCOL NO.: 0 N-01-060 PROJECT NAME (NUMBER): Author(s): Michael Kent, PacOage Engineer Name of Study Director: Peggy Shaw West Pharmaceutical Services, Inc. Contract Laboratory Services Name of Study Monitor: (if a contract study) Michael Kent Engineer I, Package Development Name/Address of Testing Facility: (if a contract study) West Pharmaceutical Services, Inc. Contract Laboratory Services 101 Gordon Drive Lionville, PA 19341 Acknowledgments: Kay Hellberg, Senior Scientist Package Development Distribution: QAU/Archives (Original) APPROVAL (S): NAME/TITLE/SIGNATURE/DATE z/b/o Michael Kent Engineer I, Package Development Summary: /1/g/Z CLvt Date W. E. McCune Assoc. Director, Package Development 21e/OZ.-Date Four different products, Travatan TM Ophthalmic Solution; - _ Xalatan® Ophthalmic Solution, and __= _ _ _ ,'were tested by three different analysts for drop size and doses per container. This limited in-use laboratory study was intended to mimic actual patient use of these products with two drops being dispensed and measured daily to simulate a QD dosing_ regimen and Xalatan, -===— _ _ _ _ _ with _ _ _ Travatan: -_-- Drop measurement continued daily until the products were exhausted. The average drop size was calculated and the total number of drops counted. The results indicated that Travatan delivered an overall average drop size of 27.63 mg, with an average of 104 drops per container. —===--== = with an average of 102 drops per container. Xalatan delivered an overall average drop_size ofr80.88 mg, with an average of 70 drops per container. = = RD14 Revised 3/99 CONFIDENTIAL PURSUANT TO THE PROTECTIVE ORDER 00063850 02035 DM-2.0 AD_EIKE001281 Case 3:12-cv-01141-SMY-DGW Document 176-13 *SEALED* Filed 12/01/14 Page 2 of 2 Case: 16-3334 Document:Page 55-30ID #2487 Filed: 02/08/2017 Pages: 2 (1011 of 1511) TECHNICAL REPORT TR NO.: REVISION NO.: 004:89:0102 PROTOCOL NO.: 0 N-01-060 PAGE: 2 2 OF 1. MATERIALS/METHODS 1.1. Test Articles 30 each of the following: Travatan (travaprost ophthalmic solution) 0.004%, Lot no. 25561F, exp.: 09/2002 --Xalatan (latanoprost ophthalmic solution) 0.005%, Lot no. CA53348, exp.: 01/2004 1.2. Test Method The drop size evaluation was conducted according to Alcon Nonclinical Protocol, "The Measurement of Drop Size and Doses per Container during an In-Use Simulation of Ophthalmic Products." Dated April 27, 2001. Protocol No.: N-01-060. Each of three analysts tested 10 samples of each product daily. Drops were dispensed according to the dosage regimen, i.e., 2 or 4 drops daily, at an approximate angle of 45 degrees onto a balance and weighed. The study was conducted at West Pharmaceutical Services, Inc. Contract Laboratory Services, 101 Gordon Drive, Lionville, PA 19341. The testing began on June 5, 2001 and ended on September 13, 2001. 3. RESULTS/DISCUSSION For detailed results and data refer to report on Protocol No. N-01-060, from West Pharmaceutical Services, Inc. Contract Laboratory Services, (report number CL00413-A, Version 1, dated October 24, 2001. 4. CONCLUSIONS The results indicated that Travatan delivered_an_overail averaae drop size of 27.63 ma. with an average of 104 drops per container. ====-=== Xalatan delivered an overall average drop size of 30.88 mg, with an average of 70 drops per container. _ 5. REFERENCES 1. Alcon Nonclinical Protocol, "The Measurement of Drop Size and Doses per Container during an In-Use Simulation of Ophthalmic Products." Dated April 27, 2001. Protocol No. N-01-060. 6. APPENDICES Not Applicable RD15 Revised 3/99 CONFIDENTIAL PURSUANT TO THE PROTECTIVE ORDER 00063850 02035 DM-2.0 AD_EIKE001282 Case 3:12-cv-01141-SMY-DGW Document 176-39 *SEALED* Filed 12/01/14 Page 1 of 2 Case: 16-3334 Document:Page 55-31ID #3281 Filed: 02/08/2017 Pages: 2 (1012 of 1511) Case 3:12-cv-01141-SMY-DGW Document 176-39 *SEALED* Filed 12/01/14 Page 2 of 2 Case: 16-3334 Document:Page 55-31ID #3282 Filed: 02/08/2017 Pages: 2 (1013 of 1511) Case 3:12-cv-01141-SMY-DGW Document 176-14 *SEALED* Filed 12/01/14 Page 1 of 52 Page ID #2488 Case: 16-3334 Document: 55-32 Filed: 02/08/2017 Pages: 52 (1014 of 1511) Allergan Regulatory Affairs Binders NAME: 1?1V1.1- 321)0 ( Product Code i Volume # / 1 or N PSG Update 3/16/05 v1.0 CONFIDENTIAL — SUBJECT TO PROTECTIVE ORDER PRODUCED BY ALLERGAN IN CASE NO. 3:12—CV-01141—DRH—DGW ARGN_0002642 Case 3:12-cv-01141-SMY-DGW Document 176-14 *SEALED* Filed 12/01/14 Page 2 of 52 Page ID #2489 Case: 16-3334 Document: 55-32 Filed: 02/08/2017 Pages: 52 (1015 of 1511) 320 LUMIGANV (bimatoprost ophthalmic solution)0.03% NDA 21-275/S-007 Amendment to Supplement for Neil Container/ Closure System 7 NovemberX2002 • CONFIDENTIAL - SUBJECT TO PROTECTIVE ORDER PRODUCED BY ALLERGAN IN CASE NO. 3:12-CV-01141-DRH-DGW ARGN_0002643 Case 3:12-cv-01141-SMY-DGW Document 176-14 *SEALED* Filed 12/01/14 Page 3 of 52 Page ID #2490 Case: 16-3334 Document: 55-32 Filed: 02/08/2017 Pages: 52 (1016 of 1511) Form Approved: OMB No. 0910-0338 Expiration Date: March 31, 2003 See OMB Statement on page 2. DEPARTMENT OF HEALTH AND HUMAN SERVICES FOOD AND DRUG ADMINISTRATION • FOR FDA USE ONLY APPLICATION TO MARKET A NEW DRUG, BIOLOGIC, OR AN ANTIBIOTIC DRUG FOR HUMAN USE APPLICATION NUMBER (Title 21, Code of Federal Regulations, 314 & 601) APPLICANT INFORMATION NAME OF APPLICANT DATE OF SUBMISSION Allergen 11/7/02 TELEPHONE NO.(Include Area Code) FACSIMILE(FAX) Number(Include Area Code) 800-347-4500 714/246-4272 APPLICANT ADDRESS(Number, Street, City, State, Country, ZIP Code or Mail Code, AUTHORIZED U.S. AGENT NAME & ADDRESS(Number, Street, City, State, and US. License number if previously issued): ZIP Code, telephone & FAX number)iF APPLICABLE N/A 2525 Dupont Drive P.O. Box 19534 Irvine, CA 92623-9534 PRODUCT DESCRIPTION NEW DRUG OR ANTIBIOTIC APPLICATION NUMBER, OR BIOLOGICS LICENSE APPLICATION NUMBER (If previously issued) NDA 21-275 ESTABLISHED NAME (e.g., Proper name, USP/USAN name) PROPRIETARY NAME (trade name)IF ANY bimatoprost Lumigan CHEMICAUBIOCHEMICAUBLOOD PRODUCT NAME (If any) CAS 155206-00-1 CODE NAME (If any) AGN 192024 DOSAGE FORM: ophthalmic solution STRENGTHS: 0.03% ROUTE OF ADMINISTRATION: topical (PROPOSED)INDICATION(S) FOR USE: Indicated for the reduction of elevated intraocular pressure in patients with open angle glaucoma or ocular hypertension who are intolerant of other intraocular pressure lowering medications or insufficiently responsive (failed to achieve target IOP determined after multiple measurements over time) to another intraocular pressure lowering medication. • APPLICATION INFORMATION APPLICATION TYPE NEW DRUG APPLICATION (21 CFR 314.50) El ABBREVIATED NEW DRUG APPLICATION (ANDA,21 CFR 314.94) (check one) 1:I BIOLOGICS LICENSE APPLICATION (21 CFR part 601) till 505(b)(1) IF AN NDA, IDENTIFY THE APPROPRIATE TYPE El 505(b)(2) IF AN ANDA, or 505(b)(2), IDENTIFY THE REFERENCE LISTED DRUG PRODUCT THAT IS THE BASIS FOR THE SUBMISSION Holder of Approved Application Name of Drug ID PRESUBMISSION 0 LABELING SUPPLEMENT 0 ORIGINAL APPLICATION 0 ANNUAL REPORT al AMENDMENT TO A PENDING APPLICATION 1:2 ESTABLISHMENT DESCRIPTION SUPPLEMENT 0 CHEMISTRY MANUFACTURING AND CONTROLS SUPPLEMENT 1:1 RESUBMISSION 0 TYPE OF SUBMISSION (check one) EFFICACY SUPPLEMENT 0 OTHER IF A SUBMISSION OR PARTIAL APPLICATION, PROVIDE LETTER DATE OF AGREEMENT TO PARTIAL SUBMISSJON. IF A SUPPLEMENT, IDENTIFY THE APPROPRIATE CATEGORY 13 CBE Cl CBE-30 CI Prior Approval(PA) REASON FOR SUBMISSION Amendment to supplement to allow for approval of MP500 series container closure system. PROPOSED MARKETING STATUS(check one) III PRESCRIPTION PRODUCT(Rx) ID OVER THE COUNTER PRODUCT(OTC) El PAPER AND ELECTRONIC 1:1 ELECTRONIC 1 THIS APPLICATION IS la PAPER NUMBER OF VOLUMES SUBMITTED ESTABLISHMENT INFORMATION (Full establishment information should be provided in the body of the Application.) Provide locations of all manufacturing, packaging and control sites for drug substance and drug product (continuation sheets may be used if necessary). Include name, address, contact, telephone number. registration number(CFN), DMF number,and manufacturing steps and/or type of testing (e.g., Final dosage form. Stability/testing) conducted at the site. Please indicate whether the site is ready for inspection or, if not, when it will be ready. • See continuation sheet Cross References(list related License Applications, INDs, NDAs,PMAs,510(k)s,IDES, BMFs,and DMFs referenced in the current application) • FORM FDA 356h (4/00) CONFIDENTIAL - SUBJECT TO PROTECTIVE ORDER PRODUCED BY ALLERGAN IN CASE NO. 3:12-CV-01141-DRH-DGW GE 1 ARGN_0002644 Case 3:12-cv-01141-SMY-DGW Document 176-14 *SEALED* Filed 12/01/14 Page 4 of 52 Page ID #2491 Case: 16-3334 Document: 55-32 Filed: 02/08/2017 Pages: 52 (1017 of 1511) , , This application contains the following items: (Check all that apply) 1. Index cJ 2. • cJ Labeling (check one) 0 Draft Labeling 0 Final Printed Labeling 3. Summary (21 CFR 314.50(c)) 4. Chemistry section A. Chemistry, manufacturing, and controls information (e.g., 21 CFR 314.50(d)(1); 21 CFR 601.2) cJ B. Samples (21 CFR 314.50(e)(1); 21 CFR 601.2(a))(Submit only upon FDA's request) C. Methods validation package (e.g., 21 CFR 314.50(e)(2)(i); 21 CFR 601.2) . cJ cJ cJ cJ cJ 5. Nonclinical pharmacology and toxicology section (e.g., 21 CFR 314.50(d)(2); 21 CFR 601.2) 6. Human pharmacokinetics and bioavailability section (e.g., 21 CFR 314.50(d)(3); 21 CFR 601.2) 7. Clinical Microbiology (e.g., 21 CFR 314.50(d)(4)) 8. Clinical data section (e.g., 21 CFR 314.50(d)(5); 21 CFR 601.2) 9. Safety update report (e.g., 21 CFR 314.50(d)(5)(vi)(b); 21 CFR 601.2) . 10. Statistical section (e.g., 21 CFR 314.50(d)(6); 21 CFR 601.2) . 11. Case report tabulations (e.g., 21 CFR 314.50(1)(1); 21 CFR 601.2) III 12. Case report forms (e.g., 21 CFR 314.50(f)(2); 21 CFR 601.2) cJ 13. Patent information on any patent which claims the drug (21 U.S.C. 355(b) or (c)) . 14. A patent certification with respect to any patent which claims the drug (21 U.S.C.355(b)(2) or (j)(2)(A) cJ 15. Establishment description (21 CFR Part 600, if applicable) I. 16. Debarment certification (FD&C Act 306(k)(1)) cJ 17. Field copy certification (21 CFR 314.50(k)(3)) - . 18. User Fee Cover Sheet(Fomi FDA 3397) el. 19. Financial Information (21 CFR Part 54) . 20. OTHER (Specify) - CERTIFICATION I agree to update this application with new safety information about the product that may reasonably affect the statement of contraindications, warnings, precautions, or adverse reactions in the draft labeling. I agree to submit safety update reports as provided for by regulation or as requested by FDA. If this application is approved, I agree to comply with all applicable laws and regulations that apply to approved applications, including, but not limited to the following: 1. Good manufacturing practice regulations in 21 CFR Parts 210, 211or applicable regulations, Parts 606, and/or 820. 2. Biological establishment standards in 21 CFR Part 600. 3. Labeling regulations in 21 CFR Parts 201,606,610,660 and/or 809. 4. In the case of a prescription drug or biological product, prescription drug advertising regulations in 21 CFR 202. 5. Regulations on making changes in application in FD&C Act Section 506A, 21 CFR 314.71, 314.72, 314.97, 314.99, and 601.12. 6. Regulations on Reports in 21 CFR 314.80, 314.81, 600.80 and 600.81. 7. Local, state and Federal environmental impact laws. If this application applies to a drug product that FDA has proposed for scheduling under the Controlled Substances Act, I agree not to market the product until the Drug Enforcement Administration makes a final scheduling decision. The data and information in this submission have been review and, to the best of my knowledge are certified to be true and accurate. A willfully false statement iS a criminal offense, U.S. Code, title 18. section 1001. Warning: SIGN ., RE OF RESPONSIBLE OFFICIAL OR G T TYPED NAME AND TITLE Stephen Buxbaum, Director, Regulatory Affairs DATE 11/7/02 TELEPHONE NUMBER 714/246-4534 ADDRESS (Street, City, S ate, and Z Code) 2525 Dupont Drive, P.O. Box 19534, Irvine, CA 92623-9534 Public reporting burden for this collection of information is estimated to average 24 hours per response, including the time for reviewing instructions, searching existing data sources, gathering and maintaining the data needed, and completing and reviewing the collection of information. Send comments regarding this burden estimate or any other aspect of this collection of information, including suggestions for reducing this burden to: Department of Heatth and Human Services . __ ._„._. ,Food.and Drug.Administration CBER, HFM-99 1401 Rockville Pike Rockville, MD 20852-1448 FORM FDA 356h (4/OO) CONFIDENTIAL - SUBJECT TO PROTECTIVE ORDER PRODUCED BY ALLERGAN IN CASE NO. 3:12-CV-01141-DRH-DGW An agency may not conduct or sponsor, and a person is not required to respond to, a collection of - information unless it displays- a currently valid OMB control number. AGE 2 ARGN_0002645 Case 3:12-cv-01141-SMY-DGW Document 176-14 *SEALED* Filed 12/01/14 Page 5 of 52 Page ID #2492 Case: 16-3334 Document: 55-32 Filed: 02/08/2017 Pages: 52 (1018 of 1511) • ESTABLISHMENT INFORMATION FOR DRUG SUBSTANCE Drug Substance Manufacturing,Packing and Control Site Establishment Telephone Number Registration No. Bimatoprost Torcan Chemicals,Ltd. 110 Industrial Parkway North P.O. Box 308 Aurora, Ontario Canada L4G 3H4 55679 (905)727-9417 Contact: Jan Oudenes, Ph.D., President ESTABLISHMENT INFORMATION FOR DRUG PRODUCT • Drug Product: LUMIGANTm (bimatoprost ophthalmic solution)0.03% Application Number: 21-275 Responsibility License No. Contact CFN=1643525 Al Erario, Manager Quality Assurance/Quality Control (254)666-8619 Not required Timothy Lindsay Plant Manager (714)246-4700 CFN=300-2806348 Patrick O'Donnell,Director Quality Assurance and Development 353-98-55254 Manufacturing,Packing and Control Site: Allergan,Inc 8301 Mars Drive Waco,TX 76712 Container/Closure Manufacturing Site: Allergan Medical Plastics 2525 Pullman Street Santa Ana,CA 92705 Finished Product On-Going Stability: Allergan Pharmaceuticals(Ireland) Ltd., Inc. Castlebar Road Westport, County Mayo IRELAND Alternate contact for all sites: Stephen Buxbaum,Director Allergan Regulatory Affairs (714)246-4534 CONFIDENTIAL - SUBJECT TO PROTECTIVE ORDER PRODUCED BY ALLERGAN IN CASE NO. 3:12-CV-01141-DRH-DGW ARGN_0002646 Case 3:12-cv-01141-SMY-DGW Document 176-14 *SEALED* Filed 12/01/14 Page 6 of 52 Page ID #2493 Case: 16-3334 Document: 55-32 Filed: 02/08/2017 Pages: 52 (1019 of 1511) . LLERGAN 4111!•■••="'''... 2525 Dupont Drive, RP. Box 19534, Irvine. California, USA 92623-9534 Telephone:(714) 246-4500 Website: WWW.aI Iergan.com emmimumm... ONIMP• November 7, 2002 Wiley Chambers, MD Deputy Director Food and Drug Administration Center for Drug Evaluation and Research Division of Anti-Inflammatory, Analgesic and Ophthalmic Drug products-(HFD-550) 9201 Corporate Boulevard, Building 2, 1st Floor Rockville, MD 20850 RE: • NDA 19-700/S-023, ACULAR® (ketorolac tromethamine ophthalmic solution)0.5% NDA 21-009/S-003, ALOCRILO(nedocromil sodium ophthalmic solution)2% NDA 20-613/S-021, ALPHAGANO (brimonidine tartrate ophthalmic solution)0.2% NDA 21-262/S-010, ALPHAGANO P(brimonidine tartrate ophthalmic solution)0.15% NDA 19-814/S-016, BETAGANC)(levobunolol hydrochloride ophthalmic solution, USP)0.25% NDA 19-219/S-024, BETAGANC)(levobunolol hydrochloride ophthalmic solution, USP)0.5% NDA 12-813/S-056, BLEPHAMIDEO (sulfacetamide sodium - prednisolone acetate ophthalmic suspension) 10%,0.2% NDA 50-091/S-045, CHLOROPTICO (chloramphenicol ophthalmic solution, USP)0.5% . NDA 16-851/S-058, FML® (fluorometholone ophthalmic suspension, USP)0.1% NDA 19-216/S-021,FML FORTE® (fluorometholone ophthalmic suspension, USP)0.25% NDA 19-525/S-014,FML-SO (fluorometholone, sulfacetamide sodium ophthalmic suspension, USP)0.1%/10% NDA 16-624/S-044, HMS® (medrysone ophthalmic suspension) 1.0% NDA 21-275/S-007, LUMIGANTm (bimatoprost ophthalmic solution)0.03% NDA 19-404/S-022, OCUFENC)(flurbiprofen sodium ophthalmic solution, USP)0.03% NDA 19-921/S-016, OCUFLOX0(ofloxacin ophthalmic solution)0.3% NDA 12-583/S-039, OPHTHETICO (proparacaine HC1 ophthalmic solution)0.5% NDA 18-155/S-027, OPTICROM® (cromolyn sodium ophthalmic solution, USP)4% NDA 50-081/S-037, POLY-PRED® (prednisolone acetate, neomycin sulfate, polymyxin B sulfate) ophthalmic suspension NDA 50-567/S-020, POLYTRIMC)(trimethoprim sulfate and polymyxin B sulfate ophthalmic solution) NDA 17-011/S-042, PRED FORTE® (prednisolone acetate ophthalmic suspension, USP)1% NDA 50-586/S-025, PRED-G® (gentamicin and prednisolone acetate ophthalmic suspension, USP)0.3%/1% NDA 17-100/S-039, PRED MILD® (prednisolone acetate ophthalmic suspension, USP)0.12% NDA 18-239/S-030,PROPINEO (dipivefrin hydrochloride ophthalmic solution, USP)0.1% ANDA 80-248, ALBALONC)(naphazoline HCI ophthalmic solution)0.1% ANDA 80-028/S-051, BLEPHO-10(sulfacetamide sodium ophthalmic solution, USP) 10% ANDA 62-452, GENOPTICO (gentamicin sulfate ophthalmic solution, USP)0.3% ANDA 74-746, TIMOLOL MALEATE. ophthalmic solution, USP 0.25% ANDA 74-747, TIMOLOL MALEATE. ophthalmic solution, USP 0.5% CONFIDENTIAL - SUBJECT TO PROTECTIVE ORDER PRODUCED BY ALLERGAN IN CASE NO. 3:12-CV-01141-DRH-DGW ARGN_0002647 Case 3:12-cv-01141-SMY-DGW Document 176-14 *SEALED* Filed 12/01/14 Page 7 of 52 Page ID #2494 Case: 16-3334 Document: 55-32 Filed: 02/08/2017 Pages: 52 (1020 of 1511) November 7,2002 Page 2 Amendment to Supplementfor New Container Closure System Dear Dr. Chambers: Reference is made to our bundled CBE-30 supplement sent to the Agency on June 24, 2002 notifying you of our intent to switch to the MP500 Series of container closure system for all of our prescription and Over-the-Counter ophthalmic drug products. Reference is also made to the facsimile from Dr. Yong-De Lu dated October 11,2002 with CMC comments. The Agency comments are provided below in bold, followed by Allergan's response. FDA CMC Comment 1. Please provide the comparison data of the drop size study conducted between the approved and the proposed bottles to determine the amount of drug delivered by both configurations. Allergan Response: Ô Please find enclosed, as Appendix 1, a copy of Technical Memorandum PDD-TM-2002-164 which describes the comparative performance of the two new dropper tips with the two current tips The study demonstrates that the two new tips are suitable replacements for Allergan's current tips. 2. For each drug product of the bundled submissions please provide the information of the currently approved and proposed substitute bottle configurations. Allergan Response: Please find enclosed, as Appendix 2, a table providing the information on the current bottle configuration and the proposed substitute bottle configuration for each drug product. Should you have any questions or require additional information, you may contact me by telephone at 714-246-4391 or fax at 714-246-4272. Sincerely, Elizabeth Bancroft Sr. Director Regulatory Affairs cc: Gary Buehler, Office of Generic Drugs(HFD-600) CONFIDENTIAL - SUBJECT TO PROTECTIVE ORDER PRODUCED BY ALLERGAN IN CASE NO. 3:12-CV-01141-DRH-DGW ARGN_0002648 Case 3:12-cv-01141-SMY-DGW Document 176-14 *SEALED* Filed 12/01/14 Page 8 of 52 7-7--Page ID #2495 Allergan, IT:. 16-3334 Case: Document: 55-32 Filed: 02/08/2017 Page Pages: Technical Memorandum PDD-TM-2002-164 1 of 16 52 (1021 of 1511) • MRMEM ggspylnerna■w azgyismossasares.Q smismaszesonimaxem ALLERGAN RESEARCH & DEVELOPMENT PHARMACEUTICAL SCIENCES TECHNICAL PACKAGING CENTER MEMORANDUM 0 0 0 0 0 0 0 0 0 0 0 0 0 0 To: Scott Geronclale From: Lon Spada Subjeca: Tip Performance Qualification for UPG9090-12 and UPG15090-12 Controlled Drop Tips Date: 9/4/02 ee: Orest Olejnik, Records Management Approvals Date on T. Spada, Sr. Project Engineer -Author Scott Gerondale, Director, Packaging Design and Development Al Syracuse, Director, QA Pharmaceutical Sciences • CONFIDENTIAL - SUBJECT TO PROTECTIVE ORDER PRODUCED BY ALLERGAN IN CASE NO. 3:12-CV-01141-DRH-DGW ARGN_0002649 Case 3:12-cv-01141-SMY-DGW Document 176-14 *SEALED* Filed 12/01/14 Page 9 of 52 Page ID #2496 Allergan, Inc 16-3334 Case: Document: 55-32 Filed: 02/08/2017 Pages: 52 (1022 of 1511) TechnicalAlemorandun1F1)1);n4-2002-164 Page 2 of 16 Table of Contents R. SUMMARY 2 2. PURPOSE 2 3. DEFINITION 4 4. EQUIPMENT AND MATERIALS 4 5. REFERENCE DOCUMENTS 5 6. METHODS 5 7 RESULTS 7 O. CONCLUSIONS 15 9. ATTACHMENTS 15 1.0 • SUMMARY Two new LDPE controlled drop-tips designed to fit on the MP500 series container closure system were tested for their suitability for ophthalmic containers and their ability to deliver the same drop weight as Allergan's current tips. The new tips, designated UP09090-12 and UPG15090-12, are designed to replace the 4167 and 4010 controlled drop tips, respectively. The conclusion of the testing is that these tips adequately deliver the same drop weight as Allergan's current tips, and they are suitable for use on ophthalmic containers. It PURPOSE This report describes the testing that was done to qualify the design of two low-density polyethylene(LDPE)controlled drop tips and to show that the two new tips deliver the same drop weight as Allergan's current tips. Allergan currently uses three different controlled drop tips for its ophthalmic products — 41351 (natural version of 40979), 4167, and 4010. The drop weights are nominally 30 • 35 j.tL, and 45 piL, respectively. The 40979(41351) will not change. The 35-gL 4167(Attachment 9.1) tip will be replaced by a new tip designated UPG9090- 12. and the 45-1.i.L 4010 tip (Attachment 9.2) Confidential - This document is the property oî Aih-r..c CONFIDENTIAL - SUBJECT TO PROTECTIVE ORDER PRODUCED BY ALLERGAN IN CASE NO. 3:12-CV-01141-DRH-DGW lcd s ntended solely for their internal use. ARGN_0002650 Case 3:12-cv-01141-SMY-DGW Document 176-14 *SEALED* Filed 12/01/14 Page 10 of 52 Page ID #2497 Allergan, Inc. 16-3334 Case: Document: 55-32 Filed: 02/08/2017 Pages: PDD-TM Technical Memorandum Page 3 of 1652 (1023 of 1511) -2002-164 • will be replaced by a new tip designated UPG15090-12. A comparison of the current tips and the new tips (as tested) is shown in Table 2.1. The TJPG9090-12 and ITPG15090-12 tips, Attachments 9.3 and 9.4 are intended for use on containers with a 15/415 neck finish, which includes Allergan's MP500 series bottles, Allergan's 21472 8-mL Boston round bottle, and Allergan's 21613 15-mL Boston round bottle. The design of these new tips is based on Allergan's qualified 41351(30 pL)drop-tip shown in Attachment 9.5. The new tips are made from the same resin, and by the same injection molding process as the current Allergan tips. Both 1UPG,tips are dimensionally identical to Allergan's qualified 41351 (40979 white) tip except the size of the top of the tip was changed to produce the desired drop weight and a better seal with the MP500 series 30425111 closure. Both UPG9090-12 and UPG15090-12 tips are made from Dupont 20-6064 LDPE resin by the same injection molding process used to make Allergan's current qualified tips. This resin has been qualified previously by Allergan's Medical Plastics division, and the results are reported in • their Drug Master File(DMF). Confidential - This document is the property of CONFIDENTIAL - SUBJECT TO PROTECTIVE ORDER PRODUCED BY ALLERGAN IN CASE NO. 3:12-CV-01141-DRH-DGW mended solely for their internal au. AIIrt 1,11 UPG_TIP_Qua At s•fl It . F ARGN_0002651 Case 3:12-cv-01141-SMY-DGW Document 176-14 *SEALED* Filed 12/01/14 Page 11 of 52 Page ID #2498 Case: 16-3334 Document: 55-32 Filed: 02/08/2017 Pages: 52 (1024 of 1511) Allergan, Inc. Technical Memorandum PDD-TM-2002-164 Page 4 of 16 Table 201. Comparison of Current Drop-Tips with New Drop-Tips Allergan Part No. 40979(41351 natural) 4167 Resin Type LDPE LDPE Resin Name Dupont 206064 Dupont 206064 1752 1752 PEG 400 (0.06) UPG9090-12 LDPE UPG1509012 _ LDPE 4010 LDPE Dupont 206064 Dupont 206064 1752 1752 1752 PEG 400 (0.06) PEG 400 (0.06) PEG 400 (0.06) PEG 400 (0.06) PolyOne 0342 LMB PolyOne 0342 LMB PolyOne 0342 LMB PolyOne 0342 LMB PolyOne 0342 LMB Medical Plastics Colorant No. 1798 1798 1798 1798 1798 Base Width, in 0.392 0.340 0.392 0.340 0.392 Tip Height, in 0.402 0.421 0.396 0.421 0.396 Medical Plastic's Resin Part No. Resin Additives(%) Colorant Name (White) Dupont 20_ 6064 Orifice Width, in 0.011-0.012 0.012 0.012 0.012 0.012 Tip Top Width, in 0.090 0.100 0.090 0.182 0.150 DEFINITIONS • 3.1 ANOVA — Analysis of Variance 3.2 ASTM — American Society of Testing and Materials 3.3 DI — Deionized (water) 3.4 Et0 — Ethylene Oxide Sterilization 3.5 LDPE — Low-Density Polyethylene 3.6 PDD — Allergan's Packaging Design and Development Department 3.7 RH — Relative Humidity 3.8 SOP — Standard Operating Procedure 3.9 UPG — United Plastics Group, Inc., Fremont, CA. Confidential - This document is the propeny k•I Nfla-r,, it. UPG_ffPr.r CONFIDENTIAL - SUBJECT TO PROTECTIVE ORDER PRODUCED BY ALLERGAN IN CASE NO. 3:12-CV-01141-DRH-DGW tntended solely for their internal use. R1 , 1 ARGN_0002652 Case 3:12-cv-01141-SMY-DGW Document 176-14 *SEALED* Filed 12/01/14 Page 12 of 52 Page ID #2499 Case: Document: 55-32 Filed: 02/08/2017 Pages: Allergan, Inc. 16-3334 Technical Memorandum PDD-TM-2002-164 Page 5 of 1652 (1025 of 1511) 4.0 EQUIPMENT a MATERIALS (All test equipment is calibrated.) • The tests reported in this document require the following equipment: 4.1. Analytical Balance, s/n 70608433 4.2. Vernier Calipers, ID # 921802 4.3. Controlled Temperature Humidity Cabinet, serial numbers 720501,0101511, 0101510 4.4. Vibrac Torque Tester, s/n 95-0094 4.5. Vacuum Oven,ID # 607302 4.6. Aluminum Trays Lined with :lotting Paper 4.7. Bottle, Allergan MP500(batch 2050B) 4.8. Bottle, Allergan MP500,Et0 sterilized p/n 21729L 4.9. Drop Tip, natural LDPE, p/n 413511.1-1 4.10. Drop Tip, natural LDPE,UPG9090-12 4.11. Drop Tip, natural LDPE, UPG15090-12 4.1.2. 4.13. REFERENCE DOCUMENTS ASTM D3/98 4.14. Environmental Stress Crack Test, SOP-TPC-025 and ASTM D 2561 4.15. Vacuum Leak Test, SOP-TPC-037 Confidential -This document is the property of Allerean. Inc CONFIDENTIAL - SUBJECT TO PROTECTIVE ORDER PRODUCED BY ALLERGAN IN CASE NO. 3:12-CV-01141-DRH-DGW and ts intended mlely for their internal use. ARGN_0002653 Case 3:12-cv-01141-SMY-DGW Document 176-14 *SEALED* Filed 12/01/14 Page 13 of 52 Page ID #2500 Allergan, Inc. 16-3334 Case: Document: Filed: 02/08/2017 Pages: 52 (1026 of 1511) Technical 55-32 Memorandum PDD-TM-2002-164 Page 6 of 16 6.10 METHODS The UPG9090-12 and UPG15090-12 tips tested in this work were "natural" color and were made with a four-cavity mold by United Plastics Group(UPG)in Fremont, CA,an approved Allergan supplier. They are made from the same materials and by the same injection molding process as Allergan's current tips. The two new tips are dimensionally identical except for the width of the top of the tip. This dimension is adjusted to produce the proper drop weight. Pitysicall Appearance Each batch is inspected by United Plastics Group for physical appearance and dimensional compliance before releasing the tip to Allergan. Allergan Packaging Design and Development or their designated consultant, Token B Technology, visually inspects the tips for cosmetic defects such as clarity, mottling, blemishes, parting line flash, mismatch and damage. 6.2 • Dimensionall Analysis This test assures that the tips produced in the prototype mold are within specification. Tip dimensions were measured and evaluated according to the drawing specifitations (Attachments 9.3 and 9.4). United Plastics Group measures the dimenSions of each batch of tips before releasing them to Allergan. Allergan's Packaging Design and Development or an approved contractor inspects the tips for dimensional compliance. 63 Vacuum Leak Test One hundred each of the UPG9090-12 and UPG15090-12 tips were placed in MP500 bottles with 30425LH closures and vacuum leak tested according to SOP-TPC-037. The MP500(21729LH) bottles were fitted with either the UPG9090-12 or the UF'G15090-12 dropper tips and capped with a 3042511-1 closure, tightened to 4 in-lb torque according to ASTM D3/98. • 6.4 Drop Weight Analysis Drop weight analysis was done on eight selected Allergan products. I Other Product land Alphagan p were tested because they are the only Allergan products that use the 354 4167 tip. The other six Confidential - This document is the property a Allergan. Io. nd t ntended solely for their internal use. UPG_TIP_QualLro..m.■n CONFIDENTIAL - SUBJECT TO PROTECTIVE ORDER PRODUCED BY ALLERGAN IN CASE NO. 3:12-CV-01141-DRH-DGW Rp. ARGN_0002654 Case 3:12-cv-01141-SMY-DGW Document 176-14 *SEALED* Filed 12/01/14 Page 14 of 52 Page ID #2501 Case: 16-3334 Document: 55-32 Filed: 02/08/2017 Pages: 52 (1027 of 1511) Allergan, Inc. Technical Memorandum P1)1)=11\4-2002-164 • Page 7 of 16 drugs were chosen because they represent "families" of Allergan products. Table 6.4.1 lists the products selected and the category of drug product they represent. The drop weight was tested by two methods — by hand and by a robotic arm. The "hand" method has a person delivering drops in the same way as someone using the product. Each drop is weighed with an analytical balance. After each drop, the container is returned to the upright position before the next drop is delivered. The drops were delivered at 90° (vertical) and 45° from vertical. For the commercial drug tips, ten drops were weighed from five different containers. Because the UPG tips came from the same controlled batch, ten drops were tested from one tip. Previous drop-weight studies showed that most of the variation that occurs in drop weight is due to different delivery techniques among people. To remove some of this variation, a robotic arm was used to deliver the drops using the same bottles and tips and by the same procedure used for • the "hand" measurements. Table 6.4.11. Drug Poducs Tested for Drop Weight Comparison Commercial Drug Productit rOther Productlklphagan P Selection Criteria Conunerciall Tip Uses the 4167 Drop tip 4167 Other Product • Confidential - This document is the property of A:1[1g.. lo. nd J. Intended solely for ;heir internal use. UPG_TIP_QvaLtikan..n Rot CONFIDENTIAL - SUBJECT TO PROTECTIVE ORDER PRODUCED BY ALLERGAN IN CASE NO. 3:12-CV-01141-DRH-DGW ARGN_0002655 Case 3:12-cv-01141-SMY-DGW Document 176-14 *SEALED* Filed 12/01/14 Page 15 of 52 Page ID #2502 Allergan, Inc. 16-3334 Case: Document: Filed: 02/08/2017 Pages: 52 (1028 of 1511) Technical 55-32 Memorandum PDD-TM-2002-164 Page 8 of 16 7.0 RESULTS • 7.1 Physical Appearance UPG inspected the original engineering samples and found that they were free of physical defects, which included clarity, mottling, blemishes, parting line flash, mismatch, and damage. The certificate of compliance for each tip is provided as Attachments 9.6 and 9.7. 7.2 Dimensionall A: alysis The "first article dimensional analysis' shows that the new tips dimensionally match the drawing specifications. The tip dimensions were measured and evaluated according to the drawing specifications (Attachments 9.3 and 9.4). United Plastics Group measured the dimensions and issued a Certificate of Compliance for each tip (Attachments 9.6-9.7). Tips from each cavity were randomly selected and the dimensions were compared to the drawing specifications by Token B Technologies, and approved Allergan vendor. Their first article analysis is shown in • Attachment 9.8. Token B Technologies concluded that all the dimensions are within specifications and that these tips are suitable for drop-weight comparisons. They noted that the average internal orifice diameter varied by less than ± 0.002. This is an acceptable variation for this dimension, because this diameter does not affect the drop weight within the normal range of orifice diameters used in Allergan's tips. Also, it is very difficult to produce a consistent 0.006"diameter hole in an injection-molded tip, and this variation is well within what we have observed for similar parts. In addition, our interest in these engineering samples was for drop weight comparison to Allergan's existing tips. Any minor changes will be made in the next mold upgrade. 7.3 Vacuum Leak Test The leak test results for the UPG9090-12 and UPG15090-12, summarized in Table 7.3.1, are mixed. The UPG9090-12 tip does not leak, but many of the UPG15090-12 tips leaked at the tip bottle interface. Neither tip leaked at the tip-cap interface. This is an important observation, • because these tips were designed for drop weight evaluation, so the top of the tip and its interaction with the cap is the most important area. The leakage observed with the UPG15090- Confidential -This document is the property Qt ntkrv... CONFIDENTIAL - SUBJECT TO PROTECTIVE ORDER PRODUCED BY ALLERGAN IN CASE NO. 3:12-CV-01141-DRH-DGW t tt,.t n Intended solely for their intenal use. ARGN_0002656 Case 3:12-cv-01141-SMY-DGW Document 176-14 *SEALED* Filed 12/01/14 Page 16 of 52 Page ID #2503 Case: Document: 55-32 Filed: 02/08/2017 Pages: Allergan, Inc. 16-3334 Technical Memorandum MD-TM-2002-164 Page 9 of 1652 (1029 of 1511) • 12 tip was due to a small amount of "flash" on the weld line below the gate. In this batch of tips, the flash is evident on cavities"C" and "D" and not on cavities "A" and B. The flash was traced to a small piece of dirt lodged in the mold, which was subsequently removed. The important point is that the tips from cavity "C" do not leak, which establishes the capability of the design. Also, the design of these tips below the flange is identical to Allergan's current 40979 tip, which has passed many leak tests. The original data is located in notebook reference R2001-6191-103. Table 7.3.1, Vacuum Leak-Test Results for UPG Tips Tip :ode Cap SOP TPC.. 037,Passed Units UPG9090-12 MP500 (21729LH) 30425LH 100/100 UPG15090-12 MP500 (21729LH) Comments All Passed , No Leaks Observed All leaks Observed at tip-bottle 74 30425LH 37/100 interface Drop Weight Measurements The drop weight results show that the two new tips are acceptable replacements for the current 4167 and 4010 tips. A summary of the drop weight results is shown in Table 7.4.1 for the 4167 tip and Table 7.4.2 for the 4010 tip. There are many factors that affect drop weight, among which are the tip dimensions and surface energy, the drug surface tension and rheology, drop angle, and the application technique of the user. Previous drop weight measurements with similar tips has shown that the user's technique is responsible for most of the variation in dropweight. Given that the new tips are made from the same process and materials as the current tips and the same drug products were used as test solutions, the dimensional differences between the • tips and user's technique are the only real variables. Confidential - This document cs the property of LC1,1r1 Es intended solely for their interne/ use. CONFIDENTIAL - SUBJECT TO PROTECTIVE ORDER PRODUCED BY ALLERGAN IN CASE NO. 3:12-CV-01141-DRH-DGW ARGN_0002657 Case 3:12-cv-01141-SMY-DGW Document 176-14 *SEALED* Filed 12/01/14 Page 17 of 52 Page ID #2504 Allergan, Inc. 16-3334 Case: Document: 55-32 Filed: 02/08/2017 Pages: 52 (1030 of 1511) Technical Memorandum PDD-TM Page 10 of 16 -2002-164 • The robotic arm essentially acts as another user, but with a very slow, consistent delivery technique. The average difference in drop weight between the "hand" measurements and the robot is much higher than the drop-weight difference between the new tips and current tips by either method. We conclude from the above considerations that an average drop-weight difference from the two methods between the current tips and UPC, tips of less than six milligrams is not significant. None of the drug products listed in Tables 7.4.1 and 7.4.2 have an average drop weight difference that high. n For Other Product]at 45°, the drop weight measurements were repeated because there was a large difference between the current commercial tip and the new tip. The same five commercialFOther Product—Isamples were used again, and three randomly selected 1UPG9090-12 or UPG15090-12 tips fitted to 1VIP500 bottles were tested. Two different operators administered drops from all eight bottles. The drops were delivered by the same method used in the previous study except the tip was wiped with a clean lab wipe between each drop. This data was combined with the original data in a two-way analysis of variance(ANOVA)for • Other Product and Other Product Thel Other Product'ANOVA results in Table 7.4.3 show that there is no difference between the 4167 tip and the UPG9090-12 tip when the 95% confidence interval is applied. When the person to person variation is removed, the difference between the tips is not significant. Thelother productIANOVA results, Table 74.4,show that at 90° there is a statistically significant difference between the 4010 and UPG15090-12 tip. When the 95% confidence interval is applied, the two tip averages can be placed at the extremes of the distribution. This has a low probability so it is statistically significant difference. It would not be significant at the 99% confidence level, and a two-milligram difference in means is not practically significant. At a 450 drop-angle, there is no statistical or practical difference between the 4010 tip and the UPG15090I 12 tip with I— pOrothdeurct The original data is located in notebook references R2001-6191-62, R2001-6191-91, and R20016191-104. • Confidential -This document is the property of Allergan. Inc and is intended solely for their internal use. UPG_TIP_Qualtfication .Rpt CONFIDENTIAL — SUBJECT TO PROTECTIVE ORDER PRODUCED BY ALLERGAN IN CASE NO. 3:12—CV-01141—DRH—DGW ARGN_0002658 Case 3:12-cv-01141-SMY-DGW Document 176-14 *SEALED* Filed 12/01/14 Page 18 of 52 Page ID #2505 Case: 16-3334 Document: 55-32 Filed: 02/08/2017 Pages: 52 (1031 of 1511) Mlerg Technical Memorandum PDD-TM-2002-. Page 11 of 16 Table 704.1. Allergan Commercial Product Drop Weight Comparison for Products that use the 4167 Tip , Iland Measured • Drug Product Commercial Tip Conunereial Product UPG9090- Difference, g Commercial Drop Wt.,g 12,g Product, Robot, g Robot Measured UPG9090-12, Difference, g Average Robot, g Difference, g L Other Product Alphagan P 4167 0.046 7045 1land 0.000 0.045 _ 41167 0.043 CONFIDENTIAL — SUBJECT TO PROTECTIVE ORDER PRODUCED BY ALLERGAN IN CASE NO. 3:12—CV-01141—DRH—DGW 0.001 0.001 Robot Measured Measured I Drug Product Commercial Tip Commercial Product UPG9090- Difference, g Commercial Drop Wt., g 12, g Product, Robot, g , Alphagon P 0.043 UPG9090-12, Difference, g Average Robot, g Difference, g Other Product 0.043 0.000 I 0.040 0.045 -0.005 -0.003 ARGN_0002659 Case 3:12-cv-01141-SMY-DGW Document 176-14 *SEALED* Filed 12/01/14 Page 19 of 52 Page ID #2506 Case: 16-3334 Document: 55-32 Filed: 02/08/2017 Pages: 52 (1032 of 1511) Allerg Technical Memorandum PDD-111-2011,4 Page 12 of 16 Table 7.4.1- Allergan Commercial Product Drop Weight Comparison for Products that use the 4010 Tip Other Product Confidential - is dm properly of Allcrgan, Inc and i, ly for ale4 iateT, UPG_TIP_Quulllicutio,Ro CONFIDENTIAL — SUBJECT TO PROTECTIVE ORDER PRODUCED BY ALLERGAN IN CASE NO. 3:12—CV-01141—DRH—DGW ARGN_0002660 Case 3:12-cv-01141-SMY-DGW Document 176-14 *SEALED* Filed 12/01/14 Page 20 of 52 Page ID #2507 Case: 16-3334 Document: 55-32 Filed: 02/08/2017 Pages: 52 (1033 of 1511) Allergan, Inc Technical Memorandum PDD-TM-2002-164 Page 13 of 16 • —0 Table 7A3 ANOVA Results folic'ther Productlat 900 and 4J Drop Angle Other Product CONFIDENTIAL - SUBJECT TO PROTECTIVE ORDER PRODUCED BY ALLERGAN IN CASE NO. 3:12-CV-01141-DRH-DGW ARGN_0002661 Case 3:12-cv-01141-SMY-DGW Document 176-14 *SEALED* Filed 12/01/14 Page 21 of 52 Page ID #2508 Case: Document: 55-32 Filed: 02/08/2017 Pages: 52 (1034 of 1511) Allergan, Inc. 16-3334 Technical Memorandum PDD-TM-2002-164 Page 14 of 16 • Table 7.4.4 AN VA Results Tor Other Product at 90° and 45° Drop Angle Other Product Confidential - This document is the propeny t ilk r :.111 1, , intended solely for their internal use. UPG_TfP_Qt CONFIDENTIAL — SUBJECT TO PROTECTIVE ORDER PRODUCED BY ALLERGAN IN CASE NO. 3:12—CV-01141—DRH—DGW ARGN_0002662 Case 3:12-cv-01141-SMY-DGW Document 176-14 *SEALED* Filed 12/01/14 Page 22 of 52 Page ID #2509 Case: Document: 55-32 Filed: 02/08/2017 PagePages: 52 (1035 of 1511) Allergan, Inc. 16-3334 Technical Memorandum PDD-TM-2002-164 15 of 16 • 8.0 CONCLUSIONS The results of the drop-weight tests shows that the UPG9090-12 and UPG15090-12 tips are suitable replacements for Allergan's 4167 and 4010 drop-tips. The design of the new UPG tips is suitable for ophthalmic containers. 9.C1 TTACHMENTS 9.1 Drawing,35 RIL Allergan Drop Tip 4167 9.2 Drawing,45 iu.L Allergan Drop Tip 4010 9.3 Drawing, 35 tat Drop Tip UPG9090-12 9.4 Drawing,45 )1.1., Drop Tip UPG15090-12 9.5 Drawing,30 ).alL Allergan,40979 or 41351 (natural) drop tip 9.6 UPG Certificate of Compliance for Tip UPG9090-12 9.7 UPG Certificate of Compliance for Tip UPG15090-12 9.8 Token B Technologies First Article Report for UPG Tips CONFIDENTIAL - SUBJECT TO PROTECTIVE ORDER PRODUCED BY ALLERGAN IN CASE NO. 3:12-CV-01141-DRH-DGW ARGN_0002663 Case 3:12-cv-01141-SMY-DGW Document 176-14 *SEALED* Filed 12/01/14 Page 23 of 52 Page ID #2510 Allergan, Case: Document: 55-32 Filed: 02/08/2017 Pages: 52 (1036 of 1511) Inc. 16-3334 Technical Memorandum PDD-TM-2002-164 Page 16 of 16 Attachments • Confidential - This docurnent is the property ol Allerv.an, !a< and ts Intended solely for their internal use. UPG_TIP_Quatdicsnon hpr CONFIDENTIAL - SUBJECT TO PROTECTIVE ORDER PRODUCED BY ALLERGAN IN CASE NO. 3:12-CV-01141-DRH-DGW ARGN_0002664 Case 3:12-cv-01141-SMY-DGW Document 176-14 *SEALED* Filed 12/01/14 Page 24 of 52 Page ID #2511 Case: 16-3334 Document: 55-32 Filed: 02/08/2017 Pages: 52 (1037 of 1511) Attachment 9.1 • Allergan 4167 Tip Drawing CONFIDENTIAL - SUBJECT TO PROTECTIVE ORDER PRODUCED BY ALLERGAN IN CASE NO. 3:12-CV-01141-DRH-DGW ARGN_0002665 Case 3:12-cv-01141-SMY-DGW Document 176-14 *SEALED* Filed 12/01/14 Page 25 of 52 Page ID #2512 Case: 16-3334 Document: 55-32 Filed: 02/08/2017 Pages: 52 (1038 of 1511) W 4 WINTSMir filltarialatiard '" ° 0.261 0.31a ø.344® .337 ø.420€> 0.050±.003 .119 .647 .430 .412 0.323±003 .100 - 30. .015 .... , R.015 R .187 .080) /dvrz./ r ZZA, .271 ACROSS FLATS Mil 2X GATE MARK .188 REF .025 ________ 5 REF ..don 0.062 ORIFICE PIN 0.090 FOR MOLD CONST. R .06 R.187 —7 (iliil., Mstgorw 30° 23° , D . 111111111t ....-..,,,,,.. .010 -.. --- Illow 1 a 3 .445 --.--I 4— .005 REF .005 R RIDGE / g .209 --.-- VIEW B SCALE 8:1 -0.381 -0.201 0.074 [ .012€> .009 ORIFICE R .12 T S 30. REF '1 1.07.4., = = t 5° ........5ar 40, 7 " 10, 0.148 SEE VIEW B CAVITY IDENT. 45° .234 A REV ( OHE -322'1.49121 ''''" NOTES: UNLESS OPIEDWISE SPECIFIED azNM ma 4 CONFIDENTIAL - SUBJECT TO PROTECTIVE ORDER PRODUCED BY ALLERGAN IN CASE NO. 3:12-CV-01141-DRH-DGW LEO OP 3 11, martmgaru'o-mae r.m---------........ -. a OPAVI DEM= IF % Saltifiaf ) "DICA " QW 13 mm CONTROL DROP TIP, .009 ONWICE E00071 I 4, l'... I =viol AA Am ---a , te-le-96 ME UJ Cg, =MOP CON11/1131 411131411/ OM NAWA AM 13 1 ARGN_O002666 Case 3:12-cv-01141-SMY-DGW Document 176-14 *SEALED* Filed 12/01/14 Page 26 of 52 Page ID #2513 Case: 16-3334 Document: 55-32 Filed: 02/08/2017 Pages: 52 (1039 of 1511) Attachment 9.2 Allergan 4010 Tip Drawing CONFIDENTIAL - SUBJECT TO PROTECTIVE ORDER PRODUCED BY ALLERGAN IN CASE NO. 3:12-CV-01141-DRH-DGW ARGN_0002667 Case 3:12-cv-01141-SMY-DGW Document 176-14 *SEALED* Filed 12/01/14 Page 27 of 52 Page ID #2514 Case: 16-3334 Document: 55-32 Filed: 02/08/2017 Pages: 52 (1040 of 1511) Nor 3 2 1 FIMI TCHEMMOMa ' ilit 0.050±.003 .647 .430 .412 0.323±.003 e. 0.421 g,0.344 .337 0.318 0.261 .119 1 D . 30° D — _ 1111101130* 23° .015 — II (ZiaN■ ---- ' 1111. mem. 11101.i. R .015 R.025 0.062 A —0 A . 4forir 10 i V R .06 0.182 ? z A C 2X GATE MARK .025 T REF , 4 - 1 Z 1 5 REF ------ .445 --w-I A ORIFICE PIN 0.0937 .209 —,..-I VI EW 30° ---,--- 13 =3- .005 REF .005 R RIDGE 4 FOR MOLD CONST. c .271 ACROSS FLATS - -4gi — 0.381 B 0.201 R .12- SCALE 81 T re -- ,„, luck", 41 a-o.,......_.iiiZi • --; 0.062 ---' 0.148 SEE VIEW B ... ir...7f. , . .rerir A_ 0.074 .012 ® .RIFICE 006 O 2 L.Jg 5° --- ; • .234 CAVITY IDENT. 45° • ,IMAM% MM WMWM A COMM M WAA. MOMOMOMIMMOMMU ...E3,22.12Mar A ...... i .. Q516 ....Wm IBM EA' AMO' 4 ' 3 A wow Am WM MAW 2 A 13 mm CONTROL NW 119, .009 09WICE 1-22: -IZTEir........ -----____El NOTES: UNLESS 0111ERWISE SPECIFIED NEDICAl i, PLAKE'ESL saw m- A m' 4,11 E00025 i om .. A rir 1 1 t CONFIDENTIAL - SUBJECT TO PROTECTIVE ORDER PRODUCED BY ALLERGAN IN CASE NO. 3:12-CV-01141-DRH-DGW ARGN_0002668 Case 3:12-cv-01141-SMY-DGW Document 176-14 *SEALED* Filed 12/01/14 Page 28 of 52 Page ID #2515 Case: 16-3334 Document: 55-32 Filed: 02/08/2017 Pages: 52 (1041 of 1511) • Attachment 93 UPG9090-12 Drawing • CONFIDENTIAL - SUBJECT TO PROTECTIVE ORDER PRODUCED BY ALLERGAN IN CASE NO. 3:12-CV-01141-DRH-DGW ARGN_0002669 Case 3:12-cv-01141-SMY-DGW Document 176-14 *SEALED* Filed 12/01/14 Page 29 of 52 Page ID #2516 Case: 16-3334 Document: 55-32 Filed: 02/08/2017 Pages: 52 (1042 of 1511) IliIF w 4 3 2 1 4MEr „' tl.L.7,C417/1L9„L„f.i" Ijr6•19. s Fy.,,,,,,,%:,̀ 0 1111111% I 1 0.250 •a• l .6 III 11111 0.028 1. 0.402±0.008 . .0 380±00 .00 02 65 r • 0.050±0.003 0.018 0.089 0.120 MIIIMENEWM ,----.--------..--T IMMIIMEW 0.412 MIDI uv1il l l l i R0.040 22' OMR DM. 0.099 0.090 0.131 0.448 90.200 0.104 011O. °A° 1 I • 131; R0.040 --Mg 0.189i0.003 I Ill , MIL i III 8 d 'mom 018. -c° 1 0.065 0.275 ----0.335 ,._ _. 0.375 , aukN, 0.392*0.006 . ' 0.030 cn — =,..,.. %NW / i CIPPUTER GEMMED OM AUTOCAD ROL Tans oft.. OO A "" CONFIDENTIAL — SUBJECT TO PROTECTIVE ORDER PRODUCED BY ALLERGAN IN CASE NO. 3:12—CV-01141—DRH—DGW 3 ;ANL WE REVISIONS .( 4 a1 M. MEDICAL A ''=•■;!`"' elmam•mote TIP. 35 uL :mr------ NOTES, UNLESS 0111004101 SPECIFIER 4 ORIGINAL ISSLE RESCRIPTIMI ....—..... ,..... MT MY REV E0151101 ...... WEI a la I 1 I ...'' . 1 I ARGN_0002670 Case 3:12-cv-01141-SMY-DGW Document 176-14 *SEALED* Filed 12/01/14 Page 30 of 52 Page ID #2517 Case: 16-3334 Document: 55-32 Filed: 02/08/2017 Pages: 52 (1043 of 1511) Attachment 9.4 UPG15090-12 Drawing CONFIDENTIAL - SUBJECT TO PROTECTIVE ORDER PRODUCED BY ALLERGAN IN CASE NO. 3:12-CV-01141-DRH-DGW ARGN_0002671 Case 3:12-cv-01141-SMY-DGW Document 176-14 *SEALED* Filed 12/01/14 Page 31 of 52 Page ID #2518 Case: 16-3334 Document: 55-32 Filed: 02/08/2017 Pages: 52 (1044 of 1511) W4 3 2 IT' V i .rtir riarrat753,L, OITA"Fie.2 . crEibro IMF 1 0 n Arrillik [0.150 5111. °A° I I 0.090 0111. °Er I — _ . r 0020 - 0.102 0.090 0.093 .., 0.4413 5 4' C 0.38030.006 Om, I 0.250 0.026 R0.200 40.040 0.40230.0013 wirg, %3.3 , 'It 111 0.018 116.,e, 0.05030.003 0.0139 0.120 1.5. - 2 It , AMU „ 1' ------.---.7....----T 22' C 0.412 - -n 0.18930.003 -- 0012 0151.-C° — 0.065 0 275 1 E "1,-0.335 0.375 , 13 3 rs ; 0.39210.008 11 3 0.030 .7,1 0 2 — ... REV =MED GENERATED DOC ATOCAD RD. ■.. A.ma mmu l NOTES; UWE= OTFIERVISE SPECIFIED I %UM DATE APPVI. PEVISIENS .. =Ir.= •r• ..11... A MGR. ISSUE DESCREPTIEN MO- MEDICAL PLASTICS 2323 MINA IL SANTA ' ..' Oa ) TIRE OKA. CA WOD-STAI A TIP, 45 uL E0191201 r A 4 CONFIDENTIAL — SUBJECT TO PROTECTIVE ORDER PRODUCED BY ALLERGAN IN CASE NO. 3:12—CV-01141—DRH—DGW 3 2 1 ARGN_0002672 Case 3:12-cv-01141-SMY-DGW Document 176-14 *SEALED* Filed 12/01/14 Page 32 of 52 Page ID #2519 Case: 16-3334 Document: 55-32 Filed: 02/08/2017 Pages: 52 (1045 of 1511) Attachment 9.5 40979(41351LH) Tip Drawing Ô CONFIDENTIAL - SUBJECT TO PROTECTIVE ORDER PRODUCED BY ALLERGAN IN CASE NO. 3:12-CV-01141-DRH-DGW ARGN_0002673 Case 3:12-cv-01141-SMY-DGW Document 176-14 *SEALED* Filed 12/01/14 Page 33 of 52 Page ID #2520 Case: 16-3334 Document: 55-32 Filed: 02/08/2017 Pages: 52 (1046 of 1511) iq 4 4 3 fo... A COPY Martaraelligginftwel R.040 0.06a/.012 0.069 0279 SECTION A-A OCIA 116/4110/ nal CAD WO 1100 0[0314010 01RM0604161110.2 SURCAORLI2 sum.••• nsv_..74 4:'4 Qirl •••■■•• mmm a. acnmr,. onyx:ma 60_114 MemitROUnaki.WILVwd itt":1=. B5nn TIP. DROPPER =ERREEFEE=I ,114:10. MIED LEIESS EMMA= SPECIFIED 4 CONFIDENTIAL - SUBJECT TO PROTECTIVE ORDER PRODUCED BY ALLERGAN IN CASE NO. 3:12-CV-01141-DRH-DGW INPPYL 118.111,1604 3 2 EMU. 1 2,t I ,. 1 1 ARGN_0002674 Case 3:12-cv-01141-SMY-DGW Document 176-14 *SEALED* Filed 12/01/14 Page 34 of 52 Page ID #2521 Case: 16-3334 Document: 55-32 Filed: 02/08/2017 Pages: 52 (1047 of 1511) Attachment 9.6 0 • UPG9090-12 Certificate of Compliance CONFIDENTIAL - SUBJECT TO PROTECTIVE ORDER PRODUCED BY ALLERGAN IN CASE NO. 3:12-CV-01141-DRH-DGW ARGN_0002675 Case 3:12-cv-01141-SMY-DGW Document 176-14 *SEALED* Filed 12/01/14 Page 35 of 52 Page ID #2522 Case: 16-3334 Document: 55-32 Filed: 02/08/2017 Pages: 52 (1048 of 1511) United Plastics Group,Inc. • Certificate of Compliance Samples Provided Customer: TOKEN B TECHNOLOGY P.O.NUMBER: 4600006692 Ship Date: March Pad Description: TIP DROPPER A-.090,B-.090,C-.012 REVISION: ENG 16, 2001 Quantity: 10 Part Number Work Order: 222880 •Material Info 1103938 Resin Type: LOPE UL Listing #: C3178-0 ÷ Trade Name: POLYPROPYLENE apat,,eee,g, UL Number: E10274055 Comments: ENG SAMPLES Resin Number: 20-6064 W/CONC.0342LMB , 9/./6)2Job #: N2309 Color: WHITE Manufacturer DUPONT Mfr Lot Number: The preceding information, andparts submitted, have been inspected and certified to conform to the applicable part number and revision. March 16, 2001 45531 Northrop Loop West, Fremont, CA 94;;8 - CONFIDENTIAL - SUBJECT TO PROTECTIVE ORDER PRODUCED BY ALLERGAN IN CASE NO. 3:12-CV-01141-DRH-DGW 10)657-5800, Fax (510)657-6019 ARGN_0002676 Case 3:12-cv-01141-SMY-DGW Document 176-14 *SEALED* Filed 12/01/14 Page 36 of 52 Page ID #2523 Case: 16-3334 Document: 55-32 Filed: 02/08/2017 Pages: 52 (1049 of 1511) Attachment 9.7 UPG15090-12 Certificate of Compliance CONFIDENTIAL - SUBJECT TO PROTECTIVE ORDER PRODUCED BY ALLERGAN IN CASE NO. 3:12-CV-01141-DRH-DGW ARGN_0002677 Case 3:12-cv-01141-SMY-DGW Document 176-14 *SEALED* Filed 12/01/14 Page 37 of 52 Page ID #2524 Case: 16-3334 Document: 55-32 Filed: 02/08/2017 Pages: 52 (1050 of 1511) United Plastics Group,Inc. • Certificate of Compliance Samples Provided Customer: TOKEN B TECHNOLOGY Part Description: TIP DROPPER Part Number A-150,B-090,C-.012 REVISION: ENG P.O.NUMBER: 4600006692 Ship Date: March 16, 2001 Quantity: 10 Work Order: 222880 •htlatertal Info Manufacturer DUPONT Resin Type: LDPE Trade Name:-POLYPROPYLENE aperutResin Number: 20-6064 W/CONC.0342LMB Color: WHITE Mfr Lot Number 1103938 UL Listing #: C3178-0 + ib6v UL Number: E10274055 Comments: ENG SAMPLES Job*: N2309 The preceding information, and parts submitted, have been inspected and certified to conform to the applicable part number and revision. March 16, 2001 SIGNATUR 45581 Northrop Loop West, Fremont, CA 94538 - (510)657-5800, Fax (510)657-6019 CONFIDENTIAL — SUBJECT TO PROTECTIVE ORDER PRODUCED BY ALLERGAN IN CASE NO. 3:12—CV-01141—DRH—DGW ARGN_0002678 Case 3:12-cv-01141-SMY-DGW Document 176-14 *SEALED* Filed 12/01/14 Page 38 of 52 Page ID #2525 Case: 16-3334 Document: 55-32 Filed: 02/08/2017 Pages: 52 (1051 of 1511) • Attachment 9.8 Token B Technology First Article Report CONFIDENTIAL - SUBJECT TO PROTECTIVE ORDER PRODUCED BY ALLERGAN IN CASE NO. 3:12-CV-01141-DRH-DGW ARGN_0002679 Case 3:12-cv-01141-SMY-DGW Document 176-14 *SEALED* Filed 12/01/14 Page 39 of 52 Page ID #2526 Case: 16-3334 Document: 55-32 Filed: 02/08/2017 Pages: 52 (1052 of 1511) • roken 13 Technology April 18, 2001 Mr. Lon Spada Sr. Project Engineer Allergan 2525 Dupont Drive Irvine, CA 92623-9534 R.E: 4-Cavity 1&t Tip Mold First Article Lori, Please review the attached first article for all 8 configurations ofthe new tip mold manufactured by UPG in Fremont California. The dimensions look good and these tips should be functional for drop size studies. When you review the data arid the reference drawing you will note that the dimension (tip diameter) is very accurate and consistent. The"G" dimension (inside orifice) was very good at .012 diameter but the small diameter at.00e had some• variation. The average diameter range was .0053" to .0079. I believe a lot of the variation was due to the difficulty in actually taking the measurement. The "I" dimension is for reference only as the radius on the outside of the tip makes it impossible to determine the true diameter. Based on an estimation diameter the tips are close to the required dimension. Still with all things considered the tips are very accurate and should perform consistently during drop size studies. Please review this first article and let me know when you are ready to order more tips from UPG for drop weight studies. We also need to consider going to UPG (if you have time)to review the sample run and tour their facility. Sincerely, • Paul Butorac Engineering Consultant 2163 I Midcrest Dr., .[..ake Forest., CA. 92K-;C CONFIDENTIAL - SUBJECT TO PROTECTIVE ORDER PRODUCED BY ALLERGAN IN CASE NO. 3:12-CV-01141-DRH-DGW Cc: Enclosure í (949) 9$1-4620', Fax (94)) 951-4620 ARGN_0002680 Case 3:12-cv-01141-SMY-DGW Document 176-14 *SEALED* Filed 12/01/14 Page 40 of 52 Page ID #2527 Case: 16-3334 Document: 55-32 Filed: 02/08/2017 Pages: 52 (1053 of 1511) Tip Mold Allergan 4-Cavity First Article Report FIRST ARTICLE 4 CAVITY TIP MOLD o BCD 008 A 0.084 0.084 0.375 I 0.000 SAMP V /SPEC > 0.392 I 0.189 I 0.446 0.05 0.396 0.00515 I 0.06412 [0.39435 I 0.05023 t 0.19045 I 0.44457 I 0.39072 I 0.37429 1 0.39112 I 0.37516 I 0.00532 I 0.06356_ 471 ûs85 0_04938 0.44574 2 0.19017 0.06356 0.39077 0.37406 ,. 0.00517 044563 0.04978 _ 0.18881 0.39459 3 0.06377 037463 0.00535 0.38956 0.1899 0.4482 4 0.04994 0.39467 _ _ 0.08384 0.37504 0.00538 0.39104 0.44566 0.18918 0.04931 0.39532 5 0.3 0.3906 0.4458 0.1897 0.3949 Mean +/-filynspeo (3).124/.064/.008 0.124 0.375 0.392 SAMP V / SPEC 0.189 0.06324 0.12342 l 0.37423 0.39042 0.0511 1 1 0.39245 0.06271 l 0.11702 0.37345 0.38986 0.1919 0.05102 0.06261 l 0.12065 0.37408 0,38973 0.18903 0.05107 I 0.39424 3 0.06276 l 0.12006 0.37507 0.39153 0.4472 0.18819 0.05042 0.39039 I 0.37415 1 0.0083 1 0.06314 l 0.12099 0.18935 0.05078 0.1204 0.0629 0.0069 0.3742 0.3904 0.1898 Mean l 0.3938 -0.0011 l -0.0036 -0.0016 © .090/.090/.006 SAMP V SPEC > I 0.391 1 0.3903 3 4 5 Mean Mean 4.1- from spec • 0.375 0.392 0.189 0.37437 0.44715 0.18929 0.37558 0.39185 0.18753 1 0.39157 1 0.05084 1 0.19852 l 0.44758 J 0.39105 J 0.37523 1 0.38879 1 0.04826 1 0.188138 l 0.44757 l 0.39079 l 0.37444 037483 0.39155 0.4487 0.1876 038993 0t4923 0.3749 0.3910 0A479 0.1884 0.0497 0.3902 0.38000 0.37793 0,37768 0.37875 0.3779 -0.0022 1 0.380 I 1 1 1 I 1 1 0.37704 0.37739 0.37788 0.37987 0.37859 0.3781 -0.0019 0.380 0.37870 0.38062 0.04973 0.0491 0.0497 0.3914 -0.0046 1 -0-0003 Performed By Paul Butorac 4/17/2001 ' CONFIDENTIAL - SUBJECT TO PROTECTIVE ORDER PRODUCED BY ALLERGAN IN CASE NO. 3:12-CV-01141-DRH-DGW 0.18858 0.1894 0.0004 0.00823 0.0075 0.ce178 0.0913 0.09107 0.00545 0.00802 l 0.0912 l 0.00774 l 0.09158 l 0.09128 0.00766 0.09066 0.00768 0.37389 0.38904 0.4422 0.0079 0.3748 0.3907 0.4454 0.0012 I -0.0006 1 -0.0013 1 -0.0002 1 0.0019 0.313W4 tti*A f 4,4 104.;;. 0.14882 0.15012 0.15094 0.1506 0.15083 0.1503 0.13003 1 1 1 1 0.3798 0.38116 0.38070 0.37890 0.37849 0.37683 0.3788 -0.0012 Page I of 3 ARGN_0002681 Case 3:12-cv-01141-SMY-DGW Document 176-14 *SEALED* Filed 12/01/14 Page 41 of 52 Page ID #2528 Tip Mold Allergan 4-Cavity Case: 16-3334 Document: 55-32 Filed: 02/08/2017 Pages: 52 (1054 of 1511) First Article Report • 1 (E).0641.064t012 SAMP V / SPEC 1 2 _ 3 ._. 4 5 Mean +/- from spec (F).124/.064/.012 SAMP V /SPEC 1 2 3 4 5 Mean +/- from spec (G).090/.090/.012 SAW, V / SPEC ,. • a. _ 1 3 5 Mean +/- from spec (H).1501.0901.012 SAMP V / SPEC P, 1 2 3 4 5 Mean +/- from spec A 0.396 0.39705 039762 a39722 0.39599 0.39802 0.3972 a0012 A a398 0.39615 0.39548 0.39406 0.39573 0.39592 0.3955 -0.0005 A 0.396 0.39337 0.39418 a39385 a39516 0.39501 a3943 -a0017 A 0 396 0.39395 0.39268 0.39348 0.39469 0.39251 0.3936 -0.0025 B 0.05 0.04797 0.04924 0.04934 005081 0.04887 0.0492 -0.0008 B 0.05 0.0486 0.04904 0.04878 0.05196 0.05082 0.0498 -0.0002 B 0.05 0.04957 0.05044 0.05026 a05084 0.05085 0.0504 00004 B a05 0.05122 0.0508 0.051 0.05068 .. 0.05158 0.0511 0.0011 C O 189 0.19124 0 18722 0.19188 0.18804 0.1898 0.1896 0 0006 D 0.448 0.44229 0.4432 a44374 044336 0.44291 0.4431 -0.0029 • 0.189 0.19059 0.19151 0.19305 0.19011 0.19003 0.1911 0.0021 C 0.189 0.19212 0.18872 a19081 0.18814 0.18889 a1897 a0007 C A189 0.18855 0.18961 0.1901 0.18793 0.18983 0.1892 0.0002 0446 0.44289 0.44105 0.44236 0.44509 0.44557 E 0.392 0.38715 0.39031 0.38918 0.3907 0.38713 0.3889 -a0031 E a392 0.38578 0.38731 0.38793 0.39075 0.38939 F 0.375 0.37239 0.37382 0.37291 0.37427 0.37414 0.3735 -0.0015 F 0.375 0.37356 0.37237 0.37292 0.37458 0.37349 G 0.012 0.0125 0.01264 0.01264 0.01251 0.01241 0.0125 0.0005 G 0.012 0.01217 0.01219 0.01223 0.01225 0.01224 0.4434 0.3882 0.3734 0.0122 -0.0026 D 0.446 0.4404 0.44603 0.44338 044557 0.44532 -0.0038 E 0.392 0.38807 0.38972 a38862 a38985 0.38931 -0.0016 F 0.375 0.37319 0.37424 0.37343 0.37489 0.37493 0.0002 G 0.012 0.01244 0.0121 a01213 0.01209 0.0123 0.1262 0.3891 0.3741 0.0122 0.0914 -0.0029 E 0.392 0.39069 0.39027 0.39119 0.39057 0.39092 0.3907 -0.0013 -0 0009 0.0002 G 0.0014 H a09 0.09127 0.08958 0.09046 0.09039 0.09124 0.0906 0.0006 0.01285 0.01275 0.01269 0.01269 0.01261 0.0127 0,0007 I 0.124 0.12537 0.12708 0.12843 0.12356 0.12631 -0.0032 J a390 0.37287 0.37578 0.37499 0.37889 0.37812 0.0831 0A441 a0/2 , 1 4' :-/ 0.3768 .4 0.3761 -0.0039 J 0.380 0.37679 0.37918 0.37689 0.37882 0.37869 0.0022 -0.0009 H 1 0.09 0.09 0.09161 0.0917 0.09001 0.09202 0.09161 ' -0.0019 D a446 0.44657 0.44506 0.44602 0.44595 0.44551 0.4458 -0.0002 F 0.375 0.37427 0.37415 0.37391 0.37191 0.37352 0.3738 -0_0014 , A J 0.380 0.37494 a37725 a37664 0.37717 0.37798 I 0.084 H 0.064 0.06352 0.0629 a08309 006299 0.0835 0.0832 -0.0008 H 0.064 0.06294 0.06298 0.0634 0.063 0.06295 0.3781 41r4 ' 1% 1 0.15 0.14789 0.14985 0.15225 0.14992 0.14736 0.1495 -0.0005 -0 0019 J a380 0.37868 0.37876 0.37791 • . 0.37683 0.37719 0.3779 -0.0021 Values are for reference only. Dimension "r is not accurate. The diameter is not clearly defined because of the edge radius. • Performed By: Paul Butorac.e4 r 4/17/2001 CONFIDENTIAL - SUBJECT TO PROTECTIVE ORDER PRODUCED BY ALLERGAN IN CASE NO. 3:12-CV-01141-DRH-DGW Page 2 of 3 ARGN_0002682 Case 3:12-cv-01141-SMY-DGW Document 176-14 *SEALED* Filed 12/01/14 Page 42 of 52 Page ID #2529 Case: 16-3334 Document: 55-32 Filed: 02/08/2017 Pages: 52 (1055 of 1511) .c.s...noo: 124 ,so (I) Page 3 of 3 r■-.1 .064/.090 (1-1) .446 CD) I 1 .310(3) -296(A) .050(B), .1135.(C) .006/.012(0) (II) Dina (I) .064 1 .064 .064 .124 .090 .090 .090 .150 .064 .064 .064 .124 .090 1 .09e .090 Tip 11) Dim(G) A j .006 B .006 1 .006 C i I) I I .006 i E .012 7-1 F 012 .012 1 G II .012 ' CM,13010.1.104 I SCAM 4/17/01 totrame. I DUPONT LDPE 20-6064 First Article Reference eArD6v. Allergan 4-Cavity Tip Mold asna IA -017 I.D0 Nor SCALE ondkarim•ra :T22 .091.a.'3 I — P. Butorac Token B Technology • CONFIDENTIAL — SUBJECT TO PROTECTIVE ORDER PRODUCED BY ALLERGAN IN CASE NO. 3:12—CV-01141—DRH—DGW ARGN_0002683 Case 3:12-cv-01141-SMY-DGW Document 176-14 *SEALED* Filed 12/01/14 Page 43 of 52 Page ID #2530 Case: 16-3334 Document: 55-32 Filed: 02/08/2017 Pages: 52 (1056 of 1511) Token B Technology Mr. Lon Spada Sr. Project Engineer Allergan 2525 Dupont Drive Irvine, CA 92623-9534 RE: 4-Cavity April 18, 2001 D Tip Mold First Article Lon, Please review the attached first article for all 8 configurations of the new tip mold manufactured by UPG in Fremont California. The dimensions look good and these tips should be functional for drop size studies. When you review the data and the reference drawing you will note that the "H" dimension (tip diameter) is very accurate and consistent. The "Cr" dimension(inside orifice) was very good at .012" diameter but the small diameter at .006" had some variation. The average diameter range was .0053" to .0079. I believe a lot of the variation was due to the difficulty in actually taking the measurement. The"r dimension is for reference only as the radius on the outside ofthe tip makes it impossible to determine the true diameter. Based on an estimation diameter the tips are close to the required dimension. Still with all things considered the tips are very accurate and should perform consistently during drop size studies. Please review this first article and let me know when you are ready to order more tips from UPG for drop weight studies. We also need to consider going to UPG (if you have time)to review the sample run and tour their facility. Sincerely, Paul Butorac Engineering Consultant 2 1 631 Miderest Dr., Lake Forest, CA. 926"il; • CONFIDENTIAL - SUBJECT TO PROTECTIVE ORDER PRODUCED BY ALLERGAN IN CASE NO. 3:12-CV-01141-DRH-DGW Ce: Enclosure (949)951-4620. Fax (949)95.1-4520 ARGN_0002684 Case 3:12-cv-01141-SMY-DGW Document 176-14 *SEALED* Filed 12/01/14 Page 44 of 52 Page ID #2531 Case: 16-3334 Document: 55-32 Filed: 02/08/2017 Pages: 52 (1057 of 1511) Tip Mold AliergaN First Article Report • .FIRST ARTICLE 4 CAVITY TIP MOLD ' A .0E14/.0844006 8 A SAMP V / SPEC > 0.398 0.05 039435 0.05023 2 0.39565 0.04938 3 0.04978 0.39459 4 0.39487 004994 0.04931 5 0.39532 0.0497 Mean 0.3849 +/- from spec -0.0011 -0.0003 8 (B).124/.084/006 A 1 S PV/SPEC> 0.390 0.05 1 110511 0.39245 0.39409 (105102 3 0.39424 0.05107 • 4 0.05042 0.39,488 0.39338 0.05078 5 0.0808 0.3938 Mean +/-from spec 0.0009 -0.0022 A 0 090/.090/.008 13 SAMP V / SPEC > 0,390 0.05 0.39032 0.04973 1 0.05055 2 0.39063 0.05084 0.39157 0.04826 4 0.38879 0.04923 0.38993 5 0.0487 0.3902 Mean 44- from spec -0.0003 -0.0058 B A (D).150/.090/.008 SAMP V / SPEC > 0.05 0.398 0.05085 0.39027 1 0.04937 039163 2 0.05003 0.39156 • • 3 0.0493 0.39214 0.0491 0.39121 5 0.0497 0.3914 Mean -0.0003 44- from spec -0.0046 • • Performed By: Paul Butorac 4/17/2001 CONFIDENTIAL - SUBJECT TO PROTECTIVE ORDER PRODUCED BY ALLERGAN IN CASE NO. 3:12-CV-01141-DRH-DGW C 0.189 0.19045 0.19017 0.18881 0.1899 0.18918 0.1897 0.0007 C 0.189 0.19062 0.1919 0.18903 0.18819 0.18935 0.1898 0.0008 C 0.189 0.18929 0.18753 0.18852 0.18888 0.1876 0.1884 -0.0008 C 0.189 0.18825 0.19108 0.18984 0.18919 0.18858 0.1894 0.0004 D 0.448 044457 0.44574 0.44563 0.4462 0.44566 0.4458 -0.0004 D 0.448 0,44685 0.44819 íE7. o.on 0.44738 0.4469 0.0009 D 0.448 044715 0.44831 0.44758 0.44757 0.4487 0.4479 0.0019 D 0.448 0.44822 0.44498 0.44722 0.44453 0.4422 0.4454 -0.0006 E 0.392 0.39072 0.39112 0.39077 0.38958 0.39104 0_3906 -0.0014 E 0.392 0.39042 0.38986 0 38973 0.39153 0.39039 0.3904 -0.0016 E 0.392 0 38979 0.39185 0.39105 0.39079 0.39155 0.3910 -00010 E 0.392 0.39299 0.39198 0.39108 0.38833 0.38904 0.3907 -0.0013 F 0.375 037429 0.37515 0.37406 0.37453 0.37504 0.3748 -0.0004 F 0.375 0.37423 0.37345 0.37406 0.37507 0.37415 0.3742 -0.0008 F 0.375 0.37437 0.37558 0.37523 037444 0.37483 0.3749 -0 0001 F 0.375 0.37592 0.37525 0.37463 0.37422 0.37389 0.3748 -0.0002 0 0.008 0.00515 0.00532 0.00517 000535 0.00538 0.0083 -00007 0 0.000 0005139 0.00579 0.00581 0.00564 0.0083 0.0089 -0.0001 0 0.008 0.00684 0.00735 0.00742 0.00745 0.00823 0.0076 0.0015 G 0.008 j 0.00845 0.00802 0.00774 0.00766 0.00768 0.0079 0.0019 H 0.084 0.06412 0.06356 0.08356 0.06377 0.08364 0.0837 -0.0003 H 0,084 0.06324 008271 I 0.084 1 •v .y. r ' , rg, I 0.124 0.12342 0.11702 0.12065 0.12006 0.12099 0.1204 -0.0038 I 0.09 0.08261 0.06276 006314 0.0529 -0.0011 H 0.09 0.09127 0.09091 0.091E35 0.09088 0.09178 0.0913 0 0.0013 g e tpa I H 0.09 I 0.15 I 0.14882 0.09107 0.15012 0.0912 0.15094 0.09158 0.1506 0.09128 0.15083 0.09066 0.1503 0.0912 0.0003 0.0012 • J 0.38000 0.37793 0.37768 0.37807 0.37682 0.37875 0.3779 -0.0022 J 0.380 0.37704 0.37739 0.37788 0.37967 0.37859 0.3781 -0.0019 J 0.380 0.37870 0.38082 0.38002 037906 0.38064 0.3788 -0.0002 J 0.380 0.38116 0.38070 0.37890 0.37849 0.37663 0.3788 -00012 i Page 1 of 3 ARGN_0002685 Case 3:12-cv-01141-SMY-DGW Document 176-14 *SEALED* Filed 12/01/14 Page 45 of 52 Page ID #2532 Case: 16-3334 Document: 55-32 Filed: 02/08/2017 Pages: 52 (1058 of 1511) Tip iViold Allergan 4-Cavity First Article Report (E).0641.064/.012 SAMP V / SPEC > A 0.398 039705 0.39762 C D 0.189 1 0.448 a44229 0.19124 1 004924 0.18722 0A432 2 3 0.39722 0.04934 0.19188 044374 4 0.18804 0.44336 0.39599 005001 5 039802 0.04887 0.1898 0A4291 0.0492 0.1896 0.4431 0.3972 Mean +/- from spec 0.0012 -a0008 0.0006 . -0 0029 D (F)1241.064/.012 B C A . SAMP V/ SPEC > 0.448 anti a05 , 0189 0.44289 1 0.19059 0.0488 1 0.39815 0.19151 s 0.44105 0.39548 . 0.04904 2 0.19305 _ 0.44236 0.04878 3 0.39406 0.44509 0.19011 4 • 0.39573 , 0.05196 0.44557 _ 0.19003 0,05082 5 0.39592 0.4434 0.1911 0.0498 0.3955 Mean -0.0026 0.0021 -14- from spec -0.0002 -0.0005 D B C (G).090/.090/.012 - A SAW V / SPEC 3, 0.448 0.398 0.189 0.05 019212 04404 039337 0.04957 1 0.18872 044603 0,39418 s 005044 2 0.39385 005026 a19081 044336 3 a39516 005064 - 0.18814 , 0.44557 4 039501 005085 0.18889 0.44532 5 0.4441 0.1897 0.0504 0.3943 Mean 0.0067 -00019 +/- from spec -0 0017 _ 00004 D C B A (H).150/.090/.012 0448 SAMP V / SPEC > 0.189 0.396 005 0.44657 _ 0.18855 0.05122 0.39395 1 0.44506 0.18961 0.0508 0.39268 2 0.44602 0.1901 0.051 0.39348 3 0.44595 0.18793 0.05068 0.39469 4 0.44551 0.18983 0.05158 0.39251 5 0.4458 0.1892 0.0511 ' 0.3935 Mean -0.0002 1T- 0.0002 0.067 -0.0025 +/- from spec 8 0.08 a04797 4 -- J 1 H F G 0.380 I0.084 0.084 I 0.012 0.375 037494 06352 0 0.0125 37239 0 0.38715 9 0.37726 0 39031 0.37382 001284 0.0629 0.37664 0.06309 0.37291 001284 0.38918 037717 0.06299 001251 037427 0.3907 0 37798 038713 0.37414 0.01241 00635 0.3768 0.0632 0.3889 , 0.3735 : 0.0125 -0 0032 -0.0008 0.0005 -0.0015 -0.0031 1 H _ J G F --y 0380 0124 0084 0.012 a a . 0.37287 0.12537 0.01217 '., 0.013294 037356 0.38578 0.12708 s 0.37578 0.37237 _ 0.01219 1 0.06296 0.38731 0.37499 0.12843 0.0634 0.01223 0.38793 s 0.37292 0.37889 0.12356 0.063 0.01225 0.39075 s 0.37458 0.37812 0.12631 0.06295 0.37349 0.01224 0.38939 0.3761 0.1262 0.0631 0.0122 0.3734 0.3882 -0.0039 0.0022 -0.0009 0.0002 -0.0016 -0.0038 J 1 H F G E 0.09 10.380 0.09 0.012 0.375 0.392 037679 0.09161 001244 0.37319 038807 037918 0.0917 a 0.0121 037424 s 038972 0.09001 0 37689 0.01213 017343 0.38862 0.37882 0.01209 , 0.09202 0.37489 0.38985 0 37869 ..1 4. 00123 , 0.09181 , 0.37493 0 38931 0_3781 'A,:e 00)14 0.0122 0.3741 0.3891 -0.0019 0.0014 ( , -0.0029 -00009 00002 .. _. J __ 1 H G F E 0380 015 009 0012 0375 0392 0.37868 0.14789 0.09127 0.37427 s 0.01285 0.39069 0.37876 0.14985 0.08958 0.01275 0.37415 0.39027 0.37791 0.15225 0.09046 0.01269 0.37391 0.39119 0.14992 0.37683 0.09039 0.01269 0.37191 0.39057 0.37719 0.09124 s. 0.14736 0.01261 0.37352 0.39092 0.1495 0.3779 0.0906 0.3736 - 0.0127 0.3907 -0.0021 -0.0005 0.0006 0.0007 -0.0014 -0.0013 E 0.392 • • reference only. Dimension T is not accurate. The diameter is not clearly defined because of the edge radius. Values are for • Performed By: Paul Butorac7,_) 4/17/2001 CONFIDENTIAL - SUBJECT TO PROTECTIVE ORDER PRODUCED BY ALLERGAN IN CASE NO. 3:12-CV-01141-DRH-DGW Page 2 of 3 ARGN_0002686 Case 3:12-cv-01141-SMY-DGW Document 176-14 *SEALED* Filed 12/01/14 Page 46 of 52 Page ID #2533 Case: 16-3334 Document: 55-32 Filed: 02/08/2017 Pages: 52 (1059 of 1511) .064/.090/.124/.1.50(1) Page 3 of 3 .0644000 al) .446C0) .380(3) .396(A) 050(13). .189(C) .006.012(0) Tip 1D, A B C D G H Dim(G) Dim(H) Dim(I) .064 .006 .064 .064 _124 , .006 • 1 .006 .090 .090 .090 .150 l .006 .064 .064 .012 .064 .1124 .012 .090 .012 .090 90 1 .012 .150 SCALM JOT2 N/A nu= 4)17101 wamme. DUPONT LDPE 20-6064 • CONFIDENTIAL - SUBJECT TO PROTECTIVE ORDER PRODUCED BY ALLERGAN IN CASE NO. 3:12-CV-01141-DRH-DGW DART HALO Allergan 4-Cavity Tip Mold A xn7i DO NOT SCALE DRAWING 1F2:2991 3 First Article Reference , 1„()hen 3Technoogy , P. fltl .11t0Tat • ARGN_0002687 Case 3:12-cv-01141-SMY-DGW Document 176-14 *SEALED* Filed 12/01/14 Page 47 of 52 Page ID #2534 Case: 16-3334 Document: 55-32 Filed: 02/08/2017 Pages: 52 (1060 of 1511) • Currently Approved and Proposed Substitute Bottle Configuration Product Name NBA/Supplement Current MP 540 Formubtion Current Waco Proposed Waco Fill/Container Sizes Bottle Type FiWContainer Sizes Bottle Type Other Product , NDA 21-262JS-010 Alphagan P 9174X 3 mL/10 nal, Boston Round 3 m1/5 niL MP 503 1 Alphagan P NDA 21-262/S-010 9I74X 5 mi./101111. Boston Round 5 InLI10 mL MP 503 Alphagan P NDA 21-2621S-010 9174X 10 In.U10 ml- Boston Round 10 mL/10 m1, MP 503 Alphagan P NDA 21-262/S-010 9174X 15 In1/15 ml, os,B ton Round 15 mL/15 rni MP 504 I Other Product jr 1 of 6 CONFIDENTIAL — SUBJECT TO PROTECTIVE ORDER PRODUCED BY ALLERGAN IN CASE NO. 3:12—CV-01141—DRH—DGW ARGN_0002688 Case 3:12-cv-01141-SMY-DGW Document 176-14 *SEALED* Filed 12/01/14 Page 48 of 52 Page ID #2535 Case: 16-3334 Document: 55-32 Filed: 02/08/2017 Pages: 52 (1061 of 1511) Currently Approved and Proposed Substitute Bottle Configuration Product Name NDA/Supplement MP 500 Current Proposed Waco Formulation Current Waco Fill/Container Sizes Bottle Type Fill/Container Sizes Bottle Type Other Product 2 of 6 CONFIDENTIAL - SUBJECT TO PROTECTIVE ORDER PRODUCED BY ALLERGAN IN CASE NO. 3:12-CV-01141-DRH-DGW ARGN_0002689 Case 3:12-cv-01141-SMY-DGW Document 176-14 *SEALED* Filed 12/01/14 Page 49 of 52 Page ID #2536 Case: 16-3334 Document: 55-32 Filed: 02/08/2017 Pages: 52 (1062 of 1511) Currently Approved and Proposed Substitute Bottle Configuration Product Name NDA/Supplement MP 500 Formulation Current Waco Proposed Waco Current Fill/Container Sizes Bottle Type Fill/Container Sizes Bottle Type Other Product 3 of 6 CONFIDENTIAL - SUBJECT TO PROTECTIVE ORDER PRODUCED BY ALLERGAN IN CASE NO. 3:12-CV-01141-DRH-DGW ARGN_0002690 Case 3:12-cv-01141-SMY-DGW Document 176-14 *SEALED* Filed 12/01/14 Page 50 of 52 Page ID #2537 Case: 16-3334 Document: 55-32 Filed: 02/08/2017 Pages: 52 (1063 of 1511) • • Currently Approved and Proposed Substitute Bottle Configuration NDAJSupplement Proposed Waco MP 500 Current Formulation Current Waco Fill/Container Sizes Bottle Type Fill/Container Sizes Bottle Type Lumigan I NDA 21-275/S-007 9106X 3 mL/8 mL Boston Round 3 mL/5 mL MP 500 Lumigan 1 NDA 21-275/8-007 9106X 5 mL/8 mL Boston Round 5 mL/10 mL MP 503 Lumtgan 1 NDA 21-275/S-007 1 9106X 7.5 mL/8 mL Boston Round 7.5 mL/10 mL MP 503 Product Name 1 J 1 Other Product 1 4 of 6 CONFIDENTIAL — SUBJECT TO PROTECTIVE ORDER PRODUCED BY ALLERGAN IN CASE NO. 3:12—CV-01141—DRH—DGW ARGN_0002691 Case 3:12-cv-01141-SMY-DGW Document 176-14 *SEALED* Filed 12/01/14 Page 51 of 52 Page ID #2538 Case: 16-3334 Document: 55-32 Filed: 02/08/2017 Pages: 52 (1064 of 1511) • • Currently Approved and Proposed Substitute Bottle Configuration Product Name NDA/Supplement IMP 500 Formulation 'Current Waco 'Current 'Proposed Waco Fill/Container Sizes'Bottle Type Fill/Container Sizes IBottle Type Other Product 5 of 6 CONFIDENTIAL - SUBJECT TO PROTECTIVE ORDER PRODUCED BY ALLERGAN IN CASE NO. 3:12-CV-01141-DRH-DGW ARGN_0002692 Case 3:12-cv-01141-SMY-DGW Document 176-14 *SEALED* Filed 12/01/14 Page 52 of 52 Page ID #2539 Case: 16-3334 Document: 55-32 Filed: 02/08/2017 Pages: 52 (1065 of 1511) Ô • Currently Approved and Proposed Substitute Bottle Configuration Product Name NDA/Supplement Current 'Proposed Waco MP 500 Formulation Current Waco Fill/Container Sizes Bottle Type Fill/Container Sizes Bottle Type Other Product ■4 ■, 6 of 6 CONFIDENTIAL - SUBJECT TO PROTECTIVE ORDER PRODUCED BY ALLERGAN IN CASE NO. 3:12-CV-01141-DRH-DGW ARGN_0002693 Case 3:12-cv-01141-SMY-DGW Document 176-40 *SEALED* Filed 12/01/14 Page 1 of 2 Case: 16-3334 Document:Page 55-33ID #3283 Filed: 02/08/2017 Pages: 2 (1066 of 1511) Case 3:12-cv-01141-SMY-DGW Document 176-40 *SEALED* Filed 12/01/14 Page 2 of 2 Case: 16-3334 Document:Page 55-33ID #3284 Filed: 02/08/2017 Pages: 2 (1067 of 1511) Case 3:12-cv-01141-SMY-DGW Document 176-15 *SEALED* Filed 12/01/14 Page 1 of 65 Page ID #2540 Case: 16-3334 Document: 55-34 Filed: 02/08/2017 Pages: 65 (1068 of 1511) Case 3:12-cv-01141-SMY-DGW Document 176-15 *SEALED* Filed 12/01/14 Page 2 of 65 Page ID #2541 Case: 16-3334 Document: 55-34 Filed: 02/08/2017 Pages: 65 (1069 of 1511) Case 3:12-cv-01141-SMY-DGW Document 176-15 *SEALED* Filed 12/01/14 Page 3 of 65 Page ID #2542 Case: 16-3334 Document: 55-34 Filed: 02/08/2017 Pages: 65 (1070 of 1511) Case 3:12-cv-01141-SMY-DGW Document 176-15 *SEALED* Filed 12/01/14 Page 4 of 65 Page ID #2543 Case: 16-3334 Document: 55-34 Filed: 02/08/2017 Pages: 65 (1071 of 1511) Case 3:12-cv-01141-SMY-DGW Document 176-15 *SEALED* Filed 12/01/14 Page 5 of 65 Page ID #2544 Case: 16-3334 Document: 55-34 Filed: 02/08/2017 Pages: 65 (1072 of 1511) Case 3:12-cv-01141-SMY-DGW Document 176-15 *SEALED* Filed 12/01/14 Page 6 of 65 Page ID #2545 Case: 16-3334 Document: 55-34 Filed: 02/08/2017 Pages: 65 (1073 of 1511) Case 3:12-cv-01141-SMY-DGW Document 176-15 *SEALED* Filed 12/01/14 Page 7 of 65 Page ID #2546 Case: 16-3334 Document: 55-34 Filed: 02/08/2017 Pages: 65 (1074 of 1511) Case 3:12-cv-01141-SMY-DGW Document 176-15 *SEALED* Filed 12/01/14 Page 8 of 65 Page ID #2547 Case: 16-3334 Document: 55-34 Filed: 02/08/2017 Pages: 65 (1075 of 1511) Case 3:12-cv-01141-SMY-DGW Document 176-15 *SEALED* Filed 12/01/14 Page 9 of 65 Page ID #2548 Case: 16-3334 Document: 55-34 Filed: 02/08/2017 Pages: 65 (1076 of 1511) Case 3:12-cv-01141-SMY-DGW Document 176-15 *SEALED* Filed 12/01/14 Page 10 of 65 Page ID #2549 Case: 16-3334 Document: 55-34 Filed: 02/08/2017 Pages: 65 (1077 of 1511) Case 3:12-cv-01141-SMY-DGW Document 176-15 *SEALED* Filed 12/01/14 Page 11 of 65 Page ID #2550 Case: 16-3334 Document: 55-34 Filed: 02/08/2017 Pages: 65 (1078 of 1511) Case 3:12-cv-01141-SMY-DGW Document 176-15 *SEALED* Filed 12/01/14 Page 12 of 65 Page ID #2551 Case: 16-3334 Document: 55-34 Filed: 02/08/2017 Pages: 65 (1079 of 1511) Case 3:12-cv-01141-SMY-DGW Document 176-15 *SEALED* Filed 12/01/14 Page 13 of 65 Page ID #2552 Case: 16-3334 Document: 55-34 Filed: 02/08/2017 Pages: 65 (1080 of 1511) Case 3:12-cv-01141-SMY-DGW Document 176-15 *SEALED* Filed 12/01/14 Page 14 of 65 Page ID #2553 Case: 16-3334 Document: 55-34 Filed: 02/08/2017 Pages: 65 (1081 of 1511) Case 3:12-cv-01141-SMY-DGW Document 176-15 *SEALED* Filed 12/01/14 Page 15 of 65 Page ID #2554 Case: 16-3334 Document: 55-34 Filed: 02/08/2017 Pages: 65 (1082 of 1511) Case 3:12-cv-01141-SMY-DGW Document 176-15 *SEALED* Filed 12/01/14 Page 16 of 65 Page ID #2555 Case: 16-3334 Document: 55-34 Filed: 02/08/2017 Pages: 65 (1083 of 1511) Case 3:12-cv-01141-SMY-DGW Document 176-15 *SEALED* Filed 12/01/14 Page 17 of 65 Page ID #2556 Case: 16-3334 Document: 55-34 Filed: 02/08/2017 Pages: 65 (1084 of 1511) Case 3:12-cv-01141-SMY-DGW Document 176-15 *SEALED* Filed 12/01/14 Page 18 of 65 Page ID #2557 Case: 16-3334 Document: 55-34 Filed: 02/08/2017 Pages: 65 (1085 of 1511) Case 3:12-cv-01141-SMY-DGW Document 176-15 *SEALED* Filed 12/01/14 Page 19 of 65 Page ID #2558 Case: 16-3334 Document: 55-34 Filed: 02/08/2017 Pages: 65 (1086 of 1511) Case 3:12-cv-01141-SMY-DGW Document 176-15 *SEALED* Filed 12/01/14 Page 20 of 65 Page ID #2559 Case: 16-3334 Document: 55-34 Filed: 02/08/2017 Pages: 65 (1087 of 1511) Case 3:12-cv-01141-SMY-DGW Document 176-15 *SEALED* Filed 12/01/14 Page 21 of 65 Page ID #2560 Case: 16-3334 Document: 55-34 Filed: 02/08/2017 Pages: 65 (1088 of 1511) Case 3:12-cv-01141-SMY-DGW Document 176-15 *SEALED* Filed 12/01/14 Page 22 of 65 Page ID #2561 Case: 16-3334 Document: 55-34 Filed: 02/08/2017 Pages: 65 (1089 of 1511) Case 3:12-cv-01141-SMY-DGW Document 176-15 *SEALED* Filed 12/01/14 Page 23 of 65 Page ID #2562 Case: 16-3334 Document: 55-34 Filed: 02/08/2017 Pages: 65 (1090 of 1511) Case 3:12-cv-01141-SMY-DGW Document 176-15 *SEALED* Filed 12/01/14 Page 24 of 65 Page ID #2563 Case: 16-3334 Document: 55-34 Filed: 02/08/2017 Pages: 65 (1091 of 1511) Case 3:12-cv-01141-SMY-DGW Document 176-15 *SEALED* Filed 12/01/14 Page 25 of 65 Page ID #2564 Case: 16-3334 Document: 55-34 Filed: 02/08/2017 Pages: 65 (1092 of 1511) Case 3:12-cv-01141-SMY-DGW Document 176-15 *SEALED* Filed 12/01/14 Page 26 of 65 Page ID #2565 Case: 16-3334 Document: 55-34 Filed: 02/08/2017 Pages: 65 (1093 of 1511) Case 3:12-cv-01141-SMY-DGW Document 176-15 *SEALED* Filed 12/01/14 Page 27 of 65 Page ID #2566 Case: 16-3334 Document: 55-34 Filed: 02/08/2017 Pages: 65 (1094 of 1511) Case 3:12-cv-01141-SMY-DGW Document 176-15 *SEALED* Filed 12/01/14 Page 28 of 65 Page ID #2567 Case: 16-3334 Document: 55-34 Filed: 02/08/2017 Pages: 65 (1095 of 1511) Case 3:12-cv-01141-SMY-DGW Document 176-15 *SEALED* Filed 12/01/14 Page 29 of 65 Page ID #2568 Case: 16-3334 Document: 55-34 Filed: 02/08/2017 Pages: 65 (1096 of 1511) Case 3:12-cv-01141-SMY-DGW Document 176-15 *SEALED* Filed 12/01/14 Page 30 of 65 Page ID #2569 Case: 16-3334 Document: 55-34 Filed: 02/08/2017 Pages: 65 (1097 of 1511) Case 3:12-cv-01141-SMY-DGW Document 176-15 *SEALED* Filed 12/01/14 Page 31 of 65 Page ID #2570 Case: 16-3334 Document: 55-34 Filed: 02/08/2017 Pages: 65 (1098 of 1511) Case 3:12-cv-01141-SMY-DGW Document 176-15 *SEALED* Filed 12/01/14 Page 32 of 65 Page ID #2571 Case: 16-3334 Document: 55-34 Filed: 02/08/2017 Pages: 65 (1099 of 1511) Case 3:12-cv-01141-SMY-DGW Document 176-15 *SEALED* Filed 12/01/14 Page 33 of 65 Page ID #2572 Case: 16-3334 Document: 55-34 Filed: 02/08/2017 Pages: 65 (1100 of 1511) Case 3:12-cv-01141-SMY-DGW Document 176-15 *SEALED* Filed 12/01/14 Page 34 of 65 Page ID #2573 Case: 16-3334 Document: 55-34 Filed: 02/08/2017 Pages: 65 (1101 of 1511) Case 3:12-cv-01141-SMY-DGW Document 176-15 *SEALED* Filed 12/01/14 Page 35 of 65 Page ID #2574 Case: 16-3334 Document: 55-34 Filed: 02/08/2017 Pages: 65 (1102 of 1511) Case 3:12-cv-01141-SMY-DGW Document 176-15 *SEALED* Filed 12/01/14 Page 36 of 65 Page ID #2575 Case: 16-3334 Document: 55-34 Filed: 02/08/2017 Pages: 65 (1103 of 1511) Case 3:12-cv-01141-SMY-DGW Document 176-15 *SEALED* Filed 12/01/14 Page 37 of 65 Page ID #2576 Case: 16-3334 Document: 55-34 Filed: 02/08/2017 Pages: 65 (1104 of 1511) Case 3:12-cv-01141-SMY-DGW Document 176-15 *SEALED* Filed 12/01/14 Page 38 of 65 Page ID #2577 Case: 16-3334 Document: 55-34 Filed: 02/08/2017 Pages: 65 (1105 of 1511) Case 3:12-cv-01141-SMY-DGW Document 176-15 *SEALED* Filed 12/01/14 Page 39 of 65 Page ID #2578 Case: 16-3334 Document: 55-34 Filed: 02/08/2017 Pages: 65 (1106 of 1511) Case 3:12-cv-01141-SMY-DGW Document 176-15 *SEALED* Filed 12/01/14 Page 40 of 65 Page ID #2579 Case: 16-3334 Document: 55-34 Filed: 02/08/2017 Pages: 65 (1107 of 1511) Case 3:12-cv-01141-SMY-DGW Document 176-15 *SEALED* Filed 12/01/14 Page 41 of 65 Page ID #2580 Case: 16-3334 Document: 55-34 Filed: 02/08/2017 Pages: 65 (1108 of 1511) Case 3:12-cv-01141-SMY-DGW Document 176-15 *SEALED* Filed 12/01/14 Page 42 of 65 Page ID #2581 Case: 16-3334 Document: 55-34 Filed: 02/08/2017 Pages: 65 (1109 of 1511) Case 3:12-cv-01141-SMY-DGW Document 176-15 *SEALED* Filed 12/01/14 Page 43 of 65 Page ID #2582 Case: 16-3334 Document: 55-34 Filed: 02/08/2017 Pages: 65 (1110 of 1511) Case 3:12-cv-01141-SMY-DGW Document 176-15 *SEALED* Filed 12/01/14 Page 44 of 65 Page ID #2583 Case: 16-3334 Document: 55-34 Filed: 02/08/2017 Pages: 65 (1111 of 1511) Case 3:12-cv-01141-SMY-DGW Document 176-15 *SEALED* Filed 12/01/14 Page 45 of 65 Page ID #2584 Case: 16-3334 Document: 55-34 Filed: 02/08/2017 Pages: 65 (1112 of 1511) Case 3:12-cv-01141-SMY-DGW Document 176-15 *SEALED* Filed 12/01/14 Page 46 of 65 Page ID #2585 Case: 16-3334 Document: 55-34 Filed: 02/08/2017 Pages: 65 (1113 of 1511) Case 3:12-cv-01141-SMY-DGW Document 176-15 *SEALED* Filed 12/01/14 Page 47 of 65 Page ID #2586 Case: 16-3334 Document: 55-34 Filed: 02/08/2017 Pages: 65 (1114 of 1511) Case 3:12-cv-01141-SMY-DGW Document 176-15 *SEALED* Filed 12/01/14 Page 48 of 65 Page ID #2587 Case: 16-3334 Document: 55-34 Filed: 02/08/2017 Pages: 65 (1115 of 1511) Case 3:12-cv-01141-SMY-DGW Document 176-15 *SEALED* Filed 12/01/14 Page 49 of 65 Page ID #2588 Case: 16-3334 Document: 55-34 Filed: 02/08/2017 Pages: 65 (1116 of 1511) Case 3:12-cv-01141-SMY-DGW Document 176-15 *SEALED* Filed 12/01/14 Page 50 of 65 Page ID #2589 Case: 16-3334 Document: 55-34 Filed: 02/08/2017 Pages: 65 (1117 of 1511) Case 3:12-cv-01141-SMY-DGW Document 176-15 *SEALED* Filed 12/01/14 Page 51 of 65 Page ID #2590 Case: 16-3334 Document: 55-34 Filed: 02/08/2017 Pages: 65 (1118 of 1511) Case 3:12-cv-01141-SMY-DGW Document 176-15 *SEALED* Filed 12/01/14 Page 52 of 65 Page ID #2591 Case: 16-3334 Document: 55-34 Filed: 02/08/2017 Pages: 65 (1119 of 1511) Case 3:12-cv-01141-SMY-DGW Document 176-15 *SEALED* Filed 12/01/14 Page 53 of 65 Page ID #2592 Case: 16-3334 Document: 55-34 Filed: 02/08/2017 Pages: 65 (1120 of 1511) Case 3:12-cv-01141-SMY-DGW Document 176-15 *SEALED* Filed 12/01/14 Page 54 of 65 Page ID #2593 Case: 16-3334 Document: 55-34 Filed: 02/08/2017 Pages: 65 (1121 of 1511) Case 3:12-cv-01141-SMY-DGW Document 176-15 *SEALED* Filed 12/01/14 Page 55 of 65 Page ID #2594 Case: 16-3334 Document: 55-34 Filed: 02/08/2017 Pages: 65 (1122 of 1511) Case 3:12-cv-01141-SMY-DGW Document 176-15 *SEALED* Filed 12/01/14 Page 56 of 65 Page ID #2595 Case: 16-3334 Document: 55-34 Filed: 02/08/2017 Pages: 65 (1123 of 1511) Case 3:12-cv-01141-SMY-DGW Document 176-15 *SEALED* Filed 12/01/14 Page 57 of 65 Page ID #2596 Case: 16-3334 Document: 55-34 Filed: 02/08/2017 Pages: 65 (1124 of 1511) Case 3:12-cv-01141-SMY-DGW Document 176-15 *SEALED* Filed 12/01/14 Page 58 of 65 Page ID #2597 Case: 16-3334 Document: 55-34 Filed: 02/08/2017 Pages: 65 (1125 of 1511) Case 3:12-cv-01141-SMY-DGW Document 176-15 *SEALED* Filed 12/01/14 Page 59 of 65 Page ID #2598 Case: 16-3334 Document: 55-34 Filed: 02/08/2017 Pages: 65 (1126 of 1511) Case 3:12-cv-01141-SMY-DGW Document 176-15 *SEALED* Filed 12/01/14 Page 60 of 65 Page ID #2599 Case: 16-3334 Document: 55-34 Filed: 02/08/2017 Pages: 65 (1127 of 1511) Case 3:12-cv-01141-SMY-DGW Document 176-15 *SEALED* Filed 12/01/14 Page 61 of 65 Page ID #2600 Case: 16-3334 Document: 55-34 Filed: 02/08/2017 Pages: 65 (1128 of 1511) Case 3:12-cv-01141-SMY-DGW Document 176-15 *SEALED* Filed 12/01/14 Page 62 of 65 Page ID #2601 Case: 16-3334 Document: 55-34 Filed: 02/08/2017 Pages: 65 (1129 of 1511) Case 3:12-cv-01141-SMY-DGW Document 176-15 *SEALED* Filed 12/01/14 Page 63 of 65 Page ID #2602 Case: 16-3334 Document: 55-34 Filed: 02/08/2017 Pages: 65 (1130 of 1511) Case 3:12-cv-01141-SMY-DGW Document 176-15 *SEALED* Filed 12/01/14 Page 64 of 65 Page ID #2603 Case: 16-3334 Document: 55-34 Filed: 02/08/2017 Pages: 65 (1131 of 1511) Case 3:12-cv-01141-SMY-DGW Document 176-15 *SEALED* Filed 12/01/14 Page 65 of 65 Page ID #2604 Case: 16-3334 Document: 55-34 Filed: 02/08/2017 Pages: 65 (1132 of 1511) Case 3:12-cv-01141-SMY-DGW Document 176-41 *SEALED* Filed 12/01/14 Page 1 of 2 Case: 16-3334 Document:Page 55-35ID #3285 Filed: 02/08/2017 Pages: 2 (1133 of 1511) Case 3:12-cv-01141-SMY-DGW Document 176-41 *SEALED* Filed 12/01/14 Page 2 of 2 Case: 16-3334 Document:Page 55-35ID #3286 Filed: 02/08/2017 Pages: 2 (1134 of 1511) Case 3:12-cv-01141-SMY-DGW Document 176-16 *SEALED* Filed 12/01/14 Page 1 of 38 Allergan Confidential Page ID #2605 Technical-Memorandum TPC-TM-2001-018 Case: 16-3334 Document: 55-36 Filed: 02/08/2017 Pages: 38 (1135 of 1511) - A~LERGAN & DEVELOPMENT PHARMACEUTICAL SCIENCES TECHNICAL PACKAGING CENTER R~SEARCH MEMORANDUM • To From Subject Date cc • • • • • • • • • • • • • Scott Gerondale Lon Spada ~jot 4-..c(' MP500IMP500W Design Qualification Report 9/25101 New Container Closure Team, Orest Olejnik, John Kent, Records Management, Approvals ~h 1h~/o( e, Manager Technical Packaging Center AI ff1.if: Director QA Phann. Sciences 2 CONFIDENTIAL – SUBJECT TO PROTECTIVE ORDER PRODUCED BY ALLERGAN IN CASE NO. 3:12-CV-01141-DRH-DGW (S.D. ILL.) 001 ARGN_LUM03_0005878 Case 3:12-cv-01141-SMY-DGW Document 176-16 *SEALED* Filed 12/01/14 Page 2 of 38 An. r, Page ID #2606 Allergan.1nc. Technical Memorandum TPC-TM-2001-018 Case: 16-3334 Document: 55-36 Filed: 02/08/2017 Pages: 38 (1136 of 1511) Page 2 of3S Table of Contents 1.0 1. 2. SUMMARY 2 PURPOSE 2 3. DEFINITION 4 4. S. EQUIPMENT AND MATERIALS 4 RrutRENCEDOCUMENTS 6. METHODS 5 5 7. RESULTS 13 8. 9. CONCLUSIONS 33 ATIACHMENTS 33 .SUMMARY The MPSOO/SOOW container closure system design was tested to assure that it is suitable for ophthalmic pharmaceutical products. The MPSOO/SOOW container closure systems consists of the MPSOO, S-mL natural LOPE bottle; the MPSOOW, S-mL white WPE bottle; the NCC E00178-1 high-impact polystyrene closure; the white 40979 tip; and the natural 413S1LH tip. Sixteen different tests were performed to test the safety, performance, and usability of the container closure system. The results show that the MPSOO/SOOW container closure system adequately protects the contents of the bottle from contamination, excessive water loss, leakage, and tampering. The system provides the correct drop weight and is easy to use. The tertiary packaging protects the container closure from damage during shipping and handling. Based on the results, our conclusion is that the MPSOOIMP500W container closure system is suitable for ophthalmic pharmaceutical products. 2.0 PURPOSE This report describes the testing that was done to qualify the design of the MP500 and MP500W container closure systems. Both systems are nominally S-mL containers made oHow-density polyethylene (LDPE). The MP500 and the MP500W are identical in every way except the MP500 is natural color and the MPSOOW is colored white by the addition of a colorant (Ti02). The New Container Closure (NCC) cap, part numbers EOO 17 8-1 and 3042SLH (EtO sterilized), was used in these studies. It is made of white high-impact polystyrene (lllPS). Two controlled dropper tips were used in these studies, part numbers 40979 and 41351LH. They are identical parts made in the same mold except one is natural LDPE (41351LH) and the other is white (40979). The components that were tested are shown in Table 2.1. Confidential- This dOC\lment is the property of Allorgon.lnc. and is intended solely for their internal use. Qunlification_MPSOO-'1"_E CONFIDENTIAL – SUBJECT TO PROTECTIVE ORDER PRODUCED BY ALLERGAN IN CASE NO. 3:12-CV-01141-DRH-DGW (S.D. ILL.) 2 002 ARGN_LUM03_0005879 Case 3:12-cv-01141-SMY-DGW Document 176-16 *SEALED* Filed 12/01/14 Page 3 of 38 Aliergan~Jnc. Page ID #2607 Technical Memorandum TPC-TM-2001-018 Case: 16-3334 Document: 55-36 Filed: 02/08/2017 Pages: 38 (1137 of 1511) OJ Page 3 of38 The MPSOO/SOOW container closure systems use the same resins and colorants as containers currently marketed by Allergan, so extractables tests were@done as part of these previoius qualifications. United States Pharmacopoeia testing (USP) and European Phamacopoeial testing (EP) were done on ethylene oxide sterilized components as part of previous submissions, and were not done as part of this qualification. Japanese Pharmacopoeia testing was done as part of this qualification. Table 2.1. Container Closure Components Bottle Bottle Tip Tip Cap Name MP500 MP500W N/A N/A NCCSCap Part Number 21729LH (particulate reduced) 21733LH (particulate reduced) 41351LH (particulate reduced 40979 white (particulate reduced) EOO178-1 (particulate reduced) 30425LH (particulate reduced, EtO) EtO EtO EtO EtO EtO MP500 MP500 EOO136 EOO136 E00178-1 Dupont 206064 Dupont 206064 Dupont 206064 Dupont 206064 Dow Styron 478 Color Natural White Natural White White Colorant None PolyOne (M.A. Hanna) 0342LMB None PolyOne (M.A. Hanna) 0342LMB PolyOne (M. A. Hanna) 0321 LMB Weight, g 2.3 2.3 N/A N/A 1.12 Fill Vol. to Shoulder, mL 5.8 5.8 N/A N/A N/A Overflow, mL 7.8 7.8 N/A N/A N/A Height, in 1.57 1.57 N/A N/A 0.767 Diameter, in 0.794 0.794 N/A N/A 0.722 Sterilization Drawing No. Resin Confidential- This doc,.."..t is the propeny of Allerg:m. Inc. ond is intended solely for their intemal Qunlifoclltio._MPSOO-,ptJ; CONFIDENTIAL – SUBJECT TO PROTECTIVE ORDER PRODUCED BY ALLERGAN IN CASE NO. 3:12-CV-01141-DRH-DGW (S.D. ILL.) use. 2 003 ARGN_LUM03_0005880 Case 3:12-cv-01141-SMY-DGW Document 176-16 *SEALED* Filed 12/01/14 Page 4 of 38 All. r'.'" Page ID #2608 Allergan. Inc. " Case: 16-3334 Document: 55-36 Filed: 02/08/2017 Pages: 38 (1138 of 1511) Technical Memorandum TPC-TM-2001-018 Page 4 of38 The following tests were done on the container closure and its components. The bottle and cap are new components so many of the tests done on these components are not done on the tip, which is an approved Allergan part. Bottle and Cap Tests: 1. Physical Appearance 2. Dimensional Analysis 3. Compression test (bottle only) Complete Container Closure System: 3.0 1. Tip Insertion Force 2. Drop Weight Test 3. Extreme Temperature Test 4. Temperature Cycling Resistance Test 5. Vacuum Leak Test 6. Freeze-Thaw Test 7. Torque Retention Test 8. Environmental Stress Crack 9. Water Loss 10. Microbial Challenge (Container Integrity) 11. Japanese Phannacopoeia 2000 (Yakuhatsu 336) 12. Tamper Evidence Test 13. Shipping and Distribution DEFINITIONS 3.1 ANSIIASQC - American National Standards Institute/ American Society of Quality Control 3.2 ASTM - American Society of Testing and Materials Confidential - This document is .he property of AIl!ifJClltion_MP500_JP'_E CONFIDENTIAL – SUBJECT TO PROTECTIVE ORDER PRODUCED BY ALLERGAN IN CASE NO. 3:12-CV-01141-DRH-DGW (S.D. ILL.) 2 007 ARGN_LUM03_0005884 Case 3:12-cv-01141-SMY-DGW Document 176-16 *SEALED* Filed 12/01/14 Page 8 of 38 AllerglUl. Inc. PageTechnical ID #2612 Memorandum TPC-TM-2001-018 Case: 16-3334 Document: 55-36 Filed: 02/08/2017 Pages: 38 (1142 of 1511) .11, f ' . . £:J. -J Page 8 of38 The Instron Model 5544 was set up and calibrated according to the manufacturer's instructions. A one-half inch aluminum rod with a flat polished face was clamped in the upper and lower jaws of the rnstron. The bottle was placed horizontally between the jaws and the gauge length was adjusted so the bottle was held with only slight pressure. The downward displacement was set to 0.25-inch and the rate to one inch per minute. Five bottles were chosen at random and the compression measurement was repeated four times on each bottle. Only one bottle was tested for each competitive or Japanese bottle. Thirty-two MP500W (W04270) bottles were tested. After each measurement, the bottle was rotated around the horizontal axis 90° to compress a new place on the wall. The user selects two points on the force displacement curve, and the internal Instron software calculates the initial slope of the displacement versus force curve and the force at the maximum displacement (0.25"). The average force at maximum displacement and the average initial slope were reported along with their respective standard deviations. 6.4 TIP INSERTION FORCE This test measures the amount of force required to insert a controlled drop tip into the bottle. The Instron Model 5544 was set up and calibrated according to the manufacturer's instructions. A special jig designed to fit the contour of the drop tip was clamped into the upper jaw of the Instron, and the bottle was held by a special jig mounted on a standard Instron compression platen that replaced the lower jaw. The tip was inserted into the bottle at 5-incheslminute. The force was measured for two commercial bottles with 15/415 neck-finish, and two versions of the MP500. The commercial bottles were Allergan's 8-mL Boston round bottIe and a Fenton Weber Jones 6-mL Boston round bottle. The two MP500 bottles were the MP500 and the MP501 both from test batch 2050B. The MP501 has the same neck finish as the MPSOO, but the body is 0.125" shorter. Thirty-two randomly selected MP500 bottles were tested with the white controlled drop tip, pIn 40979. Ten randomly selected bottles of the other types were also tested with the 40979 (white) controlled drop tip. The measurement was repeated three times on each bottle with a new tip used for each repetition. The average insertion force and standard deviation were reported. 6.S DROP WEIGHT TEST The purpose of these experiments was to show that the MP500/500W bottles do not change the drop weight delivered by a standard Allergan dropper tip. The drop weight was measured for both the MP500 and the MP500W with the Lumigan tip, part number 40979, and the nonpigmented version of this tip, part number 41351LH. Twenty MP500 and MP501 bottles were randomly selected from test batch 2050B. The bottles were filled with 3-rnL of Dr water, and a controlled drop tip (Allergan part number 40979) was inserted in the bottle. The drop weight of five individual drops was measured at 1800 (vertical) and at 45° from vertical for each bottle. The average and standard deviation were reported for each bottle at each angle. The average and standard deviation for the 20-sample lot was determined for each angle. Confidential - This documelll is 'he property o( AlJergan. /"". and i. intended solely (or their ;n.emol use. 2 CONFIDENTIAL – SUBJECT TO PROTECTIVE ORDER PRODUCED BY ALLERGAN IN CASE NO. 3:12-CV-01141-DRH-DGW (S.D. ILL.) 008 ARGN_LUM03_0005885 Case 3:12-cv-01141-SMY-DGW Document 176-16 *SEALED* Filed 12/01/14 Page 9 of 38 AJlergan, PageTechnical ID #2613 Memorandum TPC-TM-2001-018 Case:Inc. 16-3334 Document: 55-36 Filed: 02/08/2017 Pages: 38 (1143 of 1511) Page 9 of38 In another study, we measured the effect of surface tension on the drop size of the 41351UI tip with the MP500W bottle. The drop weight with distilled water was measured as part of this study. This study provides a better measurement of the variance of drop weight from a single tip rather than between tips from a production batch. Four bottles were each fined with 3-mL of solution with a different surface tension. Twenty-five drops were measured for each solution. Five averages of five drops were used to calculate the overall average and standard deviation. The drop weight was measured in the vertical position and 45° from vertica1. 6.6 EXTREME TEMPERATURE TEST The test determines the temperature resistance for theMP500/500W bottles with controlJed drop tip (pIn 40979) and the NCCS cap (pIn EOOI78-1). Fifty samples were tested according to SOPTPC-017. 6.7 TEMPERATURE CYCLING TEST This test detennines the resistance of plastic containers to rapid changes in temperature. The procedure is specified in SOP-TPC-060 and subjects the container closure to three cyclic temperature transitions between -10°C and 40°C. Three hundred units were tested. 6.8 LEAK TEST Forty MP500/501 bottles were leak tested according to SOP-TPC-027 and ASTM D5094-90. The bottles were plugged with a 40979-dropper tip and closed with a NCe cap, pIn E00178-1. The cap was tightened to 2-6 in-Ib torque according to ASTM D3/98. Another test was done to make certain that the MP5001500W design is robust enough to seal even when there is normal cavity to cavity variation in the tip mold. Thirty tips from each of the sixteen cavities from a production tip mold were inserted into MP500 (batch 2050B) bottles, capped with the EOO 178-1 closure, and torqued to 2-6 in-lb. These 480 units were leak tested according to SOP-TPC-027 and ASTM D5094-90. SOP TPC-027 is a vacuum leak test where sealed containers are submersed in an aqueous blue dye solution. A vacuum is applied to the headspace above the container and held for a specified amount of time. The container is observed for bubble emission, and any other indication of a leak. The vacuum is removed and the containers are removed and inspected for any inclusion of blue dye. ASTM D5094-90 is vacuum leak test designed to assess the ability of the container to survive the distribution environment without leaking. Partially filled and sealed containers are vibrated at specified condition and then subjected to a vacuum. The containers are inspected for any leakage around the closure threads. Confidential - This dOCUm0.027" 0 0.035 ± 0.002 N/A N/A Center wall >0.027" 0 0.035 ± 0.002 N/A N/A Bottom wall >0.027" 0 0.035 ± 0.002 N/A N/A Bottom-Center Record 0 0.034 ± 0.003 N/A N/A Confidential- This documenr is the property of AUergon, Inc. and is intended solely for .heir in.ernal use. Qualil'lC.,ion_MPSOOJpl_E CONFIDENTIAL – SUBJECT TO PROTECTIVE ORDER PRODUCED BY ALLERGAN IN CASE NO. 3:12-CV-01141-DRH-DGW (S.D. ILL.) 2 015 ARGN_LUM03_0005892 Case 3:12-cv-01141-SMY-DGW Document 176-16 *SEALED* Filed 12/01/14 Page 16 of 38 A llpro-<>n r. .tinl Allergan, Inc. PageTechnical ID #2620 Memorandum TPC-TM-2001-018 Case: 16-3334 Document: 55-36 Filed: 02/08/2017 Pages: 38 (1150 of 1511) .L'! Page 16 of38 The large Cp values show that the single cavity mold makes bottles with very high precision. The low Cpk values for the "f' and "K" dimensions indicates that the specification does reflect the process mean for these dimensions. The standard deviation of the "1" dimension is less than 0.001". Moving the specification to 0.365 ± 0.002", the process mean, would give equal Cp and Cpk values of 1.7. The same analysis would be applied to the "K" dimension, except here the specification would be moved to the process mean of 0.463" with a reduced variance of plus or minus 0.004". The Cp and Cpk would be equal at 1.3. The specification changes are justified because all performance testing has been done with bottles at the current process means, and no leaking bottles were found with these specifications. Closure The drawing of the New Container Closure (NCC) closure is shown in Attachment 9.2. The closures used in these studies were made by Marman Industries, Inc. with a two-cavity mold owned by Allergan. The closures are made from Dow Styron 478 with four parts PolyOne (formerly M. A. Hanna) 0321LMB white colorant. Dimensional analysis was done on closures from each batch of closures received in Technical Packaging. Typically, one hundred caps were randomly selected from a batch of 10,000 units, and four dimensions were measured. Only the "QC" dimensions are considered important, the other two "reference" dimensions are for quality control of the process. Table 7.2.2 shows typical dimensional results for the NCC cap. Table 7.2.2. Dimensional Analysis ofNCC E00178-1 Closure Batch 4545A. Notebook reference R1999. 4914-62 Drawing Reference Definition Drawing Specification Average± S.D. Cp Cpk QC-I Inside thread diameter 0.528 ± 0.004 0.529 ± 0.001 1.0 0.7 QC-2 Inside cap height 0.385 ± 0.006 0.385 ± 0.002 1.3 1.2 Reference -1 Closure Height 0.767 ± 0.010 0.754 ± 0.001 3.4 -0.9 Reference:-2 Closure Diameter 0.722 ± 0.010 0.718 ± 0,001 3.4 2.0 Confidential - This documenl is lhe property of AUergon, Inc. IlJ1d is inlended solely for lheir inlernal use. QullliflCntion_MP50 property of Allergan. Inc. ;md is int.nded solely for lhe>ir internal use. Qualiftcnlion_MPSOO_rpt_E CONFIDENTIAL – SUBJECT TO PROTECTIVE ORDER PRODUCED BY ALLERGAN IN CASE NO. 3:12-CV-01141-DRH-DGW (S.D. ILL.) 2 025 ARGN_LUM03_0005902 Case 3:12-cv-01141-SMY-DGW Document 176-16 *SEALED* Filed 12/01/14 Page 26 of 38 An. ( Page Technical ID #2630 Allergan. Inc. Case: 16-3334 Document: 55-36 Filed: 02/08/2017 Pages: 38 (1160 of 1511) Memorandum TPC-TM-2001-018 Page 26 of38 Table 7.8.2. Leak Test Results For MP500 (batch 2050B) with 41351LH Dropper Tip It Samples Bottles Tip Cap TPC·027 ASTM DS094-90 Results Results 30 5· mL MP500 Batch 2050B Allergan 41351LH NCe Cap. E0078-1 Pass Pass 30 5· mL MP500 Batch 2050B Allergan 41351LH NCC Cap. E0078-l Pass Pass 30 5- mL MP500 Batch 2050B Allergan 4l351LH NCe Cap. E0078-1 Pass Pass 30 5- mL MP500 Batch 2050B Allergan 41351LH NCCCap. EOO78-1 Pass Pass 30 5- mL MP500 Batch 2050B Allergan 41351LH NCe Cap. E0078-1 Pass Pass 30 5- mL MP500 Balch 2050B Allcrgan 41351LH NCC Cap. EOO78-1 Pass Pass 30 5- mL MP500 Batch 2050B Allcrgan 41351LH NCC Cap. E0078-1 Pass Pass 30 5- mL MP500 Batch 2050B Allergan 41351lH NCC Cap. E0078-1 Pass Pass 30 5- mL MP500 Batch 2050B Allcrgan 41351 LH NCC Cap. EOO78-1 Pass Pass 30 5- mL MPSOO Balch 2050B Allergan 41351 LH NCC Cap. E0078-1 Pass Pass 30 5- mL MPSOO Batch 2050B Allergan 41351 LH· NeC Cap. E0078-1 Pass Pass 30 5- mL MP500 Batch 2050B Allcrgan 41351LH NCC Cap. EOO78-l Pass Pass 30 5- mL MP500 Balch 2050B Allergan 41351LH NCC Cap. EOO78-1 Pass Pass 30 5· mL MP500 Batch 2050B AlIergan 413SILH NCC Cap. EOO78-1 Pass Pass 30 5- mL MP500 Balch 2050B AUergan 41351LH NCC Cap. EOO78-1 Pass Pass 30 5- mL MPSOO Batch 2050B Allergan 41351LH NCC Cap. EOO78-1 Pass Pass 7.9 FREEZE-THAW RESISTANCE TEST The MP500 (batch 2050B) bottle fitted with an AIlergan 40979 dropper-tip and the NCe E00178-1 cap was tested for freeze-thaw resistance according to SOP TPC-024. The results in Table 7.9.1 show that none of the MP500 samples showed evidence of a temperature related failure. The MP50l (batch 2050B) also passed the freeze-thaw test. This is the same bottle as the MP500 except the MP501 body is 0.125"shorter. The neck finish is the same for the two bottles, so any test of the sealing perfOImance would be valid for both bottles. The fact that all the MP501 units passed the Freeze-Thaw test is further confonnation of the robustness of the MP500 bottle design. The original data is in R1999-4914-78. Confidential-nus document is the propeny of AlJergnn. Inc. ond is intended solely for their intemaJ use. Quolificatio._MP50(Upt_E CONFIDENTIAL – SUBJECT TO PROTECTIVE ORDER PRODUCED BY ALLERGAN IN CASE NO. 3:12-CV-01141-DRH-DGW (S.D. ILL.) 2 026 ARGN_LUM03_0005903 Case 3:12-cv-01141-SMY-DGW Document 176-16 *SEALED* Filed 12/01/14 Page 27 of 38 AlJergan. PageTechnical ID #2631 Memorandum TPC-TM-2001-018 Case:Inc. 16-3334 Document: 55-36 Filed: 02/08/2017 Pages: 38 (1161 of 1511) Page 27 of38 Table 7.9.1. Freeze-Thaw Test Results for MP500 and MP501 Bottles. Bottle Dropper Tip Closure Number of Samples TPC·024 Results MP500 (batch 2050B) 40979 NCC, EOO178-1 30 Pass MP501 (batch 2050B) 40979 NeC, EOO178-1 30 Pass 7.10 TORQUE RETENTION TEST The torque retention results show that the MP500 bottle with the 41351LH dropper-tip and the 30425LH closure maintains an acceptable removal torque after thirty days at the test conditions. The results are plotted for 4 in-lb. application torque and 5 in-lb. application torque in Figures 7.10.1 and 7.10.2, respectively. As expected, after 28 days the removal torque had decreased more at 40°C than at 23°C. The reduction at the higher temperature appears to be a cumulative effect, and it is significant that there are no radical torque decreases between time points at 40°C. This shows that the removal torque wi11 not degrade if the container is exposed to short excursions at higher temperature, a more likely scenario than it being exposed to a month at 40°C. The results from the different application torque experiments indicate that the removal torque decrease may be first order with respect to the applied torque. Suggesting that there is a point of diminishing returns with regard to the application torque. A higher application torque may not be better if there is a faster drop rate as the plastic relaxes. It is also evident that there is a rapid relaxation period immediately after the cap is applied. The zero time-point removal torque was considerably below the set pOint for both application torques. Confidential- This document is .he propeny of AUergO!l. Inc. and is in.ended solely for .heir illlemal use. CONFIDENTIAL – SUBJECT TO PROTECTIVE ORDER PRODUCED BY ALLERGAN IN CASE NO. 3:12-CV-01141-DRH-DGW (S.D. ILL.) 2 027 ARGN_LUM03_0005904 Case 3:12-cv-01141-SMY-DGW Document 176-16 *SEALED* Filed 12/01/14 Page 28 of 38 PageTechnical ID #2632 Memorandum TPC-TM-2001-01B Case: 16-3334 Document: 55-36 Filed: 02/08/2017 Pages: 38 (1162 of 1511) ,11 ,.. Page 28 of38 Figure 7.10.1. Removal Torque Versus Time for the MP500 (2050B) bottle, 41351LH Dropper Tip, and 30425LH Closure - 4 in-lb. Application Torque 3.0 2.5 % f :to ... j 1.5 1.0 0.5 0.0 7 2 0 14 28 Figure 7.10.2. Removal Torque Versus Time for the MP500 (2050B) bottle, 413S1LH Dropper Tip, and 3042SLH Closure - 5 in-lb. Application Torque 5.0 4.5 4.0 3.5 .a 13.0 ,; " f" {! 2.5 iE 2.0 • '" 1.5 1.0 0.5 0.0 0 7 TIme,Days 2 14 21 28 Confidential - This cIocurm:n1 is .he property of AIJergon. Inc. and is imcndtd solely for .heir inu:ma1 use. Qualilicalion_MPSOOJl't...E CONFIDENTIAL – SUBJECT TO PROTECTIVE ORDER PRODUCED BY ALLERGAN IN CASE NO. 3:12-CV-01141-DRH-DGW (S.D. ILL.) 2 028 ARGN_LUM03_0005905 Case 3:12-cv-01141-SMY-DGW Document 176-16 *SEALED* Filed 12/01/14 Page 29 of 38 A 11, Allergan. PageTechnical ID #2633 Memorandum TPC-TM-200I-OI8 Case:Inc. 16-3334 Document: 55-36 Filed: 02/08/2017 Pages: 38 (1163 of 1511) Page 29 of38 7.11 ENVrn.ONMENTAL STRESS CRACK The MP500 and MP501 were tested for chemical induced stress cracking according to SOP TPC025 and ASTM D 2561. The results of the Environmental Stress Crack test in Table 7.11.1 show that the MP500 is suitable for use as an ophthalmic container. The original data is in RI999-4914-88. None of thirty samples showed any signs of stress induced cracking or crazing. The MP501 uses the same tip and closure as the MP500, and is identical to the MP500 except that the MP501 body is 0.125" shorter than the MP500. The fact that the MP501 also showed no chemical induced stress failures is further evidence of the robustness of the MP500 series design. Table 7.11.1 Environmental Stress Crack Test Results for the :MP500 and MP501 B ottJe{E to) Tip(EtO) MP500(batch 2050B) 41351LH MP50 I (batch 2050B) 41351LH 7.12 Cap{EtO) Number of Samples Nce Cap, pIn 30425lli NCC Cap, pIn 30425LH Application Torque, inlb. Results 30 4.0 No Stress Induced Failures 30 4.0 No Stress Induced Failures WATER LOSS 7.12.1 Direct Measurement of Water Loss Water loss results are summarized in Table 7.12.1. Water loss for the MP500 and MP500W were measured directly with a Mocon Permatran 3/31. The water loss was measured at a minimum of two different temperatures. The water loss (gt) for a specified time (t) and relative humidity (P) at each temperature was used to calculate the water permeability constant (PWt) using a measurement of the containers average wall thickness and surface area. (1) The activation energy of permeation Ep and the preexponential factor Po were calculated from the Pw versus temperature data. These are fundamental properties of the resin and consequently of the individual container c10sure system being studied. From the Ep and Po values, the Pw can be calculated for any temperature. This value combined with any variation of area, time, relative humidity, and wall thickness can be used to calculate the water loss at the specified conditions. Confidential - This document is the propeny of AUerg.... Inc. and is intended solely for their intemol use. Qualilication_MP500_rpt_E CONFIDENTIAL – SUBJECT TO PROTECTIVE ORDER PRODUCED BY ALLERGAN IN CASE NO. 3:12-CV-01141-DRH-DGW (S.D. ILL.) 2 029 ARGN_LUM03_0005906 Case 3:12-cv-01141-SMY-DGW Document 176-16 *SEALED* Filed 12/01/14 Page 30 of 38 Allergan ConfldeJ1tial PageTechnical ID #2634 Allergan, Case:Inc.16-3334 Document: 55-36 Filed: 02/08/2017 Pages: 38 (1164 of 1511) Memorandum TPC-TM-2001-018 Page 300£38 The 99% confidence limit for this calculation is estimated to be ± 1%, and the 95% confidence limit for the Mocon measurements is estimated to be ± 2%. Because these errors can be expected to partially offset each other at least 50% of the time, the total error in the Macon determined results is expected to slightly over ± 2%. The foil-sealed MP500 adjusted to a 0.033" average wall thickness had a water loss of 0.183 g for three years, at 25°C and 40% RH. This equates to 6.1 % water loss for a 3-mL fill. The MP500W under the same conditions showed a loss of 0.177 g or a 5.9 % loss. This shows that the white pigment has no affect on permeability. The MP500 with a tip and cap showed a 0.180g water loss or 6% for three years, showing that the cap does not affect the water loss significantly. The validity of the measured values is established by water-loss calculations based on literature values of Pw or literature values of Ep and Po. The calculated water loss for the MP500 bottle for a 0.033" wall thickness for three years at 25°C and 40% RH with a literature value of Pw was found to be 0.198 g, or 6.6% for a 3-mL fill volume. At the same conditions, the water loss calculated for Allergan's 8-rnL and 10-rnL Boston- round bottles was found to be 0.212 g and 0.368 g, respectively. This equates to a 7.1 % loss for the 8-mL bottle and a 12.3 % loss for the 10-rnL bottle. The water loss calculated from literature Ep and Po values for the MP500 at 25°CI40%RH was 0.189 g,or 6.3% for a 3-mL fill volume, again very close to the measured values. The original data is referenced in R1999-4914-47, -80, -90, -102, -120, and -146. 7.12.2 Real-Time Water Loss Measurements The results of our 90-day real-time water-loss study at 25°C/40%RH for the MP500 (0.030" wall) and the MP500W (0.033" wall), show water losses of 0.249 ± 0.006 g (8.3%, 3-mL) and 0.252 ± 0.003 g (8.4%, 3-mL fill), respectively. The original data is in RI999-4914-47, -80, -90, -102, -112, -120, and -146. Confidential- This document is the property of AUergon, Inc. and is intended solely for their intemol use. QualiflCalion_MPSO0.027" 0 0.033 ± 0.002 N/A N/A Center wall >0.027" 0 0.034 ± 0.001 N/A N/A Bottom wall >0.027" 0 0.038 ± 0.003 N/A N/A Confidential - Thi, document is the property of Allergan. Jnc. and is intended solely for their iruemal use. CONFIDENTIAL – SUBJECT TO PROTECTIVE ORDER PRODUCED BY ALLERGAN IN CASE NO. 3:12-CV-01141-DRH-DGW (S.D. ILL.) 2 131 ARGN_LUM03_0006009 Case 3:12-cv-01141-SMY-DGW Document 176-17 *SEALED* Filed 12/01/14 Page 16 of 32 Allergan Confidential Page ID #2658 Case: 16-3334 Document: 55-38 Filed: 02/08/2017 Pages: 32 (1190 of 1511) Allergan. Inc. Technical Memorandum TPC-TM-2002-023 Page 16 of32 Bottom-Center o Record 0.071± O.OOS N/A N/A The large Cp values show that the single cavity mold makes bottles with very high precision. The Cpk values show that the measured dimensions are within the specification limits. All perfonnance testing was done with bottles at the current process means, and no leaking bottles were found with these bottles. Closure The drawing of the New Container Closure (NCC) closure is shown in Attachment 9.2. The closures used with the MPS03W, lO-mL bottles are the same as those used with the MPSOO/SOOW container closure system. The dimensional qualification is reported in Technical Memorandum TPC-TM-2001-018. 7.3 COMPRESSION (SQUEEZE) TEST The results of the compression measurements show that the MPS03IMPS03W container's wall compression resistance is within the range of current commercial bottles, and they are acceptable for use as ophthalmic containers. Original data is contained in R1999-4914-198. Wall compression resistance was done on the MPS03IMPS03W by the procedure described in methods section 6.3. Two measurements were used to compare the wall compression resistance - initial slope and maximum force. The "initial slope", refers to the slope of the forcedisplacement curve at a certain rate of compression. It is a measure of the force required to move the bottle's wal1 from its resting position. The other measurement is the maximum force required to compress the bottle's wall 0.12S" on both sides. We believe the initial slope best mimics the compression resistance observed in actual use. It should be interpreted as a relative value to compare containers rather than an absolute force. Table 7.3.1shows the compression resistance of the MPS03/S03W bottle compared to Allergan's current commercial lO-mL container. Although the MPS03W is greater than the current Allergan container in both categories, it is not excessively difficult to squeeze and is within what has been observed for commercial containers. Confidential - This document is .he propeny of AIJergan. Inc. and is in.ended solely for .heir in.emaI use. CONFIDENTIAL – SUBJECT TO PROTECTIVE ORDER PRODUCED BY ALLERGAN IN CASE NO. 3:12-CV-01141-DRH-DGW (S.D. ILL.) 2 132 ARGN_LUM03_0006010 Case 3:12-cv-01141-SMY-DGW Document 176-17 *SEALED* Filed 12/01/14 Page 17 of 32 Allergan Confidential Page ID #2659 Case: 16-3334 Document: 55-38 Filed: 02/08/2017 Pages: 32 (1191 of 1511) AlJergan, Inc. Technical Memorandum TPC-TM-2002-023 Page 17 of 32 Table 7.3.1. Wall Compression Resistance for MP503W IO-mL White Bottle and Allergan's White 10-mL Boston Round Container Container Initial Slope ± SD , Iblin Max Force ± SD, Ib MP503W (W05498) 42±8 5.1 ::to.2 Allergan 10-mL Boston Round 30±4 3.7 :to.3 7.4 TIP INSERTION FORCE The MP503/S03W bottles have a modified standard 1S/41S-neck finish. The distance between the threads and the shoulder of the bottle has been reduced approximately 50% compared to the standard finish. This test was done to show that the MP5031MP503W bottle's neck finish does not present any unusual tip insertion difficulties. The test was done on the MP500/500W and MP501 5-mL bottles. The MPSOO and MP501 have the same neck finish and tip as the MP503IMPS03W 1O-mL bottles. Therefore, the tip insertion results from the 5-mL bottle are applicable to the 1O-mL bottle. The results shown in Figure 7.4.1 show that the MP500/500W does not have an unusual tip insertion force and is acceptable for use as an ophthalmic container. The original data is in R1999-4914-60, R1999-4914-74, and R1999-4914-167. The fact that the MP501 and MP500 have the same insertion force shows that an increase in modulus of the body does not increase the insertion force. This means that the addition of colorant or slight increases in wall thickness will not affect the insertion force. As a note, Allergan's PSO has filled, tipped and capped 3,000 MP500 container closures without difficulty. Figure 7.4.1 Tip Insertion Force for MP5031MP503W Container Bottle Number of Samples Tip (EtO Sterilized) Allergan 8-mL Boston Round (21472) Test #1,6/00 EtO Sterilized 10 40979 5 17 ± 1 10 40979 5 16 ± 1 Allergan 8-mL Boston Round (21472) Test Insertion Speed, Insertion Force in/min. ± SD, Ib #2,9/00 Confidential - This document is tlx: propmy of Allergan. Inc. and is intended solely for their intenutl use. 2 133 QualiflCntioo_MPS03_I'Jl'_A CONFIDENTIAL – SUBJECT TO PROTECTIVE ORDER PRODUCED BY ALLERGAN IN CASE NO. 3:12-CV-01141-DRH-DGW (S.D. ILL.) ARGN_LUM03_0006011 Case 3:12-cv-01141-SMY-DGW Document 176-17 *SEALED* Filed 12/01/14 Page 18 of 32 AUergan Confidential Page ID #2660 Case: 16-3334 Document: 55-38 Filed: 02/08/2017 Pages: 32 (1192 of 1511) AlIergan, Inc, Technical Memorandum TPC-TM-2002-023 Page 18 of32 Fenton Weber Jones, 6-mL natural LDPE 10 40979 5 18 ± 2 MP500 (Test 2050B) 32 40979 5 16 ± 1 MP501 (Test 2050B) 10 40979 5 15 ± 1 7.5 DROP WEIGHT TEST The results with water in Tables 7.5.1 and Table 7.5.2 show that the MP500 series bottles deliver a consistent drop-weight with a standard Allergan dropper tip. Regression analysis of the data from Table 7.5.1 gives vertical drop weight P values of 0.37 and 0.82 for bottle size and fill volume, respectively. At 45° drop angle, the P values are 0.39 for bottle size and 0.92 for fillvolume. This shows statistically that drop-weight is not affected by the bottle's size or fillvolume. The results in Table 7.5.2 further show the insensitivity of the drop-weight to bottle size. The MP501 bottle has the same neck finish as the MP500/500W but the bottle is 0.125" shorter at the shoulder, a significant difference for this size bottle. Again, there is no difference in drop-weight between the bottles. In another experiment (RI999-4914-142), the drop weight of the MP500W (W04270) was measured with a 41351LH natural tip. The drop weight with water was found to be 36.6 ± 0.7 milligrams for a vertical drop-angle and 31.3 ± 0.8 milligrams at 45°. The difference between this vertical drop weight and those in Table 7.5.2 and 7.5.3 may lead to the conclusion that tip color influences the drop-weight. We believe, however, that this is not a real difference and is most likely due to differences in operator technique, which is known to affect drop weight measurements. Variances as high as plus or minus five milligrams are common with this test. Furthermore, there was no difference at 45°, and an experiment with Lumigan (original reference R2001-6012-24) did not show a drop-weight difference between the 40979 white tip and the 41351LH natural tip. The average drop weight of Lumigan from five separate tips was found to be 25.5 ± 0.6 mg for the 40979 and 26.3 ± 0.4 for the 41351LH. Operator technique differences are also most likely responsible for the difference in drop-weight observed with the 40979 tip in the 21472 8-mL Allergan Boston round bottle (RI999-4914-128). Here the drop weight was found to be 38 ± 3 and 33 ± 2 milligrams for vertical and 45°, respectively. The data in Table 7.5.1 strongly argues against this being a real difference. Confidential -11lis document is the propeny of AIlergan. Inc, and is intended solely for their internal usc:, CONFIDENTIAL – SUBJECT TO PROTECTIVE ORDER PRODUCED BY ALLERGAN IN CASE NO. 3:12-CV-01141-DRH-DGW (S.D. ILL.) 2 134 ARGN_LUM03_0006012 Case 3:12-cv-01141-SMY-DGW Document 176-17 *SEALED* Filed 12/01/14 Page 19 of 32 Allergan Confidential Page ID #2661 Case: 16-3334 Document: 55-38 Filed: 02/08/2017 Pages: 32 (1193 of 1511) Allergan, Inc. Technical Memorandum TPC-TM-2002-023 Page 19 of32 Table 7.5.1. Drop -Volume Versus Bottle Size and Fill Volume (Reference R2001-6191-45) Drop Volume ± SD, J.IL Fill Vol., Bottle % Drop Tip Operator 8 Vertical 45° MPSOOW(W04270) S-mL 40 40979 CW 30±3 27 ±3 MPSOOW(W04270) S-mL SO 40979 CW 30±3 2S±3 MPS04W(W04246) lS-mL 40 40979 CW 31 ± 3 28±3 MPS04W(W04246) lS-mL SO 40979 CW 31 ±4 28 ±3 CW = C. West a. Table 7.5.2. Drop -Volume For the MP500 and MP501 Bottles (Reference R2001-6191-77) Drop Volume ± SD, JlL Bottle Dropper Tip Operator 8 Vertical 45° MPSOO(20S0B) 40979 SW 30±S 30±S MPSOO(2050B) 40979 PKIMS 32±S 33 ±2 b 40979 SW 32±S 29±4 MPSOl(2050B) b 40979 PKIMS 30±5 40±4 MPSOl(2050B) a. SW = S. Wojcik, MS = M. Shaw. PK = P. Kang, NL:: Nick Layman b. The MP501 bottle has the same neck finish as the MP500/500W. It is the same bottle except the body is 0.125" shorter. 7.6 EXTREME TEMPERATURE TEST The test determines the temperature resistance of plastic containers and follows Technical Packaging SOP TPC-O 17. Water-filled containers were subjected to alternating cycles at 5°C and 45°C. Each temperature was held for 72 hours. Three hundred MP503 bottles from batch W0549S were randomly selected and fitted with a dropper tip (pIn 40979) and a NCC EOO 17S-1 closure. The results in Table 7.6.1 show that there was no temperature-related damage observed in any of the containers. The original data is in RI999-4914-179. Confidential - This dolif"'atioo_MPS04_'l"_B CONFIDENTIAL – SUBJECT TO PROTECTIVE ORDER PRODUCED BY ALLERGAN IN CASE NO. 3:12-CV-01141-DRH-DGW (S.D. ILL.) ARGN_LUM03_0006116 Case 3:12-cv-01141-SMY-DGW Document 176-18 *SEALED* Filed 12/01/14 Page 12 of 32 Allergan Confidential Page ID #2686 Case: 16-3334 Document: 55-40 Filed: 02/08/2017 Pages: 32 (1220 of 1511) Allergan. Inc. Technical Memorandum TPC-TM-2002-002 Page 12 of32 Table 6.10.2. Torque Retention Sample Test Matrix for 5 in-Ib Cap Torque Number of Samples Time Ambient (23°C/SO% RH) 40°C/20% RH 0 10 10 24h 10 10 48h 10 10 7d 10 10 14 d 10 10 28 d 10 10 60 60 Total 6.11 ENVIRONMENTAL STRESS CRACK TEST This test is to certify that the chemicals used in an ophthalmic container do not induce stress cracking or deterioration in the container components. Table 6.11.1 shows the container closure configurations that were tested according to SOP-TPC025 and ASTM D 2561. Ethylene oxide sterilized bottles were filled to the shoulder with AGN 1920240.03% ophthalmic solution (Lumigan). The bottles are tipped and capped with EtO sterilized tips and closures, respectively. Thirty samples of each bottle configuration in two positions -15 upright and 15 inverted- were tested. Table 6.11.1. Environmental Stress Test Matrix Bottle(EtO) MP504(batch W04246) Tip(EtO) 40979 Cap(EtO) Number of Samples NCC Cap, pIn 30425LH 30 Confidential - This document is the propeny of AUergon. Inc. ond is irnended ",,!ely for their internal use. Application Torque, in-Ib 4.0 2 238 Qualilicatioo_MPS04_'l"_B CONFIDENTIAL – SUBJECT TO PROTECTIVE ORDER PRODUCED BY ALLERGAN IN CASE NO. 3:12-CV-01141-DRH-DGW (S.D. ILL.) ARGN_LUM03_0006117 Case 3:12-cv-01141-SMY-DGW Document 176-18 *SEALED* Filed 12/01/14 Page 13 of 32 Allergan Confidential Page ID #2687 Case: 16-3334 Document: 55-40 Filed: 02/08/2017 Pages: 32 (1221 of 1511) Allergan. Inc. Technical Memorandum TPC-TM-2002-002 Page J3 of32 6.12 WATER LOSS This test measures the water petmeability of ophthalmic plastic containers. A real-time weightdifference method and a direct instrumental method were used to measure water loss. 6.12.1 Direct Water Loss Measurement The water loss was measured with a Mocon Permatran 3/31. The Mocon was setup and calibrated per the manufacturer's instructions. The basic procedure is outlined in SOP TPC-015. The sample containers were filled with 5-mL DI water and sealed with a cap or aluminum foil glued across the mouth of the bottle (foil sealed). One sealed bottle was inserted into a stainless steel capture volume. Moisture loss was determined at a minimum of two temperatures (e.g., 27°C/100%RH and 35°C/100%RH), and the bottle's surface area and wall thickness were used to calculate the permeability constant (Pw) at each temperature. Regression analysis was used to determine the slope and intercept of an Arrhenius plot of the logarithm of the permeability constant (Pw) versus Iff. The slope is equal to the activation energy of permeation (Ep) divided by RT, and the intercept is equal to the permeation preexponential factor (Po). Ep and Po were then used to calculate the Pw at any temperature. The container's moisture loss at any specified temperature per unit time was calculated from the Pw and the bottle's surface area and wall thickness. 6.12.2 Real Time Water Loss The test matrix is shown below. Bottles were filled with 3-mL of DI water, and any excess water was wiped from the bottle. A tip was inserted into the bottle, and the bottle was capped to 4 in-Ib torque. One hundred test units were divided into five separate lots of 20 units each, and placed into a controlled temperature humidity cabinet to equilibrate to the test conditions for five days. After conditioning, the bottles were removed and allowed to equilibrate to lab conditions (about one hour). The lab temperature and humidity were recorded, and the weight of each 20-bottle lot was recorded. This was t = O. The bottles were returned to their respective templhumidity cabinet. At 30, 60 and 90 days, the bottles were removed from the cabinet, and allowed to equilibrate to lab conditions. Each 20-bottle lot was weighed, and the weight difference and percent water loss were detetmined at each time point. Water Loss Test Matrix Conditions Number of Units Bottle MPS04(batch W04246) w 40979 tip and E00178-1 cap 25°C/40%RH 100 40°C/20% RH 100 Confidential - This documoot is the property of AIleJEan. Inc. and is intended solely for their intemal use. CONFIDENTIAL – SUBJECT TO PROTECTIVE ORDER PRODUCED BY ALLERGAN IN CASE NO. 3:12-CV-01141-DRH-DGW (S.D. ILL.) 2 239 ARGN_LUM03_0006118 Case 3:12-cv-01141-SMY-DGW Document 176-18 *SEALED* Filed 12/01/14 Page 14 of 32 Allergan Confidential Page ID #2688 Case: 16-3334 Document: 55-40 Filed: 02/08/2017 Pages: 32 (1222 of 1511) Allergan, Inc. Technical Memorandum TPC-TM-2002-002 Page 14 of32 6.13 MICROBIAL CHALLENGE TEST (CONTAINER INTEGRITY TEST) This test assures that the contents of the container maintains sterility after exposure to a controlled aerosol environment seeded with a high concentration of Bacillus licheniformis spores. Nelson Laboratories performed this the test on sixty samples of the MP500 5-mL bottle according to their current Protocol 20027201-03 included as Attachment 9.4. The 5-mL bottle has the same neck finish, closure and tip as the 15-mL bottle. Therefore the microbial challenge results for the S-mL bottle are valid for the 15-mL bottle. 6.14 JAPANESE PHARMACOPEIA TESTING Japanese Phamacopeia testing was done by Sumika laboratories in Tokyo, Japan according to their current Protocol, Study Number 1410638-0 included as Attachment 9.S. Three bottles were tested for each test. The lP testing was done on the MP500 "natural color" S-mL bottle. The resins and process used to make the 5-mL bottle are the same as the MPS04, IS-mL bottle. The two sizes are identical except for the size of the body. Therefore, the JP test results for the S-mL MPSOO natural bottle would be applicable to the MP504 15-mL natural bottle. 6.15 TAMPER EVIDENT TESTING The purpose of this experiment was to test the cello-seal on the MP500 series bottles, and compare it to the cello seal on Allergan's 6-mL cylinder bottle. The MP500 series bottles have a larger diameter cello ring, compared to Allergan's current 6-mL cylinder bottle, to improve the grip of the cello band to the bottle and cap. This test was done on the 5-mL bottle, which has the same neck finish, closure, and tip as the IS-mL bottle. Therefore, the tamper evident results for the S-mL bottle are valid for the 15-mL bottle. The test was conducted according to the following procedure. Two male and two female volunteers were gi ven twenty cello-sealed bottles of each type, which had been labeled with an individual code number. The volunteers were asked to remove the cap from ten randomly chosen bottles of each type, and reapply the cap as carefully as possible to try and make it look like the cap had not been removed. The code numbers of the bottles that have had the cap removed were recorded. The difficulty removing and applying the cap were rated according to the following scale: (1) Very easy, (2) Easy, (3) Moderate, (4) Difficult, and (S) Very Difficult. Each set of bottles (one of each type) was gi ven to four different people, and they were asked to identify the bottles that have had the cap removed. Their results were compared against the code number sheet for the bottles that had caps removed and replaced. 6.16 SHIPPING AND DISTRIBUTION TESTING This test is done to assure that container integrity is maintained after shipping and handling. Shipping and distribution tests are done according Allergan Technical Packaging Center's current version of SOP TPC -019, "Vibration and Drop Testing of Filled Shipping Containers for Products Shipped Individually", and SOP TPC-040, "Vibration and Drop Testing of Filled Shipping Containers For Products Shipped In A Unitized Load." Confidential - This documom is rhe propeny of AlJerg:m. Inc. and is intended solely for ....ir internal use. 2 240 QuolifICDlion_MPS04_'l"_B CONFIDENTIAL – SUBJECT TO PROTECTIVE ORDER PRODUCED BY ALLERGAN IN CASE NO. 3:12-CV-01141-DRH-DGW (S.D. ILL.) ARGN_LUM03_0006119 Case 3:12-cv-01141-SMY-DGW Document 176-18 *SEALED* Filed 12/01/14 Page 15 of 32 Allergan Confidential Page ID #2689 Case: 16-3334 Document: 55-40 Filed: 02/08/2017 Pages: 32 (1223 of 1511) Allergan. Inc. Technical Memorandum TPC-TM-2002-002 Page IS of32 Ten cases of filled samples were prepared. Seven hundred and twenty MPS04W (batch W04246) bottles were filled with 15-mL of distilled water. A 40979 dropper- tip was inserted into each bottle, and the bottle was capped with an E00178-1 closure. The closure was tightened to 4 in-Ib torque. Each bottle was inserted into individual 1 1/8" x 1 1/8" x 2 29/32" (Allergan 565) carton that were printed in two colors on four sides with the words "Allergan Test". A blank "directions for use" (DFU) was placed in each carton. Seventy-two filled cartons were placed into an RSC that is 10 11/16"x 9 3/8"x 3 7/16" made from 200# C kraft. A 200-pound C kraft "pad" was placed in the bottom of the RSC and on the top of the cartons. The RSC was sealed with PET packaging tape. Attachments 9.6 to 9.9 show the secondary packaging drawings for the MP504W. The RSC were tested according to SOP TPC-019 and SOP TPC-040. 7.0 7.1 RESULTS PHYSICAL APPEARANCE Bottles made in a unit cavity mold were inspected for physical defects, which included clarity, mottling, blemishes, parting line flash, mismatch, and damage. All components passed Medical Plastic's "first article" inspection according to Medical Plastic's current SOP. Fifty samples were inspected from each batch at TPC. The bottles have a smooth, even, exterior finish, and no physical defects were observed. The original data for the MP504!MPS04W is found in R19994914-135. 7.2 DIMENSIONAL ANALYSIS Bottle Medical Plastics inspects each batch of bottles at the time of manufacture according to their current SOP. A "first article" is declared when the bottle meets the drawing specifications. The first article specifications are the same as those shown in Table 7.2.1. The minimum wall thickness is specified to be 0.027" except in the bottom comer radius where the minimum is 0.020". A dimensional analysis was done by Allergan's Technical Packaging Center on fifty bottles from each batch of bottles. The bottle's measured dimensions were compared with the drawing specifications. The design capability of the lS-mL bottle has been demonstrated by testing bottles from a unit cavity production mold. Wall thickness was changed during development to measure the effect of wall thickness on squeezability and water permeation. The final design has a 0.032 ± 0.005inch wall thickness. The neck finish was not changed during the development. A drawing of the 15-mL bottle is shown in Attachment 9.1. Table 7.2.1 shows a comparison of the important measured dimensions versus the drawing specifications. Original data is in RI999-4914-129. Confidential - This do<:wnent is the propcny of Allergon, Jnc. and is intended solely for their internal us<. 2 241 ~tion_MPS04_rpt_B CONFIDENTIAL – SUBJECT TO PROTECTIVE ORDER PRODUCED BY ALLERGAN IN CASE NO. 3:12-CV-01141-DRH-DGW (S.D. ILL.) ARGN_LUM03_0006120 Case 3:12-cv-01141-SMY-DGW Document 176-18 *SEALED* Filed 12/01/14 Page 16 of 32 Allergan Confidential Page ID #2690 Case: 16-3334 Document: 55-40 Filed: 02/08/2017 Pages: 32 (1224 of 1511) Allergan. Inc. Technical Memorandum TPC-TM-2002-002 Page 16 of32 Table 7.2.1. Dimensional Analysis of MP504W (white) Batch W04246 Property Specification # Out of Specification Average±SD Cp Cpk "f' Internal Neck 0.360 ± 0.006" 0 0.364 ± 0.001 4.1 1.4 "E" Outside neck 0.515 ± 0.006" 0 0.513 ± 0.000 4.8 3.2 "H" Neck Height 0.284 ± 0.010" 0 0.293 ± 0.001 3.1 0.5 ''T'Threadoutside 0.575 ± 0.006" 0 0.576 ± 0.0018 1.1 0.9 uK" Inside Neck Shelf 0.460 ± 0.006" 0 0.463 ± 0.001 4.1 1.9 Overflow Volume Record 0 18.5 N/A N/A Top wall thickness >0.027" 0 0.033 ± 0.002 N/A N/A Center wal1 >0.027" 0 0.034 ± 0.001 N/A N/A Bottom wall >0.027" 0 0.038 ± 0.003 N/A N/A Bottom-Center Record 0 0.071± 0.005 N/A N/A The large Cp values show that the single cavity mold makes bottles with very high precision. The low Cpk values for the "H" dimension indicates that the specification does reflect the process mean for this dimension. The "H" dimension, however, is not a critical dimension. It is adjusted with an insert during the machine setup, and does not affect the container's functionality as long as it is greater than the inside height of the closure, 0.277". The production mold will be adjusted or the specification will be changed to bring the Cpk values for the "H" and "T' dimension closer to 1.0. The specification changes are justified because all the perfonnance testing was done with bottles at the current process means, and no leaking bottles were observed. Closure The drawing of the New Container Closure (NCC) closure is shown in Attachment 9.2. The closures used with the MP504W, 15-mL bottles are the same as those used with the MP500/500W container closure system. The dimensional qualification is reported in Technical Memorandum TPC-TM-200I-018. Confidential - This document is .he property of AIlergon. Inc. and is in.ended solely for .heir internal usc. 2 242 Qua1i/ica.ion_MPS04_rpt_B CONFIDENTIAL – SUBJECT TO PROTECTIVE ORDER PRODUCED BY ALLERGAN IN CASE NO. 3:12-CV-01141-DRH-DGW (S.D. ILL.) ARGN_LUM03_0006121 Case 3:12-cv-01141-SMY-DGW Document 176-18 *SEALED* Filed 12/01/14 Page 17 of 32 Allergan Confidential Page ID #2691 Case: 16-3334 Document: 55-40 Filed: 02/08/2017 Pages: 32 (1225 of 1511) Allergan, Inc. Technical Memorandum TPC-TM-2002-002 Page 17 of32 7.3 COMPRESSION (SQUEEZABiliTY) TEST The results of the compression measurements show that the MP504IMPS04W container's wall compression resistance is within the range of current commercial bottles, and they are acceptable for use as ophthalmic containers. Original data is contained in RI999-4914-133, and R19994914-199. Wall compression resistance was done on the MPS04IMPS04W by the procedure described in methods section 6.3. Two measurements were used to compare the wall compression resistance - initial slope and maximum force. The "initial slope", refers to the slope of the forcedisplacement curve at a certain rate of compression. It is a measure of the force required to move the bottle's wall from its resting position. The other measurement is the maximum force required to compress the bottle's wall 0.12S" on both sides. We believe the initial slope best mimics the compression resistance observed in actual use. It should be interpreted as a relative value to compare containers rather than an absolute force. The results in Table 7 .3.1 show that the compression resistance of the MPS04/S04W bottle is less than Allergan's current IS-mL Boston round ophthalmic container. Table 7.3.1. Wall Compression Resistance for MPS04W IS-mL White Bottle and Allergan's White IS-mL Boston Round Container 7.4 Container Initial Slope ± SD , Ib/in Max Force ± SD, Ib MPS04W (W04246) 2S±S 3.0 ± 0.1 Allergan IS-mL Boston Round 37±8 4.3±0.2 TIP INSERTION FORCE The MPS04/504W bottles have a modified standard IS/41S-neck finish. The distance between the threads and the shoulder of the bottle has been reduced approximately SO% compared to the standard finish. This test was done to show that the MPS04IMPS04W bottle's neck finish does not present any unusual tip insertion difficulties. The test was done on the MPSOO/SOOW and MPSOI S-mL bottles. The MPSOO and MP501 have the same neck finish and tip as the MP504IMPS04W IS-mL bottles. Therefore, the tip insertion results from the S-mL bottle are applicable to the IS-mL bottle. The results shown in Figure 7.4.1 show that the MPSOO/SOOW does not have an unusual tip insertion force and is acceptable for use as an ophthalmic container. The original data is in RI999-4914-60, RI999-4914-74, and RI999-4914-167. The fact that the MPSOI and MPSOO Confidential - 1bis documen, is ,he propeny of Allergan. Inc. :md is ;",ended solely for ,heir in'.rnol usc. 2 243 Quatif"""ion_MPS04JP,_B CONFIDENTIAL – SUBJECT TO PROTECTIVE ORDER PRODUCED BY ALLERGAN IN CASE NO. 3:12-CV-01141-DRH-DGW (S.D. ILL.) ARGN_LUM03_0006122 Case 3:12-cv-01141-SMY-DGW Document 176-18 *SEALED* Filed 12/01/14 Page 18 of 32 Allergan Confidential Page ID #2692 Case: 16-3334 Document: 55-40 Filed: 02/08/2017 Pages: 32 (1226 of 1511) Allergan, Inc. Technical Memorandum TPC-TM-2002-002 Page 18 of32 have the same insertion force shows that an increase in modulus of the body does not increase the insertion force. This means that the addition of colorant or slight increases in wall thickness will not affect the insertion force. As a note, Allergan's PSO has filled, tipped and capped 3,000 MP500 container closures without difficulty. Figure 7.4.1 Tip Insertion Force for MP5041MP504W Container Bottle Number of Samples Tip (EtO Sterilized) Allergan 8-mL Boston Round (21472) Test # 1,6/00 EtO Sterilized 10 40979 5 17 ± 1 10 40979 5 16 ± 1 Fenton Weber Jones, 6-mL natural LOPE 10 40979 5 18 ± 2 MP500(Test2050B) 32 40979 5 16 ± 1 MP501 (Test2050B) 10 40979 5 15 ± 1 Allergan 8-mL Boston Round (21472) Test Insertion Speed, Insertion Force ± SD, Ib in/min. #2,9/00 7.5 DROP WEIGIIT TEST The results with water in Tables 7.5.1 and Table 7.5.2 show that the MP500 series bottles deliver a consistent drop-weight with a standard Allergan dropper tip. Regression analysis of the data from Table 7.5.1 gives vertical drop weight P values of 0.37 and 0.82 for bottle size and fill volume, respectively. At 45° drop angle, the P values are 0.39 for bottle size and 0.92 for fillvolume. This shows statistically that drop-weight is not affected by the bottle's size or fillvolume. The results in Table 7.5.2 further show the insensitivity of the drop-weight to bottle size. The MP501 bottle has the same neck finish as the MP500/500W but the bottle is 0.125" shorter at the shoulder, a significant difference for this size bottle. Again, there is no difference in drop-weight between the bottles. In another experiment (R1999-4914-142), the drop weight of the MP500W (W04270) was measured with a 41351LH natural tip. The drop weight with water was found to be 36.6 ± 0.7 milligrams for a vertical drop-angle and 31.3 ± 0.8 milligrams at 45°. The difference between this Confidential - This documeD. is .he propeny of Aile'll"" Inc. and is imeoded solely for their in.eroai usc. 2 244 Quolifocation_MPS04_tp._B CONFIDENTIAL – SUBJECT TO PROTECTIVE ORDER PRODUCED BY ALLERGAN IN CASE NO. 3:12-CV-01141-DRH-DGW (S.D. ILL.) ARGN_LUM03_0006123 Case 3:12-cv-01141-SMY-DGW Document 176-18 *SEALED* Filed 12/01/14 Page 19 of 32 Allergan Confidential Page ID #2693 Case: 16-3334 Document: 55-40 Filed: 02/08/2017 Pages: 32 (1227 of 1511) Allergan, Inc. Technical Memorandum TPC-TM-2002-002 Page 19 of32 vertical drop weight and those in Table 7.5.1 and 7.5.2 may lead to the conclusion that tip color influences the drop-weight. We believe, however, that this is not a real difference and is most likely due to differences in operator technique, which is known to affect drop weight measurements. Variances as high as plus or minus five milligrams are common with this test. Furthermore, there was no difference at 45°, and an experiment with Lumigan (original reference R2001-6012-24) did not show a drop-weight difference between the 40979 white tip and the 41351LH natural tip. The average drop weight of Lumigan from five separate tips was found to be 25.5 ± 0.6 mg for the 40979 and 26.3 ± 0.4 for the 41351LH. Operator technique differences are also most likely responsible for the difference in drop-weight observed with the 40979 tip in the 21472 8-mL Allergan Boston round bottle (R1999-4914-128). Here the drop weight was found to be 38 ± 3 and 33 ± 2 milligrams for vertical and 45°, respectively. The data in Table 7.5.1 strongly argues against this being a real difference. Table 7.S.1. Drop -Volume Versus Bottle Size and Fill Volume (Reference RlOOl-6191-4S) Drop Volume ± SO, J.LL Fill Bottle Vol., % Drop Tip Operator a Vertical 45° MP500W(W04270) 5-rnL 40 40979 CW 30±3 27 ±3 MP500W(W04270) 5-rnL SO 40979 CW 30±3 2S±3 MP504W(W04246) 15-rnL 40 40979 CW 31 ± 3 28 ± 3 MP504W(W04246) 15-rnL SO 40979 CW 31 ±4 28±3 a. CW = C. West Table 7.S.2. Drop -Volume For the MPSOO and MPSOI Bottles (Reference R2001-6191-77) Drop Volume :t SD, fJ.L Bottle Dropper Tip Operator a Vertical 45° MP500(2050B) 40979 SW 30±5 30±5 MP500(2050B) 40979 PKIMS 32 ±5 33 ±2 MP501(2050B) b 40979 SW 32 ±5 29±4 MP501(2050B) b 40979 PKIMS 30±5 40±4 a. SW = S. Wojcik, MS =M. Shaw, PK =P. Kang, NL =Nick Layman b. The MP501 bottle has the same neck finish as the MP500/500W. It is the same bottle except the body is 0.125" shorter. Confidential - lllis document is .he propeny of AlJergan. Inc. and is intended solely for .heir internal use. 2 245 QualiflCation_MPS04_rp._B CONFIDENTIAL – SUBJECT TO PROTECTIVE ORDER PRODUCED BY ALLERGAN IN CASE NO. 3:12-CV-01141-DRH-DGW (S.D. ILL.) ARGN_LUM03_0006124 Case 3:12-cv-01141-SMY-DGW Document 176-18 *SEALED* Filed 12/01/14 Page 20 of 32 Allergan Confidential Page ID #2694 Case: 16-3334 Document: 55-40 Filed: 02/08/2017 Pages: 32 (1228 of 1511) Allergan. Inc. Technical Memorandum TPC-TM-2002-002 Page 20 of32 7.6 EXTREME TEMPERATURE TEST The test determines the temperature resistance of plastic containers and follows Technical Packaging SOP TPC-017. Water-filled containers were subjected to alternating cycles at 5°C and 45°C. Each temperature was held for 72 hours. Three hundred MP504 bottles from batch W04246 were randomly selected and fitted with a dropper tip (pin 40979) and a NCC E00178-1 closure. The results in Table 7.6.1 show that there was no temperature-related damage observed in any of the containers. The original data is in R 1999-4914-140. Table 7.6.1. Extreme Temperature Test Results for the MP504 Bottle Bottle Tip Cap Temp. °C Number of Samples Result NCC Cap MP504W (batch W04246) 40979 pin EOO178-1 5 300 All Units Passed, no failures found 45 300 All Units Passed, no failures found LotM2545A NCC Cap MP504W (batch W04246) 40979 pin EOO 178-1 LotM2545A 7.7 TEMPERATURE CYCLING RESISTANCE TEST This test is designed to measure the resistance of a container closure to rapid temperature changes between -10cC and 40°C. The test procedure, sample selection, and acceptance criteria are in SOP TPC-060. Three hundred MP504W container closures were tested according to SOP TPC-060. The MP504W is the "white" version of the MP504. The identical process and mold are used to make both containers. The only difference is the MP504W contains 3.8% white pigment, which is mostly Ti02. The results in Table 7.7.1 show that after three 48-hour cycles there was no evidence of temperature stress related defects such as cracking, crazing, or splitting. The original data is in R1999-4914-139. Confidential -11lis document is the propeny of AUeJ]!1IIl. Inc. and is intended solely for their intc:rnal use. 2 246 QuaJjfu:ation_MPS04_'1't_B CONFIDENTIAL – SUBJECT TO PROTECTIVE ORDER PRODUCED BY ALLERGAN IN CASE NO. 3:12-CV-01141-DRH-DGW (S.D. ILL.) ARGN_LUM03_0006125 Case 3:12-cv-01141-SMY-DGW Document 176-18 *SEALED* Filed 12/01/14 Page 21 of 32 Allergan Confidential Page ID #2695 Case: 16-3334 Document: 55-40 Filed: 02/08/2017 Pages: 32 (1229 of 1511) Allergan, Inc. Technical Memorandum TPC-TM-2002-002 Page 21 of32 Table 7.7.1. MP504W Temperature Cycling Resistance Test Results Bottle MP504W(batch W04246) 7.8 Tip Cap 40979 NCC Cap pin EOO178-1 Temp. °C -10 to 40 Number of Samples 300 Result All Units Passed, no failures found LEAK TEST The leak test results show that the MP504/504W container closure does not leak and is suitable for ophthalmic solutions. To assure that the container closure seals completely with tip dimensional variations observed in a production tip mold, thirty tips were tested from each mold cavity. A total of 480 units were tested, and the results are shown in Table 7.8.1. The container closures were tested according to SOP TPC-037 and ASTM D5094-90. The original data is reported in R1999-4914-137. Table 7.8.1. Leak Test For the MP504 (batch W04246) Bottle, 41351LH Dropper Tip, E00178-1 NCC Closure # Samples Tip Mold Cavity No. 30 I 15- mL MP504W Balch 2050B Allergan 41351LH 30 2 15- mL MPS04W Balch 2050B 30 3 30 TPC·037 Results ASTM 05094.90 NCC Cap. E007S-1 Pass Pass Allergan 41351 LH NCC Cap. EOO7S-1 Pass Pass 15- mL MP504W Balch 2050B Allergan 41351LH NCC Cap. EOO7S-1 Pass Pass 4 15- mL MPS04W Balch 2050B Allergan 41351 LH NCC Cap. EOO7S·1 Pass Pass 30 5 15- mL MP504W Balch 2050B Allergan 41351LH NCC Cap. E007S-1 Pass Pass 30 6 IS· mL MP504W Balch 2050B Allergan 41351LH NCC Cap, EOO7S-1 Pass Pass 30 7 15- mL MP504W Balch 2050B Allergan 41351LH NCC Cap, E007S-1 Pass Pass 30 S 15- mL MP504W Batch 2050B Allergan 41351 LH NCC Cap, EOO7S-1 Pass Pass 30 9 15- mL MP504W Batch 2050B Allergan 41351LH NCC Cap. EOO7S-1 Pass Pass 30 10 15- mL MP504W Batch 2050B Allergan 41351LH NCC Cap. EOO7S-1 Pass Pass Tip· Bottles Confidential - Cap This document is the propeny of AlJergan. Inc. ond is intended solely for their internuJ use. Results 2 247 Quolifi~·l o 14 28 Tlme,days Confidential - 11lis documont is the propeny of AIlc'llan. Inc. and is intended solely for their irUernai use. 2 249 Qualiftc8tioR_MPS04_rpt_B CONFIDENTIAL – SUBJECT TO PROTECTIVE ORDER PRODUCED BY ALLERGAN IN CASE NO. 3:12-CV-01141-DRH-DGW (S.D. ILL.) ARGN_LUM03_0006128 Case 3:12-cv-01141-SMY-DGW Document 176-18 *SEALED* Filed 12/01/14 Page 24 of 32 Allergan Confidential Page ID #2698 Case: 16-3334 Document: 55-40 Filed: 02/08/2017 Pages: 32 (1232 of 1511) Allergan, Inc. Technical Memorandum TPC-TM-2002-002 Page 24 of32 Figure 7.10.2. Removal Torque Versus Time for the MP500 (2050B) bottle, 41351LH . Dropper Tip, and 3042SLH Closure - 5 in-lb. Application Torque 5.0 4.5 4.0 3.5 3.0 !± 2.5 I t 2.0 1.5 1.0 0.5 I. 23C/50%RH .. 4OC/21l"kRH 1 .. .._ - - -- ApplICation Torque 51iH1> 0.0 14 7 28 21 Time. Days 7.11 ENVIRONMENTAL STRESS CRACK The MP504W container closure system was tested for chemical induced stress cracking according to SOP TPC-025 and ASTM D 2561. The results of the Environmental Stress Crack test in Table 7.11.1 show that the MP504/MP504W is suitable for use as an ophthalmic container. The original data is in R1999-4914-190. None of thirty samples showed any signs of stress induced cracking or crazing. Table 7.11.1 Environmental Stress Crack Test Results for the MP504W Bottle(EtO) MP504W (batch W04246) 7.12 Tip(EtO) 40979 Cap(EtO) Number of Samples Application Torque, inlb. Results 30 4.0 No Stress Induced Failures NCC Cap, pIn 30425LH WATER LOSS 7.12.1 Direct Measurement of Water Loss Confidential - This dtlcun~nt is I~ propeny of AUt'rg::m, Inc. and is in1eooal ~)Iely for lheir internal u:;c. 2 250 QualifiCUIMln_MPS04_rpt_B CONFIDENTIAL – SUBJECT TO PROTECTIVE ORDER PRODUCED BY ALLERGAN IN CASE NO. 3:12-CV-01141-DRH-DGW (S.D. ILL.) ARGN_LUM03_0006129 Case 3:12-cv-01141-SMY-DGW Document 176-18 *SEALED* Filed 12/01/14 Page 25 of 32 Allergan Confidential Page ID #2699 Case: 16-3334 Document: 55-40 Filed: 02/08/2017 Pages: 32 (1233 of 1511) Allergan. Inc. Technical Memorandum TPC-TM-2002-002 Page 25 of32 Water loss results are summarized in Table 7.12.1. Water loss for the MP504W was measured directly with a Mocon Permatran 3/31 at two or more different temperatures. The water loss (gt) for a specified time (t) and relative humidity (P) at each temperature was used to calculate the water permeability constant (PWt) using a measurement of the containers average wall thickness and surface area. The activation energy of permeation Ep and the preexponential factor Po were calculated from the Pw versus temperature data. These are fundamental properties of the resin and consequently of the individual container closure system being studied. From the Ep and Po values, the Pw can be calculated for any temperature. This value combined with any combination of area, time, relative humidity, and wall thickness can be used to calculate the water loss at the specified conditions. The 99% confidence limit for this calculation is estimated to be ± 1%, and the 95% confidence limit for the Mocon measurements is estimated to be ± 2%. Because these errors can be expected to partially offset each other at least 50% of the time, the total error in the Mocon determined results is expected to slightly over ± 2%. The foil-sealed MP504W with a 0.033" average wall thickness had a water loss of 0.3497 g for three years, at 25°C and 40% RH. This equates to 2.3 % water loss for a 15-mL fill. The validity of the measured values is established by water-loss calculations based on literature values of Pw or literature values of Ep and Po. The calculated water loss for the MP504W bottle for a 0.033" wall thickness for three years at 25°C and 40% RH with a literature value of Pw was found to be 0.4138 g, or 2.8% for a 15-mL fill volume. The three-year water loss calculated from literature Ep and Po values for the MP504W at 25°C/40%RH was 0.3992 g, or 2.7% for a 15-mL fill volume, again very close to the measured values. The original data is referenced in R1999-4914-170. 7.12.2 Real-Time Water Loss Measurements The results of a 90-day real-time water-loss study at 25°C/40%RH for the MP504W (0.033" wall) container closure, shows a water loss of 0.345 ± 0.004 g or 2.76 ± 0.03% for a 15-mL fill volume. The original data is in R2001-6191-10. Confidential - nus uucunxnt is the propt:rty of Allc::rgan. Inc. ant.! is intended !/.okly tor their internal uSt:. 2 251 Qu.tific.li'!D_MP504_'l"_B CONFIDENTIAL – SUBJECT TO PROTECTIVE ORDER PRODUCED BY ALLERGAN IN CASE NO. 3:12-CV-01141-DRH-DGW (S.D. ILL.) ARGN_LUM03_0006130 Case 3:12-cv-01141-SMY-DGW Document 176-18 *SEALED* Filed 12/01/14 Page 26 of 32 Allergan Confidential Page ID #2700 Case: 16-3334 Document: 55-40 Filed: 02/08/2017 Pages: 32 (1234 of 1511) Allergan. Inc. Technical Memorandum TPC-TM-2002-002 Page 26 of32 Table 7.12.1. Water Loss Results for MPS04 and MPS04W at 25°C and 40% RH Wall Thickness, mil Average Water Loss for 3 yr., g Water Loss for 3-yr/15mL fill volume, % MP504W(W04246) w Lit Value of Pw 33 0.4138 2.8 MP504W (W04246) w Lit Value of Ep and Po 33 0.3992 2.7 MP504W 90-day Real-Time 33 0.345 ± 0.004 2.76 ± 0.03 Description 7.13 MICROBIAL CHALLENGE TEST The microbial challenge test was done on the MP500 and MP501 5-mL bottles both of which have the same neck finish, drop tip and cap as the MP504/504W 15-mL bottle. The sealing configuration for the two different size bottles is the same. Therefore, the results for the 5-mL bottle are applicable to the 15-mL bottle. The results were reported in Technical Memorandum TPC-TM- 2001-018 and are summarized below. The MP500 and MP501 bottles fitted with the 40979 dropper tip and the 30425LH closure were subjected to bacterial challenge according to Nelson Laboratories' current protocol, 20002720103. The original results in RI999-4914-107 show that the contents of the container closure remained sterile after exposure to a controlled aerosol environment seeded with a high concentration of Bacillus licheniformis spores. All tests sample plates remained sterile, and positive controls exhibited growth of the indicator organism. Nelson Laboratories concluded in their final report, Attachment 9.4, that Allergan's container closure #1 (MP500) and #2 (MP501) demonstrated a 100% sterile barrier following an extreme bacterial aerosol challenge. 7.14 JAPANESE PHARMACOPEIA TESTING The materials and design are the same for the MP504 15-mL bottle and the MP500 5-mL bottle except for the body size. Therefore, the results for the MP500 bottle are applicable to the MP504 bottle. The MP500 passed the Japanese Pharmacopoeia testing done by Sumika Chemical Analysis Tokyo, Japan. The results are in Sumika Chemical Analysis Final Report for study No. 14106380, Attachment 9.5, and are reproduced in Table 7.14.1. Confidential - This docWll critical variable; which means that it is less than 5% risk to do wrong if the value is eliminated, i.e. 282 p.1 was regarded as an outlier and the range of the volume left in the bottles was 131-207 pl with a 95% confidence interval. No other outliers were found in the sample. 2. Estimation of the range of the mean for the population. Calculation: x±txs/4n t 025 (when f=14)=2,14 x ± 2,14 x 1,2 / 415 x ± 0,66 which means that the estimated mean value of weight per drop for the population is within 28,7 - 30,1 pl. CONFIDENTIAL, SUBJECT TO PROTECTIVE ORDER, PRODUCED BY PFIZER IN CASE NO. 3:12-CV-01141-DRH-DGW (S.D. ILL.) PFIZER_XALATAN_00001542 Case 3:12-cv-01141-SMY-DGW Document 176-21 *SEALED* Filed 12/01/14 Page 13 of 16 Page ID #2728 Case: 16-3334 Document: 55-46 Filed: 02/08/2017 Pages: 16(1339 of 1511) NOTE The Notes section welcomes the following types of contributions: (1) practical innovations or solutions to everyday practice problems, (2) substantial updates or elaborations on work previously published by the same authors, (3) important confirmations of research findings previously published by others, and (4) short research reports, including practice surveys, of modest scope or interest. Notes should be submitted with AJHP's manuscript checklist. The text should not exceed four double-spaced pages, and the number of any references, tables, and illustrations should be limited. Costs of glaucoma medications RICHARD G. F1SCELLA Am) Health-Syst Pharrn. 1998; 55:272-5 G laucoma is responsible for 80,000 cases of blindness and affects approximately 2.5 million people in the United States alone." It is predicted that 67 million people worldwide will be afflicted with glaucoma and more than 6.7 million will be blind as a result of the disease by the year 2000.2 Primary openangle glaucoma is defined as an increase in intraocular pressure (10P) with resulting 'damage to the optic nerve, deterioration of visual fields, and eventual loss of vision. 10P elevation is often the result of decreased outflow of aqueous humor through the trabecular meshwork. Patients may be referred to as having ocular hypertension if they exhibit IOPs in the range of 20-30 mm Hg (normal, 10-20 mm Hg) and have other risk factors for glaucoma but no glaucomatous damage (e.g., damage to the optic nerve head, visual-field damage). The major risk factors for glaucoma are old age, family history of glaucoma, certain systemic diseases (e.g., diabetes, hypertension, hyperthyroidism), myopia, and African-American descent." Treatment for glaucoma centers around reduction of the elevated IOP, usually with medications, because this is believed to prevent or arrest deterioration of the optic nerve and visual fields. A target LOP may be difficult to attain for various reasons, including ineffectiveness of a medication, disease progression, and poor patient compliance." Poor patient compliance is believed to be one of the major reasons for failure of glaucoma treatments Glaucoma medications decrease kW by reducing aqueous humor production or in- creasing aqueous outflow through either the trabecular meshwork or the uveoscleral route-4 Laser and surgical procedures are usually reserved for those not responding to drug therapy. I wanted to determine the drug costs for glaucoma therapy, especially those for newly available glaucoma medications. Methods. The most common clinically used glaucoma medications were selected in order to determine their daily costs. The number of drops in each bottle was counted as the bottles were emptied into 5-mL (calibrated to 0.1 mL) or 10-mL (calibrated to 0.2 mL) graduated cylinders at 25 °C. The actual, not the labeled, volume was determined for each bottle. The bottles were held at an angle of approximately 135° (a bottle standing on end with the dropper up would be at 0°) as the drops were collected. When the drops ceased to flow, the bottles were inverted to 180° to obtain the last complete drops. The number of drops per milliliter was determined on the basis of the actual volume. The average from three bottles was used for many of the newer medications, and the average number of drops and the coefficient of variation were determined. The number of days a bottle would last was calculated for each medication by using the most common dosage regimen and assuming use in both eyes. For some medications there is more than one dosage regimen, and in such cases a range was reported. The average wholesale price (AWP) was obtained from the Bed Book.6 The price of each medication per milliliter was determined on the basis of the actual number of Milliliters. The price per day was calculated by dividing the AWP by the number of days per bottle. The costs per day for oral carbonic anhydrase inhibitors were determined on the basis of the number of daily doses. Results. Some differences were noted among products in the number of drops per milliliter. The drops per milliliter ranged from 14.4 (carbachol) to 37.9 (timolol solution), with a mean ± S.D. of 26.8 ± 5.5 (Table 1). Using a mean would therefore not have been G. FtscELLA, M.P.H., is Clinical Associate. Professor, Department of Pharmacy Practice, University of Illinois at Chicago, 833 S. Wood Street, ( :hicago, IL 60612 (fisc@uic.edu). RICHARD Copyright C 1998. American Society of Health-System Pharmacists, Inc. All rights reserved. 1079-2082/98/0201-0272506.00. • 272 Am J Health-Syst Pharm Vol 55 Feb 1 1998 CONFIDENTIAL, SUBJECT TO PROTECTIVE ORDER, PRODUCED BY PFIZER IN CASE NO. 3:12-CV-01141-DRH-DGW (S.D. ILL.) PFIZER_XALATAN_00001543 Case 3:12-cv-01141-SMY-DGW Document 176-21 *SEALED* Filed 12/01/14 Page 14 of 16 Page ID #2729 Case: 16-3334 Document: 55-46 Filed: 02/08/2017 Pages: 16(1340 of 1511) Glaucoma medications Note Table 1. "ally Cost of Medications Used in Treating Glaucoma , Product' Average Wholesale Price ($)° Usual Dosage Frequency° Actual Volume (mL)° Drops/mL° Cost/Day ($1 Cholinergic Agents 0.21-0.29 23.0 15.7 Pilocarpine 4% solution. 15 mL (IOLAB) 12.81 3-4/day 0.15-0.20 20.9 15.4 3-4/day Pilocarpine 4% solution. 15 mL (Schein) 7.83 Pilocarpine 4% gel, 4 g (70 single-eye doses) 0.71 25.00 1/day` (Alcon) Pilocarpine 20- or 40-µg/hr insert. box of 8 1.25 1/week' 35.06 (Alza) 0.38-0.56 14.40 2-3/day 15.00 Carbachol 3% solution. 15 mL (Alcon) 20.31 Echothiophate iodide 0.03% solution. 5 mL 0.29-0.58 32.6 5.0 1-2/day 23.58 (Wyeth-Ayerst) Nonselective Adrenergic Agents 0.27 24.3 10.6, 17.81 . 2/day Epinephrine 1% solution. 10 mL (Noon)" Dipivefrin hydrochloride 0.1% solution. 5 mL 0.40 5.4 30.3 16.03 2/day (Allergen) Dipivefrin hydrochloride 0.1% solution. 15 mL 14.8 0.30 35.44 32.0 2Jday (Pacific Pharma) Alpha? Adrenergic Agents 1.33 5.20 32.90 3/day Apraclonidine 0.5% solution, 5 mL (Alcon)" 37.20 Brimonidine tartrate 0.2% solution. 10 mL 0.67-1.01 25.40 2-3/day 10.2° 43.55 (Allergen) Beta-Adrenergic Blockers 0.46 30.8 36.56 2Jday 10.5 Betaxolol 0.5% solution. '10 mL (Alcon)" 0.63 4.99 25.40 19.38 2/day Betaxolol 0.25% suspension, 5 mi. (Alcon)" 0.36 5.49 37.90 18.41 2/day Timolol 0.5% solution. 5 mL (Merck). 0.27 2/day 2.7 29.3 10.79k Timolol 0.25% solution, 2.5-mL sample (Ciba)1 26.3 0.36 2.7 12.76' 2/day Timolol 0.5% solution, 2.5-mL sample (Ciba), 212 0.37 3.3 12.81 1/day Timotol 0.25% gel. 2.5 mi. (Merck). 0.39 22.60 26.86 1/day 5.90 Timolol 0.5% gel, 5 mi. (Mercky Levobunolol hydrochloride 0.5% solution, 0.70 18.40 2/day 5.2 20.4 5 mL (Allergen) Levobunolol hydrochloride 0.5% solution, 0.57 5.4 20.2 15.50 2/day 5 mL (Schein) Metipranolol 03% solution, 5 mL (Bausch & 0.34 5.2 28.1 12.33 2/day Lomb) Carteolol hydrochloride 1% solution, 5 mL 0.46 27.1 16.18 2/day 5.2 (Otsulta America) Carbonic Anhydrase Inhibitors 0,60-0.91 5.50 21.00 2-3/day 26.30 Dorzotamide 2% solution,'5 mi. (Merck)" Acetazolamide 125-mg tablet, 100 tablets 0.90-1.20 3-4/day 30.06 (Stolz) 0.25-0.33 8.25 3-4/day Acetazolamide 125-mg tablet. 100 tablets (URL) 1.16-1.55 38.78 3-4/day Acetazolamide 250-mg tablet, 100 tablets (Storz) 0.34-0.46 11.40 3-4/day Acetazolamide 250-mg tablet, 100.tablets (URL) Acetazolamide 500-mg capsule. 100 capsules 0.96-1.93 96.30 . 1-2/day (Storz) 1.06-1.59 Methazolamide 25-mg tablet. 100 tablets (Storz) 53.13 2-3/day 0.90-1.35 45.02 Methazolamide 25-mg tablet. 100 tablets (Akom) 2-3/day 1.58-2.38 79.30 Methazolamide 50-mg tablet. 100 tablets (Storz) 2-3/day 67.21 1.34-2.02 Methazolamide 50-mg tablet, 100 tablets (Akom) 2-3/day Prostaglandin Latanoprost 0.005% solution, 2.5 mL (Pharmacia 34.50 0.75 37.80 1/day 3.00 & Upjohn) 'Solutions, gels. inserts. and suspensions are for ophthalmic use. Tablets and capsules are for oral use. !Prices are from reference 6 and. unless otherwise noted. are for the package size studied. °Unless otherwise noted. each dose of ophthalmic preparations is one drop in each eye. For oral medications. one dose is one tablet or capsule. dUnless otherwise noted. determined from one container. 'One dose is 0.5 inch of gel in each eye. tOne dose is one insert in. each eye. Wean from three containers (coefficient of variation s4.7%). 'Given as the hydrochloride salt. 'Given as timotol maleate. 'Given as timolol hemihydrate. ',Price is for the 5-mL container. Vol 55 Feb 1 1998 Am J Health-Syst Pharm 273 CONFIDENTIAL, SUBJECT TO PROTECTIVE ORDER, PRODUCED BY PFIZER IN CASE NO. 3:12-CV-01141-DRH-DGW (S.D. ILL.) PFIZER_XALATAN_00001544 Case 3:12-cv-01141-SMY-DGW Document 176-21 *SEALED* Filed 12/01/14 Page 15 of 16 Page ID #2730 Case: 16-3334 Document: 55-46 Filed: 02/08/2017 Pages: 16(1341 of 1511) Note Glaucoma.medications appropriate, so the actual number of drops per milliliter for each medication was used to determine the real cost. The daily cost of a single medication ranged from a low of $0.15 for generic pilocarpine solution (one drop to each eye three times daily) to a high of $2.38 for brand-name methazolamide 50-mg tablets (one taken three times daily). The cost of cholinergic agents ranged from $0.15 to $1.25 per day. Pilocarpine solutions varied little among products in terms of the number of drops per milliliter (21-23). The daily cost was based on three- or four-times-daily dosages and ranged from $0.15 to $0.29. Carbachol is formulated in a viscous methylcellulose vehicle, producing a larger drop size and therefore fewer drops per milliliter (14), with a daily cost of $0.38 to $0.56. Echothiophate iodide (0.03%) is the only glaucoma medication that still contains a separate dropper and may be administered once or twice daily. It is often used in lower concentrations for glaucoma patients, and the daily cost ranged.from $0.29 to $0.58. The AWPs for the different strengths of echothiophate iodide did not vary much. The nonselective adrenergic agents ranged in AWP from $0.27/day for epinephrine solution to $0.40/day for brand-name dipivefrin (a prodrug of epinephrine). The daily costs of afagonists ranged from $0.67 for brimonidine to $1.33 for apraclonidine. The daily cost of 8-adrenergic antagonists ranged from a low of $0.27 for twice-daily brand-name timolol 0,25% (as the hemihydrate) to a high of $0.70 for brand-name levobunolol hydrochloride 0.5%. The number of drops per milliliter for the carbonic anhydrase inhibitor dorzolamide averaged 26.3 for the. 5-mL bottle. The daily cost of dorzolamide was $0.91 assuming use of three drops per eye daily. If this agent were used twice daily in combination with other glaucoma products, the daily cost would decrease to $0.60. The prostaglandin latanoprost averaged 102 drops per bottle and had an average daily cost of $0.75. Discussion, With the availability of various glaucoma medications, stepwise treatment options for glaucoma and ocular hypertension may vary. Traditionally, patients have therapy initiated with a topical 8-blacker unless there are contraindications (e.g., asthma)."..7-" Additional agents of other pharmacologic classes, such as pilocarpine, dipivefrin, and acetazolamide, are often added if IOP is not controlled. Dorzolamide has recently been considered in place of systemic carbonic anhydrase inhibitors because of its minimal risk of systemic adverse effects.12 The a2-adrenergic blacker brimonidine may be an alternative first- or second-line therapeutic option because of its minimal adverse ocular and systemic effects and effective IOP lowering ability."'" Latanoprost, because of its oncedaily administration schedule and potent 10P-lowering effects, is used as adjunctive and often primary therapy.15 '6 There is some belief that the miotic agents and epinephrine (or dipivefrin) will be reserved for last-step therapy because of their ocular adverse-effect profile." Latanoprost, brimonidine, and dorzolamide, along with a-blockers, might soon become primary and secondary agents in the treatment of glaucoma. This was not strictly a cost-minimization study, because that term implies that all therapies discussed are equally effective, and that is not the case with glaucoma medications. There are different indications and uses among products. Apraclonidine is approved for short-term (three-month) adjunctive therapy only, while other medications (e.g., echothiophate, acetazolamide), because of bothersome adverse effects, are often used as third- or fourth-line agents. The number of drops per milliliter and the cost per bottle are helpful in determining the daily treatment costs for patients with glaucoma. Others have examined these variables for the various ophthalmic 8-blockers.''-2° The results of my study did not vary much from the findings of those investigators. The daily costs among their studies and mine were within $0.05, except in the case of betaxolol 0.25% (as the hydrochloride) suspension. That product is a carbopol gel and is rather thick and opaque, which could account for some of the variability in the number of drops per bottle. Also, because of bubbles, the thickness of the gel, and the cloudiness of the drop, it is hard to visualize the actual volume in the graduated cylinder. The daily cost of traditional maximal .treatment, including pilocarpine gel or drops ($0.71 or $0.20), dipivefrin ($0.30), brand-name acetazolamide tablets 250 mg four times daily ($1.55), and brand-name timolol solution ($0.36), would total $2.92 or $2.41. Newer treatment options may instead include latanoprost ($0.75), brimonidine ($0.67 to $1.01), and timolol and would cost $1.78 to $2.12 per day. If dorzolamide were substituted for brimonidine, the daily cost would be similar. If dorzolamide were added to therapy, the additional cost would range from $0.60 to $0.91 per day (total, $2.38 to $3.035. Cost analysis must take into account other costs besides those of the medications themselves. Obviously, missed doses and wastage are important considerations. This study is a best-case scenario. If a patient is missing his or her eye when applying a medication, the cost per day will increase. Although some medications might cost more on a daily basis, such costs could be outweighed by improved compliance, the need for fewer medications to control IOP, fewer patients requiring other interventions (e.g., surgical), and a better•adverse-effect profile. It is therefore likely that the cholinergic agents and epinephrine compounds will see limited use. One of the main reasons for glaucoma treatment failures is poor patient compliance. Compliance may be inhibited by a limited understanding of the disease. Patients who understand their disease improve their 274 Am,' Health-Syst Pharm Vol 55 Feb 1 1998 CONFIDENTIAL, SUBJECT TO PROTECTIVE ORDER, PRODUCED BY PFIZER IN CASE NO. 3:12-CV-01141-DRH-DGW (S.D. ILL.) PFIZER_XALATAN_00001545 Case 3:12-cv-01141-SMY-DGW Document 176-21 *SEALED* Filed 12/01/14 Page 16 of 16 Page ID #2731 Case: 16-3334 Document: 55-46 Filed: 02/08/2017 Pages: 16(1342 of 1511) Glaucoma medications regimen compliance by a factor of 10.5 Recent drug -t-yelopments offer more convenient dosage regimens d more tolerable adverse-effect profiles, which can Lontribute to improved compliance. Improved compliance could lessen the progression of the disease and reduce the need for laser and surgical procedures, although this remains to be seen. Conclusion. The costs of medications used in the treatment of glaucoma vary widely. Factors other than cost-adverse effects, effectiveness, and compliancemust also be considered in planning glaucoma therapy. References 1. Glaucoma Panel. Primary open angle glaucoma suspect: preferred practice pattern. San Francisco: American Academy of Ophthalmology; 1995:4-6. 2. Quigley HA. Number of people with glaucoma worldwide. Br 1 Ophthalmol. 1996; B0:389-93. 3. Consensus Panel on Open Angle Glaucoma. Care of the patient with open angle glaucoma: optometric clinical practice guideline. St. Louis: American Optometric Association; 1995:3-10. 4. Ritch R, Shields MB, Krupin T. Chronic open-angle glaucoma: treatment overview. In: Ritch R, Shields MB, Krupin T, eds. The glaucomas. 2nd ed. St. Louis: Mosby; 1996:1507-19. 5. Zimmerman T. Facilitating patient compliance in glaucoma therapy. Sury Ophthalmol. 1983; 289(suppl):252-7. 6. Cardinle V. Drug Topics red book. Montvale, NJ: Medical Economics; 1996. 7. Serie JB. Pharmacological advances in the treatment of glaucoma. Drugs Aging. 1994; 5:156-70. 8. Novack GD, Robin AL, Derick RJ. New medical treatments for glaucoma. Int Ophthalmol Clin. 1993; 33:183-202. Monane M, Bohn RL, Gurwitz JH et al. Topical glaucoma Note 12 medications and cardiovascular risk in the elderly. Clin Phar- macol Ther. 1994: 55(1):76-83. 10. Fraunfeder FT. Meyer SM. Systemic adverse reactions to glaucoma medications. lntOplrtlralrtrol Clin. 1989; 29:1143-6. 11. O'Donoghue E. Beta-blockers and the elderly with glaucoma: are we adding insult to injury? Br I Ophthalmol. 1995; 79:794-6. 12. Donohue EK, Wilensky JT. Trusopt, a topical carbonic anhydrase inhibitor. J Glaucoma. 1996; 5:68-74. 13. Schuman JS, Horwitz B, Choplin NT et al. A 1-year study of brimonidine twice daily in glaucoma and ocular hypertension. A controlled, randomized, multicenter clinical trial. Arch OpIttlialinol. 1997; 115:847:52. 14. Wilensky J. The role of brimonidine in the treatment of open-angle glaucoma. Sury Ophthalmol. 1996; 41(suppl 1):S3-7. 15. Camras CB and the U.S.A. Latanoprost Study Group. Comparison of latanoprost,and timolol in patients with ocular hypertension and glaucoma. Ophthalmology. 1996; 103:13847. 16. Watson P, Stiernschantz J, and the U.S.A. Latanoprost Study Group. A six-month, randomized, double-masked study comparing latanoprost with timolol in open-angle glaucoma and ocular hypertension. Ophthalmology. 1996; 103:12637. 17. Weiss MA, Hendrickson JR. Information on drop size needs to be eyed closely. Aug I Hosp Phann. 1994; 51:2969-70. Letter. 18. Ball 5F, Schneider E. Cost of beta-adrenergic receptor blocking agents for ocular hypertension. Arch Ophthalmol. 1992; 110:654-7. 19. Hartnbaum D, Stek M, Haggert Bet al. Quantitative and cost evaluation of three antiglaucoma beta-blocker agents: Timoptic-XE versus two generic levobunolol products. Am I Manag Care. 1996; 2:157-62. 20. Schwartz J, Christensen RE, Lee DA. Comparison of timolol maleate and levobunolol: doses and volume per bottle. Arch Ophthalmol. 1989; 107:17. Letter. Vol 55 Feb 1 1998 Am J Health-Syst Pharm 275 CONFIDENTIAL, SUBJECT TO PROTECTIVE ORDER, PRODUCED BY PFIZER IN CASE NO. 3:12-CV-01141-DRH-DGW (S.D. ILL.) PFIZER_XALATAN_00001546 Case 3:12-cv-01141-SMY-DGW Document 176-47 *SEALED* Filed 12/01/14 Page 1 of 42 Page ID #3368 Case: 16-3334 Document: 55-47 Filed: 02/08/2017 Pages: 42 (1343 of 1511) Case 3:12-cv-01141-SMY-DGW Document 176-47 *SEALED* Filed 12/01/14 Page 2 of 42 Page ID #3369 Case: 16-3334 Document: 55-47 Filed: 02/08/2017 Pages: 42 (1344 of 1511) Case 3:12-cv-01141-SMY-DGW Document 176-47 *SEALED* Filed 12/01/14 Page 3 of 42 Page ID #3370 Case: 16-3334 Document: 55-47 Filed: 02/08/2017 Pages: 42 (1345 of 1511) Case 3:12-cv-01141-SMY-DGW Document 176-47 *SEALED* Filed 12/01/14 Page 4 of 42 Page ID #3371 Case: 16-3334 Document: 55-47 Filed: 02/08/2017 Pages: 42 (1346 of 1511) Case 3:12-cv-01141-SMY-DGW Document 176-47 *SEALED* Filed 12/01/14 Page 5 of 42 Page ID #3372 Case: 16-3334 Document: 55-47 Filed: 02/08/2017 Pages: 42 (1347 of 1511) Case 3:12-cv-01141-SMY-DGW Document 176-47 *SEALED* Filed 12/01/14 Page 6 of 42 Page ID #3373 Case: 16-3334 Document: 55-47 Filed: 02/08/2017 Pages: 42 (1348 of 1511) Case 3:12-cv-01141-SMY-DGW Document 176-47 *SEALED* Filed 12/01/14 Page 7 of 42 Page ID #3374 Case: 16-3334 Document: 55-47 Filed: 02/08/2017 Pages: 42 (1349 of 1511) Case 3:12-cv-01141-SMY-DGW Document 176-47 *SEALED* Filed 12/01/14 Page 8 of 42 Page ID #3375 Case: 16-3334 Document: 55-47 Filed: 02/08/2017 Pages: 42 (1350 of 1511) Case 3:12-cv-01141-SMY-DGW Document 176-47 *SEALED* Filed 12/01/14 Page 9 of 42 Page ID #3376 Case: 16-3334 Document: 55-47 Filed: 02/08/2017 Pages: 42 (1351 of 1511) Case 3:12-cv-01141-SMY-DGW Document 176-47 *SEALED* Filed 12/01/14 Page 10 of 42 Page ID #3377 Case: 16-3334 Document: 55-47 Filed: 02/08/2017 Pages: 42 (1352 of 1511) Case 3:12-cv-01141-SMY-DGW Document 176-47 *SEALED* Filed 12/01/14 Page 11 of 42 Page ID #3378 Case: 16-3334 Document: 55-47 Filed: 02/08/2017 Pages: 42 (1353 of 1511) Case 3:12-cv-01141-SMY-DGW Document 176-47 *SEALED* Filed 12/01/14 Page 12 of 42 Page ID #3379 Case: 16-3334 Document: 55-47 Filed: 02/08/2017 Pages: 42 (1354 of 1511) Case 3:12-cv-01141-SMY-DGW Document 176-47 *SEALED* Filed 12/01/14 Page 13 of 42 Page ID #3380 Case: 16-3334 Document: 55-47 Filed: 02/08/2017 Pages: 42 (1355 of 1511) Case 3:12-cv-01141-SMY-DGW Document 176-47 *SEALED* Filed 12/01/14 Page 14 of 42 Page ID #3381 Case: 16-3334 Document: 55-47 Filed: 02/08/2017 Pages: 42 (1356 of 1511) Case 3:12-cv-01141-SMY-DGW Document 176-47 *SEALED* Filed 12/01/14 Page 15 of 42 Page ID #3382 Case: 16-3334 Document: 55-47 Filed: 02/08/2017 Pages: 42 (1357 of 1511) Case 3:12-cv-01141-SMY-DGW Document 176-47 *SEALED* Filed 12/01/14 Page 16 of 42 Page ID #3383 Case: 16-3334 Document: 55-47 Filed: 02/08/2017 Pages: 42 (1358 of 1511) Case 3:12-cv-01141-SMY-DGW Document 176-47 *SEALED* Filed 12/01/14 Page 17 of 42 Page ID #3384 Case: 16-3334 Document: 55-47 Filed: 02/08/2017 Pages: 42 (1359 of 1511) Case 3:12-cv-01141-SMY-DGW Document 176-47 *SEALED* Filed 12/01/14 Page 18 of 42 Page ID #3385 Case: 16-3334 Document: 55-47 Filed: 02/08/2017 Pages: 42 (1360 of 1511) Case 3:12-cv-01141-SMY-DGW Document 176-47 *SEALED* Filed 12/01/14 Page 19 of 42 Page ID #3386 Case: 16-3334 Document: 55-47 Filed: 02/08/2017 Pages: 42 (1361 of 1511) Case 3:12-cv-01141-SMY-DGW Document 176-47 *SEALED* Filed 12/01/14 Page 20 of 42 Page ID #3387 Case: 16-3334 Document: 55-47 Filed: 02/08/2017 Pages: 42 (1362 of 1511) Case 3:12-cv-01141-SMY-DGW Document 176-47 *SEALED* Filed 12/01/14 Page 21 of 42 Page ID #3388 Case: 16-3334 Document: 55-47 Filed: 02/08/2017 Pages: 42 (1363 of 1511) Case 3:12-cv-01141-SMY-DGW Document 176-47 *SEALED* Filed 12/01/14 Page 22 of 42 Page ID #3389 Case: 16-3334 Document: 55-47 Filed: 02/08/2017 Pages: 42 (1364 of 1511) Case 3:12-cv-01141-SMY-DGW Document 176-47 *SEALED* Filed 12/01/14 Page 23 of 42 Page ID #3390 Case: 16-3334 Document: 55-47 Filed: 02/08/2017 Pages: 42 (1365 of 1511) Case 3:12-cv-01141-SMY-DGW Document 176-47 *SEALED* Filed 12/01/14 Page 24 of 42 Page ID #3391 Case: 16-3334 Document: 55-47 Filed: 02/08/2017 Pages: 42 (1366 of 1511) Case 3:12-cv-01141-SMY-DGW Document 176-47 *SEALED* Filed 12/01/14 Page 25 of 42 Page ID #3392 Case: 16-3334 Document: 55-47 Filed: 02/08/2017 Pages: 42 (1367 of 1511) Case 3:12-cv-01141-SMY-DGW Document 176-47 *SEALED* Filed 12/01/14 Page 26 of 42 Page ID #3393 Case: 16-3334 Document: 55-47 Filed: 02/08/2017 Pages: 42 (1368 of 1511) Case 3:12-cv-01141-SMY-DGW Document 176-47 *SEALED* Filed 12/01/14 Page 27 of 42 Page ID #3394 Case: 16-3334 Document: 55-47 Filed: 02/08/2017 Pages: 42 (1369 of 1511) Case 3:12-cv-01141-SMY-DGW Document 176-47 *SEALED* Filed 12/01/14 Page 28 of 42 Page ID #3395 Case: 16-3334 Document: 55-47 Filed: 02/08/2017 Pages: 42 (1370 of 1511) Case 3:12-cv-01141-SMY-DGW Document 176-47 *SEALED* Filed 12/01/14 Page 29 of 42 Page ID #3396 Case: 16-3334 Document: 55-47 Filed: 02/08/2017 Pages: 42 (1371 of 1511) Case 3:12-cv-01141-SMY-DGW Document 176-47 *SEALED* Filed 12/01/14 Page 30 of 42 Page ID #3397 Case: 16-3334 Document: 55-47 Filed: 02/08/2017 Pages: 42 (1372 of 1511) Case 3:12-cv-01141-SMY-DGW Document 176-47 *SEALED* Filed 12/01/14 Page 31 of 42 Page ID #3398 Case: 16-3334 Document: 55-47 Filed: 02/08/2017 Pages: 42 (1373 of 1511) Case 3:12-cv-01141-SMY-DGW Document 176-47 *SEALED* Filed 12/01/14 Page 32 of 42 Page ID #3399 Case: 16-3334 Document: 55-47 Filed: 02/08/2017 Pages: 42 (1374 of 1511) Case 3:12-cv-01141-SMY-DGW Document 176-47 *SEALED* Filed 12/01/14 Page 33 of 42 Page ID #3400 Case: 16-3334 Document: 55-47 Filed: 02/08/2017 Pages: 42 (1375 of 1511) Case 3:12-cv-01141-SMY-DGW Document 176-47 *SEALED* Filed 12/01/14 Page 34 of 42 Page ID #3401 Case: 16-3334 Document: 55-47 Filed: 02/08/2017 Pages: 42 (1376 of 1511) Case 3:12-cv-01141-SMY-DGW Document 176-47 *SEALED* Filed 12/01/14 Page 35 of 42 Page ID #3402 Case: 16-3334 Document: 55-47 Filed: 02/08/2017 Pages: 42 (1377 of 1511) Case 3:12-cv-01141-SMY-DGW Document 176-47 *SEALED* Filed 12/01/14 Page 36 of 42 Page ID #3403 Case: 16-3334 Document: 55-47 Filed: 02/08/2017 Pages: 42 (1378 of 1511) Case 3:12-cv-01141-SMY-DGW Document 176-47 *SEALED* Filed 12/01/14 Page 37 of 42 Page ID #3404 Case: 16-3334 Document: 55-47 Filed: 02/08/2017 Pages: 42 (1379 of 1511) Case 3:12-cv-01141-SMY-DGW Document 176-47 *SEALED* Filed 12/01/14 Page 38 of 42 Page ID #3405 Case: 16-3334 Document: 55-47 Filed: 02/08/2017 Pages: 42 (1380 of 1511) Case 3:12-cv-01141-SMY-DGW Document 176-47 *SEALED* Filed 12/01/14 Page 39 of 42 Page ID #3406 Case: 16-3334 Document: 55-47 Filed: 02/08/2017 Pages: 42 (1381 of 1511) Case 3:12-cv-01141-SMY-DGW Document 176-47 *SEALED* Filed 12/01/14 Page 40 of 42 Page ID #3407 Case: 16-3334 Document: 55-47 Filed: 02/08/2017 Pages: 42 (1382 of 1511) Case 3:12-cv-01141-SMY-DGW Document 176-47 *SEALED* Filed 12/01/14 Page 41 of 42 Page ID #3408 Case: 16-3334 Document: 55-47 Filed: 02/08/2017 Pages: 42 (1383 of 1511) Case 3:12-cv-01141-SMY-DGW Document 176-47 *SEALED* Filed 12/01/14 Page 42 of 42 Page ID #3409 Case: 16-3334 Document: 55-47 Filed: 02/08/2017 Pages: 42 (1384 of 1511) Case 3:12-cv-01141-SMY-DGW Document 176-22 *SEALED* Filed 12/01/14 Page 1 of 2 Case: 16-3334 Document:Page 55-48ID #2732 Filed: 02/08/2017 Pages: 2 (1385 of 1511) INTRODUCTION The Xalatan bottle is supplied as 2.5 mL of 0.005% (50 ug/rnl.) latanoprost in a 5 mL bottle. 1 In accordance with the manufacturing instructions, the Xalatan bottle is filled to approximately 3.0 mL to ensure that the complete amount of medication is dispensed.i'" As stated in the package insert, the recommended dose is 1 drop (1.5 ug) in the affected eye (s) once daily in the evening. If one dose is missed, treatment should continue with the next dose as normal. Once a bottle is opened for use, it may be stored at room temperature up to 25° C (77° F) for 6 weeks. 1 Prior to integration with Pfizer Inc., Pharmacia conducted a study designed to simulate practical use of the latanoprost bottle. The aim of the study was to determine the total yield, drop size, and number of drops per bottle. The bottles contained 2.8 mL (including 0.3 mL of overfill). The results showed that each drop had a mean size of 29.4 ilL, and the mean number of drops was 91 per bottle.2,3 Based on calculations derived from this study data, and assuming administration of one drop in each eye once daily, approximately 45.5 days of therapy could be expected per bottle of latanoprost. As of November 15, 2010, a computerized search of the published medical literature has identified a relevant article published in 2003 that discusses the daily cost and the expected days of therapy per latanoprost bottle. A summary of the article follows. PUBLISHED DATA Fiscella et al conducted an experimental, controlled, prospective study to determine the number of drops per bottle and to evaluate the cost of glaucoma medications. Several bottles of glaucoma medications were obtained from a wholesaler. The solutions were emptied into 5 or 10 mL graduated cylinders calibrated to 0.1 and 0.2 mL, respectively. The number of drops per mL was determined based on actual, rather than labeled volume from each bottle. Using the average from 15 bottles, latanoprost contained an average volume of 3.05 mL with an average 32 drops/mL. Based on this study, there were an average 97 drops per bottle of lata no prost. Assuming 1 drop is administered in each eye once daily, approximately 48 days of therapy would be expected per bottle of latanoprost." In the study, expected days of therapy were extrapolated from reported data. The study was conducted under laboratory conditions and may not reflect actual patient use. Some patients may experience a much shorter duration of use than expected from the results obtained under laboratory conditions. Expectations of duration of therapy are highly dependent on the proper administration of 1 drop per eye as specified in the package insert. Approximately one month of therapy can be expected, however, patient administration can make this variable. CONFIDENTIAL, SUBJECT TO PROTECTIVE ORDER, PRODUCED BY PFIZER IN CASE NO. 3:12-CV-01141-DRH-DGW (S.D. ILL.) PFIZER_XALATAN_00024279 Case 3:12-cv-01141-SMY-DGW Document 176-22 *SEALED* Filed 12/01/14 Page 2 of 2 Case: 16-3334 Document:Page 55-48ID #2733 Filed: 02/08/2017 Pages: 2 (1386 of 1511) In conclusion, although the laboratory studies described above have demonstrated that up to 48 days of therapy may be expected from a bottle of Xalatan, Pfizer advises that once a bottle is opened for use, it may be stored at room temperature up to 25° C (77° F) for 6 weeks. 1 Refs 1. 2. 3. 4. Xalatan (latanoprost ophthalmic solution) Package Insert. Data on file (3) - Pfizer Inc. Data on file (5) - Pfizer Inc. Fiscella RG, Green A, Patuszynski D, et al. Medical therapy cost considerations for glaucoma. Am J Ophthalmo12003; 136: 18-25. CONFIDENTIAL, SUBJECT TO PROTECTIVE ORDER, PRODUCED BY PFIZER IN CASE NO. 3:12-CV-01141-DRH-DGW (S.D. ILL.) PFIZER_XALATAN_00024280 Case 3:12-cv-01141-SMY-DGW Document 176-48 *SEALED* Filed 12/01/14 Page 1 of 41 Raymond -Filed: 2/27/2014 Page ID #3410 Case: 16-3334 Document:Alan 55-49 02/08/2017 Pages: 41 (1387 of 1511) 1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18 19 20 21 22 23 24 25 UNITED STATES DISTRICT COURT SOUTHERN DISTRICT OF ILLINOIS EAST ST. LOUIS DIVISION CHARLENE EIKE, SHIRLEY ) FISHER, JORDAN PITLER, ) AND ALAN RAYMOND, on ) behalf of themselves and ) all others similarly ) situated, ) Plaintiffs, ) vs. ) ALLERGAN, INC., ALLERGAN ) USA, INC., ALLERGAN SALES ) LLC, ALCON LABORATORIES, ) INC., ALCON RESEARCH LTD., ) FALCON PHARMACEUTICALS, ) LTD., SANDOZ, INC., BAUSCH ) AND LOMB INCORPORATED, ) PFIZER INC., MERCK & CO., ) INC., MERCK, SHARP & DOHME) CORP., AND PRASCO, LLC, ) Defendants. ) Case No. 3:12-cv-01141-DRH-DGW VIDEOTAPED DEPOSITION OF ALAN RAYMOND TAKEN ON BEHALF OF THE DEFENDANT PFIZER FEBRUARY 27, 2014 PAGES 1 - 160 Page 1 Veritext National Deposition & Litigation Services 866 299-5127 Case 3:12-cv-01141-SMY-DGW Document 176-48 *SEALED* Filed 12/01/14 Page 2 of 41 Raymond -Filed: 2/27/2014 Page ID #3411 Case: 16-3334 Document:Alan 55-49 02/08/2017 Pages: 41 (1388 of 1511) 1 UNITED STATES DISTRICT COURT 2 SOUTHERN DISTRICT OF ILLINOIS 3 EAST ST. LOUIS DIVISION 4 5 CHARLENE EIKE, SHIRLEY ) FISHER, JORDAN PITLER, ) 6 AND ALAN RAYMOND, on ) Case No. behalf of themselves and ) 3:12-cv-01141-DRH-DGW 7 all others similarly ) situated, ) 8 Plaintiffs, ) 9 vs. ) 10 ALLERGAN, INC., ALLERGAN ) USA, INC., ALLERGAN SALES ) 11 LLC, ALCON LABORATORIES, ) INC., ALCON RESEARCH LTD., ) 12 FALCON PHARMACEUTICALS, ) LTD., SANDOZ, INC., BAUSCH ) 13 AND LOMB INCORPORATED, ) PFIZER INC., MERCK & CO., ) 14 INC., MERCK, SHARP & DOHME ) CORP., AND PRASCO, LLC, ) 15 Defendants. ) 16 17 VIDEOTAPED DEPOSITION OF WITNESS, 18 ALAN RAYMOND, produced, sworn and examined on the 19 27th day of February, 2014, between the hours of 20 eight o'clock in the forenoon and six o'clock in 21 the afternoon of that day, at the offices of The 22 Simon Law Firm, 800 Market Street, St. Louis, 23 Missouri, before Tara Schwake, a Certified Realtime 24 Reporter and Notary Public within and for the State 25 of Illinois. 1 FOR THE ALLERGAN DEFENDANTS, AND BAUSCH AND LOMB 2 INC.: 3 SHOOK, HARDY & BACON, L.L.P. 4 2555 Grand Boulevard 5 Kansas City, Missouri 64108-2613 6 (816) 474-6550 7 by: Ms. Lori C. McGroder 8 9 Mr. Douglas Maddock, Jr. (via phone) lmcgroder@shb.com 10 11 FOR THE DEFENDANTS MERCK, SHARP AND DOHME; PRASCO 12 LLC: 13 BRYAN CAVE, LLP 14 One Metropolitan Square, Suite 3600 15 St. Louis, Missouri 63102 16 (314) 259-2000 17 by: Mr. Randy J. Soriano 18 rjsoriano@bryancave.com 19 20 ALSO PRESENT: 21 Ms. Tara Schwake, CRR, RPR 22 Mr. John Niehaus, Videographer 23 24 25 Page 2 1 APPEARANCES 2 FOR THE PLAINTIFFS: 3 THE SIMON LAW FIRM 4 800 Market Street, Suite 1700 5 St. Louis, Missouri 63101 6 (314) 241-2929 7 by: Ms. Stephanie H. To 8 sto@simonlawpc.com 9 10 FOR THE DEFENDANT PFIZER INC.: 11 KIRKLAND & ELLIS, LLP 12 333 South Hope Street 13 Los Angeles, California 90071 14 (213) 680-8673 15 by: Mr. Shaun Paisley 16 shaun.paisley@kirkland.com 17 18 FOR THE DEFENDANTS ALCON RESEARCH LTD.; FALCON 19 PHARMACEUTICALS LTD.; SANDOZ INC.: 20 GREENBERG TRAURIG, LLP 21 3333 Piedmont Road NE, Suite 2500 22 Atlanta, Georgia 30305 23 (678) 553-2100 24 by: Mr. David F. Norden 25 nordend@gtlaw.com Page 4 1 INDEX 2 WITNESSES 3 ALL WITNESSES PAGE 4 For Defendant Pfizer 5 Alan Raymond 6 Examination by Mr. Shaun Paisley 7 Examination by Mr. David Norden 8 Examination by Ms. Lori McGroder 9 10 11 12 13 14 15 16 17 18 19 20 21 22 23 24 25 Page 3 10 110 136 Page 5 2 (Pages 2 - 5) Veritext National Deposition & Litigation Services 866 299-5127 Case 3:12-cv-01141-SMY-DGW Document 176-48 *SEALED* Filed 12/01/14 Page 3 of 41 Raymond -Filed: 2/27/2014 Page ID #3412 Case: 16-3334 Document:Alan 55-49 02/08/2017 Pages: 41 (1389 of 1511) 1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18 19 20 21 22 23 24 25 RAYMOND EXHIBITS NO. PAGE Exhibit 1 Bates AR 17 through AR 30, medical records of prescriptions 21 Exhibit 2 AR 31 through 33, medical records of prescriptions 21 Exhibit 3 AR 40 through 42, medical records of prescriptions 21 Exhibit 4 Bates marked AR 1 through AR 15, medical records from Dr. Hill 25 Exhibit 5 Class Action Complaint for Damages, Punitive Damages, and Injunctive Relief 74 Exhibit 6 First Amended Class Action Complaint for damages, Punitive Damages, and Injunctive Relief 76 Exhibit 7 Plaintiff's Responses to Defendant Pfizer, Inc.'s First Set of Interrogatories Directed to Plaintiff Alan Raymond 78 1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18 19 20 21 22 23 24 25 Exhibit 12 Plaintiff Alan Raymond's First Supplemental Responses to Defendants Alcon Laboratories, Inc., Alcon Research, Ltd., Falcon Pharmaceuticals, Ltd., and Sandoz, Inc.'s First Set of Interrogatories to Plaintiff Alan Raymond 85 Exhibit 13 Plaintiff Alan Raymond's First Supplemental Responses to Defendant Allergan, Inc.'s First Set of Interrogatories Directed to Plaintiff Alan Raymond 85 Exhibit 14 Prescription records 94 (Exhibits attached to transcript.) Page 6 1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18 19 20 21 22 23 24 25 Exhibit 8 Plaintiff's Response to Defendant Pfizer, Inc.'s First Requests for Production Directed to Plaintiff Alan Raymond 78 Exhibit 9 Plaintiff's Responses to Defendants Alcon Laboratories, Inc., Alcon Research Ltd., Falcon Pharmaceuticals, Ltd., and Sandoz, Inc.'s First Set of Interrogatories to Plaintiff Alan Raymond 85 Exhibit 10 Plaintiff's Responses to Defendant Allergan, Inc.'s First Set of Interrogatories Directed to Plaintiff Alan Raymond 85 Exhibit 11 Plaintiff Alan Raymond's First Supplemental Responses to Defendant Pfizer, Inc.'s First Set of Interrogatories Directed to Plaintiff Alan Raymond 85 Page 8 1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18 19 20 21 22 23 24 25 IT IS HEREBY STIPULATED AND AGREED by and between Counsel for the Plaintiffs and Counsel for the Defendants that this deposition may be taken by Tara Schwake, Notary Public and Certified Realtime Reporter, thereafter transcribed into typewriting, with the signature of the witness being expressly waived. ***** (Deposition commenced at 9:59 a.m.) THE VIDEOGRAPHER: Good morning. We're on the record at approximately 9:59 a.m. on February 27, 2014. This is the videotaped deposition of Alan B. Raymond. My name is John Niehaus here with the court reporter Tara Schwake. We are here from Veritext National Deposition and Litigation Services at the request of counsel for Defendant. This deposition is being held at the Simon Law Firm in the City of St. Louis, State of Missouri. The caption of this case is Alan Raymond, et al. versus Allergan, Inc., et al. Case Number 3:12-CV-01141-DRH-DGW. Please note that audio and video recording will take place unless all parties agree to go off the record. Microphones are sensitive and may Page 7 Page 9 3 (Pages 6 - 9) Veritext National Deposition & Litigation Services 866 299-5127 Case 3:12-cv-01141-SMY-DGW Document 176-48 *SEALED* Filed 12/01/14 Page 4 of 41 Raymond -Filed: 2/27/2014 Page ID #3413 Case: 16-3334 Document:Alan 55-49 02/08/2017 Pages: 41 (1390 of 1511) 1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18 19 20 21 22 23 24 25 pick up whispers, private conversations and cellular interference. At this time will counsel and all present identify themselves for the record. MS. TO: Stephanie To on behalf of the plaintiffs. MR. PAISLEY: Shaun Paisley for Defendant Pfizer. MR. NORDEN: My name is David Norden on behalf of Alcon, Sandoz, and Falcon Pharmaceuticals. MR. SORIANO: Randy Soriano for Merck and Prasco. MS. McGRODER: Lori McGroder for Allergan and Bausch and Lomb. THE VIDEOGRAPHER: On the phone? MR. MADDOCK: Dough Maddock for the Allergan defendants and Bausch and Lomb. THE VIDEOGRAPHER: Will you please swear in the witness? ALAN RAYMOND, Of lawful age, having been produced, sworn, and examined on the part of the Defendant Pfizer, testified as follows: EXAMINATION QUESTIONS BY MR. PAISLEY: 1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18 19 20 21 22 23 24 25 Q If you don't understand a question I ask, just let me know and I'll do my best to rephrase it so that you do understand it. But if you answer the question I ask, I'm going to assume that you understood the question as phrased. Is that fair? A Fair. Q You are free to take a break generally at any time. If you need to stretch your legs, use the restroom, any of that, just let me know. And the only thing I ask is that you don't take a break while a question is pending, but you answer the question, and then you can request a break; is that fair? A Fair. Q And then the only other thing I'll note is that the way this works, your counsel here, Stephanie, may object to some of the questions that I ask. Usually that's just for the record, to preserve objections for later use in court. Only in a circumstance where she actually instructs you not to answer do you not answer the question. Otherwise, you wait for the objection and then answer. Understood? A Understood. Yes. Page 10 1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18 19 20 21 22 23 24 25 Q Good morning, Mr. Raymond. A Good morning. Q Have you ever been deposed before? A No. Q So let me just go over some of the sort of basic ground rules to orient you. It's basically a question and answer session. I ask questions; you provide me with the answers. And you understand that the oath you just took is the same one you would take in a court of law? A Correct. Q The court reporter is here taking down what we say, so I'd ask you to make your answers audible rather than nodding or shaking your head. A Yes. Q And because the court reporter is here as well, normally in conversation you tend to sort of anticipate what the other person is going to say. Sometimes you answer before they've finished their thought. So it would be good for the court reporter and the record if you wait until I finish my question before you provide an answer. Understood? A Yes, understood. Page 12 1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18 19 20 21 22 23 24 25 Q Are you taking any medication currently that might have an effect on your memory? A No. Q Do you have any medical condition currently that might affect your memory? A No. Q Anything else you can think of that might impact your memory and your ability to remember events here today? A No. Q Is there any reason you can think of, whether a medical condition or medication or anything else that you might have difficulty understanding the questions that I ask today? A No. Q And is there any reason, whether a medical condition or something else, that would impact your ability to sit here for several hours today and answer questions in this deposition? A No. Q Okay. Can you state and spell your full name? A Alan B -- excuse me. Alan Beryl Raymond. A-l-a-n, B-e-r-y-l, R-a-y-m-o-n-d. Q When were you born? Page 11 Page 13 4 (Pages 10 - 13) Veritext National Deposition & Litigation Services 866 299-5127 Case 3:12-cv-01141-SMY-DGW Document 176-48 *SEALED* Filed 12/01/14 Page 5 of 41 Raymond -Filed: 2/27/2014 Page ID #3414 Case: 16-3334 Document:Alan 55-49 02/08/2017 Pages: 41 (1391 of 1511) 1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18 19 20 21 22 23 24 25 A September 10th, 1939. Q Where do you currently reside? A St. Louis County. Q What's your address? A 1702 Heatherdale Drive, St. Louis, Missouri 63146. Q How long have you lived at that address? A Ten years. Q And you are married; correct? A Correct. Q Your wife is Myra Rosenthal; is that right? A Yes, that's right. Q How long have you been married? A Ten years. Q Does anyone else live at the address you just gave besides you and your wife? A No. Q You are currently retired? A Correct. Q How long have you been retired? A Since 2004. Q And before you retired, what did you do for a living? 1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18 19 20 21 22 23 24 25 '04, I'm sorry. I'm very sorry. '82 to '04. Q Okay. So twenty-two years. A Right. Sorry. Q That's okay. And then where were you a CPA before that? A Oh, I had various employers throughout the years. Q What's the highest level of education you have attained? A Bachelor's degree. Q Where did you get that? A Washington University. Q What did you major in? A Business administration. Q Are you currently receiving treatment for any eye conditions? A Yes. Q What eye conditions are you receiving treatment for? A Glaucoma. Q Any others? A Yeah. I've got something wrong with my -- with the cornea. Q Do you know what the medical terminology for that is? Page 14 1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18 19 20 21 22 23 24 25 A I was a financial planner, and prior to that I was a Certified Public Accountant. Q When did -- well, let me step back. When you were a financial planner, you were self-employed? A Correct. Q How long were you a self-employed financial planner? A Let me -- let me rephrase the last question. I was part of a firm, but I was living on commission. And I had to obey their rules and regulations and all the regulations of the securities industry. Q Okay. And what firm was that? A First Financial Planners. Q How long did you work at First Financial Planners? A About fourteen, fifteen -- fourteen years. Q Okay. So from about 1990 to 2004, roughly? A About 1982 to '94. What is that? That's twelve years, isn't it? Q Oh, 1982 to '94. A '94 -- no, excuse me. Excuse me. Page 16 1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18 19 20 21 22 23 24 25 A No. Q Can you describe in layman's terms what it is that's wrong with your cornea? A Yeah, they take photographs. They can take photographs now of the inside of the eye and a slight tear, just a slight, very slight tear in a portion of the cornea. Q And how does that impact you? A Not at all. Q But you are receiving treatment for it? A They're just watching it, observing it periodically. Q With respect to your glaucoma, when were you first diagnosed with that? A I just don't remember. It's been -I can give you a vague answer, but I -Q I mean, if you have an estimate, that would be great. A I would estimate more than fifteen years ago. Q Now, are you currently taking medication for the glaucoma? A Yes, sir. Q What medication or medications are Page 15 Page 17 5 (Pages 14 - 17) Veritext National Deposition & Litigation Services 866 299-5127 Case 3:12-cv-01141-SMY-DGW Document 176-48 *SEALED* Filed 12/01/14 Page 6 of 41 Raymond -Filed: 2/27/2014 Page ID #3415 Case: 16-3334 Document:Alan 55-49 02/08/2017 Pages: 41 (1392 of 1511) 1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18 19 20 21 22 23 24 25 you currently taking? A Latanoprost. Q Latanoprost is an eye drop? A Yes, sir. Q Did you happen to bring the bottle of medication with you today? A Yes. Here it is. Q Great. Do you mind if I take a look? A Go right ahead. Q Thanks. So what you handed me there and what I just handed to counsel for one of the co-defendants here is a bottle of latanoprost manufactured by Sandoz? A Falcon, I believe, works with Sandoz somehow. I believe it says Falcon on there, doesn't it? Falcon Pharmaceuticals, it says. Q Okay. Besides the medication you just showed me there, is there any other medication that you are currently taking to treat your glaucoma? A No, sir. Q Is there any other medication you are currently taking for any eye conditions? A No. Q Do you take the latanoprost on a 1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18 19 20 21 22 23 24 25 specifically remember if I took it or not. Q Do you remember taking Lumigan? A No. Q Do you remember taking Vigamox? A No. Q So besides timolol, you don't know the specific recollection of taking any other eye drop medications? A Right. Q Besides latanoprost, which you are currently taking. A Right. Q Do you recall when you started taking timolol? A No. Q Do you remember when you stopped taking timolol? A No, sir. Q Do you remember why you stopped taking timolol? A The doctor prescribed this as a substitute. Q And when you refer to "this," you are referring to the latanoprost? A That's right. Page 18 1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18 19 20 21 22 23 24 25 daily basis? A Yes, sir. Q Do you use it in both eyes? A Yes, sir. Q How many drops do you administer per eye daily? A One drop. Q When do you administer that drop? A At bedtime. Q How long have you been using latanoprost for your glaucoma? A I'm not certain. Q Are there other prescription eye drop medications that you've taken in the past, whether for glaucoma or for something else? A Yes. Q Can you remember which ones those are? A Timolol. T-i-m-o-l-o-l, I believe. Q Any others? A Not to my memory, no. Q Let me give you a few names and see if they refresh your recollection at all. Do you remember ever taking Xalatan? A I remember the name, but I don't Page 20 1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18 19 20 21 22 23 24 25 Q I'm going to hand some -- the court reporter is going to hand you some documents. MR. PAISLEY: Would you mark that as 1? (Exhibit 1, Exhibit 2, and Exhibit 3 marked for identification by the court reporter.) Q (BY MR. PAISLEY) So what I've handed to you -- the court reporter has handed to you are three documents. For the record, these will be marked as Raymond 1 through 3. Raymond 1, it should have a little Exhibit 1 tab in the corner there, just for the record, is Bates stamped. And when I refer to Bates stamps, it's these little page numbers that are in the bottom corner here. So Raymond 1 is Bates marked AR 17. Final page of it is actually AR 16 because it was produced out of order. But it's AR 17 through AR 30. And the final page of it is AR 16. Then Raymond Exhibit 2 is AR 31 through 33. Raymond Exhibit 3 is AR 40 through 42. First of all, do you -A Excuse me. You're right, 40 to 42. Okay. Q First of all, do you recognize these documents? Page 19 Page 21 6 (Pages 18 - 21) Veritext National Deposition & Litigation Services 866 299-5127 Case 3:12-cv-01141-SMY-DGW Document 176-48 *SEALED* Filed 12/01/14 Page 7 of 41 Raymond -Filed: 2/27/2014 Page ID #3416 Case: 16-3334 Document:Alan 55-49 02/08/2017 Pages: 41 (1393 of 1511) 1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18 19 20 21 22 23 24 25 A Yes. Q And what are they? A These are medical records of prescriptions. Q Did -- did you obtain these, or did your counsel obtain them? A Counsel obtained them. Q And if you look at the -- I'll draw your attention to Exhibit 1. If you look at the bottom of the first page, AR 17, at the bottom of the page there you see the date range? January 1, 2000, to August 10, 2012? A Right. Q You see that? A Yeah, I see it. Q Would you agree that this, in redacted form, represents the -- all of the prescriptions that you filled during that time period? A Yes. Q And the same question, if you look at Exhibit 2, you see the date range August 6, 2012, to March 23, 2013, at the bottom of AR 31? A Yes. Q And that, again, in redacted form, 1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18 19 20 21 22 23 24 25 Pharmacy in St. Louis? A Yes. Q Is that the only place where you filled prescriptions during these time periods? A Yes. Q Now, if you look at Exhibit 1, which is the largest of the three documents -A Mm-hmm. Q -- and if you look at the first four pages of the exhibit, they're all redacted. And then you go to the fifth page, which is AR 21, and the first entry you see there is November 1st, 2007. You see that? A Right. I see it. Q You did use prescription eye drop medication earlier than November 2007; correct? A If that's what the documents say. I don't see anything here before -- before 2007. MR. PAISLEY: Okay. I guess maybe this is a question for you, Stephanie, is whether the -- the prior prescription records have been redacted because of the proposed class period or because they've been redacted because there was no prescription eye drop medication before that time? MS. TO: Well, I mean, it's not my Page 22 1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18 19 20 21 22 23 24 25 represents all of the prescriptions you filled during that time period? A All the prescriptions regarding this case. I have had other prescriptions, obviously. They're for other -- other medications. They are not part of this. You said, "all," and I am saying that -Q Right. I guess I -- I tried to frame it as being in redacted form. My understanding is that the redactions were done by your counsel. Is that your understanding too? A That's my understanding. Correct. Q And my understanding is that those were redacted because they weren't related to the case. A Oh, all right. Okay. I just tried to be specific. Q Actually, let me ask a more specific question. Would you agree that Exhibits 1 through 3, for the time periods reflected, contain all of the prescription eye drop medications that you filled during these time periods? A Yes. Q Now, Exhibits 1 through 3 reflect prescriptions that were filled at Dierberg's Page 24 1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18 19 20 21 22 23 24 25 deposition, but -- and without looking back at the document, I don't know what it says. MR. PAISLEY: Okay. MS. TO: We can have further discussion about this after the depo too. MR. PAISLEY: Sure. And we can request it separately, but I guess I'll request now that if there is information about prescription eye drops earlier than November 2007 that's been redacted, that that be unredacted. MS. McGRODER: Can we go off the record for a second? MR. PAISLEY: Sure. THE VIDEOGRAPHER: We're going off the record at approximately 10:22 a.m. (Off the record.) (Exhibit 4 marked for identification by the court reporter.) THE VIDEOGRAPHER: We're back on record at approximately 10:24 a.m. Q (BY MR. PAISLEY) Okay. If you can take a look at what's been marked as Exhibit 4? It was just handed to you, I believe. Exhibit 4 is Bates marked AR 1 through AR 15. And do you recognize this document Exhibit 4 as medical Page 23 Page 25 7 (Pages 22 - 25) Veritext National Deposition & Litigation Services 866 299-5127 Case 3:12-cv-01141-SMY-DGW Document 176-48 *SEALED* Filed 12/01/14 Page 8 of 41 Raymond -Filed: 2/27/2014 Page ID #3417 Case: 16-3334 Document:Alan 55-49 02/08/2017 Pages: 41 (1394 of 1511) 1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18 19 20 21 22 23 24 25 records that were obtained from your eye doctor by your counsel in this case? A Yes. Q Can you take a look at AR 11? If you look at the top of the page there, there's an entry at the top of the page there that says, "Patient Raymond Alan." Do you see that? A I see it. Q And then above that there are two notations with dates. Do you see those? A Yes. Q And the first one is January 16, 2007? A Correct. Q And it says, "Xalatan (3) okayed Don at Dierberg's," and then a telephone number. Do you see that? A Yes, I see it. Q Then there's another entry which appears to be March 1, 2007? Do you see that? A Yes, I see it. Q It says, "Timolol (4) okayed at Dierberg's." Do you see that? A Yes. Q Does that appear to you to reflect 1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18 19 20 21 22 23 24 25 side. One says, "TP Total Amt Paid," and then the other says, "PT Pay Amt Total." A Yeah, I see that. Q The "TP Total Amt Paid," does that reflect, to your understanding, the amount that was covered by a third payer or an insurer? A I'm not certain. I thought that was the portion that I paid. I really don't understand either one. I just don't understand. Q Okay. Do you have any recollection as to how much you generally paid out of pocket for eye drop medications as opposed to how much your insurance would have covered? A I can only recall the last year, which used to run $7. Q Okay. Well, let's take a look at Exhibit 3, which might help decipher these documents. If you look at Exhibit 3, it reflects some of the prescription eye drops that were filled in 2013. A Correct. Q And you look at these columns for latanoprost, for example, the entry on March 24, 2013, the first one on the page; you see that? A I see it. Page 26 1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18 19 20 21 22 23 24 25 that prescriptions were filled in the early part of 2007? A Yes. Q For eye drop medications? A Yes. Q Do you have any reason to doubt these medical records that you, in fact, were taking Xalatan and timolol in January and March of 2007? A No. Q Like to turn back to Exhibit 1, which is the largest of the prescription record documents. I just want to go through a few of the entries in a little more detail. Take a look at AR 21. A Okay. Q You see the first entry on the page there, first unredacted entry is November 1, 2007? A Yes. Q You see it says, "Xalatan 0.005 percent eye drops"? A Yes. Q Now, the column towards the right that says, "TP Total Amt Paid," do you see that? A Yes. Excuse me, was that TP, or PT? Q Sorry, there are two columns side by Page 28 1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18 19 20 21 22 23 24 25 Q And there you see, again, the "TP Total Amt Paid" column and the "PT Pay Amt Total" column? A I see it, yes. Q And you said you recall paying $7 for these prescriptions? A Correct. Q And you see that the $7 is under the "PT Pay Amt Total" column? A All right. Q So is that consistent with an understanding that the PT pay amount reflects the patient pay amount? MS. TO: I'm going to object. I mean, he's testified he doesn't know what this means. There's no evidence that he created this record, has any conception of who created the record. So, I mean, to the extent that he has a guess as to what that means, he can go ahead and answer. A The question again is do I understand what the PT column means; is that right? Q (BY MR. PAISLEY) Yes. A I understand it means patient -patient's portion. Page 27 Page 29 8 (Pages 26 - 29) Veritext National Deposition & Litigation Services 866 299-5127 Case 3:12-cv-01141-SMY-DGW Document 176-48 *SEALED* Filed 12/01/14 Page 9 of 41 Raymond -Filed: 2/27/2014 Page ID #3418 Case: 16-3334 Document:Alan 55-49 02/08/2017 Pages: 41 (1395 of 1511) 1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18 19 20 21 22 23 24 25 Q Okay. So let's go back to -- let's go back to Exhibit 1, the same page we were looking at, AR 21. And the same entry we were looking at before, which is the November 1, 2007, entry for Xalatan, you see that? A Correct. Q And so there the amount that you paid for the medication was $58; correct? MS. TO: Same objection as to the authenticity or how these records were created or what any of these columns mean. You can answer if you know. A I don't know. Q (BY MR. PAISLEY) You just don't have any recollection one way or another of how much you paid for Xalatan in 2007? A That's right. Q If this document reflects that you paid $58, do you have any reason to doubt that? MS. TO: I'm going to object. That assumes facts not in evidence. You can answer if you know. A I don't remember paying that much, but I don't doubt the records either. Q (BY MR. PAISLEY) Okay. If you can 1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18 19 20 21 22 23 24 25 prescribed. Q So absent your doctor prescribing Xalatan at some point in the future, you have no present intention yourself to take Xalatan? A Correct. Q I guess the same question of Lumigan. It last appears in these records, and you can look for yourself at AR 23 if you want to. It last appears on these records on October 23, 2008. That's the last prescription you filled. Do you see that entry? A I see October 26. You said October 26? Q I'm sorry, I may have misspoken. I think I said October 23rd. A That's right. That's what I heard. Q I'm sorry. My question is about Lumigan rather than timolol. So if you look on the fourth entry there on AR 23? A October 23. Yes. Q And so that's the -- that's the last entry that appears for Lumigan on these prescription records; okay? A I'd have to look through the rest of the records to -- Page 30 1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18 19 20 21 22 23 24 25 turn the page to AR 22 and the second to last entry on the page there, which is June 21, 2008? A Right. Q And again, the product is Xalatan. You see that? A Right. Q Now, this entry on June 21, 2008, I'll represent to you that this is the -- the latest entry on these records where Xalatan appears. A Okay. Q Do you have any reason to believe that you took Xalatan at any point from 2009 through the present? A I don't recollect it. I have no recollection of that. Q If you had taken Xalatan at any point from 2009 through the present or from the last half of 2008 through the present, would there be any other records we could consult to find that out? A Not to my knowledge. Q Do you have any intention of taking Xalatan in the future? A Yes. Excuse me, I'm very sorry. I correct that. The answer is no, unless it's Page 32 1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18 19 20 21 22 23 24 25 Q You are free to do that. A That's the last -- correct, that's the last time it appears. Q Do you have any reason to believe that you did in fact fill a prescription for Lumigan at any point after October 23, 2008? A No. Q Do you have any intention, absent your doctor prescribing that drug, to take Lumigan in the future? A No. Q Same questions with respect to Vigamox. The last entry for that appears on the same page there, AR 23. You will see the entry on December 11, 2008. A Yeah, I see that right. Q Do you agree that that's the last entry in these prescription records? A Yes, I agree. Q Do you have any reason to believe that you in fact did fill a prescription for Vigamox at any point after December 2008? A No. Q Absent your doctor prescribing you that drug again in the future, do you have any Page 31 Page 33 9 (Pages 30 - 33) Veritext National Deposition & Litigation Services 866 299-5127 Case 3:12-cv-01141-SMY-DGW Document 176-48 *SEALED* Filed 12/01/14 Page 10 of 41 Raymond -Filed: 2/27/2014 Page ID #3419 Case: 16-3334 Document:Alan 55-49 02/08/2017 Pages: 41 (1396 of 1511) 1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18 19 20 21 22 23 24 25 present intention to use Vigamox in the future? A No. Q And then with respect to timolol if you look at AR 27, you see the last entry there, July 29, 2011? A Yes. Q You would agree that that's the last entry that appears in these prescription records, where you filled a prescription for timolol? A It's the last entry that appears -it's the last entry that appears in this section. I'd have to look beyond this section to -Q Oh, you can look at Exhibits 2 and 3 as well, but I'll -- you know, you'll see there that it's just latanoprost for Exhibits 2 and 3, but you can confirm that. A Yes, I agree. Q Do you have any reason to believe that you did in fact fill a prescription for timolol after July 29, 2011? A I'm sorry, what page? Where was I? Q AR 27 in Exhibit 1. A All right. July 29 of 2011? The question was do I have any -Q Do you have any reason to believe 1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18 19 20 21 22 23 24 25 one drop in each eye. Oh, and excuse me. I also hold it -- hold my finger like that. Q When you hold your finger like that, you're using your left hand to open -A Yes. Q -- your eye. When you put the drop in your right eye, you use your left hand to open the eye? A Yes, I use my left hand. Q And do you do the inverse? A No. Q You always use your left hand to open the eye -A Right. Q -- your right hand to administer the drop? A Correct. Q And when you are using your hands there, you are using one finger to pull up the upper lid and another finger to pull down the lower lid? A Yes. Q What -- you gave me a demonstration, but roughly how far from the eye do you put the drop? I know you said you were careful not to Page 34 1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18 19 20 21 22 23 24 25 that you in fact filled a prescription for timolol after that date? A No. Q Absent your doctor prescribing you that drug, do you have any present intention to use timolol at some point in the future? A No. Q Do you ever use over-the-counter eye drops? A No. Q Have you ever used over-the-counter eye drops? A No. Q Can you tell me how you generally go about administering an eye drop into your eye? What's your method of doing that? And if it's easier, you can sort of demonstrate physically for the camera. A I'll verbally describe what I'm doing so that it goes on record. Q That would be great. A Remove the lid. I tilt my head back so I can be facing the ceiling and parallel with the floor, and I just hold it above the eye, taking care not to touch the eyeball, and gently squeeze Page 36 1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18 19 20 21 22 23 24 25 touch, but what's the distance? A I would estimate a quarter of an inch perhaps. Q Where do you -- whereabouts in the eye do you aim to administer the drop? Is it at the center of the eye? Closer to the bridge of the nose, or on the outer edge? A I'm aiming it for the center of the eye. Q At what angle do you generally hold the bottle? A I would say 180 degrees from -- close to 180 degrees from the floor. Q Okay. So it's directly pointed down at the floor? The dropper tip is? A Close. Yeah. Close. Q And your head is tilted back about, like about 45 degrees there. Would that be about right? A No, I think my head is tilted back 90 degrees. Q Okay. A I'm estimating 90 degrees. Q Okay. You said you gently squeezed. Do you always squeeze the bottle to get a drop out? Page 35 Page 37 10 (Pages 34 - 37) Veritext National Deposition & Litigation Services 866 299-5127 Case 3:12-cv-01141-SMY-DGW Document 176-48 *SEALED* Filed 12/01/14 Page 11 of 41 Raymond -Filed: 2/27/2014 Page ID #3420 Case: 16-3334 Document:Alan 55-49 02/08/2017 Pages: 41 (1397 of 1511) 1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18 19 20 21 22 23 24 25 A I gently squeeze the bottle. Q Right. But do you always gently squeeze the bottle to get a drop out? A Yes. Q Have you ever tapped the bottle? A No. Q When do you know to stop applying pressure to the bottle? A You feel the drop in your eye. I feel the drop in my eye, excuse me. Q And then as soon as you feel the drop, you stop squeezing? A Yes. Q Do you apply the same amount of pressure every time you administer the eye drops? A Yes. Q Are there any factors that would cause you to apply more or less pressure than usual? A No. Q What about when the bottle is close to empty? Do you squeeze it any harder then? A No. Q What about with different medications? Do you find you have to squeeze it 1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18 19 20 21 22 23 24 25 Q How have they differed? A Formerly there was a much larger bottle. Q Besides size, is there any other difference you can recall as to the designs of the bottles? A No. Q How did you develop this method of administering drops in your eyes? A I -- I developed it from the beginning. Just seemed to work, and I used it. Q Is it the same method you have used from the very first time you administered eye drops? A Yes. Q Have you ever read any literature on how to dispense eye drops? A Not that I remember, no. Q Any directions or instructions that come with the prescription drugs? Have you ever read those to see if they have advice on how to dispense eye drops? A I get two sets of instructions. Instructions come with the prescription itself, and the pharmacist gives a list of comments about the Page 38 1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18 19 20 21 22 23 24 25 harder for some than for others? MS. TO: I'm going to object to form. I'm not sure what you mean by "other medications"? A Are you saying prior medications? Q (BY MR. PAISLEY) Okay. You've used different medications, different eye drop medications over the years; correct? A Correct. Q Have you found that you had to squeeze some of them harder than others in order to administer a drop? A Not that I -- no. Q And generally, setting aside the squeezing, just talking about your overall method of dispensing drops, has that varied at all depending on the particular medication you were taking? A No. Q Does your method vary depending on the design of the bottle that you are using? A No. Q To your recollection, have all of the bottles of eye drop medication you have used over the years, have the designs been the same? A No. Page 40 1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18 19 20 21 22 23 24 25 medication. Q And have any of those instructions that you just referred to included something about how to administer the drops, to your recollection? A Not that I remember, no. Q Has any doctor ever gone over the method of administration of eye drops with you? A No. Q What about pharmacists? Have any pharmacists gone over that with you? A No. Q When you dispense drops, has the dropper ever touched the surface of your eye? A Yes. Q How often would you say that happens? A Very seldom. Q Are you able to put a ballpark percentage on it? A 2 percent. Q When you squeeze the bottle, has the drop ever missed your eye? A I don't recall. Q Do you recall whether the drop ever partially missed your eye, maybe hit your eyelid? A No, I don't recall that either. Page 39 Page 41 11 (Pages 38 - 41) Veritext National Deposition & Litigation Services 866 299-5127 Case 3:12-cv-01141-SMY-DGW Document 176-48 *SEALED* Filed 12/01/14 Page 12 of 41 Raymond -Filed: 2/27/2014 Page ID #3421 Case: 16-3334 Document:Alan 55-49 02/08/2017 Pages: 41 (1398 of 1511) 1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18 19 20 21 22 23 24 25 Q When you say you don't recall, are you saying that it never happened, or just that you don't remember whether it happened or not? A I am saying I don't remember if it ever happened or not. Q Are you ever not sure whether the drop has actually made it into your eye? A Never. Q Do you ever get more than one drop at a time when you squeeze? A No. Q Never in all the -A Excuse me. Excuse me. I retract that answer. The question was have I ever had one drop, more than one drop? Q Yes. A The answer is no, I have never had more than one drop. Q How do you know that? A I want a question -- when you say a drop, are you talking about the amount that's being dispensed, or do you mean separate drops, like rain drops? Q Well, I mean -- okay, so the goal of dispensing a drop, your dosage is one drop; 1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18 19 20 21 22 23 24 25 Q Did this issue of more than one drop coming out at once, or the solution streaming out, did that ever cause you to run out of the medication early? A When you say "early," does it mean like prior to 30 days? Q Yeah. I mean prior to the normal period that you'd have to refill. A No. The answer is no. Q So there was always enough in the bottle to account for that extra solution that came out? A It was a larger bottle. The answer is yes. Q When you use eye drop medication, do you always use every last drop that's in the bottle? A Yes, I try to. Sure. Q Is there ever a time that you haven't done that? A No. I -- I've always used it all. Q Do you have any medical conditions that affect your ability to get the drop into your eye? A No. Page 42 1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18 19 20 21 22 23 24 25 correct? A Right. Correct. Q Have you ever had a situation where you've squeezed the bottle and either two drops have come out or the liquid has streamed out? So you were getting more than your dose? A Oh, that's happened -- that used to happen frequently. Q How frequently did that happen? A Just about every single time. Every single time. Q Does it still happen with the latanoprost that you are currently using? A No. Q But it did happen with some of the prior eye drop medications that you used? A Yes. Q Do you recall which ones specifically? A It was just in the past, the best I can recall. Q Even though you don't recall which one specifically, do you remember whether it did happen with one medication more than others? A No, I don't recall that. Page 44 1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18 19 20 21 22 23 24 25 Q Do you have any arthritis? A No. Q Any hand tremors? A No. Q Have you ever used any kind of delivery aid to assist in administering drops? A I don't know what a delivery aid is. Q Okay. Let me give you an example. There is a -- have you ever heard of Xal-Ease? A No. Q There are some -- I'll tell you, it's some sort of plastic contraption that you put the bottle in, and you push a button, and it administers a drop. But since you've never heard of it, I am assuming you've never used it. A That's right. Q Now, you said with latanoprost, that you are currently dispensing that one time daily before bedtime? A Correct. Q Do you always remember to take the medication at that time? A Yes. Q How do you remember to do that? A Becomes a habit. Page 43 Page 45 12 (Pages 42 - 45) Veritext National Deposition & Litigation Services 866 299-5127 Case 3:12-cv-01141-SMY-DGW Document 176-48 *SEALED* Filed 12/01/14 Page 13 of 41 Raymond -Filed: 2/27/2014 Page ID #3422 Case: 16-3334 Document:Alan 55-49 02/08/2017 Pages: 41 (1399 of 1511) 1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18 19 20 21 22 23 24 25 Q Have you ever forgotten to take a dose? A Not that I recall. Q With respect to the prior eye drop medications that you used, did you also dispense them at the same time of day? Or did it vary depending on the medication? A It varied. Q Did you always follow the instructions as to when to dispense those medications? A Yes. Q And you never departed from those instructions for any of those eye drop medications? A No. Q Where do you generally store your eye drop medication? A These medications are supposed to be refrigerated until you use them for the first time, so I store them from the pharmacy to the refrigerator. And then from the refrigerator, I use them and keep them in the bathroom. Q So you keep them in a medicine cabinet? A No. I keep them just on a -- on a 1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18 19 20 21 22 23 24 25 around there? A Perhaps, yes. Q Fair to say the first time you met had nothing to do with this lawsuit? A Correct, yes. Q How did you first meet? A How did I first meet Mr. Cornfield? We belong to the same congregation. Q And that's United Hebrew in St. Louis? A Correct. Q Is your wife also a part of that congregation? A Yes. Q Is Mr. Cornfield's wife part of the congregation? A Yes. Q Do you know Mrs. Cornfield? A Yes. Q Does your wife know Mrs. Cornfield? A Yes. Q Are you and Mr. Cornfield part of any groups or committees together at United Hebrew? A No. Excuse me. We are on a -- yes, we're on a committee. Page 46 1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18 19 20 21 22 23 24 25 little upright vertical shelf that we have hung against the back wall. Q When you administer the drops, are you sitting or standing? A Standing. Q And that's always true? A Always. MR. PAISLEY: All right. I think we're at a good break point, and we're almost out of tape, so let's take a short break. THE VIDEOGRAPHER: We're going off the record at approximately 10:55 a.m. (Off the record.) THE VIDEOGRAPHER: We're back on the record on tape two at approximately 11:07 a.m. Q (BY MR. PAISLEY) Mr. Raymond, you ready? A Yes, sir. Ready. Q You are represented by Rick Cornfield in this lawsuit; right? A Correct. Q How long have you known Mr. Cornfield? A Perhaps three years. Q So since about 2011, 2010? Somewhere Page 48 1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18 19 20 21 22 23 24 25 Q What committee are you on together? A The Israel committee. Q What does the Israel committee at United Hebrew do? A We follow developments in the State of Israel. Q How often do you meet -- does the committee meet? A Not regularly. Perhaps four times a year, maybe five. Q Are you involved with AIPAC at all? The American Israel Public Affairs Committee? A Formerly. Q Do you or did you have any interactions with Mr. Cornfield related to AIPAC? A At AIPAC you say? Or regarding AIPAC? Q Regarding AIPAC. A Only that we attended a convention in Washington, DC. Q When was that? A Two or three years ago. Q Was it a group of you who attended the convention? A We didn't attend as a group. Page 47 Page 49 13 (Pages 46 - 49) Veritext National Deposition & Litigation Services 866 299-5127 Case 3:12-cv-01141-SMY-DGW Document 176-48 *SEALED* Filed 12/01/14 Page 14 of 41 Raymond -Filed: 2/27/2014 Page ID #3423 Case: 16-3334 Document:Alan 55-49 02/08/2017 Pages: 41 (1400 of 1511) 1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18 19 20 21 22 23 24 25 Q Was it just you and Mr. Cornfield? A No. What I am saying is we didn't all stay in the same hotels. We didn't eat together and spend time with each other at the convention. Q I guess I am asking whether you -you and Mr. Cornfield just happened to be at the same convention at the same time or whether you planned to attend together? A I knew he was attending, and he -- we planned to attend together, yeah. Q But was it part of a -- were you part of a larger group who had planned to attend together? A Yes, part of a larger group. Q Okay. What was that larger group? A Are you asking how many? Q Yeah. A I don't remember. Q I mean, was it five people? A dozen people? Hundreds of people? A Oh, it was a small group. I don't -I don't recall the numbers that attended from our group. Q Setting aside any meetings that 1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18 19 20 21 22 23 24 25 A Perhaps every other month. Q Would you describe him as a friend? A No. Q Have you ever had any business arrangements with Mr. Cornfield? A No. Q Ever managed his financial affairs? A Never. Q Same questions with respect to Mrs. Cornfield. Have you ever managed her financial affairs? A Never. Q Any business interactions with her? A No. Q You're also represented by the Simon Law Firm, Stephanie To, who is here, and John Simon; correct? A Yes. Q Do you have any relationship with them outside of this lawsuit? A No. Q When did you first get the idea to file this lawsuit? A I don't recall. Q When did you first decide to retain Page 50 1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18 19 20 21 22 23 24 25 relate to this lawsuit, how often do you see Mr. Cornfield? A Your question is outside of things relating to this? Q Yes. A The answer is seldom. Q Can you quantify that for me? A I may occasionally see him at services. Q Have you ever seen Mr. Cornfield socially? A No. Q Do you ever have any social interactions with Mrs. Cornfield? A No. Q Does your wife have any social interactions with Mrs. Cornfield? A No. Q Does your wife have any interactions with -- social interactions with Rick Cornfield? A No. Q So since you've known -- since you've met Mr. Cornfield in around 2010, 2011, how frequently would you say that you've had occasion to interact with Mr. Cornfield? Page 52 1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18 19 20 21 22 23 24 25 Mr. Cornfield to be your attorney in this lawsuit? A I don't remember. Q Did you approach Rick Cornfield about potentially filing a lawsuit, or was it the other way around? A I don't remember that. Q You don't remember how you first became involved in the lawsuit? A It's been more than two years or about two years. And I don't remember the initial meetings regarding this, no. Q So you don't recall if it was you who came up with the idea, "I think eye drop medication manufacturers are doing something wrong, and I want to file a lawsuit about it"? MS. TO: Objection, asked and answered. You can answer again. Q (BY MR. PAISLEY) You don't have any recollection of whether that was your idea? A No, I don't remember. I got involved with this, but I don't remember the circumstances. Q Do you know who the other plaintiffs are who are proposed class representatives in this lawsuit? A I've seen their names in print, but Page 51 Page 53 14 (Pages 50 - 53) Veritext National Deposition & Litigation Services 866 299-5127 Case 3:12-cv-01141-SMY-DGW Document 176-48 *SEALED* Filed 12/01/14 Page 15 of 41 Raymond -Filed: 2/27/2014 Page ID #3424 Case: 16-3334 Document:Alan 55-49 02/08/2017 Pages: 41 (1401 of 1511) 1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18 19 20 21 22 23 24 25 no, I don't know them. Q You don't know Jordan Pitler? A No. Q Do you know Marilyn Pitler? A No. Q Okay. And so you don't know Shirley Fisher? A No. Q You don't know Charlene Eike? A No. Q Do you know Margie Levy? A No. Q Leslie Yoeffi? A No. Q Daniel Raskas? A Samuel Raskas? Q Daniel. A Oh, Daniel Raskas. Um -MS. TO: I'm going to just object. I don't think that's relevant. I'm not sure who these people are or what this has to do with this lawsuit since they're not class representatives identified here. But you can answer. A There was a president of our congregation whose name was Raskas, and I don't 1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18 19 20 21 22 23 24 25 objections concise as under the rules. MR. SORIANO: I join. MS. McGRODER: Also join. MR. NORDEN: Me too. A I -- the question is the size of the drop? Q (BY MR. PAISLEY) Yeah. So I'll repeat the question. Take the latanoprost in front of you. Are all of the drops you dispense of latanoprost exactly the same size as each other? MS. TO: Same objection. A I can't tell how much. I don't really know how -- the size of the drop. Q (BY MR. PAISLEY) Did you notice a difference in the size of the drop that you dispensed last night as opposed to the drop you dispensed the night before that? A No. MS. TO: Same objection. Q (BY MR. PAISLEY) What about with Xalatan? When you used that product, was there any difference in the size of the Xalatan drops you administered from day to day? MS. TO: Same objection. You can answer. Page 54 1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18 19 20 21 22 23 24 25 remember his first name. Could have been Daniel Raskas. Could have been somebody else. Q (BY MR. PAISLEY) But it sounds like, since you don't know what his first name was, you're not -- it's not like you're friends with him? A Oh, no. Certainly not. Q You would agree that you have administered hundreds, probably thousands of eye drops into your eye over the years? A Yes. Q Were all of those drops the same size? A No. No. Q For the same medication -- let's take the latanoprost that's in front of you. Are all of the drops you dispense exactly the same size as each other? MS. TO: I'm going to object. I mean, that's calling for expert testimony as to what the size may be. Certainly he can answer in a lay capacity as to what he thinks the size of the drops are. MR. PAISLEY: I'm sorry. It's a speaking objection. If you can just keep your Page 56 1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18 19 20 21 22 23 24 25 A I don't specifically remember the -the name of the product, but I do remember the size of the bottle. And when I had a larger bottle, it dispensed a larger quantity in the eye. Eyes couldn't handle it. Q (BY MR. PAISLEY) Okay. So when you had larger bottles of medication, those dispensed larger drops? A Correct. Q What's the medication you have used that has the smallest size drop? A Latanoprost. MS. TO: Same objection. Q (BY MR. PAISLEY) And what's the medication you have used that has the largest size drop? MS. TO: Same objection. You can answer. A To the best I can recall, these other -- other than latanoprost, they came in large -larger bottles. Greater quantity in the bottle. That's all I'm saying. Q (BY MR. PAISLEY) And based on your perception, the size of the drop increases proportionally with the size of the bottle? Page 55 Page 57 15 (Pages 54 - 57) Veritext National Deposition & Litigation Services 866 299-5127 Case 3:12-cv-01141-SMY-DGW Document 176-48 *SEALED* Filed 12/01/14 Page 16 of 41 Raymond -Filed: 2/27/2014 Page ID #3425 Case: 16-3334 Document:Alan 55-49 02/08/2017 Pages: 41 (1402 of 1511) 1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18 19 20 21 22 23 24 25 A Yes. Q Did you notice any difference in the size of the drops based on the viscosity of the solution? A I never paid attention to the viscosity of the solution. Q Have you noticed that the viscosity varies from medication to medication? A Only on paper, by looking at these numbers. But I couldn't tell by the dispensing the drops. Q Have you ever made any effort to measure the size of the drops that you are dispensing? A No. Q Do you know how many microliters of eye drop solution your right eye is capable of holding? A No, I don't know. Q What about your left eye? A I don't know that either. Q Based on the US population, do you know if the capacity of your eye is average, larger than average, or smaller than average? A I don't know that either. 1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18 19 20 21 22 23 24 25 taking a medication with those larger bottles; correct? A That's right. Q Now, when you were using that medication in the larger bottles, is -- is the issue of the solution running down your cheek, is that something that would happen with every drop you dispensed, or some of the time? A Every drop. Q And how could you tell that some of the drop had been wasted, in your view? A I couldn't absorb it. It would just run down the cheek, my cheek. Q Was it the same amount that ran down your cheek every time? A I couldn't measure that. Q You never made any effort to measure how much was running down your cheek? A No. Q Now, the -- you testified earlier about an issue you had previously with other eye drop medications that you were getting more than one drop at a time or the solution was streaming out the bottle. Do you remember that testimony? A Did I say more than one drop at a Page 58 1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18 19 20 21 22 23 24 25 Q Can you explain for me in your own words why you are suing the defendants in this case? A It's a question of fairness. The -the drops were being wasted. Q When you say, "The drops were being wasted," are you just referring to when they were packaged in larger bottles? A No. What I'm -- the specific answer is I would apply the drops, and the drops were more than the eye could hold. The excess would run down the cheeks. Q Is that -- is that still a problem with the smaller latanoprost bottle that you used to? A No, it's not. Q So you're not making any claim related to the latanoprost bottle that you have in front of you there? A Yes, that's right. I am not making a claim. Q Okay. So your claim is only related to the medications that you formerly took? A My claim is to the larger bottles. Q And those are -- you're not currently Page 60 1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18 19 20 21 22 23 24 25 time? I don't know if I said that. Q Well, you did have an issue with solution streaming out of the bottle? A Okay. Yes. The fact that it was putting out more than the eye could hold. It was dispensing more than the eye could absorb. Q Do you know if it was dispensing more than one drop at a time and that's why it was more than the eye could hold? A No, I don't know. It was just one drop, to my knowledge. And the eye -- eye couldn't absorb it all. Q But the current bottle of solution that you're using, the size of that drop is -- is fine. It doesn't run down your cheek? A Correct. Q Do you keep any log or other written record related to your usage of eye drops? A No. Q When was the first time you observed the problem of too much eye drop solution coming out of the bottle? A I can't answer specifically. All I could say, it was probably from the time I began to use it. Page 59 Page 61 16 (Pages 58 - 61) Veritext National Deposition & Litigation Services 866 299-5127 Case 3:12-cv-01141-SMY-DGW Document 176-48 *SEALED* Filed 12/01/14 Page 17 of 41 Raymond -Filed: 2/27/2014 Page ID #3426 Case: 16-3334 Document:Alan 55-49 02/08/2017 Pages: 41 (1403 of 1511) 1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18 19 20 21 22 23 24 25 Q Okay. So we're talking a lot of years? A Yes. Q Have you ever spoken about this issue with too much eye drop solution coming out of the bottle with anyone? A No, not -- no, I haven't. Q Does your wife use prescription eye drop medication? A No, not to my knowledge. Q Do you know other people who do? A No. Q You have three adult children; right? A Yes. Q Have you ever talked to them about the eye drop solution issue that you have? A No. Q Have you ever talked with them about the lawsuit? A No. Q What do your children do for a living? A My oldest son is in public relations for the City of Baltimore. My daughter, middle child, is married and helps her husband in his 1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18 19 20 21 22 23 24 25 there was an issue with too much solution coming out of the bottle, did you consider filing a lawsuit? A No. Q Why not? A It just seemed like the natural state of affairs at the time. Q What -- why did your view change on that? A Over a period of time it seemed like a waste. It was being wasted. Q When was the first time you considered filing a lawsuit? A Perhaps two years ago. Q After that time, did you retain the empty bottles of medication that you used? A Yes. Q So you have all of those -A No, wait a minute. No, I didn't retain them, empty bottles. I retract that. I did not retain the bottles. I retained the cartons. Q Okay. So you have all of the cartons from the medication you've used since you considered filing the lawsuit? A I don't know that I have them all. I Page 62 1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18 19 20 21 22 23 24 25 business. My youngest son works as a mortgage broker. Q Have you ever talked to your eye doctor about the issues you have with eye drop solution and the -- too much solution coming out? A No. Q Why not? A I -- it never occurred to me. Q So you didn't ask him whether there might be some alternative out there? A No. Q Have you looked into whether there are any -- well, at the time you were dispensing eye drops that you believed were too large, did you ever look into whether there were any alternatives with smaller drops? A No. Q Did you ever look into whether there were any alternatives to eye drop solution, whether topical medication or pills? A No. Q Did you ever ask your doctor about that? A No. Q When you first noticed that the -- Page 64 1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18 19 20 21 22 23 24 25 think I kept a few. Q And the remainder you threw away? A To the best of my memory, yes. Q Okay. We've gone over a little bit what your claims are and, you know, what you're not claiming. I just want to delve into that in a little more detail. You're not claiming that any of the medications you have taken over the years have been ineffective in treating your eye conditions; right? A That's right. Q You are not claiming any of the medications you have used have been unsafe; correct? A Correct. Q You are not claiming that any of the defendants in this lawsuit have made false statements to you; correct? A No. I mean, yes, that's correct. Q You're not claiming that any of the defendants concealed material information from you; correct? A Yes. Q The only claim is that some of the medications you have used over the years, the -- Page 63 Page 65 17 (Pages 62 - 65) Veritext National Deposition & Litigation Services 866 299-5127 Case 3:12-cv-01141-SMY-DGW Document 176-48 *SEALED* Filed 12/01/14 Page 18 of 41 Raymond -Filed: 2/27/2014 Page ID #3427 Case: 16-3334 Document:Alan 55-49 02/08/2017 Pages: 41 (1404 of 1511) 1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18 19 20 21 22 23 24 25 the drop is too big, and you believe that that's unfair; is that a fair summary? A Yes, that's right. Q Who are you suing in this lawsuit? A Approximately eight different pharmaceutical companies. Q Can you recall which ones those are? A By name? Q Yeah. A Well, this one is Falcon Pharmacies and the name Sandoz. Q But that's the -- that's the product you are not making a claim about; correct? A Their name -- this particular size bottle is effective, but these people are now a part -- are named in the suit. Q Okay. But they're -- your belief is that they're named in this suit related to a larger size bottle? A That's right. That's right. Q Okay. Besides the defendants you just named, can you recall the names of other defendants in the lawsuit that you are suing? A No, I don't recall them. Q How did you go about selecting which 1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18 19 20 21 22 23 24 25 other basis on which to base a damages claim? A On behalf of the group. There's perhaps hundreds of thousands of people who were -who have used the same medication. Q Do you know how they would go about measuring the damages that they experienced? A No. Q In addition to -- well, let me just ask about damages. Are you only claiming a portion of the amount that you paid out of pocket for the medication? Or are you also claiming some or all of the amount that the insurance companies -A I am claiming for all parties involved. Q When you say you are claiming for all parties involved, what do you mean by that? A I mean the insurance companies were also paying a portion, or in some cases a large portion of the cost. Q And so you would seek to recover for yourself what the insurance companies paid for the medication? A Not for myself, no. Q So you believe that the -- you would be recovering -- Page 66 1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18 19 20 21 22 23 24 25 defendants to file suit against? A I didn't make that selection. Q That was made by your counsel? A Right. Q What are you seeking to accomplish in this lawsuit? What do you want the court to do? A Compensate all the people who wasted a lot of money over a long period of time. Q And that's financial compensation? A Right. Q How much are you personally seeking to recover in damages? A I have no specific amount. Q How would you go about measuring the damages that you're claiming? A I'd make an estimate. I could make an estimate over how much was wasted over a long period of time. Q How would you go about doing that? A I -- I don't know how to measure how much was wasted. But it felt like perhaps half or more of the drops were going down my cheek every day, and I'm only guessing at the half. I have no -- no certainty on that. Q Besides that guess, do you have any Page 68 1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18 19 20 21 22 23 24 25 A Excuse me. Excuse me. Yeah, because I paid premiums to the insurance companies. I paid premiums for Medicare supplement since I was 65. That's nine years. And... Q So are you seeking to recover a portion of those premiums? Or a portion of the amount that the insurance company actually paid? A A portion -- portion of the -- I am seeking to recover for all parties involved. Q Does that mean you are seeking to recover a portion of the premiums or a portion of the amount that the insurance company actually paid? A A portion of the amount that the insurance companies paid, because I feel that was a factor in setting the premiums. Q Okay. And that portion of the amount that the insurance companies paid would then go to you? That's what you'd like the court to order? A Yes. Q Now, are you also seeking some kind of what's called injunctive relief? Basically asking the court to order defendants to do something or to stop doing something? Or are you just seeking damages? Page 67 Page 69 18 (Pages 66 - 69) Veritext National Deposition & Litigation Services 866 299-5127 Case 3:12-cv-01141-SMY-DGW Document 176-48 *SEALED* Filed 12/01/14 Page 19 of 41 Raymond -Filed: 2/27/2014 Page ID #3428 Case: 16-3334 Document:Alan 55-49 02/08/2017 Pages: 41 (1405 of 1511) 1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18 19 20 21 22 23 24 25 A I'm just seeking damages. Q So you -- you have no interest in requiring the defendants to stop manufacturing the bottles with the -- what you believe are large drops? A That's in their best interest to do it, but I -- I don't -- I don't tell the manufacturers what to do. Q Okay. So you don't want the -you're not asking the court to tell the manufacturers what to do either? A No. Q Do you want the court to order the companies to redesign the bottle so that they dispense smaller drops? A Yes. Q So you do want the court to do that? A Yeah. Q Do you know what that alternative design would look like? A It would look like this. Q So if all of the defendants in this lawsuit manufactured droppers to the specifications of the latanoprost that's in front of you, the Sandoz Falcon latanoprost, you would be fine with 1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18 19 20 21 22 23 24 25 the larger bottle, so the ones with the drops that ran down your cheek, why do you think that the drops were that size? MS. TO: Same objection. A I don't know why the drops were that size. Q (BY MR. PAISLEY) If it was to ensure that everyone got the right amount of medication, everyone across the population, would you agree that that's a legitimate reason to make the drop size what it was? MS. TO: Objection. It assumes facts not in evidence. It's also calling for expert testimony. To the extent that you can answer it, you can go ahead. A Repeat the last question again. Q (BY MR. PAISLEY) Sure. If defendants' droppers -- I am talking about the droppers that dispense the what you perceive to be larger drops -- were designed that way to ensure that everyone across the US population got the right amount of medication, would you agree that that's a legitimate reason to make the drop size what it was? MS. TO: Same objection. Page 70 1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18 19 20 21 22 23 24 25 that? A If it's effective for the other products, yes. Q So in addition to wanting the defendants to redesign the bottle so that it's like the one in front of you, you would also allow them to continue to sell the what you've articulated to be larger bottles? MS. TO: Objection to the extent that misstates his prior testimony. You can answer. Q (BY MR. PAISLEY) I'll rephrase. Would you allow the defendants to sell both the redesigned bottle and the current bottles? MS. TO: Same objection. You can answer. A They've got a -- they've got a right to sell at their own risk whatever they want. Q (BY MR. PAISLEY) Why do you think -why do you think the drop sizes are the way they are? MS. TO: Objection to the extent that calls for expert testimony. You can answer if you know. A Do you mean now, or in the past? Q (BY MR. PAISLEY) So taking the -- Page 72 1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18 19 20 21 22 23 24 25 A I have no -- I have no idea about other people's eyes besides my own. Q (BY MR. PAISLEY) If developing a smaller dropper resulted in the eye drop medication being more expensive than it is today, would you still want the court to order a redesign? MS. TO: Objection, assumes facts not in evidence. You can answer. A I think the answer would have to be how much more expensive and would the person be any better off from a financial viewpoint. So that -that's a vague question. Q (BY MR. PAISLEY) If it was more expensive and the patient wouldn't be any better off from a financial viewpoint, would you still want the court to order that change? A No. Q You understand this is a proposed class action lawsuit; correct? A Yes, I understand. Q You understand that you are proposed as one of the class representatives? A Right. Q What was your understanding of your responsibilities as a class representative? Page 71 Page 73 19 (Pages 70 - 73) Veritext National Deposition & Litigation Services 866 299-5127 Case 3:12-cv-01141-SMY-DGW Document 176-48 *SEALED* Filed 12/01/14 Page 20 of 41 Raymond -Filed: 2/27/2014 Page ID #3429 Case: 16-3334 Document:Alan 55-49 02/08/2017 Pages: 41 (1406 of 1511) 1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18 19 20 21 22 23 24 25 A I have a responsibility to all the -all the victims that were wronged. Q And can you describe for me what some of those specific responsibilities are? A To simply have the others to get reimbursed for their losses. Q But what do you personally have to do as a class representative? What's your role? A To simply testify of my own experience. Q Besides testifying like you're doing here today, do you have any other responsibilities as a class representative, to your understanding? A Not that I'm aware of, no. Q The court reporter is going to hand you what will be marked as Exhibit 5. (Exhibit 5 marked for identification by the court reporter.) Q (BY MR. PAISLEY) You've probably seen this many times before. A Thank you. Q You can take a look at Exhibit 5, Mr. Raymond, and let me know if you've seen it before. A Yes, I've seen this before. Q What is Exhibit 5? 1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18 19 20 21 22 23 24 25 pages, no. Q How much of it have you read? A I can't estimate that. Q Are you saying you just skimmed it, or did you read specific portions of it that relates it to you? A I -- I read portions of it. Q But you don't remember which ones? A No. Q Are you aware that -- of whether an amended version of this document has been filed in the litigation? A No. Q If there is an amended version of this document, have you read that? A I'm not aware that -- the answer is no. Q So you didn't provide any information or furnish any information to draft an amended version of this complaint? A I don't remember, no. I don't remember anything about an amended declaration. Q I'll hand you what will be marked as Exhibit 6. (Exhibit 6 marked for identification Page 74 1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18 19 20 21 22 23 24 25 A You asked me what is Exhibit 5? It's the class action complaint for damages. Q Did you help prepare this document? A No. Q Did you -A Wait a minute. No, I did not help prepare this document. I'll agree to that. Q Did -A I furnished information. Q And you furnished information to help in the drafting of the document? A Right. Q Did you review the complaint before it was filed? A I don't remember. Q You can see a -- it's actually on the top of the -- each page of the exhibit, the date of the filing was November 1, 2012. You don't remember whether you reviewed it before it was filed? A No, I did not review. Q Have you ever read it? A Yes. Q You've read it all? A No, I'm not sure I've read all 63 Page 76 1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18 19 20 21 22 23 24 25 by the court reporter.) Q (BY MR. PAISLEY) Take a look at Exhibit 6 and let me know if you recognize that. And to help you, if you look at the top of the page again, there is the filing date there, which is February 22, 2013. A So the question is have I seen this before? Q Yeah. A I may have seen it before, but I don't specifically remember seeing it. Q And you don't recall whether you provided any information to help in the drafting of -A That's right. Q -- Exhibit 6? A That's right. Q Do you know that there's a Motion to Dismiss the lawsuit that's been filed with the court by the defendants? THE VIDEOGRAPHER: One moment. Your microphone. It just snaps on. A The question is is there a Motion to Dismiss? Am I aware of that? Q (BY MR. PAISLEY) Right. Yeah. Page 75 Page 77 20 (Pages 74 - 77) Veritext National Deposition & Litigation Services 866 299-5127 Case 3:12-cv-01141-SMY-DGW Document 176-48 *SEALED* Filed 12/01/14 Page 21 of 41 Raymond -Filed: 2/27/2014 Page ID #3430 Case: 16-3334 Document:Alan 55-49 02/08/2017 Pages: 41 (1407 of 1511) 1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18 19 20 21 22 23 24 25 A The answer is yes, I'm aware of that. Q Do you know whether the court has ruled on the Motion to Dismiss? A No, I don't know what's happened. Excuse me. I answered incorrectly. I do remember. The court has not ruled. Q Have you read the Motion to Dismiss that was filed? A No. Q I hand to you what will be marked as Exhibit 7 and 8. (Exhibits 7 and 8 marked for identification by the court reporter.) Q (BY MR. PAISLEY) Take a look at Exhibits 7 and 8 and let me know if you recognize them. A Yeah, I believe I recognize these. Q So take a look at Exhibit 7, first of all. A All right. Q Actually, take a look at Exhibit 8 first. What is Exhibit 8, to your understanding? A Is it to my understanding? Yes. Q What is Exhibit 8? A What is it? 1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18 19 20 21 22 23 24 25 A Yes, it is. Yes. Q Where you affirmed that the answers in this document are true, correct, and complete under oath; correct? A Yes. Yes. Q Did you review this document before it was served on the defendants? Well, let me rephrase that. Did you review the document before you signed that last page of Exhibit 7? A Yes, I -- yes, I did. Q How long did you take to review the responses to the interrogatories in Exhibit 7? A I don't -- I didn't measure the time, but I'm pretty sure I reviewed -- I reviewed the whole document. Q Without revealing any communications with your counsel, can you just walk me through the process of how this document was put together, Exhibit 7? MS. TO: I'm going to object. It's going to invade attorney-client privilege. There's no way he can answer that without revealing those communications. Q (BY MR. PAISLEY) Okay. Did you Page 78 1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18 19 20 21 22 23 24 25 Q Yes. 1 A It's response to a -- to -- just what 2 it says here, "First Request for Production." 3 Production of evidence, I suppose. 4 Q You see there's a number of requests 5 and then a number of responses? 6 A Right. 7 Q Were you involved in preparing the 8 responses at all? 9 A Not directly involved, no. I simply 10 answered the questions of the inquiries that were 11 made of me. 12 Q Did you -- have you ever reviewed 13 this document before? Before today? 14 A No, not to my memory. 15 Q Okay. Take a look at Exhibit 7. 16 What's your understanding of what Exhibit 7 is? 17 A This is an exhibit of objections to 18 -- to the -- to the defendants' appeal or to the 19 defendants' defense of the case. 20 Q Have you seen -- well, let me ask you 21 to turn to the last page of Exhibit 7. 22 A Okay. 23 Q Is that your signature on the last 24 page of Exhibit 7? 25 Page 80 draft the answers in Exhibit 7 yourself? A No. Q Did your counsel draft the answers in Exhibit 7? A Yes. Q Did you -- how did you have any input into the answers? Did you -- let me step back. Did you -- was your role to review the answers and determine whether they were accurate or not? MS. TO: I'm going to object to that. That's still calling for attorney-client privileged information in terms of communications and the role of the client with the attorney. MR. PAISLEY: I am not asking for any communications. I'm just asking whether he -- what his role was in reviewing the document. MS. TO: Well, his role in reviewing the document has to do with relationship with his counsel and discussions that we have had to that extent. Q (BY MR. PAISLEY) Okay, just to be clear, I am not asking for any communications. I'm just asking did you -- I'm just asking you to tell me what the process was. Did your attorneys send Page 79 Page 81 21 (Pages 78 - 81) Veritext National Deposition & Litigation Services 866 299-5127 Case 3:12-cv-01141-SMY-DGW Document 176-48 *SEALED* Filed 12/01/14 Page 22 of 41 Raymond -Filed: 2/27/2014 Page ID #3431 Case: 16-3334 Document:Alan 55-49 02/08/2017 Pages: 41 (1408 of 1511) 1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18 19 20 21 22 23 24 25 you this document with the answers already in it and then you reviewed it? MS. TO: It's still attorney-client privileged. If we sent him stuff, if we talked to him about it, that's privileged. MR. PAISLEY: Okay. Are you instructing the witness not to answer the question? MS. TO: Yes. MR. PAISLEY: Okay. Q (BY MR. PAISLEY) Did you prepare for today's deposition at all? A Yes. Q How did you prepare for the deposition? MS. TO: I'm going to ask the -instruct the client not to reveal any attorney-client communications that we have had. But outside of that, if there's anything else beyond that, you can answer. A I was merely informed about the procedures and what to expect. That's all. Q (BY MR. PAISLEY) I'm sorry. I'm not asking for any communications you had with your attorneys. Did you meet with your attorneys in preparation for this deposition? 1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18 19 20 21 22 23 24 25 A An hour perhaps? Q Is that the same people in attendance or different -A No. Mr. Cornfield. Q And Stephanie? A Stephanie. Q Did you review documents to prepare for your deposition? MS. TO: You can answer. A No. Q (BY MR. PAISLEY) Besides these two meetings to prepare for your deposition here today, how many times have you met in person with your counsel since the lawsuit was filed? A I'll just say occasionally. I couldn't count how many times we've met. You mean meaning outside of the legal parameters of an office? Is that what you're asking? Q No. I guess I'm asking anywhere. If you've met anywhere in person with your counsel to discuss the lawsuit. A The answer is none. Q None besides those two meetings to prepare for the deposition? A That's right. That's right. Page 82 1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18 19 20 21 22 23 24 25 MS. TO: You can answer. A Yes. Q (BY MR. PAISLEY) When did you meet with them? A On two occasions within the last month. Q For how long did you meet on the first occasion? A I don't know. Perhaps -- perhaps two hours. Q And which of your attorneys did you meet with on that first occasion? A On the first occasion, Mr. Cornfield, Mr. Simon. Only -- only spent a very short time. And another attorney whose name I don't recall. Q Do you know whether the attorneys from Mr. Simon's office or Mr. Cornfield's office? A Yeah. The -- Mr. Cornfield and Mr. Simon, who I said stayed a short time, and a third attorney who I presume was from this office here, Simon's office. Q And then when was the second meeting to prepare for the deposition? A This past week. Q And how long did you meet then? Page 84 1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18 19 20 21 22 23 24 25 Q What about calls about the lawsuit? How many calls have you had with your counsel since the lawsuit was filed? A Perhaps one or two where they came to visit to obtain some information. MR. PAISLEY: Okay. I think it's probably a good time to break for lunch because we're almost out of tape. THE VIDEOGRAPHER: Going off the record at approximately 12:02 p.m. (Off the record.) (Exhibits 9 through 13 marked for identification by the court reporter.) THE VIDEOGRAPHER: We're back on the record on tape three at approximately 12:58 p.m. Q (BY MR. PAISLEY) Good afternoon, Mr. Raymond. A Good afternoon. Q Are you ready to go again? A Ready. Q So first of all, I'm going to have the court reporter -- I'll just hand you Exhibits 9 and 10. And these are similar to what you looked at before. They are responses to interrogatories that were served by the defendants in this case. Page 83 Page 85 22 (Pages 82 - 85) Veritext National Deposition & Litigation Services 866 299-5127 Case 3:12-cv-01141-SMY-DGW Document 176-48 *SEALED* Filed 12/01/14 Page 23 of 41 Raymond -Filed: 2/27/2014 Page ID #3432 Case: 16-3334 Document:Alan 55-49 02/08/2017 Pages: 41 (1409 of 1511) 1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18 19 20 21 22 23 24 25 The only difference is that the prior responses were to Pfizer, and these, as you see, are to different defendants. Do you see that, on 9 and 10? A Okay. Yeah, I see that. Q If you turn to the last page of Exhibit 9, is that your signature on the last page of Exhibit 9? A Yes, it is. Q And do you believe that all the responses in Exhibit 9 are accurate? A Yes. MS. McGRODER: For the record, Shaun, which defendant? Q (BY MR. PAISLEY) I'm sorry. So Exhibit 9 you will see on the front page there is defendants Alcon Laboratories, Inc., Alcon Research Limited, Falcon Pharmaceutical and Sandoz, Inc., do you see that? A I see it, yeah. Q Same question on Exhibit 10, which are Plaintiffs' Responses to Defendant Allergan Inc.'s First Set of Interrogatories. If you turn to the last page of Exhibit 10, is that your signature there? 1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18 19 20 21 22 23 24 25 through 13? Or have you ever reviewed them before today? A I'm not certain if I did or not. Q If you turn to the last page of 11, you'll see there is no signature from you; correct? A That's right. Q Do you know whether the contents of the responses in Exhibits 11 through 13 are true and accurate? Or do you believe them to be true and accurate? A I don't know if they're true and accurate, but I have no reason to disbelieve it. Q But you didn't participate in providing these responses? A No, not -- not to my memory, no. Q Do you still have the bottle of medication of latanoprost that we were looking at before? A Yeah. Q Do you mind if I just take a quick look at that? Thanks. Here, Mr. Raymond. If you look at the side of the bottle -- the side of the box where there's a bar code, yep, that side there, you'll see there's also a quantity there? Page 86 1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18 19 20 21 22 23 24 25 A Yes, it is. Q You believe that all of the responses given in Exhibit 10 are true and accurate? A Yes. Q Okay. I'm going to hand to you three exhibits. They are numbered Exhibits 11 through 13. Exhibit 11 is titled plaintiff Alan Raymond's First Supplemental Responses to Defendant Pfizer Inc.'s First Set of Interrogatories Directed to Plaintiff Alan Raymond. Exhibit 12 is entitled Plaintiff Alan Raymond's First Supplemental Responses to Defendant Alcon Laboratories, Inc., Alcon Research Limited, Falcon Pharmaceuticals Limited, and Sandoz, Inc.'s First Set of Interrogatories to Plaintiff Alan Raymond. And Exhibit 13 is Plaintiff Alan Raymond's First Supplemental Responses to Defendant Allergan, Inc.'s First Set of Interrogatories Directed to Plaintiff Alan Raymond. First of all, do you recognize Exhibits 11 through 13? A No, I don't recognize these. Q Did you ever review Exhibits 11 Page 88 1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18 19 20 21 22 23 24 25 A Yes. Q And that's 2.5? A Right. Q And so the bottle of latanoprost, which is the one you're taking currently, is a 2.5 milliliter bottle; correct? A Correct. Q When you referred to the bigger bottle that you were making a claim about and that you believe dispenses larger drops, what size of bottle were you talking about there? A I don't know the size, but I'm -- it was probably more than twice this size. Q More than twice the size, so maybe a 10 milliliter bottle? A Maybe. Maybe. Maybe larger. Q Maybe larger than 10 milliliters? A Yes. Maybe. Q And it's only those larger bottles that you're making a claim about; correct? A Correct. Q With respect to insurance coverage, we touched on it generally, but I didn't ask you questions about the specific coverage that you've had over the years, so I just want to do that now. Page 87 Page 89 23 (Pages 86 - 89) Veritext National Deposition & Litigation Services 866 299-5127 Case 3:12-cv-01141-SMY-DGW Document 176-48 *SEALED* Filed 12/01/14 Page 24 of 41 Raymond -Filed: 2/27/2014 Page ID #3433 Case: 16-3334 Document:Alan 55-49 02/08/2017 Pages: 41 (1410 of 1511) 1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18 19 20 21 22 23 24 25 Throughout the time you've had eye drop medications or you've taken eye drop medications, you have had medical insurance that covers at least part of the cost of the medications; correct? MS. TO: I'm just going to object to this entire line of questioning -- I'm assuming you have more questions regarding insurance -- as to relevance and some of the other objections that we've previously asserted in our written responses. But at this point you can go ahead and answer the question. A I have had Medicare since I was 65. And I've also -- I had a Medicare supplement all that time. Q (BY MR. PAISLEY) You also have private insurance? A A Medicare supplement? Yes. Q And is that with Coventry? A Now it is, yeah. Q And it was previously with United; is that right? A Right. I believe. I think there could have been a name change. I'm not sure about that. I don't know if it's a separate and distinct 1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18 19 20 21 22 23 24 25 Q Yeah. And then one in -- was there one last year? A That was a different procedure. That was a capsulectomy, I believe it's called. Q Can you tell me what a capsulectomy or a capsulotomy is? A Some people that have cataract operations have something that grows behind the cataract -- the cataract lens is an artificial lens replaces your natural lens. But the capsulectomy is a growth of some sort that takes place behind the lens, and it distorts your vision; although, I don't remember having any severe vision problems from it. And the doctor can destroy it with a laser. Takes 30 seconds or so. Q Okay. So that's what the -A Cure it. I shouldn't have said destroy it. Q So that's what the operation was, a fairly minor operation, but that's what the operation was last year? A Yeah. I was an outpatient. Yeah. Q How is your vision following that surgery in 2013? A No problems. Page 90 1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18 19 20 21 22 23 24 25 company anymore. Q Do you know what coverage you've had over what periods? A No. Q Your current eye doctor is Gregory Hill; is that right? A Right. Q How long has he been your eye doctor? A Perhaps more than six -- perhaps more than six or seven years. Q And before that, who was your eye doctor? A Dr. Berg. Ed Berg, B-e-r-g. Q And how long was he your eye doctor? A Twenty years, I suppose. Approximately twenty years, let's say. Q We -- we've had a chance to review some of your medical records because they were produced in the litigation. I notice that you've had a couple of eye surgeries in the past maybe six years? That sound right? A Yeah. Correct. Q So there was one, I think, in 2008; right? A You talking about cataracts? Page 92 1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18 19 20 21 22 23 24 25 Q When you go to your Doctor, your eye doctor, Dr. Hill, how do you go about choosing the prescription eye drop medications that you will take? A I don't choose them. Q Dr. Hill chooses them for you? A Right. Q Is that a collaborative process at all? Do you discuss the medications that will be prescribed? A No, not really. Q Are there any occasions on which he's presented different potential options of eye drop medication and asked you to choose? Or does he just give a prescription? A He gives me a prescription. Has changed the prescription over the years, as you can tell from the evidence. Q Does he tell you -- when he does change the prescription, does he tell you why he is doing that? A Well, yeah. Only that the prior one is ineffective. Q Have you ever asked him to change a medication that he had prescribed to you? Page 91 Page 93 24 (Pages 90 - 93) Veritext National Deposition & Litigation Services 866 299-5127 Case 3:12-cv-01141-SMY-DGW Document 176-48 *SEALED* Filed 12/01/14 Page 25 of 41 Raymond -Filed: 2/27/2014 Page ID #3434 Case: 16-3334 Document:Alan 55-49 02/08/2017 Pages: 41 (1411 of 1511) 1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18 19 20 21 22 23 24 25 A No. Never. Q Has he ever prescribed you something and you didn't fill the prescription, for whatever reason? A Never. MR. PAISLEY: Can we just go off the record for literally ten seconds? THE VIDEOGRAPHER: Going off the record at approximately 1:11 p.m. (Off the record.) THE VIDEOGRAPHER: We're back on the record at approximately 1:12 p.m. MR. PAISLEY: The court reporter is going to hand to you what will be marked as Exhibit 14. (Exhibit 14 marked for identification by the court reporter.) Q (BY MR. PAISLEY) I'll give you that copy too; although, we only have two, so I'll just do it from memory. So Exhibit 14 my client didn't have in its production, so when I asked you earlier about the prescription records, I didn't have this to hand, but this had been produced to one of our co-defendants. Do you recognize the document 1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18 19 20 21 22 23 24 25 A I also see some doctors' names on here that I don't recognize. So this must have been -- could have been for somebody else and not me. I don't know. Q (BY MR. PAISLEY) Well, it was -let's go off the record a second. THE VIDEOGRAPHER: We're going off the record at approximately 1:14 p.m. (Off the record.) THE VIDEOGRAPHER: We're back on the record at approximately 1:14 p.m. MS. TO: One other thing with regards to this Exhibit 14, I mean, I don't know what copy the witness has in front of him, but the copy I have has pages out of order and pages that are missing. So, I mean, to the extent this is supposed to be some sort of complete record, I would object to that aspect or characterization of it. Q (BY MR. PAISLEY) Okay. I'm representing to you the defendants obtained this record after request for your medical records following your medical authorization. A Okay. Q If that's the case, do you have any Page 94 1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18 19 20 21 22 23 24 25 that's Exhibit 14? A I recognize the doctors' names, yes. Q And it includes Dr. Berg's name there; correct? A Right. Q So Exhibit 14 is a more complete copy of prescription records; right? It shows prescriptions that were filled for you over the years? MS. TO: Objection to the form to the extent you're characterizing the document. But you can answer. A This goes back fifteen years. And I presume it's correct. Q (BY MR. PAISLEY) And it reflects prescriptions that were filled by you; is that your understanding? A That's what this looks like, yes. Q So you have no reason to doubt that that's an accurate record of the prescriptions that have been filled by you? MS. TO: I'm going to object. I'm not sure exactly where this document came from or what you're -- hang on a second. Of what you're characterizing this as being. Page 96 1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18 19 20 21 22 23 24 25 reason to doubt that the records in there as to the prescriptions you filled are accurate? MS. TO: I'm going to object as to the foundation, but you can answer if you know. A Well, there's a couple of cases where I don't recognize the doctors' names. So no, I don't remember getting -- Dr. Jay Piccirillo, I don't know who that is. And Judith Nations I do remember. She was an internist, not an eye doctor, and she's recommending nose drops here. That goes back fifteen years, so I don't remember the nose drops. Q (BY MR. PAISLEY) To the extent it reflects that you were taking eye drop medical designation as many as fifteen years ago, does that seem accurate to you? A Yes. Q Okay. You can put Exhibit 14 aside. Besides this lawsuit, have you ever been the plaintiff in any other lawsuit? A Once I took somebody to small claims court. Q How long ago was that? A Oh, perhaps twenty years ago. Q What was that dispute about? Page 95 Page 97 25 (Pages 94 - 97) Veritext National Deposition & Litigation Services 866 299-5127 Case 3:12-cv-01141-SMY-DGW Document 176-48 *SEALED* Filed 12/01/14 Page 26 of 41 Raymond -Filed: 2/27/2014 Page ID #3435 Case: 16-3334 Document:Alan 55-49 02/08/2017 Pages: 41 (1412 of 1511) 1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18 19 20 21 22 23 24 25 A I performed some services for a client who paid me and then stopped payment on the check. Q Did you prevail in small claims court? A Yes. Q Have you ever been the defendant in a lawsuit? A No. Q Other than being a plaintiff or a defendant, have you otherwise been involved in a lawsuit, as a witness maybe? A No. Q Okay. I'm going to ask you a series of questions about the defendants in this lawsuit. They may seem a little bit repetitive, but I'm going to try and get through them as quickly as possible. Prior to this lawsuit, had you ever heard of Alcon Laboratories, Falcon Pharmaceuticals, or Sandoz? A Yes. Q What had you heard about any one of those companies? A Sandoz, I thought, was a European 1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18 19 20 21 22 23 24 25 companies' headquarters? A No. Q You haven't called their patient service line or customer complaint line? A No. Q You haven't written to them? A No. Q Or otherwise made any complaints to them? A No. Q Other than possibly your attorneys, have you spoken with anyone about Alcon, Falcon, or Sandoz? A No. Q To your knowledge, have any of your friends or family members spoken with anyone at Alcon, Falcon, or Sandoz? A No. Q Other than how you've already articulated your claim about the drop size, do you allege any other unfair practices against Alcon, Falcon, or Sandoz? A No. Q Have you ever read or reviewed any product literature from Alcon, Falcon, or Sandoz? Page 98 1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18 19 20 21 22 23 24 25 company. I thought it was a Swiss company. I could be wrong about Switzerland, but I believe they were based in Europe. That's all. And Falcon, I only know the name from these. I don't remember them prior to the lawsuit, no. Q And what about Alcon Labs? A I'm not familiar with them, no. Q So besides what you just told me about Falcon and Sandoz, do you have any knowledge or did you have any knowledge before the lawsuit was filed about either of those companies? A No. Q As you sit here today, do you know which of the products you've taken over the years were manufactured by Alcon, Falcon, or Sandoz besides the one that is sitting in front of you there? A No, I don't. Q Besides the products that are -well, let me skip that. Have you ever spoken with anyone at Alcon Laboratories, Falcon Pharmaceuticals, or Sandoz? A No. Q Have you ever called any of those Page 100 1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18 19 20 21 22 23 24 25 A Have I reviewed any product literature you're asking? No. Q Have you reviewed any package inserts or product labeling from these companies? A I have reviewed the instructions that come with this. Q Do you do that every time you fill your prescription? A No. Q How often do you do that when you fill your prescription? A Occasionally. Q When you review it, what -- what's the purpose of your reviewing it? A Just curiosity, I suppose. Q Do you review anything in particular on the insert? A No. Q Have you received any correspondence from any of these companies? A No. Q Prior to this lawsuit being filed, had you ever heard of either Merck or Prasco? A I've heard of Merck. Who is the other one, Prasco? Page 99 Page 101 26 (Pages 98 - 101) Veritext National Deposition & Litigation Services 866 299-5127 Case 3:12-cv-01141-SMY-DGW Document 176-48 *SEALED* Filed 12/01/14 Page 27 of 41 Raymond -Filed: 2/27/2014 Page ID #3436 Case: 16-3334 Document:Alan 55-49 02/08/2017 Pages: 41 (1413 of 1511) 1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18 19 20 21 22 23 24 25 Q Prasco. A No, I've never heard of Prasco. Q What have you heard about Merck? A It's a large pharmaceutical company based in this country, to my knowledge. Q Beyond that, do you know anything else about Merck? A No. They're just one of the top -- I would guess they're one of the top ten in the nation. Q As you sit here today, do you know whether any of the products you have taken in the past were manufactured by Merck or Prasco? A No, I don't know which ones they manufacture. Q To your knowledge, have you ever purchased or used any products manufactured or sold by those companies? A To my knowledge, I just don't have no memory of using their products, no. Q Have you ever spoken with anyone at those companies? A No. Q So I'm presuming you've never called their headquarters? 1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18 19 20 21 22 23 24 25 A Product literature. No. Q Have you reviewed any package inserts or product language from Merck or Prasco, to your knowledge? A No. Q Have you received any correspondence from these companies? A No. Q Okay. With respect to Pfizer -- let me just lump these together. With respect to Pfizer, Allergan, and Bausch and Lomb, before filing this lawsuit, had you heard of any of those companies? A Yes. Q Which ones? A Bausch and Lomb, Pfizer, and what was the other one? Q Allergan. A I haven't heard of Allergan. Q With respect to Pfizer and Bausch and Lomb, what had you heard about those companies before you filed this lawsuit? A Pfizer, again, is one of the largest in the country, and Bausch is Lomb is known for their eye medications, including vitamins. Page 102 1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18 19 20 21 22 23 24 25 A That's right. Q You've never called their patient service line or customer complaint line? A That's right. Q You've never written to them? A No. Q You never made any complaints to those companies; correct? A That's correct, yes. Q Other than possibly your attorneys, have you spoken with anyone about Merck and Prasco? A No. Q To your knowledge, have any of your friends or family members spoken with anyone at Merck or Prasco on your behalf? A No. Q Other than the alleged unfair practiced that you've already described here today, do you allege any other unfair practices against Merck or Prasco? A No. Q Have you read or reviewed any product literature from Merck or Prasco, to your knowledge? A Any unfair literature? Q Any product literature? Page 104 1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18 19 20 21 22 23 24 25 Q And beyond that knowledge, do you have any other knowledge about the companies? A No. Q As you sit here today, do you know whether any of the products you have taken in the past, the eye drop products, were manufactured by Pfizer, Allergan, or Bausch and Lomb? A Do I have any knowledge? Or do I have a memory, you're saying? Q Do you know whether any of them were. A No, I don't know. Q To your knowledge, have you ever purchased or used any products manufactured or sold by those companies? A Not to my knowledge, no. Q Have you ever spoken with anyone at those companies? A No. Q So you've never called their headquarters? A No. Q Never called their patient service line? A No. Q Or customer complaint line? Page 103 Page 105 27 (Pages 102 - 105) Veritext National Deposition & Litigation Services 866 299-5127 Case 3:12-cv-01141-SMY-DGW Document 176-48 *SEALED* Filed 12/01/14 Page 28 of 41 Raymond -Filed: 2/27/2014 Page ID #3437 Case: 16-3334 Document:Alan 55-49 02/08/2017 Pages: 41 (1414 of 1511) 1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18 19 20 21 22 23 24 25 A No. Q Have you written to them? A No. Q So you've never made any complaints to those companies? A No. Q Other than possibly your attorneys, have you spoken with anyone about Pfizer, Allergan, or Bausch and Lomb? A No. Q To your knowledge, have any of your friends or family members spoken with any one of those companies? A No. Q Other than the unfair practices that you've already described here today with respect to drop size, do you allege any other unfair practices against these companies? A Well, I hate to bring this up. Their TV advertising, while it may not be unfair, it's -it's always the newest, most expensive drugs they have on the market. Q Is that a claim you are making in this lawsuit? A No, it's not a claim. It's just a 1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18 19 20 21 22 23 24 25 Q Have you reviewed any package inserts or product labeling from any of these companies besides the vitamins that you just mentioned? A No. Q Have you received any correspondence from these companies? A No. Q Other than the -- let's go off the record for a minute. THE VIDEOGRAPHER: We're going off the record at approximately 1:27 p.m. (Off the record.) THE VIDEOGRAPHER: We're back on the record at approximately 1:28 p.m. Q (BY MR. PAISLEY) Mr. Raymond, can I just ask you to turn finally to Exhibit 7? It is the -- it's your responses to Defendant Pfizer Inc.'s First Set of Interrogatories Directed to Plaintiff Alan Raymond. Can I ask you to turn to page 9, and I'm going to draw your attention to Interrogatory Number 16. It's at the top of the page. You see it says, "state whether you have ever read, heard, or viewed any advertising regarding Xalatan. And if so describe the type and Page 106 1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18 19 20 21 22 23 24 25 1 personal opinion. 2 Q Is there a specific company that you 3 hold that opinion about? 4 A Most of them. All the prominent drug 5 manufacturers will say, "See your doctor about so 6 and so." And from what I read, I understand people 7 walk in and ask their doctors for name brand 8 prescriptions. 9 Q But you understand that's not part of 10 this lawsuit? 11 A That's right. You asked my opinion, 12 and that's my opinion. 13 Q Have you ever read or reviewed any 14 product literature from Pfizer, Allergan, or Bausch 15 and Lomb, to your recollection? 16 A I'm using some eye drops manufactured by Bausch and Lomb right now. Excuse me, did I say 17 18 eye drops? I'm sorry. Erase that. 19 I'm using some vitamins. And the 20 directions are on the bottle. 21 Q Okay. So you've read those. 22 A Yeah. 23 Q But you're not making any claim about 24 the vitamins? 25 A No. Page 108 content of the advertising, the source of the advertising, e.g., name of publication or TV or radio station and the date or dates you read, heard, or viewed the advertising." You see that? A I see it, yeah. Q And then the answer, subject to objections, is, "Plaintiffs state that he may have looked up Xalatan online when it was first prescribed to him but does not recall what he saw or when." Do you remember where you looked up Xalatan online? A No, I don't remember. Q Is it true that you looked up Xalatan online when it was first prescribed to you? A It says I may have looked it up. I don't specifically remember doing that. Q Okay. So you have no recollection at all as to what website you might have visited? A That's right. Q And you have no recollection as to what information you may have read? A That's right. MR. PAISLEY: All right. I have no further questions at this time. I pass the Page 107 Page 109 28 (Pages 106 - 109) Veritext National Deposition & Litigation Services 866 299-5127 Case 3:12-cv-01141-SMY-DGW Document 176-48 *SEALED* Filed 12/01/14 Page 29 of 41 Raymond -Filed: 2/27/2014 Page ID #3438 Case: 16-3334 Document:Alan 55-49 02/08/2017 Pages: 41 (1415 of 1511) 1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18 19 20 21 22 23 24 25 witness. EXAMINATION QUESTIONS BY MR. NORDEN: Q Mr. Raymond, my name is David Norden. I represent three of the defendants in this case, Alcon, Falcon and Sandoz. Shaun has done a thorough job already today, and I have some followup questions in regard to my clients. Do you understand that? A Say them again? Alcon and... Q Alcon, Falcon and Sandoz. A Okay. Q Mr. Raymond, over the past number of years, you've been prescribed eye medications by two physicians; right? Dr. Berg and Dr. Hill? A Right. Q And during those number of years, those doctors have always recommended what medications for you to take; correct? A Correct. Q Have you ever walked into Dr. Berg's office or Dr. Hill's office and asked for a particular eye medication? A No. Q So when it comes down to deciding 1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18 19 20 21 22 23 24 25 possible that you may not have had the eye drops running down your cheek since 2006; is that right? MS. TO: Objection to the extent that mischaracterizes his testimony. But you can answer. A I don't remember the -- I'll repeat. I don't remember the time we switched over to the smaller bottle. I think it was only about two years ago. Approximately two years ago. Q (BY MR. NORDEN) So could you pinpoint for us, Mr. Raymond, when exactly was the last time you experienced these drops running down your cheek? A No, I don't remember. Q So you don't know if it was 2006, 2010, 2011, do you? MS. TO: Objection. It's been asked and answered, but you can answer again. A No, I don't remember exactly when. Q (BY MR. NORDEN) As we sit here today, you cannot tell us exactly when the last time these eye drops ran down your cheek; right? A That's right. Q I want to direct you to what's been marked as Defendant's Exhibit 9, if Stephanie could Page 110 1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18 19 20 21 22 23 24 25 what eye medications that you should take for your glaucoma or other eye-related issues, you leave that or those decisions up to your doctors? A Right. Q Do you ever recall an instance where you approached Dr. Hill or Dr. Berg and asked for a particular eye medication? A No. Q Mr. Raymond, you testified that for the past number of years you have been taking latanoprost, which you have in front of you; right? A Correct. Q You have been on eye medications for the past fifteen years or so? A More. Q Possibly longer than fifteen years? A Well, the record shows 1999, so that's -- yeah, that's fifteen years. Q And it's fair to say that since 2006 you have not had this issue of the drops running down your cheek; is that right? A I don't know the specific date. I don't remember when we switched over to the smaller bottle. Q But you would agree with me that it's Page 112 1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18 19 20 21 22 23 24 25 place that in front of you. MS. TO: Sure. 9? MR. NORDEN: Yes. The Alcon discovery responses. Q (BY MR. NORDEN) Do you have those in front of you, Mr. Raymond? A Yes, I do. Yes. Q And you recognize these to be the Plaintiffs' Discovery Responses to interrogatories from plaintiffs -- I should say the Defendants Alcon Labs, Alcon Research, Falcon Pharmaceuticals, and Sandoz; is that correct? A Correct. Q And you already testified that you signed these under oath August 12 of 2013; correct? A Correct. Q And Mr. Raymond, you provided the information for these discovery responses; right? A You're asking if I provided the responses? Q Yes. A No. I believe the attorneys did this. Q Let me rephrase the question, Mr. Raymond. You provided the information to your Page 111 Page 113 29 (Pages 110 - 113) Veritext National Deposition & Litigation Services 866 299-5127 Case 3:12-cv-01141-SMY-DGW Document 176-48 *SEALED* Filed 12/01/14 Page 30 of 41 Raymond -Filed: 2/27/2014 Page ID #3439 Case: 16-3334 Document:Alan 55-49 02/08/2017 Pages: 41 (1416 of 1511) 1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18 19 20 21 22 23 24 25 attorneys so that they could put together these responses for you? A That's right. Q So when we look for whoever provided the information for these discovery responses, there is one person, and that's you, Mr. Raymond? A That's right. Plus -- plus the other plaintiffs. Q Provided this particular information for your discovery responses? A Oh, no, no. This is for me. I'm sorry. Q Mr. Raymond, if you could turn to page 8 of Exhibit 9? Do you have that in front of you? A I have it. Q Interrogatory Number 14 we ask, "For each medication identified in your answer to Interrogatory Number 11, describe in detail: (a) the reasons expressed by each health care professional for Raymond prescription; and (b) the information, if any, each health care professional provided to you about the medication when he or she prescribed it to you, whether delivered orally or in writing, including but not limited to the 1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18 19 20 21 22 23 24 25 MS. TO: Can we go off the record? Doug got dropped off the call, so I would like to phone him back in. THE VIDEOGRAPHER: We're going off the record at approximately 1:37 p.m. (Off the record.) THE VIDEOGRAPHER: We're back on record at approximately 1:38 p.m. Q (BY MR. NORDEN) Mr. Raymond, when co-defendant's counsel dropped off the line, we were discussing Interrogatory 14 and your response; correct? A Right. Q You said that, as far as verbal directions that Dr. Gregory Hill gave you regarding dosage administration, it was just the time of day to take the medication; correct? A Right. Q And what else? A One drop in each eye. Q Did he give you any further instructions ever about how to apply the medication? A No. Q You did not mention Dr. Berg in this Page 114 1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18 19 20 21 22 23 24 25 package insert or any information." A Yes, sir. Q And your answer is that, "Plaintiff states he was given prescriptions for Vigamox, latanoprost, and timolol to decrease his eye pressure"; correct? A Correct. Q You go on to say, "Plaintiff was not given anything more than verbal directions from Dr. Gregory Hill on dosage administration"; is that correct? A Correct. Q Mr. Raymond, what were those verbal directions that you were given from Dr. Gregory Hill on dosage administration? A What time of the day to take them, either morning or night, and how many drops in each eye. One drop in each eye, best of my memory, yeah. Q And how many times did Dr. Hill relay that information to you? A I don't remember that. Q Did he relay it to you one time? A I don't remember that either. Q Did he relay the -- Page 116 1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18 19 20 21 22 23 24 25 interrogatory response; correct? A Well, correct that his name does not appear here, so I guess -- incidentally, for the record, Dr. Berg has been deceased for five or six years. Q And you would agree with me that Dr. Berg was one of the two physicians who prescribed you eye drop medications; correct? A Correct. Q And Dr. Berg, did he ever provide you with any verbal directions regarding dosage administration for the products at issue in this case? A No. Q He never did? It was only Dr. Hill? A To the best of my memory, that's right. Q Mr. Raymond, is there anything about these eye drop medications that you discussed with either Dr. Berg or Dr. Hill that you have not already told us about today? A No. Q Mr. Raymond, take a look at Interrogatory Number 15. We asked, "If any directions, instructions or warnings concerning the Page 115 Page 117 30 (Pages 114 - 117) Veritext National Deposition & Litigation Services 866 299-5127 Case 3:12-cv-01141-SMY-DGW Document 176-48 *SEALED* Filed 12/01/14 Page 31 of 41 Raymond -Filed: 2/27/2014 Page ID #3440 Case: 16-3334 Document:Alan 55-49 02/08/2017 Pages: 41 (1417 of 1511) 1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18 19 20 21 22 23 24 25 use of any medication identified in your answer to Interrogatory Number 11 were provided to you at any time, state: (a) the exact contents of such directions, instructions, or warnings; (b) the place and manner in which such directions, instructions or warnings were given to you; and (c) the person or person who provided such directions instructions or warnings." As far as your answer is concerned, there are some objections, and you go on to say, "Plaintiff states that he was given nothing further than verbal dosage instructions and whatever other materials came with the medications, such as inserts. Plaintiff was told to put the drops in each eye once a day at bedtime by his eye doctor, Dr. Gregory Hill." Do you see that doctor? A I see it, yes. Q And do you agree with this discovery response that you've given here? Is that still true today? A True. Q And as far as the verbal dosage and suggestions, have you already testified regarding what those were? A You mean today? 1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18 19 20 21 22 23 24 25 medications such as inserts, et cetera? A Well, I told you, physician -- the pharmacy would give you a written list of procedures and risks or warnings and what the purpose of the drug was for. Q And I'm getting more at what Dr. Hill gave you, if you can recall. A Are you asking if he gave me any written instructions? Q Well, your answer is, "Plaintiff states he was given nothing further than verbal dosage suggestions and whatever other materials came with the medication, such as inserts." So what are these other materials when you say, "Such as inserts, et cetera"? A The only other materials would be the, as I said, what the pharmacy provides. Q Dr. Berg didn't give you anything extra? A No. Q In response to Interrogatory Number 17 -- and let me just state for the record the interrogatory. "State whether you have ever read, heard or viewed any advertising related to Alcon eye medication. And if so, describe the type and Page 118 1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18 19 20 21 22 23 24 25 Q Right. A Sure. Yes. Q Just what you told us about in response when we discussed Interrogatory 14; correct? A Correct. Q And again, as far as this discovery response is concerned, as far as Dr. Berg is concerned, you never discussed even dosage suggestions with him; right? A I have no recall. He's been deceased more than six years now, five or six years or more. Q But as we sit here today, you can't recall having any type of discussions with Dr. Berg about any dosage suggestions he might have given you? A That's right. Q In terms of the, quote-unquote, materials that came with the medications, are you referring to the package insert that came inside the box? A No. Just -- no. Q What are you referring to here in your response to Interrogatory Number 15 when you say, quote-unquote, other materials came with the Page 120 1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18 19 20 21 22 23 24 25 content of the advertising and source of advertising, e.g., the name of publication or TV or radio station and the dates that you read, heard, or viewed the advertising." You said that yes, you "...may have looked up Vigamox, latanoprost and timolol online when they were first prescribed to him, but does not recall when [sic] he saw or when." So as we sit here today, Mr. Raymond, can you tell us what you recall looking up about Vigamox? A No. Q Can you tell us when you recalled looking anything up about Vigamox? A No. Q And you don't really know whether or not you looked up anything about Vigamox, do you? A No. Q Mr. Raymond, as far as latanoprost, do you recall whether you ever looked up any information about latanoprost? A Not specifically, no. Q You wouldn't be able to tell us what exact day or when you looked up anything about latanoprost, because you don't even know if you Page 119 Page 121 31 (Pages 118 - 121) Veritext National Deposition & Litigation Services 866 299-5127 Case 3:12-cv-01141-SMY-DGW Document 176-48 *SEALED* Filed 12/01/14 Page 32 of 41 Raymond -Filed: 2/27/2014 Page ID #3441 Case: 16-3334 Document:Alan 55-49 02/08/2017 Pages: 41 (1418 of 1511) 1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18 19 20 21 22 23 24 25 did? A That's right. Q Would your answers also apply to timolol, Mr. Raymond? A Yes. Q Interrogatory Number 19 on page 11, Mr. Raymond, we asked you, "State whether you are aware of any oral or written statements made by any one of the Alcon Defendants or their agents, servants, or employees pertaining to the subject matter of this lawsuit. If so, state the date and place where each such statement was made. Provide a description the statement. Identify the individual who made it, the individual to whom it was made, whether the statement was written or oral, and if written or reduced to writing, please identify the custodian thereof. If you contend that any statement identified in the answer to this interrogatory is a statement against interest or an admission by Alcon, identify each such statement." In response to Interrogatory Number 19, Mr. Raymond, you say you're, "...not aware of any oral or written statements made by Alcon besides," quote, "statements or publications generally made to the public concerning the subject 1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18 19 20 21 22 23 24 25 asks you, "If any doctor, nurse, pharmacist or other individual with or without medical training has ever expressed to you or in your presence or to your knowledge has ever expressed in the presence of some other person any opinion relating to whether -(Whereupon, the court reporter asked for clarification.) MR. NORDEN: So you can pick it up off the discovery response. Let me start over. Q (BY MR. NORDEN) Interrogatory Number 22, "If any doctor, nurse, pharmacist or other individual with or without medical training has ever expressed to you or in your presence or to your knowledge has ever expressed in the presence of some other person any opinion relating to whether any of the Alcon defendants were or were not at fault with regard to the damages alleged in the complaint, please indicate in reasonable detail as to each such statement, who said it, where and when it was made, what was said, and who was present." And there is an objection. But I want to get your answer to that question. A I have never heard any statements regarding this. Page 122 1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18 19 20 21 22 23 24 25 medications and drop sizes," end quote. So Mr. Raymond, tell me what you mean by these statements or publications generally made to the public concerning the subject medications. A I suppose what I was saying here was that I may have seen an ad in a magazine or something like that, but that's -- that's -- that's the best of my knowledge of it. Q Well, what you said in your interrogatory response were there are these statements or publications generally made to the public concerning these subject medications and drop sizes, and I want to know what you mean by that. MS. TO: Objection. He's answered that question, but you can answer again. A I have no memory of making any statements in this matter. Q (BY MR. NORDEN) It's not whether you made the statements. It's what statements you're saying that Alcon generally made about the products and the drop sizes. You can't remember any of them, can you? A No. Q Mr. Raymond, Interrogatory Number 22 Page 124 1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18 19 20 21 22 23 24 25 Q You can put those aside, Mr. Raymond. Mr. Raymond, in terms of the products that the medical records reflect that you -- that you took, we have talked about the latanoprost; correct? A Right. Q Vigamox, is that not a product that you recall taking? A I believe it was named in here, wasn't it? Q But do you recall taking Vigamox? A No. Q So you wouldn't know if it's in a large bottle or small bottle, would you? A I believe everything I've ever taken was in a large bottle, to the best of my recollection. Q With the exception of the latanoprost? A Right. Q And how again is it that you define what a large bottle is? A I define it as being more than twice the size of this one. Q More than twice the size of the Page 123 Page 125 32 (Pages 122 - 125) Veritext National Deposition & Litigation Services 866 299-5127 Case 3:12-cv-01141-SMY-DGW Document 176-48 *SEALED* Filed 12/01/14 Page 33 of 41 Raymond -Filed: 2/27/2014 Page ID #3442 Case: 16-3334 Document:Alan 55-49 02/08/2017 Pages: 41 (1419 of 1511) 1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18 19 20 21 22 23 24 25 latanoprost bottle that you have in front of you? A Yes. Q Do you recall taking Nevanac? A No. Q Do you recall taking timolol gel forming solution? A Gel forming solution? No. Q Other than the different sizes of the bottles, do you draw any distinctions among the products that you took for your eye-related issues over the past fifteen years or so? MS. TO: Object to form. It's vague. You can answer. A Repeat the last portion of that question. Q (BY MR. PAISLEY) Thinking about all the eye medications that you have taken since 1999 or earlier, do you draw any distinctions among them other than the size of the bottle? Large or small? MS. TO: Same objection. You can answer. A No. Q (BY MR. PAISLEY) Have you ever filed for bankruptcy? A Yes. 1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18 19 20 21 22 23 24 25 you started having concerns about the drop sizes in your eye being too big? A I was aware of it for a long time. Q And what year did you first become aware of that? A Probably from the initial time I was taking the drops. Q You testified that you never called anyone at Alcon or Falcon or Sandoz regarding the size of the drops and complained about it; right? A That's right. Q Tell me why you didn't do that. A Well, for a long time I used to think it was my fault. I used to think I was doing something wrong. Q How is that? A Well, I tried very hard not to overdose, to speak, and it -- it happened consistently. Q You're a smart guy; you're a financial planner; you went to Wash U; right? That's considered a good University; correct? A Correct. Q And you know you could have called the FDA and complained about the size of the drops, Page 126 1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18 19 20 21 22 23 24 25 Q When did you file for bankruptcy? A It's more than ten years ago. Probably closer to fifteen years ago. Q Can you be more specific? A Yes. I had a bicycle accident, and I had a hospital bill, and I had an insurance company that refused to pay. Q You went through the process of filing what type of bankruptcy? A One of the chapters, either 9 or 11, I'm guessing. I don't know which one. Q Approximately one year -- what year was that, Mr. Raymond, if you could possibly be more specific? A Oh, goodness. I'm going to guess. Let's go back to '84? No, no. Perhaps around 1990. Q Were you living in St. Louis at the time? A Yes. Q So if we wanted to find out the exact date, the best way for us to do that would be to check the court files? A Yes. Q When again was it, Mr. Raymond, that Page 128 1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18 19 20 21 22 23 24 25 couldn't you? A Yes. MS. TO: Object to the form. Q (BY MR. NORDEN) Yes? A I could have called the FDA, yes. Q Why didn't you? A It just didn't occur to me that -- at the time that the -- it was just part of living, I guess. You know. Q So you thought the best recourse for the eye drops being too big and running down your cheek was, for a number of years, was not; number one, to call the manufacturer of the drug; number two, not to call the federal government who regulates these eye drops. You thought the best thing to do would be wait until two years ago and then get involved in a lawsuit? A No. No. MS. TO: Objection. I mean, you're being argumentative the way you are phrasing the question. You are -A The best thing -MS. TO: Sir, you got to let me finish my objection. I object to the fact that it's argumentative. Also assumes facts not in Page 127 Page 129 33 (Pages 126 - 129) Veritext National Deposition & Litigation Services 866 299-5127 Case 3:12-cv-01141-SMY-DGW Document 176-48 *SEALED* Filed 12/01/14 Page 34 of 41 Raymond -Filed: 2/27/2014 Page ID #3443 Case: 16-3334 Document:Alan 55-49 02/08/2017 Pages: 41 (1420 of 1511) 1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18 19 20 21 22 23 24 25 evidence. Now you can answer. A My response was to try very hard not to let it run down my cheek with the idea that I'm -- I'm doing something wrong. Q (BY MR. NORDEN) How could you have been doing something wrong? A I could have been doing something wrong. I thought maybe you squeeze the bottle too hard and -- but it was happening consistently. Q And so that should have led you to call one of the manufacturers or the FDA; right? MS. TO: Objection. That's argumentative. You can answer. A Not necessarily, no. Q (BY MR. NORDEN) But you would agree with me, though, that, number one, you never complained about this over a fifteen-year period to the drug manufacturers; right? A That's right. Q And you never called the FDA and complained and said, "FDA, you know, you're in charge here. You have to do something." You never did that? A Right. Q And what you did do was get involved 1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18 19 20 21 22 23 24 25 able to get answers as to why the doctors changed your eye drop medications over a 15-year-plus period, the people to ask about that would be -well, not Dr. Berg, because he passed away. But it will be Dr. Hill? MS. TO: Objection. He's answered your question. But go ahead. A You could ask them if you want to know. Q (BY MR. NORDEN) Were any of these changes related to the size of the drops? A No. Q And you never complained to Dr. Hill or Dr. Berg about the size of the drops ever? A No. Q Right? A Right. Q Never in your life? A No. Q Mr. Raymond, your testimony a minute ago was about your pressure sometimes would go up with some of the eye medications that you were taking, and that, as far as you're concerned, may have been the reason for some of the changes in medications? Page 130 1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18 19 20 21 22 23 24 25 in a complaint in this case a couple years ago with someone from your church; right? MS. TO: Object to the form. You can answer. Q (BY MR. NORDEN) Correct? A With someone from my congregation, right. Q Now, again, I just have a few more questions. Over the past number of years we know you've been on a number of different eye medications; right? A Right. Q As we sit here today, can you tell us what the reasons were for any of the changes in medications that you have had over this 15-year time period? A The reason for the changes was, apparently, they weren't performing like they were supposed to, and the doctor changed to a different medication. The pressures would go up. They measure the pressures every time you go in there. And if the pressures were higher, they had a problem -- I had a problem. And they prescribed something else. Q So Mr. Raymond, in terms of being Page 132 1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18 19 20 21 22 23 24 25 A Yes. Q Did you ever complain to Dr. Berg or Dr. Hill about a medication not particularly working for you? A No. Q And so how would Dr. Hill have known to change your medications? Just from measuring the pressure? A It was his professional judgment, yeah. Q And did you ever have any complaints whatsoever with any of these eye products that you reported to Dr. Berg or Dr. Hill? A No. Q One last question regarding the interrogatory responses. If you could go to page 12. MR. NORDEN: Stephanie, if you could put that back in front of him. MS. TO: Exhibit 9? MR. NORDEN: Right. MS. TO: And I'm sorry. What page are you on? MR. NORDEN: Page 12, Interrogatory Number 21. Page 131 Page 133 34 (Pages 130 - 133) Veritext National Deposition & Litigation Services 866 299-5127 Case 3:12-cv-01141-SMY-DGW Document 176-48 *SEALED* Filed 12/01/14 Page 35 of 41 Raymond -Filed: 2/27/2014 Page ID #3444 Case: 16-3334 Document:Alan 55-49 02/08/2017 Pages: 41 (1421 of 1511) 1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18 19 20 21 22 23 24 25 Q (BY MR. NORDEN) Do you have that, Mr. -A Yes, I have it. Q (BY MR. NORDEN) The question here that we asked you in Interrogatory Number 21, "State whether there have been any communications between you and any other person regarding whether the drop size for any eye medication or eye medications generally can or should be made smaller and include a description of any such communications, the name of the persons with whom you communicated and the dates any such communications." And what you said was that you talked to your wife regarding the size of the eye drops; right? A Yes. Q Is that true? A Yes. Q When did you talk to your wife about the size of the eye drops? A Since this came up. Since this developed. Q How long you been married to your wife? 1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18 19 20 21 22 23 24 25 the record at approximately 1:59 p.m. (Off the record.) THE VIDEOGRAPHER: We're back on the record on tape four at approximately 2:07 p.m. EXAMINATION QUESTIONS BY MS. McGRODER: Q Mr. Raymond, I'm Lori McGroder, and I represent the Allergan defendants and Bausch and Lomb. I know it's been a long day for you. I have just a very few questions; okay? A Sure. Q You understand you're still under oath and all the rules that the other attorneys talked with you about still apply. A Right. Q Have you ever talked with your doctor about this lawsuit? A Only on the last visit. Q And when was the last visit? A Couple weeks ago. Q And is that Dr. Hill? A Yes. Q At no time before February of 2014 had you ever talked to your doctor about this lawsuit; is that correct? Page 134 1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18 19 20 21 22 23 24 25 A Over nine years. Q And what's the best estimate as to the year that you, quote-unquote, talked to your wife regarding the size of the eye drops? A 2012, I guess. Q And that's the first time and only time you talked to your wife regarding the size of the eye drops? A To the best of my knowledge, yes. Q And what was that conversation like? A I don't remember the course of the conversation. Just mentioned it matter of factly. Q And the prior six or seven years that you were married to your wife you never had any conversation with her about the eye drops being too big, the drops running down your face? A No. Q She never came to you and said, "Gee, Alan, the drops are running down your face. Let's do something about this"? A No. MR. NORDEN: Okay. That's all the questions I have. THE VIDEOGRAPHER: One moment, please. I have to switch tapes. We are going off Page 136 1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18 19 20 21 22 23 24 25 A No. Q Why did you talk to Dr. Hill about the lawsuit a couple weeks ago? A I was there for a routine, periodic exam. I wanted to make certain he understood he was not being sued, and I don't make it a practice to sue doctors anyway. I don't make it a practice to go around suing anybody. And he shrugged and said, "Yeah, I understand." He knew that all the paperwork that they had to go through to dig up files, and he dismissed it like it's -- he's not overly concerned. Q What did you tell him about the lawsuit? A We were suing pharmaceutical companies. Q What else did you tell him? A The reason being behind the lawsuit. Q The reason being? I'm sorry. A The reason was the waste of the medication. Q Tell me exactly what you said to your doctor. A I don't remember exactly what I said Page 135 Page 137 35 (Pages 134 - 137) Veritext National Deposition & Litigation Services 866 299-5127 Case 3:12-cv-01141-SMY-DGW Document 176-48 *SEALED* Filed 12/01/14 Page 36 of 41 Raymond -Filed: 2/27/2014 Page ID #3445 Case: 16-3334 Document:Alan 55-49 02/08/2017 Pages: 41 (1422 of 1511) 1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18 19 20 21 22 23 24 25 to my doctor other than something to the effect of make sure he understood it was only pharmaceutical companies and not physicians. Q How did it come up? A I brought it up. Q Because your doctor had gone through the effort of producing your medical records in the case? A Well, his people did, yeah. Q Okay. And that's something that you knew when you went in for your last visit? A I knew it because I had already had some of this evidence presented to me. Like I could see where he submitted a bill for printing costs or something. Q He submitted a bill to you for the printing costs? A No, no. To the attorneys. Q And so you felt it would be important to discuss with your doctor the fact that you had brought this lawsuit and it didn't involve him? A Yes. Q What did he say? A He knew that, and he didn't seem to be at all involved or concerned. 1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18 19 20 21 22 23 24 25 that you've taken should be smaller? That the drop size should be smaller? A There was no reference to that, no. Q So he didn't say, "I agree with your theory of the case"? A He didn't say that, no. Q Let's say your doctor was thinking to himself, "You know what? I don't agree with that theory of the case. This has never been a problem for any of my patients. I don't think this is legitimate"; would that cause you to rethink your lawsuit? MS. TO: I'm going to object. That's an improper hypothetical and assumes facts not in evidence. You can answer. Q (BY MS. McGRODER) You can answer. A I don't -- I have no idea what he was thinking other than what he communicated. Q Well, my question is a little bit different. I'm not asking you what he was thinking. I'm asking you what you would think if your doctor just didn't agree with the theory of your lawsuit. MS. TO: Same objection. You can answer. Page 138 1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18 19 20 21 22 23 24 25 Q And did you tell him that the theory of the lawsuit was that the eye drops are too big and, therefore, they run down your cheek and cause waste? Did you tell him that part? A Yeah. Essentially, yes. Q What exactly did you say about that? A Something -- the same thing you just said. Q And did he have a response? A No. Q Did he tell you, "Well, Mr. Raymond, I think that is a really good theory for a lawsuit and I'm glad you brought it"? A No, he didn't say that. Q Did he say, "I've always known with all my patients that they have this problem of too large of drops and the solution running down their cheek"? Did he say that? A No. Q Did he say, "I have had many patients come in and complain to me about the eye drops running down their cheeks"? Did he say that? A No. Q Did you get any sense whether your doctor agrees with your position that the eye drops Page 140 1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18 19 20 21 22 23 24 25 A I would proceed with this. Q (BY MS. McGRODER) You would proceed anyhow? A Yeah. Q In other words, your doctor's medical judgment about whether the size of eye drops is too large is not something you're concerned with? MS. TO: Objection to the extent that mischaracterizes his testimony. But you can answer. A I just feel my position is right. My opinion is right. Q (MS. McGRODER) And you don't really care whether your doctor agrees with it or not; right? A That's all hypothetical that it -it's beyond belief, actually. Q Well, I mean, did you ask him, "Do you agree with my theory?" A No. Q So it's possible he doesn't agree with your theory; right? A Possible. Q And if he doesn't agree with your theory, that's not something you're concerned with; Page 139 Page 141 36 (Pages 138 - 141) Veritext National Deposition & Litigation Services 866 299-5127 Case 3:12-cv-01141-SMY-DGW Document 176-48 *SEALED* Filed 12/01/14 Page 37 of 41 Raymond -Filed: 2/27/2014 Page ID #3446 Case: 16-3334 Document:Alan 55-49 02/08/2017 Pages: 41 (1423 of 1511) 1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18 19 20 21 22 23 24 25 correct? A I don't know. I just don't know how to answer. We didn't -- this just never came up. Q Right. And I mean it did come up, the idea of the lawsuit did come up in why are visit with your doctor; correct? The fact that you filed the lawsuit. You already said that, right? A Right. Q So to the extent your Doctor, to the extent Dr. Hill absolutely just doesn't in his medical judgment agree with your lawsuit, you'd still proceed with it anyway; correct? MS. TO: Same objection. I mean, it's an improper hypothetical, and he's already answered the question at this point. But go ahead. MS. McGRODER: You know what? You can restrict your objections to the form, and there's no need for a speaking objection. MS. TO: It's not a speaking objection. I am explaining to you why your question is proper. But go ahead and answer. Q (BY MS. McGRODER) You can answer. MR. SORIANO: I join. It's a speaking objection. A I probably -- I probably would have 1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18 19 20 21 22 23 24 25 bottle? A The best of my knowledge, yeah. Q Has there ever been a time that you attempted to get insurance coverage for one of your eye drop medications and the insurer refused to cover it? A No. Q Is it your contention that every eye drop manufacturer in the United States purposely manufactures drops that are larger than necessary so patients have to pay more for medications that you believe are wasted? A It appears that way, yes. Q Are you aware of any eye drop medication sold in the United States that has a drop smaller than 15 microliters? A I don't remember offhand if microliters is the normal dose or not. Maybe you can inform me. Q So as you sit here today, you can't tell me right now whether the drops you're taking are larger or smaller than 15 microliters; correct? A My best opinion is that they're smaller enough to do the job properly. Q So whatever the size of those eye Page 142 1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18 19 20 21 22 23 24 25 pursued it because I felt strong about this because it went on for a long time. Q (BY MS. McGRODER) Okay. Now, when you say that the issue of the eye drops running down your cheek had gone on for a long time, I believe your testimony is it went back to the very first time you took an eye drop back in, approximately, 1999; is that correct? A To the best of my memory, yes. Q And then would you say that it stopped, the problem of wasted eye drops running down your cheeks stopped at the time that you started latanoprost; is that correct? A Yes. Q For that period of time that you believe there was a problem with eye drops running down your cheeks, are you able to identify for us any product that that happened with? Can you name a specific eye drop problem that that occurred with? A To the best of my memory, it occurred with all of them, all the ones I took. Q And so the only distinction you make about whether the product, the size of the drops in the product caused wastage is the size of the Page 144 1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18 19 20 21 22 23 24 25 drops are that you're taking there, latanoprost, whatever the drop size is for those -- for that product, that's the drop size you believe should be used in the United States of America? MS. TO: Objection to the extent you're asking for expert testimony. You can answer. A That is the question. Everybody has the same eye capacity. I don't really know. All I know is what works for me properly. Q (BY MS. McGRODER) So you would agree with me that there may be a legitimate reasons manufacturers make eye drops larger than 15 microliters? MS. TO: Objection. It's argumentative. It's already been asked and answered. MS. McGRODER: I wasn't even finished with my question. Let me start again. And can you please limit your objections to form or non-speaking objections? Q (BY MS. McGRODER) I'll restate the question, Mr. Raymond. Would you agree with me that there are legitimate reasons why a manufacturer might make an eye drop that's larger Page 143 Page 145 37 (Pages 142 - 145) Veritext National Deposition & Litigation Services 866 299-5127 Case 3:12-cv-01141-SMY-DGW Document 176-48 *SEALED* Filed 12/01/14 Page 38 of 41 Raymond -Filed: 2/27/2014 Page ID #3447 Case: 16-3334 Document:Alan 55-49 02/08/2017 Pages: 41 (1424 of 1511) 1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18 19 20 21 22 23 24 25 1 than 15 microliters? 2 MS. TO: Same objection. Q (BY MS. McGRODER) For example, as you 3 4 said, some people have bigger eyes. 5 A I'm not certain about that. I have 6 no idea. I'm not a scientist or physician. It's 7 just a possibility. 8 Q Will you agree with me some people have larger eyes and some people have smaller eyes; 9 10 right? 11 A I'm sure that's probably the case. 12 Q And if a manufacturer believes that 13 the eye drops need to be large enough to accommodate differences among people's eye sizes, 14 15 for example, people with larger eyes, you would 16 agree that's a legitimate basis for a manufacturer 17 to make an eye drop larger than 15 microliters; 18 correct? 19 MS. TO: Objection. That assumes 20 facts not in evidence. You can answer. 21 A Perhaps for some people, but that's 22 not my experience. Q (BY MS. McGRODER) For example, if a 23 24 manufacturer believes that if you make eye drops 25 too small, it might cause some patients to under A No. Q So really, what you care about in terms of this lawsuit is how the eye drops running down your cheeks has affected you? A And presumably other people like myself. Q But you just don't know whether they exist or not, these other people like yourself? A I don't have evidence, no. Q Would you agree that a manufacturer would not want to make an eye drop that was too small for some people to get the correct dosage? MS. TO: Objection to the extent that's asking for expert testimony. You can answer. MR. SORIANO: And that's a speaking objection. Just for the record, Randy Soriano, I just want to make an objection that, on behalf of my clients, we're going to reserve the right to bring this to the judge. We're in federal court here, and the employer -- plaintiff's lawyer has been asked several times to stop making speaking objections. She's continued to do that over our objections, so I just want to make a record and reserve our rights, bring that up to Judge -- Page 146 1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18 19 20 21 22 23 24 25 dose their eyes, would you agree that's a legitimate basis for the manufacturer to make the size of eye drops that it's currently making? MS. TO: Objection, assumes facts not in evidence. You can answer. A I have never thought very much about anybody else using these and any other problems. I had a problem, and I thought everybody had the same problem, and I still think they do. Q (BY MS. McGRODER) So what have you done to determine whether other people in the United States have the same problem that you have? A I haven't -- I haven't ever made a survey. Q Have you talked to any other, for example, named plaintiffs in this lawsuit to ask them whether they have had the same problem in the same way that you have? A I don't know the plaintiffs in this lawsuit. Q Have you talked to anybody, for example, at your congregation or anybody who are former co-employees about whether they have ever had trouble with eye drops running down their cheeks? Page 148 1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18 19 20 21 22 23 24 25 MS. TO: And I'd like to point out it's not a speaking objection. I am explaining the form of the objection. MR. SORIANO: Anything other than form and foundation under the federal rules is a speaking objection. So thanks. MR. NORDEN: We'll join in that. MS. McGRODER: Again, I would just add, to the extent you have an objection to form, go ahead and make it. And if I want to understand better what the form of the objection problem is, I'll ask. MS. TO: Thanks for telling me how to do my job, but go ahead. Q (BY MS. McGRODER) Mr. Raymond, do you remember the question? A The question was about other people, whether the dose was too small? Is that what you said? Q Yeah. Let me reask it just because we got distracted here. So what I'm asking is if you would agree that it makes sense that a manufacturer might not want to make a drop that's too small so that it might under dose some of the people who are taking that medication and they Page 147 Page 149 38 (Pages 146 - 149) Veritext National Deposition & Litigation Services 866 299-5127 Case 3:12-cv-01141-SMY-DGW Document 176-48 *SEALED* Filed 12/01/14 Page 39 of 41 Raymond -Filed: 2/27/2014 Page ID #3448 Case: 16-3334 Document:Alan 55-49 02/08/2017 Pages: 41 (1425 of 1511) 1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18 19 20 21 22 23 24 25 wouldn't get the proper safe and effective dose. Would you agree that's a legitimate reason a manufacturer might not want to make a smaller dose? MS. TO: Same objection. A That seems highly unlikely to me, because I -- I think that -- I don't -- based on my own experience, my own history. And I -- what the manufacturer thinks is beyond me. Q (BY MS. McGRODER) Okay. So again, for purposes of your involvement in this lawsuit, you're basing it on your own history and your own interest in the dosing for you; correct? A Not exactly, no. Because I feel that this very likely happened to thousands of other people. Q But you don't know that; right? A I can't produce that, no. Q Has anybody ever told you this has happened to thousands of other people? A No. Q Did your doctor ever tell you this has happened to any one of his other patients? A I never asked, no. Q Well, you had a conversation with your doctor about the lawsuit; right? 1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18 19 20 21 22 23 24 25 that if you made a dropper tip that produced a smaller drop, it might not be safe for use with people, would you agree that's a legitimate reason for the manufacturers not to make smaller drops? MS. TO: Same objection. A I believe your question is is the manufacturer's motive to make -- to make a -- make it useful for everybody. You're trying to say even if we overdose some people. And I don't think the manufacturer has that motive. I don't know what the manufacturer's motive was. Q (BY MS. McGRODER) I appreciate your answer, but I don't think it answers my question. So let me try again, okay? A Okay. Q All I want to know is what you think, okay? I'm not asking you to understand what the motive of the manufacturers is, okay? I just want to hear what you think. So do you think that if the manufacturers are concerned about making a tip for the bottle that produces a smaller drop size but it also is more dangerous to consumers, is that a legitimate reason to continue to make drop sizes the way they are made now? Page 150 1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18 19 20 21 22 23 24 25 A Very briefly. Q And he had the opportunity to tell you, "You know what, I have had that problem with other patients"; right? A He had the opportunity. Q And he didn't tell you that, did he? A That's right. Q Is it fair to say you wouldn't want a manufacturer to redesign a bottle if, for technical or other reasons, it wouldn't be safe and effective for dosing to other patients? MS. TO: Same objection. A I cannot imagine how a manufacturer could decide who gets what. I mean, a drop is a drop, and I used to get a lot more than a drop. Q (BY MS. McGRODER) If the manufacturers agree that the current size bottle tips they make are safer than tips that would deliver a smaller dose, would you agree that would be a legitimate reason for making the current size drops these manufacturers make? MS. TO: Same objection. A Say that -- please say that again. Q (BY MS. McGRODER) Sure. Maybe I said it badly. Let's say the manufacturers here agree Page 152 1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18 19 20 21 22 23 24 25 MS. TO: Same objection. A Is that a legitimate reason for them to make the new drops, the new orifice on the top of the bottle? Q (BY MS. McGRODER) Yeah. What I'm saying is is it a legitimate basis to make drop sizes the way they are made if, to the extent they were made smaller, that dropper tip might be dangerous to consumers? Do you think that's a legitimate basis to continue to make droppers, drop sizes, the way they are now? MS. TO: Same objection. A You're asking about policies on part of the manufacturers and -Q (BY MS. McGRODER) I'm just asking for your thoughts. I just want to know what you think about that. MS. TO: Same objection. A I'm certain they want their product to be effective. That's all I can tell you. All I can say. Q (BY MS. McGRODER) And you would agree they want their product not to be dangerous to a consumer; correct? MS. TO: Same objection. Page 151 Page 153 39 (Pages 150 - 153) Veritext National Deposition & Litigation Services 866 299-5127 Case 3:12-cv-01141-SMY-DGW Document 176-48 *SEALED* Filed 12/01/14 Page 40 of 41 Raymond -Filed: 2/27/2014 Page ID #3449 Case: 16-3334 Document:Alan 55-49 02/08/2017 Pages: 41 (1426 of 1511) 1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18 19 20 21 22 23 24 25 A I would hope they would want their product not to be dangerous, yeah. Q (BY MS. McGRODER) Is it true you've never seen an advertisement for Lumigan? A Yes, to the best of my knowledge. Q Is it true you've never seen an advertisement for any one of the products manufactured by any one of these defendants? MS. TO: Just for clarification -MS. McGRODER: Let me restate. Q (BY MS. McGRODER) Is it true that you've never seen an advertisement for any of the eye drop products that you've taken that are manufactured by the defendants in this lawsuit? A Yes, that's true. Q The interrogatories that you looked at and that Mr. Norden went over with you, one of them asked about -- well, in response to one, there is an answer that suggests you've looked up information on the internet for some of these products. Do you remember that? A I remember seeing it on here, but I don't remember the activity of looking them up. Q So is it true you've never looked up any information about any one of the eye drop 1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18 19 20 21 22 23 24 25 A It's a vitamin. Q An oral vitamin? A Specifically for eye problems. Q Okay. And for how long have you been taking that? A About nine months. Q And you have no claims about that product in this lawsuit; correct? A Correct. Q Have your eyes ever watered or teared after applying your eye drops? A No. Q Have you ever had stinging or burning from any of the eye drops you've ever taken? A No. Q Have you ever, when instilling an eye drop, blinked and then the medication came out as a result of blinking? A No. Q Never one time have you blinked when you were putting the eye drop medication in and, therefore, the eye drop product came out of your eye and rolled down your cheek? A No. I told you I prop the eyes like this to make sure I have a big target area. Page 154 1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18 19 20 21 22 23 24 25 products that are manufactured by the defendants in this lawsuit? A To the best of my memory, I don't remember looking them up. Q As you sit here today, you can't think of a time that you ever got on the internet and looked up information about the eye drop products that are involved in the lawsuit; is that correct? A That's right. Q Have you ever received eye drop samples from any of your doctors? A Not that I recall, no. Q I think you testified that you were taking vitamins that were manufactured by Bausch and Lomb? A Yes. Q Can you tell me what kind of vitamins you're taking? A Areds 2. Q How do you spell it? A A-r-e-d-s 2. Q And is that a -- an eye drop product? A No. Q What kind of product is it? Page 156 1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18 19 20 21 22 23 24 25 Q And so you never blink when you do that? A No. Q Have you ever measured whether the drop size in the latanoprost bottle that sits before you now is any different from the drop size of any of the medications that you have taken in the past? A I've never measured them, no. Q You've never measured the size of any drop for product you've ever taken; correct? A I wouldn't know how to measure a drop. Q And therefore, you haven't done it; correct? A Correct. Q You took, for some period of time, a product called Betimol, B-e-t-i-m-o-l? Do you remember that? A No. Q It was prescribed to you by Dr. Berg. Do you have any memory of taking that product? A B-e-t-i-m-o-l. Q Betimol? A No, I don't remember that. Page 155 Page 157 40 (Pages 154 - 157) Veritext National Deposition & Litigation Services 866 299-5127 Case 3:12-cv-01141-SMY-DGW Document 176-48 *SEALED* Filed 12/01/14 Page 41 of 41 Raymond -Filed: 2/27/2014 Page ID #3450 Case: 16-3334 Document:Alan 55-49 02/08/2017 Pages: 41 (1427 of 1511) 1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18 19 20 21 22 23 24 25 Q Do you know whether the Betimol you took had the problem of running down your cheek the way that you claim some of the other products have? A I don't remember that product. Q And so you don't know one way or the other whether Betimol ran down your cheek when you installed the eye drop or not? A That's right, I don't remember. MS. McGRODER: I believe that's all the questions I have. MS. TO: Anything else, guys? Okay. We'll waive signature. THE VIDEOGRAPHER: Going off the record at approximately 2:30 p.m. THE REPORTER: Randy, can you tell me what format you like your transcript in? MR. SORIANO: Yeah. I'll take an E-tran. MS. McGRODER: I think what they've been doing is e-mailing the condensed and the full, I guess. MR. NORDEN: Whatever we got last time if you were doing. MR. PAISLEY: Same here. Same as last time. 1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18 19 20 21 22 23 24 25 CERTIFICATE OF REPORTER I, TARA SCHWAKE, a Registered Professional Reporter and Notary Public within and for the State of Illinois, do hereby certify that the witness whose testimony appears in the foregoing deposition was duly sworn by me; that the testimony of said witness was taken by me to the best of my ability and thereafter reduced to typewriting under my direction; that I am neither counsel for, related to, nor employed by any of the parties to the action in which this deposition was taken, and further that I am not a relative or employee of any attorney or counsel employed by the parties thereto, nor financially or otherwise interested in the outcome of the action. _________________________ Notary Public in and for The State of Illinois Page 158 1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18 19 20 21 22 23 24 25 Page 160 THE REPORTER: And does anybody need a rough draft? MR. SORIANO: Yes. MR. PAISLEY: Yes, please. We ordered one. MS. McGRODER: Yes. MR. NORDEN: Yes. Thank you. MS. TO: We'll have a condensed. And we'll take a rough draft, too. (Wherein, the taking of the instant deposition ceased at 2:30 p.m.) (By agreement between Counsel and with the consent of the witness, the signature is expressly waived.) Page 159 41 (Pages 158 - 160) Veritext National Deposition & Litigation Services 866 299-5127 Case 3:12-cv-01141-SMY-DGW Document 176-23 *SEALED* Filed 12/01/14 Page 1 of 57 Page ID #2734 Case:DAVID 16-3334 Filed: 02/08/2017 DAVID Pages: 57 (1428 of 1511) WALKER 2/182014 Document: 55-50 WALKER 21184014 Pagel 1 UNITED STATES DISTRICT COURT Pege3 1 APPEARANCES 2 SOUTHERN DISTRICT OF ILLINOIS 2 3 EAST ST. LOUIS DIVISION 3 4 x 4 BY - RICHARD S. CORNFELD, ESQ. CHARLENE EIKE, ET AL., ON . • 5 LAW OFFICE OF RICHARD S. CORNFELD 6 BEHALF OF THEMSELVES AND ALL : Cause No. 6 1010 Market Street, Suite 1720 7 OTHERS SIMILARLY SITUATED, : 3:12-CV-01141-DRA- 7 St. Louis, Missouri 63101 : 8 Tel: 314-241 5799 5 8 Plaintiffs, 9 10 vs. r ALLERGAN, INC., ET AL, 11 DGW 9 : Defendants. 12 FOR THE PLAINTIFF: . 13 10 BY - JOHN G. SIMON, ESQ. 11 THE SIMON LAW FIRM, P.C. 12 BOO Market Street, Suite 1700 13 St. Louis, Missouri 63101 Tel: 314-241-2929 14 Videotaped deposition of MERCK, 14 15 By and through its Designated Representative, 15 16 DAVID WALKER 16 FOR THE DEFENDANTS MERCK: 17 Philadelphia, Pennsylvania 17 BY • STEPHEN G. STRAUSS, ESQ. 18 Tuesday, February 18, 2014 18 BY - TIMOTHY J. MASKER, ESQ. 19 9:56 A.M. 19 BRYAN CAVE LLP 20 One Metropolitan Square 20 21 22 23 24 25 Reported by: www.wldwestlithNnomeom S. Arielle Santos MIDWEST LITIGATION SERVICES Phone: 1.600.280.3376 Fhx: 314.644.1334 21 211 North Broadway, Suite 3600 22 St. Louis, Missouri 63102-2750 23 Tel: 314-259-2000 24 E-mail: Sgstrauss@bryancave.com 25 E-mail: Tim.Wasken@bryancave.com MIDWEST LITIGATION SERVICES www.nialwoUltigation.com Phone: 1.800.280.3376 DAVID WALKER 2/18/2014 Fax: 314.644.1334 DAVID WALKER 2/182014 Page 2 1 2 Videotaped deposition of DAVID WALKER, held Pape 1 at the office of: APPEARANCES CONTINUED 2 3 4 3 FOR THE DEFENDANTS ALCON LABORATORIES, INC., ALCOR RESEARCH, 4 LTD., SANDOZ, INC., AND FALCON PHARMACEUTICALS: 5 BY - JULIA R. EMFINCER, ESQ. 6 Reed Smith LLP 6 BY - GREGORY E. OSIFELD, ESQ. 7 2500 One Liberty Place 7 GREENBERG TRAURIG, LLP 1650 Market Street B 77 West Wacker Drive, Suite 2500 9 Philadelphia, Pennsylvania 19103 9 Chicago, Illinois 60601 10 11 12 13 14 10 Tel: 312.456.8400 11 E-mail: Emfingerj@gtlaw.com 12 E-mail: Ostfeidg@gtlaw.com 13 Pursuant to Notice, before B. Arielle Santos, 15 Registered Professional Reporter, Certified Shorthand 16 Reporter, Certified LiveNote Reporter and Notary Public. 17 18 19 20 21 14 FOR DEFENDANTS ALLERGAN AND BAUSCH 6 LOMB, INCORPORATED: 15 BY - DOUGLAS B. MADDOCK, JR., ESQ. 16 SHOOK, HARDY & BACON L.L.P 17 2555 Grand Blvd. 18 Kansas 19 Tel: 816-4/4-6550 20 E-mail: Dmaddock@shb.com City, 21 22 22 23 23 24 24 25 25 miowFsr LITIGATION SERVICES www.midwestlitigation.aron Missouri 64108 Phone: 1.400.200.3376 Fax: 314.644.1334 www.nidweedidgation.com MIDWEST LITIGATION SERVICES Phone: 1.800.2802376 Fax: 314.644.1334 Case 3:12-cv-01141-SMY-DGW Document 176-23 *SEALED* Filed 12/01/14 Page 2 of 57 Page ID #2735 Case:DAVID 16-3334 Document: 55-50 Filed: 02/08/2017DAVID WALKER Pages: (1429 of 1511) 2/1/1/2014 57 WALKER 2/18/2014 Page 7 Page 5 APPEARANCES 1 DOCUMENTS REQUESTED 1 CONTINUED 2 2 PAGE DESCRIPTION FOR DEFENDANTS: 3 HY - AUSTIN C. NORRIS, ESQ. 4 1. Minutes prepared by Dr. William Roberts 84 KIRKLAND & ELLIS LLP 5 2. Copy of submission, January 18, 2000, 84 333 South Hope Street 6 7 Los Angeles, California 90071 7 8 Tel: 213-680-8400 8 E-mail: Austin.norris@kirkland.com 9 4. Records, test that formed the basis for 10 Merck's statement to the FDA on Page 3 4 5 6 9 10 VF referred on MERCK PRASCO 10376 3. Merck, phone conversations with the FDA on 166 June 23rd and July 3, 2003 11 ALSO PRESENT: 11 9692 regarding the number of drops per 12 BY - MARC LEVIN, In-House Counsel, MERCK 12 milliliter of COSOPT 13 MICHAEL E. CILIBERTI, Legal Videographer 13 14 14 15 15 16 16 17 17 18 18 19 19 20 20 21 21 22 22 23 23 24 24 172 25 25 —..„.„....- ,... . www.mIthrestlitIgation.com MIDWEST LITIGATION SERVICES Phone: 1.800.280.3376 Far: 314.644.1334 MIDWEST LITIGATION SERVICES Phone: 1.8002803376 erww.nidereetlltIgation.aem Fax: 314.644,1334 DAVID WALKER 2/18/2.014 DAVID WALKER 2/18/2414 Page 8 Page 6 THE VIDEOGRAPHER: 11 C ONTENTS 2 3 EXAMINATION OF DAVID WALKER BY mR. CORNFELD 4 PAGE 8 2 record. o 2014. 4 9156. We are on Today's date is February 18, i pp This is the videotaped 5 5 6 EXHIBITS 6 deposition of David Walker in the matter 7 (None marked) 7 of Eike versus Allergen, Incorporated, et 46 8 al., Case No. 312-CV-01141. 8 MERCK PRASCO 1 through 15 This deposition is being held 9 MERCK PRASCO 328 through 353 51 9 10 MERCK PRASCO 371 through 431 63 10 at 1650 Market Street, Philadelphia, 63 11 Pennsylvania. 72 12 Arielle Santos. 77 13 Ciliberti. 11 12 MERCK PRASCO 432 through 435 MERCK PRASCO 457 through 458 The reporter's name is My name is Mike I am the certified legal 13 Bates 10376 through 81 14 MERCK PRASCO 1470 through 1474 77 14 videographer, and we are with 15 MERCK PRASCO 10376 through 10381 78 15 Midwest Litigation Services. 16 MERCK PRASCO 9235 through 9258 87 16 17 9259 through 9654 87 17 18 PL 3605 through 3609 94 18 19 MERCK PRASCO 9660 through 9696 157 19 DAVID WALKER, PhD, 770 Sumneytown Pike, West Point, 20 PL 437 173 20 Pennsylvania 19486, Having been duly sworn, Testifies as follows; Would the court reporter please swear in the witness. 21 PRASCO 1 through PRASCO 94 176 21 22 PRASCO 1 through PRASCO 94 178 22 23 PL 001049 199 23 HY MR. CORNFELD: Q 24 PL 1049 through 1056 199 24 25 MERCK PRASCO 100034 through 56 206 25 www.mlOwestlidgatIon.com . . „ . .. MIDWEST LITIGATION SERVICES 1.800.2803376 Phone: Fax: 314.644.1334 EXAMINATION www.midwentlitigation.com Would you state your name MIDWEST LITIGATION SERVICES Phone: 1.800.2803376 Far 314.644.1334 Case 3:12-cv-01141-SMY-DGW Document 176-23 *SEALED* Filed 12/01/14 Page 3 of 57 Page ID #2736 Case:DAVIDWALKER 16-3334 Document: 55-50 Filed: 02/08/2017 DAVID WALKER Pages: 57 (1430 of 1511) 2/1812014 211812014 Page9 1 Pagel! pleaSe, sir. 1 A Yes. Q All right. 2 A David Walker. 2 3 Q And, Mr. Nalkor, what is your 3 So if we just taw "Merck," we 4 business address? 4 will understand that we are referring to the 5 defendant. in this cam., correct? 5 6 A 7 8 770 Sumneytown Pike, West Point, Pennsylvania 19486. Q A Yes. 7 Q How long haw you been employed Sir, whore -- excuse me, by whom are you employed? 9 A Merck. 10 Q All right. 11 12 6 My name is Rick Cornfeld, and I rot:resent the plaintiff. in this 1 i 8 by Merck? 9 A Eleven years. 10 Q What it your current position? 11 A Associate director. 12 Q we were given information from 13 will be asking you question. today in this 13 your attorney indicating that, at least at 14 deposition, and you understand that if at any 14 the time that we were provided that 15 time I -- after I have asked you the question 15 information, which was sometime last year, 16 you don't understand the question or you 16 you were associate director of engineering at Merck, comma, FCC, dash, trip sterile. 17 haven't heard the question or maybe there's 17 18 some issue with the video tranmismion, you 18 19 will let we know and I will repeat the 19 A 20 question for you. 20 Q 21 22 A 23 Q 24 25 is that -- You understand that, don't you? 21 Yes. 22 A 23 cl All right. Thank you. And you understand that this is That is correct. -- your current position? Okay. All right. 24 • deposition where you are appearing as a 25 It that your position? Yes. What does "PCT" mean? A Pharmaceutical ..-„, www.roldwestlhigstion.com MIDWEST LITIGATION SERVICES Phone: 1.800.280.3376 Far: 314.644.1334 MIDWEST LITIGATION SERVICES Phone: 1800280.3376 www.nAdwestlitigatlon.com DAVID WALKER 2/182014 DAVID WALKER 2/18/2010 Page 10 1 corporate designee on behalf of Merck? 3 4 6 And do you understand what that A Yas. Q What do you understand that to moan? 8 9 Yon. Q A That I am to answer questions 10 business and my responsibilities and understanding of our products. 12 Q p And what is "PATO sterile"? 3 A Pharmaceutical packaging 4 technology and development for sterile liquid 5 products. 6 5 7 responsibilities? 9 10 11 And you understand that you are commercialization technology. 2 8 that I understand about the nature of our 11 page 12 1 means to be a corporate designee? 5 7 A 12 In that job what are your A The selection and evaluation of packaging components for new sterile liquid products. You said 'selection" and Q something. I missed that word. 13 testifying not just to what you know 13 A Evaluation. 14 personally but to what your cowpony Merck 14 0 Selection and evaluation of 15 know. and what your company has done? 16 17 A As best I understand those issues. 18 Q All right. And sir, you have 19 used the tern "Merck.. 20 have two entities that go by the nowt In this lawsuit we 15 packaging components for new sterile liquid 16 products? 17 A Yes. 18 Q Is that right? 19 A 20 0 products? 21 "Merck.; one of them is Merck 6 Company, 21 22 Inc., and the other is Merck Sharp 6 Dohme 22 23 Corp. 24 25 Do you use that term "Merck. just to refer to those companies? wwwiradwestlitigationcem MIDWEST LITIGATION SERVICES Phone: 1.800.2803376 Fax: 314.644.1334 Fax: 314.6441334 (Nodding Head.) What are sterile liquid A So these would be products that 23 would be injected as their route of 24 administration. 25 They may be inhalation products. www.midwest/Egadonkom They may be nasal products. They may be MIDWEST LITIGATION SERVICES Phone: 1.800.280.3376 Fax: 314.644.1334 Case 3:12-cv-01141-SMY-DGW Document 176-23 *SEALED* Filed 12/01/14 Page 4 of 57 Page ID #2737 Case:DAVID 16-3334 Document: 55-50 Filed: 02/08/2017DAVID WALKER Pages: (1431 of 1511) 2/18/2014 57 WALKER 2/1/12014 Page 15 Page 13 Merck would produce a corporate ophthalmic products. Any product that's 2 representative to testify about the drop sire You said -- 3 from the packaging and container closure for They may be ophthalmic 4 the prescription dorsolamide Any products that require that 6 they be sterile when they are administered to 7 required -Q 3 A 4 hydrochloride -timolol maleate drug. products. patients. 8 9 10 Q Row long have you had this job? A At Merck or the position of associate director? 11 12 Q The position you have today. 13 A Three years. I'm sorry, that was 14 three years? 15 A 16 17 18 A 22 Yes. Q And we were also told that 10 nevelt would produce • corporate 11 representative to testify about the MDA 12 submissions and correspondence relating to 13 drop site from the packaging and container 14 closure system for the prescription drug 15 dorsolamide hydrochloride -timolol Imamate. Is that an area where you are 16 17 18 A Yes; aspects of that. I was a research fellow in the 19 • And I know we have a witness For how long did you have that 21 A 9 And before that, what was your same area. 20 8 Yes. job? 19 Is that an area where you are prepared to testify? prepared to testify? 20 scheduled for tomorrow; that's Scott 21 Grossman. Do you have en understanding as 22 position? to where -- the area where you would be 23 A Eight years. 23 24 Q So that takes um back to when 24 prepared to testify ends and where he would 25 be prepared to testify begins? 25 you were first hired at Merck in -- around wwwaddwesdidEadm.mm MIDWEST LITIGATION SERVICES Phone, 1100.280.3376 Far 314.641.1334 wwwakhadadvdmume MIDWEST LITIGATION SERVICES Phone: 1400.280.3376 DAVID WALKER 2/1812014 DAVID WALKER 728/2014 Page 16 Fage14 A 2003? Yes. 2 A Yes. 2 Can you explain that? Mt. Walker, have -- by the way, 3 Well, portions of the NDA 3 Q 4 5 4 pertaining to packaging design, I can testify It works with me. 5 towards. Portions concerning clinical Okay. 6 efficacy, CMC sections, I could not testify Mr. Walker, have you seen the 7 to those portions. is it "Mr. Walker"? A Q 7 deposition notice that was served on morels in 9 9 this case? 10 Q What ars CMC sections? A Chemistry, manufacturing and control. 10 A Yes. 11 Q All right. 11 ▪ what is that? And you reviewed that? 12 A That is more about the 13 synthesis and the formulation of the drug 14 product. And there's the API. There's the 12 13 A Yes. 14 Q We received a letter from your 15 attorney saying that merck would produce 15 drug substance that's formulated into a drug 16 witnesses to testify about different aspects 16 product. The manufacturing is all the 17 within that notice or pertaining to that 17 manufacturing equipment and validation used 18 notice. One was the design and specification 18 to support that we have good manufacturing of the packaging and container closure system 19 practices for making an approved drug for the prescription drug doraolamide 20 product. And, Of course, the controls that hydrochloride-cimolol maleate. 21 maintain those good manufacturing practices. 19 20 21 23 24 25 22 Is that en area where you are 22 23 prepared to testify? A Q www.midwestlidgadonsom Q You used a term "API"; did I understand that correctly? Yes. 24 A Yes. we -- we were also told that 25 Q What is "API"? MIDWEST LITIGATION SERVICES Phone: 1.800.280.3376 Fax: 314,644.1334 Fax: 314.644.1334 www.uildwestlidgation.cem MIDWEST LITIGATION SERVICES Phone: 1800.280.3376 Fax: 314.644.1334 Case 3:12-cv-01141-SMY-DGW Document 176-23 *SEALED* Filed 12/01/14 Page 5 of 57 Page ID #2738 Case:DAVID 16-3334 Document: 55-50 Filed: 02/08/2017 Pages: 57 (1432 of 1511) WALKER 2 8/2014 /1 DAVID WALKER 1118/2014 Page 17 A 2 Page 19 Active pharmaceutical 1 deal with generic COSOPT. When I have worked 2 with this formulation, we have referred to it Mr. Walker, before we go 3 as "COSOPT." ingredient. 3 Q 9 further, as you know we will be talking about 4 5 • drug that goos by the generic name 5 dorsolaside hydrochloride-timo101 =sleets. 7 Q Okay. So we will call it that. We will accept Mr. Strays's suggestion and call I would imagine the court 7 it "generic COSOPT." 9 he just made, when I referred to the product reporter would appreciate it if during a 9 10 11 Rut does Merck use a shorter term when it refers to that product? 12 13 In light of the objection that break you give her the yelling. MR. STRAUSS: Objection to the form of the question. 14 10 going by the generic nay dorsolamide 11 hydrochloride-timolol maleate, what wee 12 incorrect about what I said, if anything? 13 Go ahead. 14 15 THE WITNESS: We had marketed a 15 16 product with those ingredients as COSOPT. 16 17 BY MR. CORNFELD. 18 Q 19 A That was the brand name COSOPT? Yes. 20 All right. MR. STRAUSS: Are you asking me7 MR. CORNFELD: No, I'm asking the wit ness. 17 MR. STRAUSS: Oh, I withdraw my 18 objection. 1 was trying to help you, but 19 the word -- I only objected because of 20 your use of the word "generic," which has 21 Did I -- we have a little bit 21 a different context, because in this 22 of a time lag here, as I'm sure you noticed. 22 particular case we have a drug sold by 23 24 25 A Did I interrupt your anyer? 23 Fresco, and when Merck sells the exaCt We marketed that product as 24 same product, it's called COSOPT, and 25 when Prasco sells it, it's generic COSOPT COSOPT. MIDWEST LITIGATION SERVICES Phone: 1.000.2803376 wwwnildwastlidgadon-com Fan 314.644.1334 www.nddresditigadon.com MIDWEST LITIGATION SERVICES Phone: 1.800.280.3376 DAVID WALKER 2/18/2014 DAVID WALKER 2/180014 Page 18 Page 20 MR. STRAUSS: You didn't 3 4 but it has a longer name. answer. x mean, I objected InCem2cupG 2 You can call it "COSOPT," and only because you said, Rick, that it was 3 we all know what you are talking about. a generic -- it was the generic name of 4 So I withdraw my objection. 6 Thanks. it. It's not the generic name of it. 6 1.22,. CORNFM,D, Hut for purposes of the deposition, to make it easier, we are 7 BY MR. CORNFELD: 9 You'd do just to make the record ae clear as fine if you refer to the product sold to 9 I think what -- what maybe we Plaintiff Fisher as generic COSOPT. So 10 you can pick how you want to call it, but 10 11 we -- we agree you don't have to say the 11 name product sold by -- by Merck, if we use 12 long chemical descriptive name every time 12 the term "COSOPT," and if we talk about the 13 you talk about it. 13 product that Merck sold to Prase° and that 14 15 MR. CORNFELD: I was trying to come up with some Shorthand way. 16 BY MR. CORNFELD: 17 Q 18 19 Lot no just ask you again, Mr. possible, if we are talking about the brand 14 Pryco then re -cold, if we talk about 15 "generic COSOPT," would that be agreeable, 16 mr. walker? 17 Walker. Maybe "generic COSOPT" would be an appropriate term. 20 When you refer to -- within the And do you understand that? 18 A Yes. 19 Q Also, Mr. Walker, at times I 20 might aide you • question that you don't know 21 company, when you refer to dorrolamide 21 the answer to and it would be within the 22 hydrochloride-timolol maleate, do you use the 22 responsibility of tomorrow's witness and if 23 that's the case, it's only because I may not 23 24 25 tern "generic COSOPT"? A That term doesn't come up normally in my discussions because I don't grun.mktwestlidgation.00m MIDWEST LITIGATION SERVICES Phone: 1.800.280.3376 Fax: 314.644.1334 Fax: 314.644.1334 24 understand where one area ends and another 25 begins, even though you did explain it to en. www.m1drestlidgadonrom MIDWEST LITIGATION SERVICES Phone: 1.800.280.3376 Fax: 314.644.1334 Case 3:12-cv-01141-SMY-DGW Document 176-23 *SEALED* Filed 12/01/14 Page 6 of 57 Page ID #2739 Case: 16-3334 Document: 55-50 Filed: 02/08/2017DAVID WALKER Pages: 57 (1433 of 1511) 21180014 2/180014 DAVID WALKER Page23 Page 2l 2 you don't have knowledge and you expect that 3 Groesean does have knowledge, would you Mr. Grossman All right. Q 6 There was an examination of how studies. Yes. A cost of the medications in some of these 2 let am know? 4 5 There were comparisons of the 1 But if I do ask a question and 1 4 many drops each bottle could dispense for the 5 various brands of medication, and there were 6 tables of the volume of drops administered from these different medications in different packages. 7 In preparation for this 7 8 deposition today, what did you review? 8 Did the Studio. deal with Merck I reviewed some published 9 Q 10 articles, some patents pertaining to the 10 products? 11 design as the Ocumeter Plus package and 11 A Yes. 12 portions of the prior approval Supplement 12 Q Did they all? 13 pertaining to -- 13 A I think so, yes. 14 4 Which Nerck product.? 15 A There were more than one. A 9 14 The prior -- I'm sorry, go Q ahead. 15 A 16 17 Right. 16 There was COSOPT, timolol, TIMOPTIC, Portions of the prior approval 17 TIMOPTIC -XS. 18 supplement pertaining to the marketing of 18 19 COSOPT in the Ocumeter Plus package. 19 What published article. did you Q 20 review? 21 I don't recall the titles or A 22 They were provided as TROSOPT. Q Did you mention TROSOPT? 20 A Yea. 21 0 Did they deal with TROSOPT? 22 A Yes. 23 Q You said you reviewed patents? 23 the specific authors. 24 part of the materials that you shared with my 24 A Yes. employer's attorneys. 25 0 Row many patents did you -- how 25 www.mldwestlItirdion.rom MIDWEST LITIGATION SERVICES Phone: 1.800.280.3376 Fax: 314.644.1334 www.mIdwestUdgstion.rom MIDWEST LITIGATION SERVICES Phone: 1.800.280.3376 DAVID WALKER 2/18/2014 DAVID WALKER 2/18/2014 Page 2A Pmr22 1 Q 2 A 4 5 There were six that I reviewed. 2 A Four. 3 0 whet were those patents on? 4 A They were pertaining to design Yes. 8 medications. 12 13 Do you recall the authors of Did you bring anything with you to the deposition? 8 A I did not, other than a phone. 9 0 You don't have -- I's sorry, other than -- I don't recall the authors' 11 A A phone. Some of them may sound familiar if 12 Q Okay. A names. Q 7 10 those studies? 11 features for the Ocumeter Plus package. 6 Some of cost of ophthalmic medications. these dealt with the use of ophthalmic Q 5 Some of these dealt with 7 9 many patents did you review? . - - ,a. - e.33 -- -e.e ern 6 10 1 Row wany articles were there? subject was? A Q 15 reported? SO you did net bring those 13 they were repeated. 14 14 Can you recall what the studies patents? 15 A I did not. 16 0 Why did you review the patents? A Because they pertain to the 16 A Portions, yes. 17 Q Tell see what you recall. 17 A I recall there being a high 18 Ocumeter Plus package that the brand -- 18 19 degree of variability of how patients use 19 sorry, the generic form of COSOPT is marketed 20 ophthalmic medications, how they use their 20 in. 21 ophthalmic delivery systems, the number of 21 22 drops they administer, where they administer 22 23 the drops, that at times they touche their 23 24 eye with the dropper tip, that at times they 24 25 don't get the medication in their eye. 25 www.wIdemllithmtlenrom MIDWESTLITIGATIONSERVICFS Phone: 1900.2803376 Fsx: 314.644.1334 MR. CORNFELD: Steve, Merck has not produced any patents to us. MR. STRAUSS: Yeah, and they are publicly available. The patents on the Ocumeter MIDWEST LITIGATION SERVICES Fax: 314.644.1334 wwwaddweaRtIgadonsom Phone: 1.800.280.3376 Fax: 314.644.1334 Case 3:12-cv-01141-SMY-DGW Document 176-23 *SEALED* Filed 12/01/14 Page 7 of 57 Page ID #2740 Case: 16-3334 Document: 55-50 Filed: 02/08/2017 Pages: 57 (1434 of 1511) DAVID WALKER 2/16/2014 DAVID WALKER 2.98/2014 Page 25 Page 27 Plus bottle? 2 how the bottle is designed so that it doesn't MR. CORNFELD: The patents that 3 the witness said he reviewed. 4 2 roll, how the bottle is translucent so 3 patients can see their medication in -- MR. STRAUSS: Right. They are 5 4 within the bottle, how the bottle avoids 5 streaming of medication because it cannot be Do you want a copy of them? 6 forcefully squeezed in a manner that many MR. CORNFELD: We requested 7 publicly available patents. them. You objected. 9 MR. STRAUSS: Well, I don't 10 11 of the patents I will be glad to give them to you. 13 15 MR. STRAUSS: Sure. (Whereupon a Discussion is Held 17 Off the Record.) 22 Nt. Walker, did you talk to A I spoke with attorneys involved in this litigation. 23 Q to be flexed so a controlled amount is administered with each use. Q You said that the Ocumeter Plus 14 controls how drops are administered and 15 controlled, but I may have missed a word you 16 said. 18 anybody in preparation for this deposition/ 21 11 12 17 BY MR. CORNFELD: 19 thin segment on one part of the bottle wall and that is the only portion that's designed 13 them here? 16 20 10 MR. CORNFELD: Can you e-mail 14 18 9 agree with that. But if you want a copy 12 Other ophthalmic bottles can be squeezed but rather it has a very small, or I should say a A So the Ocumeter Plus bottle cannot be squeezed like many ophthalmic 19 bottles. Many ophthalmic bottles can be 20 deflected significantly. If more force is 21 applied, they collapse more and drops are 22 administered more rapidly from them. Did you speak to anybody else 23 24 other than attorney, in preparation for this 24 there is a portion of the sidewall that is 25 deposition? 25 thinner than the rest of the bottle and only www.midwestlitligation.corn MIDWEST LITIGATION SERVICES Phone: 1.800.2803376 Fax: 314.644.1334 With the Ocumeter Plus bottle, www.midwestlitigationoom DAVID WALKER 2/182014 MIDWEST LITIGATION SERVICES Phone: 1.800.280.3376 DAVID WALKER 2/18/2014 Page 26 A 3 4 6 Q mho was that? Art Lifshey. Q Can you say that again? A Art LifsheY. Q Row do you spell his name, the that portion is designed to be deflected when 2 4 7 A L 1 , F S H E Y. Q Did you speak to anyone else 11 A No. 12 Q All right. A He's the inventor of the 13 15 Ocumeter Plus package. 17 18 19 Q About the design features of A No. Q Wee he employed by morck when 11 he invented the Ocumeter -- the Ocuneter 12 Plus? 13 A Two. 14 Q All right. Where is he today? A He resides in New Jersey, but I do not know specifically where he is. 18 Q Is he employed by someone else? 19 A I don't know. What did he tell you? 20 Q When did he leave Merck? Several things; about how the 21 A Approximately eight years ago. 9 Did he leave to take other 22 package operates, how the cap opens, the 23 dropper tip that's hermetically sealed and is 24 then punctured so that drops are administered 25 in a controlled manner and can be re-closed, www.mldweetAtigatennom Mr. Lifahey; is he still 10 16 the Ocumeter Plus package. A Q 9 17 20 21 That's the design intent. lb What did you speak to him about? A A employed by Merck? Who in Art Lifshey? 16 from the bottle with each use. One drop, correct? other than Mr. LifiGney and attorneys? 14 patients press on it and therefore only a limited amount of medication is dispensed last nano? 10 Pagan Yes. A MIDWEST LITIGATION SERVICES Phone: 1800.280.3376 Fax: 314.644.1334 22 23 Fax: 314.644.1334 employment? 24 A I think he retired. 25 Q Do you know what city in New www.midwestUthetionnom MIDWEST LITIGATION SERVICES Phone: 1.800280.3376 Fax: 314.644.1334 Case 3:12-cv-01141-SMY-DGW Document 176-23 *SEALED* Filed 12/01/14 Page 8 of 57 Page ID #2741 Case: 16-3334 Document: 55-50 Filed: 02/08/2017DAVID WALKER Pages: (1435 of 1511) 2/18/2014 57 DAVID WALKER 2/182014 Page 31 Pegs 29 at least I underatood from something that you Jeremy he's in? 2 3 A I CIO not. 2 said earlier that you no longer hese Q I assume that you have contact 3 responsibility for generic COSOPT or for 4 COSOPT? information for him if we ask for that? 4 A Yeah. I no longer -- information on him, so we can -- you Q You no longer -- all right. know, we can talk about it later. Yep. A I no longer have involvement. Q Did you at one time? 9 A No. 10 Q MR. STRAUSS: I have 5 7 MR. CORNFELD: Okay. BY MR. CORNFELD: 9 Did you take any notes in your Q 10 12 13 A Yes. Q Okay. All right. You never had involvement with 11 conversation with Mr. Lifshey? 11 either COSOPT or generic COSOPT? 12 MR. STRAUSS: Object to the 13 form of the question. 14 Do you have those notes? 14 15 MR. STRAUSS: I object to any 15 THE WITNESS: I never had involvement. The product was developed 16 notes or other information related to the 16 17 conversation with Mr. Lifshey since 17 18 counsel was a participant in the 18 19 conversation, but I am letting him answer 19 20 factually about what he talked about with 20 21 Mr. Lifshey. 21 A Yes. 22 O Both or just one? A I am unsure, but I think it's portions of the call are not -- 22 and launched prior to my joining Merck. EY MR. coRNFELO: Does Merck Q Still manufacture either COSOPT or generic COSOPT? 23 are protected by the attorney-client 23 24 privilege, but you can continue to answer 24 both. There's limited branded COSOPT and 25 your questions. That's my objection. 25 then we manufacture the generic form marketed wwstadwadMaskatam MIDWEST LITIGATION SERVICES Phone: 1.800.280.3376 Far: 314.644.1334 wwwwMwistUdgatleamw MIDWEST LITIGATION SERVICES Phone: 1.800.280.3376 DAVID WALKER 2/18/2014 DAVID WALKER 211/1/2014 Page 32 Page 30 by Prasco. THE WITNESS: Sorry, could you 2 3 4 5 7 9 11 3 5 A Not here today. 6 Q But you do have them, correct? 7 A Yes. 8 All right. 9 Q 11 personally? 12 A Yes. 12 13 Q All right. 13 I would ask that you maintain 14 Is Fresco still marketing COSOPT? MR. STRAUSS: Object to the form and foundation. THE WITNESS: I am uncertain. My understanding is they are marketing generic COSOPT. BY MR. CORNFELD: Q 10 And those are note. you took 14 generic 4 Do you have your notes from your conversation with Rt. Lifshey? 10 Q 2 repeat the question. BY MR. coRNFELo, • Is Merck still marketing branded COSOPT? MR. STRAUSS: Object to the form and foundation. THE WITNESS: I believe we sell some branded COSOPT. 15 those notes. I understand counsel's 15 16 objection. But I would ask that you not to 16 destroy those notes while this litigation is 17 Q going on. 18 A I don't know. Q I saw new. items indicating 17 18 19 20 A 21 All right? 20 that a company named Acorn had purchamsd MR. STRAUSs: I agree with him 21 COSOPT from Derck. 22 23 No big deal. 23 swwtoldwaMdsahnesan 25 Mt. Walker, you said that MIDWEST LITIGATION SERVICES Phone: 1800.280.3376 Are you familiar with that at all? MR. STRAUSS: Objection to the 24 BY MR. CORNFELD: Q To whom do you sell it? (Nodding Head). Yes. 22 25 BY MR. CORNFELD: 19 on that. So just, you know, keep them. 24 Fat: 314.644.1334 form and foundation. MIDWEST LITIGATION SERVICES Far: 314.644.1334 wwwaddwardidgedmumm Phone: 1.800.280.3376 Fee: 314.644.1334 Case 3:12-cv-01141-SMY-DGW Document 176-23 *SEALED* Filed 12/01/14 Page 9 of 57 Page ID #2742 Case: 16-3334 Document: 55-50 Filed: 02/08/2017 Pages: 57 (1436 of 1511) 2/18/2014 2/1812014 DAVID WALKER DAVID WALKER Page 33 THE WITNESS: Page 35 I have heard, form and foundation. 2 yes, that Acorn bought our ophthalmic 2 3 products, yes. 3 a lot about our ophthalmic's business. I 4 am not involved in the ophthalmic's 6 development. So that's why you're 7 getting a lot of uncertainty about these 9 arrangements. 4 BY MR. CORNFELD: And what do you understand Q 6 business. I am involved in packaging about that relationship and that transaction? A I have very little understanding of it. 9 10 Q questions -- about the business In Merck manufacturing COSOPT for Acorn? 10 11 A I do not know. 11 12 Q Do you understand when COSOPT 12 13 wan introduced? 14 15 A 17 I do not know the exact date that it was introduced. 16 Q Around 1998; does that sound A Yes. 20 Q Doe. Merck have an ophthalmic business today, to your knowledge? 13 A Yes. 14 Q What ophthalmic product, doe. 15 Merck have today? 17 18 BY MR. CORNFELD: 16 right? 19 THE WITNESS: You're asking me MR. STRAUSS: Object to the form and foundation. 18 All right. 19 Did Merek apply to the FDA for THE WITNESS: We have saflutan in a unit dose preservative-free product. 20 And we have a combination product of 21 approval of COSOPT in 1997, and it was 21 saflutan with one of the components of 22 approved in April of 1998? 22 COSOPT, again, in a unit dose 23 A That sounds right. 23 preservative-free format. And we have a 24 Q Other than -- other than 24 unit dose preservative-free format of 25 COSOPT for Japan in development. 25 COSOPT, Merck, at leant in the past, had MIDWEST LITIGATION SERVICES Phone: 1.800.280.3376 www.mIdweatIlligatIon.com DAVID WALKER Fax: 314.644.1334 MIDWEST LITIGATION SERVICES Phone: 1.800280.3376 wee 2/18/2014 DAVID WALKER 2/182014 Page 34 other product. we have talked about or that 2 you mentioned. There was TIMOPTIC and TRUSOPT, 4 correct? A All right. 7 8 9 TIMOPTIC was. approved way back time. 2 Q 3 A Saflutan. 4 Q Yes. A SAFLUTAN. That's the MR. STRAUSS: Objection to the 13 Q What in the branded name? A Zioptan, Z-I-O-P-T-A N. Q Are you !hone sold in the 11 12 THE WITNESS: I am not sure 13 when that product was introduced. 15 BY MR. CORNFELD: 16 Q generic name. 7 10 form and foundation. Can you spell "saflutan"? 8 9 Does that bound right? 11 14 BY MR. CORNFELD: 6 in the late 1970, and introduced at that 10 12 Page 36 1 Yes. 6 United Staten? A Yes, Zioptan is sold in the United States. Q 14 All right. Does -- does Merck have an 15 ophthalmic product today that's acid in Generic versions came out in 16 multi-use bottles? Does that sound right? 18 19 MR. STRAUSS: Same objection. 19 20 THE WITNESS: Yes. 17 the mid-1990e. 18 17 21 BY MR. CORNFELD: 22 Q 23 pharmaceutical company a few years ago, 24 TIIPTIC was, correct? 25 www.midwestlitigeden.com 20 22 MR. STRAUSS: Object to the MIDWEST LITIGATION SERVICES Phone: 1800.2803376 A MR. STRAUSS: Objection to the form and the foundation . THE WITNESS: I don't know all the products that are still sold in the 23 Ocumeter Plus. I do know we are still 24 filling Ocumeter Plus bottles. 25 Fax/ 314.644.1334 Yes. What products doe, it have? 21 And it was sold to another Fax: 314.644.1334 BY MR. CORNFELD: www.midwestlItIgabon.mm MIDWEST LITIGATION SERVICES Phone: 1.800180.3376 Fax: 314.644.1334 Case 3:12-cv-01141-SMY-DGW Document 176-23 *SEALED* Filed 12/01/14 Page 10 of 57 Page ID #2743 Case:DAVID 16-3334 Document: 55-50 Filed: 02/08/2017DAVID WALKER Pages: (1437 of 1511) 228/2014 57 WALKER 2/182014 Page 39 Page 37 2 3 Plus bottles for Pram207 1 What -- what product. are you Q 1 aware that I4.rck has in OCumeter Plus 2 A Yes. bottle.? 3 Q How long has HUMID been manufacturing the Odometer Plus bottle*? 4 A I think COSOPT is one of them. 4 5 Q Any others? 5 A I am unsure. A I do not know. 6 Q I. there a time when somebody Q Do you know if Merck in still 7 7 selling TRUSOPT in Odometer Plus bottles? 8 9 10 A I don't know. Q Were you involved in the 11 gathering and production of document. in this 12 ca..? oda. manufactured the Odometer Plus bottles? 8 A Yes. 9 Q Who was that? 10 A Betts, B-E-T-T-S. 11 Q Where did they manufacture those bottles? 12 13 A No. 13 14 Q Are you familiar with what was 14 A I don't know. Q Approximately when was the manufacturer transferred from Setts to Reseam? 15 done with respect to the gathering and 15 16 production of documents in this case? 16 A I don't know. No. 17 Q Is that becalm. ROL= bought You have no knowledge about 18 19 A That's not my understanding. 20 Q What is your understanding? 21 A I think we chose a second A 17 Q 18 that? 19 I don't know how the documents A 20 21 were obtained. Do you know anything about that Q 22 prods..? 23 Betts? 22 supplier of the bottles; maybe someone more 23 local to the manufacturing site in Mirabel. 24 A No. That process is new to me. 24 25 Q Do you know what documents were 25 MIDWEST LITIGATION SERVICES Phonot1.300.280.3376 www.mldwesaltamtleerom Fax: 314.644.1334 we have been provided with a Q supply and distribution agreement between wee. nidwestiftigedemeom MIDWEST LITIGATION SERVICES Phone: L800.280.3376 DAVID WALKER 2/18/2014 DAVID WALKER 2/182014 Page 40 Page 35 merck and Prance. looked for? 3 Q Where was -- where was COSOPT manufactured? 8 A Mirabel, France. 9 Q That's M-I-R-A-S-S-L, is that 10 12 15 Q Have you ever seen it? 6 A No. 7 Q Do you have any understanding 9 A No. Q Do you have an understanding Yes. 11 that under the agreement Prance was to buy, Q Where were the Odometer Plus 12 distribute and sell its requirements for 13 generic COSOPT from Merck? A Rex., 15 form of the question. Lack of foundation. Q Where was that done? 16 A France. 17 Do you know when COSOPT lost 18 20 Q MR. STRAUSS: Object to the 14 They were manufactured by 17 19 of the tem. of that agreement? 10 16 18 I'm not familiar with the agreement. A bottles manufactured? 14 A 5 8 right? 11 13 4 THE WITNESS: No. BY MR. CORNFELD: 6 7 3 answered. 4 5 Are you familiar with that? 2 MR. STRAUSS: Asked and 2 its exclusivity and generic COSOPT came on 19 the market? 20 THE WITNESS: Sorry. Repeat the question, please. BY MR. CORNFELD: Q Do you have an understanding 21 A No. 21 that under the agreement with merck, Prase* 22 Q Did Merck manufacture the 22 was to buy, distribute and sell it, 23 requirements for generic COSOPT from Merck? 23 generic version of COSOPT for Prance? 24 A Yes. 24 25 Q Did Merck supply the Ocuarater 25 wwwaddwarMigedonerm Fax: 314.644.1334 MIDWEST LITIGATION SERVICES Phone: 1100.280.3376 Fax:314.6441334 A That Makes sense to me. I mean, I haven't seen the agreement, but I www.midwestlitiptheicom MIDWEST LITIGATION SERVICES Phone: 1.800.200.3376 Fax: 314.644.1334 Case 3:12-cv-01141-SMY-DGW Document 176-23 *SEALED* Filed 12/01/14 Page 11 of 57 Page ID #2744 Case: 16-3334 Document: 55-50 Filed: 02/08/2017 Pages: 57 (1438 of 1511) DAVID WALKER 2/18/2014 DAVID WALKER 2/18/2014 Page 41 Page 43 understand Prasco is selling COSOPT that 2 Merck fills. 3 2 O 4 6 7 You mean the specifications for All right. 3 Generic COSOPT? 4 A Correct. Q Prance doesn't sell COSOPT under the brand nano the medicine, Rick, or for the container? MR. CORNFELD, I am referring to the specifications that were produced to us. 6 COSOPT, is that right? MR. STRAUSS: Well, 7 A Correct. 9 Q It never did, correct? 10 A Correct. 10 11 Q Under the agreement with 11 ^specifications'. is vague. MR. CORNFELD: Go ahead, sir. 9 THE WITNESS: I have not seen the specifications. BY MR. CORNFELD: 12 Preens, is it your underntanding that Merck 12 13 had the responeibility to maintain the NDA 13 the manufacturer of generic COSOPT after 14 for COSOPT? 14 Prance started calling it compared to when it 15 was sold an the branded COSOPT by Merck? 15 16 MR. STRAUSS: Objection to the foundation. 17 THE WITNESS: I don't know that Q Were there any difference. in 16 A I don't know. 17 0 Are you aware of any 18 that's the case. That would make sense 18 19 to me. 19 A No. 20 BY MR. CORNFELD: 20 Q -- other than the -- other 21 Q Nee there a new NDA or ANDA Cr 21 22 supplemental ADA that was submitted in 22 23 connection with the agreement between 23 24 and Prance for COSOPT? 25 Merck differences than, of course, the name on the bottle? I 24 MR. STRAUSS: Object to the 25 I'm not -- Q -- Sold it an COSOPT Phase: 1-800.280.3376 Fax: 314.644.1334 go ahead. MIDWEST LITIGATION SERVICES wwwaddwwW8ti0ationAmm mean, Merck -- A wwweedwesdhigadon.cum DAVID WALKER 2/18/2014 MIDWEST LITIGATION SERVICES Phone: 1.800.280.3376 DAVID WALKER 2/18/2014 Page 42 Page 44 foundation. A 2 THE WITNESS: I don't know the 2 3 particulars of that. Regarding RDA's, I 3 4 think the witness scheduled for tomorrow 4 6 questions. would be better able to answer those 7 Mr. Grose an? A Yes. 10 Q You do understand Fresco sold The -, So Reams and before Mean -10 generic COSOPT in the same °coaster Plus 11 12 13 COSOPT in, correct? Are you familiar with the specifications for 17 generic 19 MR. STRAUSS: Object to the You've 25 MR. STRAUSS: Object to the form. MIDWEST LITIGATION SERVICES Phone: 1.800.280.3376 Fax: 314.644.1334 Since the Ocumeter Plus was 15 changes that were made in it? 16 A No. 17 Q And there was just one Ocumeter 21 specification.? wire.midwestlitigationrom Q first introduced, ars you aware of any 20 never seen the The bottle and tip are one item 14 18 BY MR. CORNFELD: 24 A in the Ocumeter Plus design. PIA, 19 THE WITNESS: No. 22 23 and branded -- and form. 20 21 COSOPT COSOPT? 18 I'm sorry, go ahead. 13 Yes. 15 The dropper tip is part of the 8 bottle that Merck had been selling branded 16 A bottle. There is no separate dropper tip. 12 A Did Netts and then Reran 7 11 14 Q manufacture the dropper tips on the °counter Plus? BY MR. CORNFELD: 8 I am not aware of any differences. 6 9 Fox: 319.644.1334 It didn't vary by where Merck sold it or by product, correct? A It did not vary with geography. 22 There were different -- there were different 23 formats of the bottle. There were designs 24 that allowed a smaller volume of fill with 25 the bottle. So there were different design www.mIdweatlithpaloo.com MIDWEST LITIGATION SERVICES Phone: 1.800.280.3376 Fax: 314.644.1334 Case 3:12-cv-01141-SMY-DGW Document 176-23 *SEALED* Filed 12/01/14 Page 12 of 57 Page ID #2745 2/182014 57 Case:DAVID 16-3334 Document: 55-50 Filed: 02/08/2017DAVID WALKER Pages: (1439 of 1511) WALKER 2/18/2014 Page 47 ' Page45 1 plugs for the bottle that went into the 1 a one and then the last page is the same 2 bottom of the bottle. 2 except for after the bunch of ...roes, there 3Q All right. 3 is a 15, correct? 4 Other than those different 4 A Correct. Q All tight. 5 design plugs that went into the bottom of the 5 6 bottle, were there any differences in the 6 7 variOul Ocumeter Plus bottles that Merck 7 cumbersome of a record, what I will do in 8 sold? 8 referring to documents by Rates number is I 9 will refer to -- I will ignore the zeroes. That's why we called it No. A 9 11 The abbreviation was "OWI," Q correct? 12 14 just call this MERCK PRASCO 1 through MERCK 12 PRASCO 15. All right? 13 Pra.co simply bought the 14 A Yes. 10-milliliter sire, correct? 15 Q You will understand what I Q 15 11 Yes. A 13 16 A I don't know. 16 17 Q You don't know if Fresco bought 17 A (Nodding Head). 18 0 Okay. more than one sine of the Ocumeter Plus? 18 19 20 I will ignore the reference to NDA, and I will 10 the Ophthalmi c Worldwide Image. 10 Just so we don't have too mean? Are you familiar with this A I don't know. 19 Q You told me that if I wanted to 20 document? 21 ask about clinical studies on COSOPT, I 21 A No. 22 should ask Mr. Grossman -- 22 Q You have never seen it before? 23 24 A Yea. 23 A I have never seen it before. Q -- is that right? 24 Q Can you take a look at it and www.reldwestlitigallertrom 25 Objection to the MR. STRAUSS: 25 MIDWESTLITIGAT1ONSERVICES Phone: 1.800.280.3376 Fox 314.644.1334 tell me if you ..e familiar with this type of www.vdderestlItigation.cem MIDWEST LITIGATION SERVICES Phone: 1.800.2803376 Page 48 Page 46 form. MR. CORNFELD: 2 Arielle, can you 1 document? 2 A (Reviewing.) I haven't seen something like 3 3 get out of the box of documents, it 4 should be the first folder, the 4 5 document -• 5 0 6 A I have not. 7 0 Maybe you can still help me Actually, Tim MR. STRAUSS: 6 He's got 7 Harken from my office is here. 8 them right here. 9 numbers, and he'll -- he'll give it to 10 8 You just tell him the this before. Okay. You have not? with some of what's on here. Do you see that there are 9 the witness. 10 column heading. on the first line, on the 11 first page? 11 MR. CORNFELD: 12 NDA MERCK PRASCO 1 through 11. 12 A Yes. 13 MR. STRAUSS: Some sort 13 Q The first column says "dossier 14 Okay. 14 of spreadsheet or something? MR. CORNFELD: 15 MR. STRAUSS: 16 ID." Do you have any idea what that ia? A 15 I'm sorry? 16 Yeah, it's some I presume that is a document with the FDA. So the first line says 168982 sort of spreadsheet. 17 18 Okey-doke. 18 on MLR= PRASCO Page 1, under the dossier ID 19 THE WITNESS: 19 column. 17 20 21 22 23 He's got it. (Reviewing.) 9 what does that number refer to? 20 BY MR. CORNFELD: Q All right. 21 Sir, you have in front of you a 22 23 document that bears the Bates number in the A I am unsure. 0 You said you thought this had to do with the FDA. 24 lower right-hand corner RDA im...CX PRASCO and 24 A I think so. 25 then there are a bunch of serum.s and there is 25 Q The PDA -- www.mithrestilftstionxom Far: 314.644.1334 DAVID WALKER 2/11E2014 DAVID WALKER 2/18/2014 1 . MIDWEST LITIGATION SERVICES Phone: 1.800.280.3376 Fs:: 314.644.1334 wwwasidwortlifigation.com MIDWEST LITIGATION SERVICES Phone: 1.800.280.3376 Fax: 314.644.1334 Case 3:12-cv-01141-SMY-DGW Document 176-23 *SEALED* Filed 12/01/14 Page 13 of 57 Page ID #2746 Case: 16-3334 Document: 55-50 Filed: 02/08/2017 Pages: 57 (1440 of 1511) DAVID WALKER 2/18/2014 DAVID WALKER 2/18/2014 Page 49 2 A I said I am unsure. Q Okay. 3 Page 51 DO you have any idea? I think it's an NoA with the - A 7 aside, and what I would like now to ohOw you 6 MAACK PRASCO 328. 7 A is the document that begin, with the page This is soma number that goes to a document with the FDA? That's what I think that IS. I A 9 9 Q 11 nuober infer. to? And what do you think this 10 11 12 MR. STRAUSS: If you don't -- 12 13 THE WITNESS: I said it before. 13 14 (Reviewing.) MR. STRAUSS) Take a look at don't know. 10 15 No. You can put that document 4 a document with the FDA. Q A Q 2 What do you think it is? I think it's a document with the FDA. THE WITNESS: (Reviewing.) BY MR. CORNFELD: Q 14 BY MR. CORNFELD) And the last page of this document is WRACK PRASCO 353. Do you see that? lb A Yes. You see the second column says 16 Q Are you familiar with this 11 that -- the column heading is compound ID and 17 document? 18 than every line in that coluan is 507-A. 18 A 16 Q 19 Do you woo that? 19 No. aotually, I should toll you -- 20 A Yes. 20 I should point out that you will see on the 21 Q Do you have an understanding of 21 upper right-hand corner, the document starts 22 on the first page with A-2 and a number 2. 22 what 507-A is? 23 A Yes. 23 24 Q What is that? 24 not include_ / don't think we need it for 25 A We refer to compounds and 25 the questions I am going to ask, but Page 1 wwwadelovnafignkoren MIDWEST LITIGATION SERVICES Phone: 1.800.280.3376 Fan 314.644.1334 There was a Page 1 that I did www.midwestabgatIon.rom DAVID WALKER 2/18/2814 MIDWEST LITIGATION SERVICES Phone: L8130.280.3376 DAVID WALKER 2/180014 Page 50 Page 52 combinations of compounds internally by 3 is simply the organisation of the technical numeric means and so the numeric designation 2 for CoSOPT internal to Merck 3 Out I would like to ask you, Do you woe thorn's a column 4 and maybe even though you haven't seen this Yes. 6 Do you have an understanding a, 7 4 was 0507- A. eexiwa MMTD, A 7 A :section of this ADA submission. document, maybe you can help me with it. to what that refers to7 9 I am not exactly sure, but my 10 assumption is that refers to electronic comm 11 and technical documents. 9 Do you recognise this as part of the ADA for CO8OPT? A It appears to be that. Q All right. 10 You see it says, "Chemical and 11 pharmaceutical manufacturing and control documentation" in the upper left? 12 Q What doee that mean? 12 13 A I am unsure but I think it's a 13 A Yes. 14 Q Do you -- do you know what that 14 way of submitting documents to the FDA. 15 16 17 18 19 Either electronically or by 15 hard copy? A Correct. Q You see the last column on refers to? 16 A Yes. 17 Q What does that refer to? A That's about the manufacturing 18 MRACK PRASCO Page 1 -- 19 of the drug product from the drug substances. 20 A (Reviewing.) 20 21 Q -- says "official archive." 21 would be not your area but Mr. Grossman's, is 22 A 22 that right? 23 24 25 Yes. Can you help me with what that refers to? A wwwvoldwannhmlinunm Fan 314.644.1334 No. MIDWEST LITIGATION SERVICES Phone: 1.800.280.3376 So this would be something that 23 A Yes. 24 0 Would you look at the page with 25 Fin: 314.644.1334 Q the mates number HAACK PRASCO 348. www.midwestatigolion.com MIDWEST LITIGATION SERVICES Phone: 1.800.280.3376 Far: 314444.1334 Case 3:12-cv-01141-SMY-DGW Document 176-23 *SEALED* Filed 12/01/14 Page 14 of 57 Page ID #2747 Case: 16-3334 Document: 55-50 Filed: 02/08/2017 Pages: 57 (1441 of 1511) DAVID WALKER 2/18/2014 DAVID WALKER 2/18/2014 Page 55 Page 53 2 Q 3 1 products were marketed by Merck at that 1 am there. 2 time. All right. 3 predates my employment. (Reviewing.) A 1 7 TINOPTIC and TRuiloPT at the time? A Yes. 6 Q And that would be your area, 7 correct? 8 Yes. 9 A 10 Q 11 Do you know that Merck marketed Q 5 A (2)(0)(1) (F)(4) that's headed "Packaging"? 6 BY MR. CORNFELD: 4 You see there is a Section 4 5 This is from May 1997, which Do you have an -- 8 A I don't know. 9 Q -- understanding -- is that All right. 10 And if you would take a look at 11 your understanding? A Yes. Q The second paragraph in the 12 it, can you confirm for me this -- that this 12 13 is the description in the NDA submission for 13 section on Page 348, meaning the last how COSOPT was going to be packaged? 14 paragraph on the page, refers to clinical and 15 stability preparations. 14 Yes, it describes how COSOPT A 15 16 17 17 It was going to be in the same Q what is meant by that? 16 was packaged. 18 container as Merck'. other ophthalmic 18 19 solutions, TRUSOPT and T/MOPTIC, correct? 19 20 A 21 A (Reviewing.) These are containers that were used for clinical studies and formal (Reviewing.) 20 stability studies to justify the expiree It doesn't say so. 21 dating assigned to the product. And those were the llama -- the 12 Well, do you see the first 22 23 sentence says, "During the development of 23 sane bottles that were ultimately used when 24 this product, the memo packaging components 24 the product was marketed? 25 used for other commercially available 25 22 Q wervieldvmeilltigationsem MIDWEST LMGATION SERVICES Phone: 1800.280.3376 Pow: 314.644.1334 A Same design bottles, yes. wwwieldwestalwadonmem MIDWEST LITIGATION SERVICES Phone: 1.800.280.3376 DAVID WALKER 2/18/2014 DAVID WALKER 2/18/2014 Page 56 Page 54 1 ophthalmic products marketed by Merck were 1 2 elec. utilised"? 2 5 Q All right. And on the next page, Page 349, Do you see that? 3 4 you see that? A I see that. 4 Q And it says, "These components 5 A Yes. will also be used for the market product." Do 6 Q what is that? 7 A I see that. 7 A That was a white opaque bottle 8 Q Do you see that? 8 made of low-density polyethylene that's 9 easily squeezed. 6 And market product would be the 9 product after it was going to be sold by 10 11 Merck, correct? 11 referring to in contradistinction to the 12 °coaster Plus when you were describing the MR. STRAUSS: 12 THE WITNESS: 14 15 16 Objection to the form. Correct. Q 13 features of the °coaster Plus earlier; 1.• 14 that right? 15 BY MR. CORNFELD: Q That's the bottle you were 10 13 A And -- and the other That's correct. So this is a three-part bottle: 16 a bottle, a tip and a cap. 17 commercially available ophthalmic products 17 18 marketed by Merck at the time were TRUSOPT 10 and TIMOPTIC, correct? 19 lines from the top, on Page 349, you see it 19 Pam 314.644.1334 Q If you jump down to about five 20 refers to the Ocuneter tips and it says, "The 21 form and foundation, the scope; the fact 21 tips are specially designed to deliver a 22 that it's not on the notice; the fact 22 controlled drop sire." 23 that it's irrelevant. 23 mR. STRAUSS: 20 Object to the 24 You can answer. 25 THE WITNESS: www.mIderstlitiyadoncom I don't know what . . MIDWEST LITIGATION SERVICES Phone: 1808.1803376 Fee:314A44.1384 Do you am that? 24 A 25 Q veemIderestaamion.rom Yes. What-- what is meant by that? MIDWEST LITIGATION SERVICES Phone: 1808.2803376 Far:314.644.1334 Case 3:12-cv-01141-SMY-DGW Document 176-23 *SEALED* Filed 12/01/14 Page 15 of 57 Page ID #2748 Case:DAVID 16-3334 Document: 55-50 Filed: 02/08/2017 DAVID WALKER Pages: 57 (1442 of 1511) WALKER 2/18/2014 2/18/2014 Page 57 2 A I am unsure. 9 Do you know what is meant by Page 59 Ocumeter was opaque because COSOPT was 2 "controlled drop eine"? 4 A sensitive to light when in solution? 3 A My understanding of the Ocumeter is that the tip had a narrow opening Earlier you said the °coaster 6 within the tip so that when patients squeezed 6 7 on the bottle, drops would not come out 7 rapidly but would be metered out slowly due 9 10 Plus was translucent. Was there an issue regarding sensitivity to light? to the resistance of that small diameter MR. STRAUSS: Objection to the feature, and so that controlled the delivery 11 of the medication rather than allowing it to 12 stream out. 13 10 form and foundation. 11 12 What i■ -- what he your 9 I see that. All right. THE WITNESS: What do you mean? Sensitivity to light in the Ocumeter 13 Plus? 14 understanding of what is meant by "controlled 14 BY MR. CORNFELD: lb drop size"? 15 A 16 17 Well, by limiting how rapidly 16 the medication could come out of the dropper 17 Right. I mean, since the Ocumeter was opaque and -- in order to protect the drug 10 tip, the drop sloe would be more reproducible 18 against light but the Ocumeter Plus was not 19 by each use Of the patient. 19 opaque, was something done to protect it from 20 light in the Ocumeter Plus? 20 g Do you see here that the 21 discussion does not nay what that drop six. 22 wan, correct? 21 22 23 MR. STRAUSS: Objection to the 24 form. 25 THE WITNESS: I don't see any — wwx.andwestlingedon.com - A So the Ocumeter Plus was stored in cartons when the medication was shipped, 23 distributed, stored, prior to a patient 24 receiving the medication, plus the walls of 25 the Ocumeter Pius bottle are thicker. — MIDWEST LITIGATION SERVICES Phone: 1.800.2803376 Fan 314.644.1334 www.ogdwestalgationcom DAVID WALKER 2/18E2014 MIDWEST LITIGATION SERVICES Phone: L800-2823376 DAVID WALKER 2/18/2014 Page 53 Page 60 mention of drop size. 2 3 BY Meaning what; less light would MR. CORNFELD: 9 2 get in? Do you have en understanding as 4 to whether -- strike that. 6 to whether Merck told the FDA in its NDA for 4 A Yes. Q Okay. Do you have an understanding as so there wee no problem with 6 COSOPT what the drop aline would be? MR. STRAUSS: Object to the 9 form and foundation. 10 11 12 we reported the drop size for Ocumeter. BY MR. CORNFELD: 14 16 24 If you look at Page 360. 9 I think I have a typo. Wait ■ MR. STRAUSS: Objection. 15 14 25 Did Merck know what the drop form and foundation. THE WITNESS: I do not know. A Yes. 18 Q Okay. And you see there it say., "The 20 market presentation i. an °Punster container 21 with a dropper tip and yellow cap." 22 BY MR. CORNFELD: At the bottom of the page, do you wee on Peg. 349 it indicates that the www.miehreatEliptionrom Fag. 350, the next page. 17 19 MR. STRAUSS: Object to the MIDWEST LITIGATION SERVICES Phone: 1200.280.3376 minute. 16 site was at the time? Q specifications as approved. Pardon me, what page number? Q 23 11 A 18 21 Correct. The package protected the product as needed to meet the product's 0 THE WITNESS: I am not aware. 22 A 10 13 BY MR. CORNFELD: 19 the COSOPT within it free light and thereby the COSOPT being ineffective, correct? You ere not aware that Merck 17 20 7 8 12 did, correct? 15 the °punster Flue in -- in failing to protect 9 THE WITNESS: I don't know that 13 Fax: 314.644.1334 A Yes. 24 9 What's meant by the phrase 25 Fax: 314.644.1334 Do you ales that? 23 "market presentation"? www.midweallingatIonsona MIDWEST LITIGATION SERVICES Phone: 1.800280.3376 Fox: 314.644.1334 Case 3:12-cv-01141-SMY-DGW Document 176-23 *SEALED* Filed 12/01/14 Page 16 of 57 Page ID #2749 Case:DAVID 16-3334 Document: 55-50 Filed: 02/08/2017DAVID WALKER Pages: 57 (1443 of 1511) WALKER 2/U4014 manom Page 63 Ragan( 1 Objection to the MR. STRAUSS: 1 2 look through the specifications, these would 3 be areas that you are not prepared to testify entire assembly of the bottle tip and Cap 4 on and I should ask Mt. Grossman about; is and the label that would be included on 5 that correct? the product marketed. 6 foundation. 2 That is the THE WITNESS: 3 4 5 6 8 9 13 description of the container that is 14 going to be sold. 15 presentation is what is going to be sold. Now, I would like to show you 12 It's a THE WITNESS: So you can put that aside. 0 11 12 That is -- the market I am not prepared BY MR. CORNFELD: 10 Objection to the MR. STRAUSS: form. 11 Object to the to testify about these specifications. 9 that a phrase that'. used by marketers? 10 THE WITNESS: B So "market presentation,. is Q MR. STRAUSS: form and foundation. 7 BY MR. CORNFELD: 7 Just to confirm, if you would Q 13 the document that begin. with MRCS BRAS= 14 Pegs 15 432 and ends with Page 435. A (Reviewing.) Si And you saw earlier we looked 16 It's not another form that's used in 16 17 clinical trials or on stability studies. 17 at a reference to Section C-6 regarding the le container closure system for COSOPT. BY MR. CORNFELD: 18 19 Q 20 21 All right. 19 I would like to now show you 20 the document that has -- strike that. Aleo on Page 350, just the 22 Does this appear to be that eection? 21 A Yes. 22 Q Again, in the there', that same phrase we looked at before, "Boston round °coaster." 23 24 Mr. Walker, it says, "See Section C-6, 24 25 'Container Closure System,' for further 25 MIDWESTLITIGATIONSERVICES Phone: 1.600.2003376 Wwwandweafitigadoorom Fox: 314.644.1334 first paragraph, 23 following sentence we were just looking at, Do you see that? wwwad4wealiflydionsem MIDVUISTLIIIGATIONSERVICES Phone: 1.600.2003376 DAVID WALKER 2/18/2014 DAVID WALKER 2482014 Page 64 Page 62 1 1 details.. DO 2 3 A Yaw. 4 0 That's referring to another 5 4 5 eection of the NDA, Correct? A 6 0 8 2 you see that? 3 Yes. 6 All right. 7 Be will look at that in a moment. But first 1 would like to show 9 A Yes. 4 The actual term of the container or the bottle is Ocumeter, correct? A That is a trademarked description of the bottle. 0 All right. And "Boston round" is simply 8 referring to the type of bottle that it was, 9 correct? 10 you the document beginning with =ROE PRASCO 10 A The Shape of the bottle. 11 Page 371 and ending in 431. 11 CI All right. 12 A (Reviewing.) 12 13 Q Do you recognine this document 13 14 MR. STRAUSS: THE WITNESS: 17 Q 21 It i. -- 17 You can get Boston round glass Q All right. 19 All right. 20 And the first page is headed, 21 Methods.. 23 A bottles. This was -- this was a Boston round plastic bottle, of nooses. What is that shape? A So it is characterized by Do you see that? 24 having a flat base, cylindrical walls and Yes. 25 nearly circular curvature at the top of the „ wwwmidvmdftmlioncom That's the shape of the bottle. You can get Boston round -- A 22 24 A Q "Section C-5, "Specifications and Test 22 It's known as a Boston round, is that right? 16 18 BY MR. CORNFELD: 20 25 .„ .- It appears to be part of an NDA. 18 23 15 Object to the foundation. 16 19 14 as another section of the NDA for COSOFT? 15 MIDWESTLfTRUAlIONSERVICES Phone: 1.000.280.3376 Far: 314.644.1334 Fax: 314.644.1334 www4ddwodfUgadmicom MIDWEST LITIGATION SERVICES Phone: 1.8002003376 Fax: 314.644.1334 Case 3:12-cv-01141-SMY-DGW Document 176-23 *SEALED* Filed 12/01/14 Page 17 of 57 Page ID #2750 Case: 16-3334 Document: 55-50 Filed: 02/08/2017 DAVID WALKER Pages: 57 (1444 of 1511) 2/18/2014 DAVEDAVAL1WR 2/10/2014 Pege 65 Page 67 bottle, at the shoulder, below -- where the 2 Q Would you look at the second 2 to the critical parameter. and 3 specifications." page of this document, Page 433. 5 7 received from the suppliers for conformance dropper tip would be applied. 3 4 1 4 (Reviewing.) A Yes. Q And do you see in the second Q Earlier in response to a paragraph it Metes, "Tips and caps are 7 manufactured according to purchase 9 10 question you mentioned critical specification.. specifications which define the approved What -- what were those -- or ream s'? 11 10 what type. of things were thee. specifications? Do you see that? 11 12 A Yes. 12 13 Q What does that mean? 13 A That means there are drawings 14 15 Do you see that? A MR. STRAUSS: Object to the form. Foundation and scope. 14 and specification documents between Merck and THE WITNESS; So I don't know 15 what the specifications were for these 16 the supplier that determine what the critical 16 components, but dimensions are certainly 17 dimensions are, their values, their 17 included. Other items that at times are 18 tolerances and the resins that must be used 18 included in specifications, not 19 for making the components. 19 necessarily these, would include the AQL 20 21 Q All right. The neat sentence etatee, "Am incoming packaging component., 20 levels for defects for the components, 21 what's an acceptable or reject level for defects and there are different 22 tip. and caps are subject to dimensional 22 23 requirements only." 23 categories of defects and different 24 What doe. that mean? 24 levels above which components would be 25 (Reviewing.) 25 rejected. wnwJedwestlidpitionone MIDWEST LITIGATION SERVICES Phone: 1.800.280.3376 Fax: 314.644.1334 www.mitheestlltIgetion.com MIDWEST LITIGATION SERVICES Phone: 1.800.280.3376 DAVID WALKER 2E18/2014 DAVID WALKER 2/18/2014 Page 66 Page 68 Unsure. 2 3 • It would mean that there were 4 requirements for the dimensions of the tip. and caps, correct? 6 7 SY MR. CORNFELD: 2 dimensional requirements, meaning 5 A 4 Yes, but it sounds like 6 something else was excluded, and I don't know 7 what was excluded. 9 Q If you would look at Page 434 9 for? Q What doe. "MIL" stand for? A Unsure. 0 You used the term. A Yes. I'm not • What do you think it etands I'm sorry? A I em unsure. I don't know. Q What does it mean? 10 in the first paragraph, beginning in the 10 A I don't know. I know our -- 11 third line it says, "Merck visually and 11 Q You used the term. 12 dimensionally checks and inspect, each line 12 13 of tip. and cape received from the suppliers 13 14 for conformance to the critical parameters 14 group uses a category -- category of defects 15 and specifications." 15 and assigns different action -- I believe it 16 17 18 A I'm sorry. Qo ahead. A I know our supplies inspection Do you see that? 16 is action quality level. So different I'm sorry, I may be on the 17 defects have different AQL settings above 18 which they would be rejected. wrong page. What page are you on? 19 Q 434, MERCK PRASCO Page 434. 19 20 A Yes. 20 (Reviewing.) 21 Q Okay. 22 I've never heard of the term -- the acronym 23 before, but all right. 21 22 23 And in the third line it 24 states, "Merck visually and dimensionally 24 25 checks and inspects each lot of tips and caps 25 wwwwildwetlithedmunm MIDWEST LITIGATION SERVICES Phone: 1.800.280.3376 Fax) 314.644.1334 Foe: 314.644.1334 We get so used to using certain acronyms, we forget their meanings. Q I am just a simple lawyer. So Doe. -- do the critical dimensions that Merck would inspect on the www.nedwesMtigeionann MIDWEST LITIGATION SERVICES Phone: 1.800.280.3376 Fax: 314,644.1334 Case 3:12-cv-01141-SMY-DGW Document 176-23 *SEALED* Filed 12/01/14 Page 18 of 57 Page ID #2751 Case: 16-3334 Document: 55-50 Filed: 02/08/2017 Pages: 57 (1445 of 1511) DAVID WALKER 2/18/2014 DAVRYWAIKFR 2/182014 Page 71 Page 69 Geometer, do they include the size of 2 outer orifice of the bottle -- or of the tip 3 rather? 2 component. 4 something is stirred, correct? 6 component. It's not something we inspect. You can measure the speed when I don't know. I haven't seen A 4 Do you know if Merck told the Q 6 It's part of a process. So a parameter is a 7 FDA what those specifications were for the 7 setting in a process. Ocuneter? would look at it. 14 parameters and specifications? 14 THE WITNESS: That's how I 13 Is there a difference between 13 form. 12 parameters and specifications. 12 MR. STRAUSS: Object to the 11 The phrase in the sentence says Q 11 in terms of packaging, is that right? 10 the specifications. 10 That's how you would look at it Q 9 I don't know if we told the FDA A 9 But a stirring vessel is not a A the specification for the components. 5 Something I can measure on a A 1 the 15 A Yes, there could be. 15 Could we take a break here? 16 Q What is a parameter and what's 16 MR. STRAUSS: Yeah. 17 a specification? 17 Rick, can he take a restroom break here, about 10 minutes or so? 18 So a specification might be a A 18 19 dimension, and a parameter might be a process 19 MR. CORNFELD: Absolutely. 20 variable. So, for example, these components 20 THE WITNESS: Thank you. 21 are sterilized before they were used, so a 21 22 processing parameter would be the dose of 22 23 radiation used to sterilize the components, 23 24 but that's not a components specification. 24 wwwandweadlOgsdnumm MIDWEST LITIGATION SERVICES Phone: 1.500.200.3376 This marks the end of Tape 1 in the deposition. The time is 11:24. 25 If the -- if the parameter is Q 25 THE VIDEOGRAPHER: Going off the record. Fee 314.644.1334 www.oidwestlIdgatIon.com MIDWEST LITIGATION SERVICES Phone: 1.S00.2303376 DAVID WALKER 2/182014 DAVID WALKER 2118/2014 Page 72 Page 70 (Whereupon a Recess Commenced the degree of sterilisation, would the 2 specification for that parameter be the result that you wood co mcRsw.wo for 4 2 at 11:24 and Testimony Recommenced at 3 11:47.) sterilisation? record. 7 THE WITNESS: I'm sorry, could the deposition. The time is 11:47. 8 you clarify the question. 9 This begins Tape Number 2 of 6 form of the question. 7 THE VIDEOGRAPHER, Back on the 4 MR. STRAUSS: Objection to the 6 9 BY MR. CORNFELD: BY MR. CORNFELD: Sir, do you have in front of Well -- sure. 10 What I an wondering is, is 11 you the document with the Bates number WMACK parameter something like the type of issue 12 PBASCO 457 through 4587 13 that you are looking at, and the 13 A Yes. 14 specification is the result you have to get 14 Q And do you se, the second 15 on the test for it to pass? 15 section on the first page refers to user 16 tests? Q 10 11 12 So the issue might be 16 5 17 sterilization and the specification might be 17 A Yes. 18 whatever that result is on the sterilisation 18 Q Are you familiar with user 19 test? 19 20 A To me, parameter is a setting 21 in a process: how long Something goes, the 22 temperature of a process, the speed at which 23 24 25 www.midwestlitIgatioacom A Yes. 21 Q All right. Then what is meant 22 by ■ "user twit"? 24 And the specification is what 25 as opposed to that? MIDWEST LITIGATION SERVICES Phone: 1.800.280.3376 Fax: 314.644.1334 tests? 20 23 it's stirred. Q Fle 314.644.1334 A So a user test is to simulate -5 WWWMMWOOMM110011.COm Let me -MIDWEST LITIGATION SERVICES Phone: 1.800.280.3376 Fax: 314.644.1334 Case 3:12-cv-01141-SMY-DGW Document 176-23 *SEALED* Filed 12/01/14 Page 19 of 57 Page ID #2752 Case:DAVID 16-3334 Document: 55-50 Filed: 02/08/2017 DAVID WALKER Pages: 57 (1446 of 1511) WALKER 228/2014 2/182014 Page 73 2 3 A Go ahead. Q Actually, let me stop you Page 75 1 because what I an referring to is the user 4 test in this context where it says, 5 test was conducted to simulate the condition MR. STRAUSS: Well, object to 2 the form. That's very interesting. 3 you have a question? user MR. CORNFELD: Yeah. BY MR. CORNFELD: of use by the patient." • What is the purpose Of that 7 MR. STRAUSS: Object to the 9 Does this indicate that that a specification applies to a parameter? test? MR. STRAUSS: Object to the 9 10 Do form. form and foundation. 10 11 Go ahead. 12 THE WITNESS: Okay. User tests THE WITNESS: No, the way I 11 read this is that after use, all 12 parameters tested were within controlled 13 are done so that the product can be 13 specifications. 14 evaluated in terms of its quality after 14 15 the products been used in a manner 15 So all the parameters tested in this case appears to mean the 16 similar to how the customer would use the 16 concentration of the active components of 17 product. So, for example, for an 17 the preservative were within the 18 ophthalmic product, the product would be 18 specifications, the limits agreed upon 19 dispensed on a regular basis and then the 19 and proposed by Merck to the FDA. 20 product within the bottle after that 20 21 dispensing period would be checked for 21 22 its quality to make sure the product 22 that was tested, there was a specification, 23 within the bottle still meets the product 23 correct? 24 specifications. 25 BY MR. CORNFELD: MIDWEST LITIGATION SERVICES Phone: 1.800.2803376 www.midwestlItIgationsom Fen 314.644.1334 BY MR. CORNFELD: Q So for each of the parameter. 24 A Yes. 25 Q And so the specification www4oldemlifthmdoncom MIDWEST LITIGATION SERVICES Phone: 1.1100.2803376 DAVID WALKER 2/18/2014 DAVID WALKER 518/2014 Page 74 1 2 3 4 7 applied to that parameter, correct? In this instance, the containers were tested by expelling two drops a day for 18 days for the two and a half 4 A Yes. Q If you look at the second page, do you see that there are the results? milliliter bottle and different amount. for A Yes. the bigger bottles, correct? Q Are you familiar with these A Yes. 8 9 Page 76 All right. Q 7 kinds of And then the -- then the product is tested? 10 A 11 bottle is tested. 12 Q testa? A Yes. Q All right. 9 Yes, the product within the 10 These are these 11 specifications for the product, for COSOPT, All right. 12 correct? Do you see that the second 13 A Yes. paragraph under user test says, "The results 14 Q There was a specification for 15 indicated that after use, all parameter. 15 appearance, a specification for PH, and ■ o 16 tested were within controlled 16 forth, correct? 17 specifications"? 13 14 18 19 A 20 21 17 A Yes. Do you see that? 18 Q There is no specification for Yes. 19 And that's one of the 20 reference. where I got this idea that a 21 22 specification would apply to a parameter 22 23 because it says all parameters were within 23 24 specifications. 25 aanxddsestlitigetiolume drop size, correct? A 25 Fen 314.644.1334 I did not see a specification for drop size. Q Do you know why there was no specification for drop aim. on COSOPT? 24 Do you see that? MIDWEST LITIGATION SERVICES Phone: 1.800.2803376 Fez: 314.644.1334 MR. STRAUSS: Objection to form. neresmideenalltigatIon.com MIDWEST LITIGATION SERVICES Phone: 1.800.280.3376 Fan 314.644.1334 Case 3:12-cv-01141-SMY-DGW Document 176-23 *SEALED* Filed 12/01/14 Page 20 of 57 Page ID #2753 Case: 16-3334 Document: 55-50 Filed: 02/08/2017 Pages: 57 (1447 of 1511) DAVID WALKER VNAOH DAVID WALKER LUMPS Page79 Page77 THE WITNESS: 1 I don't know why there was no specification for drop size. 2 4 4 5 A Yes. 4 So this indicates that Merck You can put that document aside 5 applied for the Ocumeter Plus on February 23, 6 2000, correct? 7 through 81. ask questions about the Ocumeter Flue. MR. STRAUSS: You are such a giver. 11 10376; MERCK MR. CORNFELD: 14 PRASCO 10376. 15 MR. STRAUSS: 16 a Yes. 9 Q At that time COSOPT had been on 10 the market for • couple of years and was sold 11 in the deumnier, correct? 13 again, Rick? 13 (Reviewing.) 12 I'm sorry, what was the number 12 A 7 Just to make you happy, I'll 9 subedited for the Ocumeter Plus? 4 and if you would bring out Document 10376 10 2 All right. 6 8 supplemental new drug application that Merck 3 BY MR. CORNFELD: 3 1 So the next Plus for Merck's other ophthalmic drugs, 16 correct? 18 through 1474. 18 20 MR. STRAUSS: THE WITNESS: 21 Right. One O. MR. CORNFELD: This is what you -- this is TIMOPTIC end TRUSOPT were also Q sold in the Ocumeter Plus, weren't they? 22 23 what you produced to us last week. 23 A Yes. 24 reason -- the reason it's out of order in 24 Q All right. number is that's how you produced it to 25 25 wwwmddweedltigedonsom The MODWESTLITIGATIONSERVICES Phone: 1800.280.3376 Fax: 314.644.1334 I don't know. BY MR. CORNFELD: 20 22 Object to the foundation. 19 - no, he's Okay. 21 There were similar applications 15 17 Are you going to 4 at this time for approval of the °ammeter 17 going to one 0. Yes. 14 folder in line is MERCK PRASCO 1 -- 1470 19 A Didn't Merck apply for approval www.midwestildnatIoncom MIDWEST LITIGATION SERVICES Phone: 1.8002803376 DAVID WALKER 2/182014 DAVID WALKER 2/182014 Page80 Page78 1 1 of the Ocumeter Plus for those drugs at about 10376? 2 the came time? Yes. 3 Okay. 4 us STRAUSS: 2 MR. CORNFELD: 3 Found it. 4 MR. STRAUSS: 5 See, I knew it would be my 6 fault there, Rick. 7 MR. CORNFELD: Everything -- 9 MR. STRAUSS: This wasn't -- MR. CORNFELD: 10 the Ocumeter Plus. 8 timing of when those applications were 9 Everything 11 point it out. 12 that goes wrong in this deposition -- 12 That's right. 13 MR. STRAUSS: It's like a -- it's like standing 15 objection to me. 16 THE WITNESS: (Reviewing.) 17 MR. STRAUSS: We got it. 18 19 14 d I am unsure of the made. BY MR. CORNFELD: Q Would you look at the first paragraph on Page 10376. And do you sae that about five lines down -- four to five lines down, there 15 is a reference to a single Ophthalmic 16 Worldwide Image. Do you see that? 17 18 A Yes. Okay. 19 Q And ie that what you referred Do you see, sir, that MERCK 20 to earlier, "Ophthalmic Worldwide Image" or "ma"? BY MR. CORNFELD: 20 We had to apply 7 11 13 THE WITNESS: for the approval to market any product in 10 14 Object to the 6 I shouldn't even He's right. MR. STRAUSS: foundation. 5 So really this isn't 8 21 PRASCO 10376 through 10311 is a document 21 22 dated February 23, 2000, that was submitted 22 A Yes. 23 by Merck to the FDA? 23 Q Can you explain what that 24 A Yes. 24 25 Q And be this part of the 25 www.mklwesUMgMionxom MIDWEST LITIGATION SERVICES Phone: LS00.2603376 Fan: 314.644.1334 Pao: 314.644.1334 means? www.mldwestlitimadon.com I moan, the word "image" to se MIDWEST LITIGATION SERVICES Phone: 11100.280.3376 Pao: 314.644.1334 Case 3:12-cv-01141-SMY-DGW Document 176-23 *SEALED* Filed 12/01/14 Page 21 of 57 Page ID #2754 Case: 16-3334 Document: 55-50 Filed: 02/08/2017 Pages: 57 (1448 of 1511) DAVID WALKER 2/18/2014 DAVID WALKER 2/18/2014 Page 81 1 2 3 Page 83 means a picture. 1 How is "image" being used in 2 this context? 4 MR. STRAUSS: 5 minutes of the meeting that Merck prepared? 3 A I see that sentence. Object to the 4 Q All right. So "image. in 6 of the meeting submitted by Dr. William foundation. 6 You see there's a reference to Q 5 THE WITNESS: It says that there ware minutes 7 this context is how a pharmaceutical 7 Roberts of WWI, a division of Merck a 8 product is presented or sold or marketed, 8 Company, Inc., on July 6, 1998. 9 that is, the combination of the contents 9 10 and the package containing the contents. 10 11 So in a way -- 11 12 BY MR. CORNFELD: 13 14 12 You see the second -- I'm 0 You see that? To clarify, that's MRL, Merck Research Laboratories. 13 sorry. 0 14 A 15 So in a manner, it is kind of 15 I see that. A Thank you. And that -- okay. And that's -- that is a division of Merck? 16 like a picture because it's now you see the 16 A Yes. 17 product. 17 Q Who io Dr. William Robe Roberta? 18 Qsee And you the first sentence 18 A I don't know. 19 on Page 10376 refers to a meeting hold on 19 Q Do you have any idea? 20 February 2, 1998, between representatives of 20 A No. 21 the FDA and Merck to discuss this new 21 Q Have you ever heard of him 22 worldwide image or the -- namely, the 22 23 0cm...ter Plus? 24 23 A No. (Reviewing.) 24 Q Have you seen the minutes that Are you referring to the last 25 A 25 wwwnildwesUfthmdoncom before? MIDVVESILITIGATIONSERVICES Phone: 1.100.280.3376 Ma: 314.644.1334 he prepared? www.addawn0flgodoexem M1DWESTLITIGATIONSERVICES Phone: 1.8002805376 DAVID WALKER 2/18/2014 DAVID WALKER 2/18/2011 Page 12 1 sentence of the first paragraph? 2 0 sentence of the first -- it is 4 the last sentence too? 5 No. Mentioned in 2 0 Do you know if they exist? 3 A 4 A Yes. I see that. 6 Q Okay. 7 6 7 Pegs 84 A 1 No, I am referring to the first 3 Yes. 5 8 Who attended that meeting? 8 9 MR. STRAUSS: 9 10 THE WITNESS: 10 I don't know. BY MR. CORNFELD: 13 14 Object to the foundation. 11 12 Q Do you know who attended L.= Merck? I don't know. MR. CORNFELD: Steve, I haven't seen those, but I would request those. MR. STRAUSS: Okay. I will respond to your request. BY MR. CORNFELD: Q Do you ...e, sir, that the next sentence refers to a January 18, 2000, 11 submission updating the agency on the 12 progress of the Ocumeter Plum end providing 13 information in reopense to agency conments 14 made during the February 2, 1998, meeting? 15 A No. 16 Q Do you have any understanding? 16 A Yes. 17 A No. 17 Q Have you seen that submission? Q Do you know anything about this 18 A No. 19 Q Do you know whether that 18 19 20 A No. Q I mean, you have no information 22 you can toll me about thie seeing other than 23 what M. stated here? 24 25 15 meeting? 21 A 20 21 23 Nothing other than what's MIDWEST LITIGATION SERVICES Phone: 1.8002803376 Do you see that? submission still exists? A 22 stated here. www.miawestgtIgadon.com Fam314644J334 Pm: 314.644.1334 No, I don't know. MR. CORNFELD: Steve, I would also request a copy of that submission, 24 the January 18, 2000, submission, both of 25 those documents referred to on MERCK www.mldweallklgodoexone MIDWEST LITIGATION SERVICES Phones 1.800.280.3376 Fax: 314.644.1334 Case 3:12-cv-01141-SMY-DGW Document 176-23 *SEALED* Filed 12/01/14 Page 22 of 57 Page ID #2755 Case: 16-3334 Document: 55-50 Filed: 02/08/2017 Pages: 57 (1449 of 1511) DAVID WALKER 2/15/1014 DAVID WALKER 21S/2014 Page 82 Page 85 these. PRASCO Page 10376. MR. STRAUSS: 2 4 4 contact? 6 with someone in regulatory affairs. referred to in this document? 6 • affairs? Do you have any idea who would We were 9 know? 9 A No. 11 Q Based on how Merck keeps it. 11 A I'm not sure of his position. Q Would you take a look at 141.ROX 12 files, could it be that these minute. and 12 13 this submission would be in the file, for 13 TIMOPTIO or TRUSOPT? 14 15 A I don't know. 16 Q I submission or -- strike that. 17 PRASCO Page 925 -- orCuse me, 9235. MR. CORNFELD: 9235. And also would you look at the Q 15 mean, if -- if this told his title is regulatory liaison. 10 10 14 Is Mr. Grossman in regulatory • 7 No. A 7 I think I would have to start A on what the agency comment. were that were 5 Who would you think you would Q 3 Sir, can you provide any light Q BY MR. CORNFELD: 2 okay. BY MR. CORNFELD: 3 16 document that starts 17 apologise, that's About 9259 through 400 9654, and I pages. And I em 18 If the supplemental new drug 18 only going to ask you about a few of those 19 applications for COSOPT was done along with 19 400 20 supplemental new drug application, for other 20 went through the documents where one document 21 drugs, could it be that minutes that are 21 began and one document ended. 22 referred to here, if that meeting pertained 22 to all three drugs night have been filed by 23 Merck in connection with those other drugs? 24 23 24 www.midweallitlgationsom MIDWEST LITIGATION SERVICES Phame: 1 800 VW 3176 But first I an going to ask you about Fax: 314.644.1334 9235 through 9258. MR. STRAUSS: He's got that 25 MR. STRAUSS: Objection to the 25 page., but it was sometimes unclear as I one. wwwaidowstlltigatIon.com MIDWESTUDGATIONSERVIGN Phone 1.800.280.3376 Fax: 314644.1334 DAVID WALKER 1/18/2014 DAVID WALKER 2/18/2014 Page 88 Page 86 1 form. Foundation. Calls for 2 speculation. 2 THE WITNESS: I don't know how 3 they are compiled or archived. 4 BY MR. CORNFELD: Q 6 Is that possible? form. THE WITNESS: Is what possible? 9 10 BY MR. CORNFELD: Q 11 That if we wanted to find the and Control Documentation"? A Yes. 6 Q What does that mean? A It's a description of how the 8 drug product is manufactured from starting 9 materials such as APIs, buffers, et cetera. 10 Q What are "M."? 11 A Active pharmaceutical minute. of this meeting and the record of the agency Cements in the response that Merck 13 14 nada in January of 2000, that we should look 19 15 in the files pertaining to one of the other 15 16 drugs that was involved with the Ocumeter 16 17 Plus submission? 20 21 A Q If you wanted to find them, 18 what would you do? Is not sure who I would contact to find www.midwestEdgation.cam MIDWEST LITIGATION SERVICES Phone: 1.800.280.3376 Fax: 314.644.1334 this something that is more within Mk. Grossman'• area than yours? MR. STRAUSS: Object to the form and foundation. THE WITNESS: I am not responsible for such sections and 21 filings. 23 THE WITNESS: I am unsure. I'm All right. You told Me that 20 22 MR. STRAUSS: Object to the form. Foundation. 24 25 Q before. x'm sorry. 19 22 23 ingredients. 17 be. headed, 4 13 19 9235 is 5 12 18 Do you see Page "Chemical and Pharmaceutical Manufacturing 12 I don't know where they would Q 3 MR. STRAUSS: Object to the 8 BY MR. CORNFELD: BY MR. CORNFELD: Q Well, look at -- I have ■ few 24 questions and if you can answer thee, great, 25 and if you can't, I know you will tell me. wwwaMdwavlidwmUmxum MIDWEST LITIGATION SERVICES Phone: 1.800.280.3376 Fax: 314.644.1334 Case 3:12-cv-01141-SMY-DGW Document 176-23 *SEALED* Filed 12/01/14 Page 23 of 57 Page ID #2756 Case: 16-3334 Document: 55-50 Filed: 02/08/2017 Pages: 57 (1450 of 1511) DAVID WALKER 2/18/2014 DAVID WALKER 2/11/2014 Page 19 Page 91 So if you would turn to Page 2 9245. 2 3 A 4 (Reviewing.) And before I ask you about what 5 is written on this page, let me ask you this: 6 /hi. document -- this submission relates to 7 after filling. Q The things you just outlined 3 are mentioned in that first paragraph under 4 introduction on Page 9245, correct? A (Reviewing.) 6 Yes. what became known a. the Ocumeter Plus, Merck refers to customer need., correct? 9 A 10 specifically ease of handling, non-rollaway (Reviewing.) 9 Yes. And the Ocunater Clue replaced bottle, readily dispenses one drop at a time, 10 this invisible liquid level, in explaining 11 the benefit. of the Ocumeter Plus over the 12 the °coaster as the package for Merck' • 12 Ocumeter, correct? 13 ophthalmic drug mold in multi-use bottle.? 13 A Yes. 14 Q And it also indicate. that it 14 A Yes. 15 Q Shy did Merck replace the 16 15 Ocumater with the Ocumater Plus? 17 So there were many design enhanced manufacturing efficiencies, correct? 16 A Yes. 17 Q And it creates a unique 18 features that were identified as being 18 identity for all of the ophthalmic products 19 beneficial to customers who use the 19 of Merck, correct? 20 ophthalmic products marked -- that Merck was 20 21 marketing at the time. 21 Since the Ocumeter Plus had a 22 di.tinctive appearance, anyone looking at it 23 would know that was a Merck product. 22 Patients using glaucoma 23 medications tend to be older patients, tend 24 to have dexterity issues, so they have 24 25 trouble handling the bottle in a manner such 25 awandchwedlidgdienbam MIDWEST LITIGATION SERVICES Phone: 1100.200.3376 Pax: 314.644.1339 A Yes. That's what is being referred to here, correct? www.midweseltigation.com MIDWEST LITIGATION SERVICES Pb.., n 1.800280.3376 DAVID WALKER 2/18/2014 DAVID WALKER 2/18/2014 Pogo 90 Page 92 that they can control the position of the MR. STRAUSS: Object -- sorry. 2 bottle, that they can grasp the bottle 3 adequately to dispense drops to their eyes, 3 9 that they can hold the bottle in the proper 4 question is finished. 6 question. Calls for speculation. 5 position, that they can set the bottle down 6 and not have it -- the tip contaminated. 7 Are you finished, Rick? MR. CORNFELD: Yeah, my MR. STRAUSS: Objection to the And so Merck took on an effort Go ahead. to respond to these needs for these patients 9 THE WITNESS: It was a to create the Ocumeter Plus. And so in different appearance bottle. Yes. But 10 designing the Ocumeter Plus, we made a larger 10 would everyone know immediately it was 11 bottle easier to hold, a bottle that didn't 11 Merck's bottle; only if they had 12 have to be squeezed much to dispense drops in 13 a controlled manner, rather just a small 14 portion of the side of the bottle needed to 15 be pressed upon so that a single drop would 16 come out. 17 better assured in terms of its sterility 19 because the product in Ocumeter Plus is 20 filled into a hermetically sealed bottle. 21 There's no open tip after the product's been 12 understanding prior to seeing the bottle 13 that it was from Merck. 14 15 The quality of the product was 18 BY MR. CORNFELD: .2 Well, physicians might when 16 they prescribe a medicine or pharmacist. 17 would, correct? 18 19 MR. STRAUSS: Objection to the form. 20 THE WITNESS: I don't know how 21 well educated the physicians or pharmacists would have been. It was a 22 filled. The bottle's been heat-sealed, and 22 23 so we are sure that it's well closed, product 23 unique appearing bottle. It looked 24 doesn't leak out before the patients get the 24 different from the Boston rounds. 25 bottle and that the sterility is maintained wwwauldwesfiftlgisdoexmv MIDWEST LITIGATION SERVICES Phone: 1.800.280.3376 Pax: 314.699.1334 25 Rim 314.644.1334 BY MR. CORNFELD: wwwwidweetlitigmioo...m MIDWEST LITIGATION SERVICES Phone: 1.800.280.3376 Fee: 314.644.1334 Case 3:12-cv-01141-SMY-DGW Document 176-23 *SEALED* Filed 12/01/14 Page 24 of 57 Page ID #2757 2/18/2014 57 Case:DAVID 16-3334 Document: 55-50 Filed: 02/08/2017DAVID WALKER Pages: (1451 of 1511) WALKER 2/18/2014 Page 95 Page 93 But Can you tell me where this By the way, at the bottom of Q 1 fit. in with those four patents? 2 the Page 9245 you see there is a data, 28 2 3 January 2000? 3 A I am not sure what you mean. Q I mean, this is one patent. 4 A Yes. 4 5 Q Do you have an understanding of S 7 I understand the date. A Row do they relate to each 6 what is meant by that date? 6 There are three others. other? MR. STRAUSS: Objection to the What is meant by it? 9 A The 28th of January 2000. 10 Q Out is that the date the form. Foundation. 9 THE WITNESS: The patents cover 10 11 document was prepared or -- I mean, why is 11 12 that date there? 12 A 13 Ocumeter Plus bottle. BY MR. CORNFELD: 13 this was the I don't know different aspects of the features of the What -- what features does this Q 14 date the document was prepared or submitted. 14 15 I don't know the particular significance. 15 -- or what aspects dose PL 3605 through 3609 cover? We know the document -- the 16 17 submission was in February because we just 17 18 saw that on the previous document. 18 Okay. 19 Sc what -- so if this isn't the 20 16 Q A 19 20 Q 21 22 THE WITNESS: Well, some of the features are described in the abstract. Thick-ridged walls with a date it was Submitted, is this the document 21 -- the date it ca. written? 22 limited flexible area so that only a 23 portion of the bottle is used for MR. STRAUSS: Objection to the 23 form and the foundation. 24 MR. STRAUSS: Object to the form. Foundation. THE WITNESS: 25 www.midwestlitiptlomeom I don't know. MIDWEST LITIGATION SERVICES Phone: 1.8002803376 Fu: 314.644.1334 24 dispensing a limited amount of 25 medication. (Reviewing.) www.lokhreellle/gadonsom MIDWEST LITIGATION SERVICES Phone 1.800280.3376 DAVID WALKER 2/18/2014 DAVID WALKER 2/18/2014 Page 96 Page 94 That the dropper tip is HY MR. CORNFELD: 2 Q Take a look et the nest page, 2 integral with the bottle. They are not separate components. That there is a 3 Page 9246, and you see it gam "The Ocumeter 3 4 Plus" -- in the second paragraph, "The 4 5 Ocumeter Plus container closure system is • 6 patented design developed within I4erek 7 Company, Inc." 8 9 A Q 11 bottle can dispense medication. And that the bottle has a plug that is heat-sealed I see that. 8 Do you see that? 9 10 11 document PL 3605 through 3609. 12 sealed tip that has a thin membrane that's punctured to open the tip so the Could you take a look at 10 to close the bottle after filling. BY MR. CORNFELD: Q And two different mires of plugs, correct? Do you have that? 12 A Yes. Q All right. Yes. 13 14 (Reviewing.) 14 15 Is this a patent for the 15 plug and a long plug, and you use the short 13 16 17 A Q 18 19 20 16 plug if you wanted more liquid in the bottle 17 and • short plug to fill up -- secy.e se, the It's one of the patents 18 long plug to fill in some of that space if 19 you wanted less liquid, correct? pertaining to Ocumeter Plus. Q 21 There is what is called a short (Reviewing.) Ocumeter Plus? A All right. 20 A Yes. And you know that -- you 21 Q Without looking at each of the 22 mentioned earlier that you had looked at four 22 ether patents that were 6-mailed to me 23 patents, and they mere -- a few minute. ago. 23 earlier, without looking at them right now, They were 10-sailed to se. I haven't had a 24 can you tell me generally how they differ, chance to look at then. 25 what they relate to? 24 25 wwwmIldwesdiUgMhmrum Fara 314.644.1334 MIDWEST LITIGATION SERVICES Mee: 1800.2003376 Fax: 314.644.1334 www.mldwertatIgatIon.tem MIDWEST LITIGATION SERVICES Phase: 1.800.2803376 Fax: 314644.1334 Case 3:12-cv-01141-SMY-DGW Document 176-23 *SEALED* Filed 12/01/14 Page 25 of 57 Page ID #2758 Case: 16-3334 Document: 55-50 Filed: 02/08/2017 Pages: 57 (1452 of 1511) 2/18a014 DAVID WALKER DAVID WALKER 2182014 Page97 1 A Fege99 Some of the features described 1 marketed this patent? with COSOPT that is not covered by 2 in the other patents include, for example, 2 3 the ability to pierce the dropper tip with a 3 4 motion used for unscrewing the cap from the 4 Calla for a -- objection to the form of 5 bottle. 5 the question. 6 question. 6 So the cap had a feature inside MR. STRAUSS: Object -- that The foundation of the It's irrelevant to the case. 7 of it for opening this thin membrane so the 7 It's not on the notice. 8 dropper tip could dispense medication, but 8 discovery order by the judge, and it calls for a legal conclusion. 9 patients didn't need any sort of different 9 10 training to be able to open the bottle and 10 11 pierce the membrane and the tip. 11 They simply 12 unscrewed the cap, and the cap did the 12 13 opening of the tip. 13 14 Q 15 patent in PL 3605? Isn't that also covered in the The notice did MR. STRAUSS: notice did not cover patent claim construction at all and -- A (Reviewing.) 16 Q If you would look at Page 3608, 17 the column that's headed 4, at line 50, MR. CORNFELD: cover patents, but go ahead. 14 16 in Subject to that, you can answer. 15 17 18 It's beyond the 18 MR. CORNFELD: Excuse me. The I am not going to -- I am not going to argue about it. 19 doesn't that refer to the process. you just 19 You will allow the witness to answer. 20 mentioned 20 would like his understanding. 21 top when you open the bottle' 22 A 23 Q 24 25 about breaking the mmmbrane at the It describes that. MR. STRAUSS: Okay. THE WITNESS: I don't Okay. 23 understand why there were different So that'. covered in this 24 patents filed other than this one. patent as well, correct? wvflwaddweddligadonnom 21 22 25 BY MR. CORNFELD: MUDPOSTTLITIGA11014SERVICTS Mae: 1200.280.3376 Fes: 314344.1334 I wwv,midwedlidgadon.com MIDWEST LITIGATION SERVICES Phew: 1.8002803376 DAVID WALKER 2ne2014 DAVID WALKER 2n82014 Page 90 1 2 4 5 Object to the 1 2 Down:eater THE WITNESS: (Reviewing.) 3 by the patent that's in PL 3605? There's descriptions of that BY MR. CORNFELD: 7 Q 9 I an not • patent lawyer and -- here. MR. STRAUSS: 5 form. 6 legal conclusion. 8 separate patents for that when it'. covered 9 But what I -- you know, I read this Is there a feature of the Plus as marketed that i. not covered 7 so I don't know why they would submit 10 Q 4 feature here. 6 8 Page 100 MR. STRAUSS: form. 3 10 The foundation. THE WITNESS: covers most of the - Object to the It calls for a This patent or all of the features as I understand are possessed by Ocumeter Plus. 11 patent and as we go through it or we talk 11 BY MR. CORNFELD: 12 about it, if there ix something that it 12 Q 13 different from the Ocumeter Plus product that 13 14 was marketed, you will let ma know, okay? 14 Ocumeter Plus that's not covered by this 15 MR. STRAUSS: 15 patent, PL 36057 16 17 No. Object. He won't let you know. I 16 form. MR. CORNFELD: 18 conclusion. Well, then tell 19 20 21 23 MR. STRAUSS: 17 19 22 All right. Can you think of any feature of mean, what kind of question is -- 18 MR. STRAUSS: What kind of 20 question is that? 21 BY MR. CORNFELD: 0 Well, 22 I'm asking, in looking at Foundation. Object to the Calls for a legal THE WITNESS: No. BY MR. CORNFELD: Q If you turn to the page with the Bates number PL 3607, do you :see in 23 column 1 there is a discussion of the 24 the patent that ' • 3605 to 3609, is there 24 background of the invention? 25 anything about the Odometer Ply. that was 25 www.midwestlidgatIonrom MIDWEST LITIGATION SERVICES Phone: 12001E03376 Fez: 314.644.1334 Fax: 314.644.1334 A wee.nidweellidgation.corti ( Reviewing. ) MIDWEST LITIGATION SERVICES Phone: 1.500.2110.3376 F.: 314.644.1334 Case 3:12-cv-01141-SMY-DGW Document 176-23 *SEALED* Filed 12/01/14 Page 26 of 57 Page ID #2759 Case:DAVID 16-3334 Document: 55-50 Filed: 02/08/2017DAVID WALKER Pages: (1453 of 1511) 2/18/2014 57 WALKER 2/182014 Page 103 1,' Page 101 1 Q 2 Yes. 1 And in the third paragraph it 2 BY MR. CORNFELD: You would have the fluid in the Q bottle, the patient would turn over the 3 states that one problem associated with 3 4 conventional eye droppers is the difficulty 4 bottle in order to omit a drop, and for the in accurately controlling the amount of 5 medication to get from the bottle into the medication dispensed, i.e., the number of 6 tip so it could be dispensed in the eye, drop. dispensed, correct? 7 there would be a very tiny hole it would have to go through, correct? 5 6 7 8 9 A I see that. 8 4 And that's -- that's the 9 A Yes. 10 0 Sometimes called en orifice, we were talking about -- at least one of the 10 correct? 11 ilseues that the °coaster Plus was designed to 11 12 address, making sure only one drop, not more 12 A Yes. 13 than one drop, would be dispensed, correct? 13 Q Sometimes called an inner 14 orifice, correct? MR. STRAUSS: 14 form. 15 16 17 time. 18 to the outer orifice, which is the opening in 19 the tip through which the drop is emitted so 20 that it can enter the patient's eye? BY MR. CORNFELD: 19 20 So that is a "yes" to my Q Well, inner orifice as opposed cl MR. STRAUSS: 21 question. 21 I hadn't heard that term used. Ocumeter Plus was THE WITNESS: 18 I don't know. A 15 Foundation. designed to help administer one drop et a 16 17 Object to the 22 form. 22 This issue of eye droppers THE WITNESS: 23 dispensing more than one drop was an issue 23 24 that the Ocumeter Plus was designed to 24 25 address, correct? 25 wwwroldwateUgadonrem allIPNESTLfrIGATODNSERVICES Phone:1.800.28033Th Fa:314.644.1334 Objection to the Foundation. I understand the distinction you have made. BY MR. CORNFELD: www.coldwestlitlgalienrom MIDWEST LITIGATION SERVICES Phone: 19002803376 DAVID WALKER 1182014 DAYD3WALKER 2/182014 Page 104 Page 102 1 2 So if I -- if I refer to that A Yes. 1 Q And the patent goes on in the 2 little orifice -- that tiny orifice between 3 the bottle and the tip as the inner orifice, Q 3 paragraph, "We have been looking at to say 4 that most conventional eye dropper dispensers 4 you will know what I am referring to, 5 utilised one of two or a combination of these 5 correct? method. to achieve single drop control." 6 6 7 Do you see that? 7 8 A Yes. Q And if I refer to the opening in the tip that the drop comes out of so that S A Yes. 9 Q And then there's a discoeetion 9 10 in the neat two paragraphs of those methods, 10 outer orifice, you will know what I as 11 correct? 11 referring to, correct? it can drop into the patient's eye as the 12 A Yes. 12 A Yes. 13 Q The Ocumeter was the first 13 Q The problem that is discussed 14 method, correct? 15 A 14 in this patent in the paragraph regarding 15 method 1, at least one problem is that by 16 using this method, tail flow restriction, it 17 made the bottle difficult to use by some 18 older people or people with disabilities, And the way that method worked 19 correct? 20 was to have the fluid enter the tip through a 20 21 very tiny orifice from the bottle resulting 21 22 in a flow restriction, correct? 17 18 19 Object to the form. BY MR. CORNFELD: '2 23 fe Yes. MR. STRAUSS: 16 MR. STRAUSS: Object to the THE WITNESS: Yes. form. 25 wwwwildwestIlligstionsom MIDWEST LITIGATION SERVICES Phone: 1.800.280.3376 Far: 314.644.1334 Fax: 314.644.1334 MR. STRAUSS: Object to the 22 THE WITNESS: (Reviewing.) 23 It says it made dispensing of form. 24 drops more difficult, especially for 25 older patients, as well as those with war w.mlelwestlitlgationron. MIDWEST LITIGATION SERVICES Phone: 1.300280.3376 Far: 314.644.1334 Case 3:12-cv-01141-SMY-DGW Document 176-23 *SEALED* Filed 12/01/14 Page 27 of 57 Page ID #2760 Case:DAVID 16-3334 Document: 55-50 Filed: 02/08/2017 DAVID WALKER Pages: 57 (1454 of 1511) WALKER 2/18/2014 2/18/2014 Page 105 Page 107 physical disabilities. control flow from their bottle. BY MR. CORNFELD: 3 2 And another problem with that Q 4 tiny orifice occurred in manufacturing, 5 Correct? 3 4 column 1, was to make the walls of the bottle rigid, correct? 6 MR. STRAUSS: Object to form. 7 THE WITNESS: It does say that 6 making the small inner orifices does pose 9 So -- the second method that's • referred to in the patent on Page 3607, A Yes. Q But the patent states that that would make the bottle difficult to use for manufacturing challenges. 9 older people and also (INAUDIBLE) -- 10 BY MR. CORNFELD: 10 (Court reporter clarification.) 11 Q 11 MR. STRAUSS: Rick, I'm sorry, 12 Because those orifices or -- I'm sorry, I got to start over. 13 The inner orifice can be as 12 the court reporter didn't hear your 13 question. 14 small as .005 inches or .13 millimeters, 19 15 correct? 15 16 A Yes. 16 17 Q That moans five one-thousandth. 17 18 of an inch, correct? 19 20 Could you report - could you repeat it. MR. CORNFELD: Yeah, sure. BY MR. CORNFELD: 18 The second method was to make Q A Yes. 19 the walls of the bottle rigid and that would Q Is it your understanding that 20 create problems for older people in trying to 21 it can be difficult to manufacture a bottle 21 use it, correct? 22 with a tip that has an orifice that smell? 22 23 24 25 A Yes. 23 Q It would be done by pins or 24 something like that and they can break during MIDWEST LITIGATION SERVICES Phone: 1.800.280.3376 wwwadthwealltlgabeaeom 25 Fes: 314.644.1334 MR. STRAUSS: Object to the form. THE WITNESS: It's described that way. MIDWEST LITIGATION SERVICES Phone: 1.800280.3376 www.midwestlItigadon.com DAVID WALKER 2/18/2014 DAVID WALKER 2/18/2014 Page 106 1 manufacturing and cause problems with that 2 process to manufacture? 3 Page 108 BY MR. CORNFELD: 2 MR. STRAUSS: Objection to the 4 Q And that's true, isn't it? 3 form. Foundation. 4 MR. STRAUSS: Object to the foundation. THE WITNESS: Yes. 6 THE WITNESS: A stiffer bottle BY MR. CORNFELD: would be harder to squeeze, and older Do you have an understanding as 7 to whether other companies also used method 9 10 11 B 1? 9 A I do believe other companies 10 use a similar method. 11 12 Q Which companies do that? 12 13 A I have seen Pfizer's kALATAN 13 19 bottle, and it looked like there was a narrow 14 15 opening within their tip to control the flow 15 16 of medication. 17 Q 18 A 19 20 21 22 patients generally have less grip strength. BY MR. CORNFELD: Q It also 84:ye that the Method 2 bottle would lead to streaming. Do you see that? A Yes. Q So one drop at a time, but it led -- it actually 17 led to even a wore, problem, meaning No. 18 streaming. I mean, other company's bottles 19 How did that happen? 20 I haven't looked at other company's bottles closely. MR. STRAUSS: Object to the 21 form and foundation. Mi scharacterizes 22 the document. 23 Q One way or the other? 23 24 A I haven't looked at other 24 HY MR. CORNFELD: 25 Q 25 company's bottles to determine how they wvom.mldweatIldgetion.eom this was a method designed to prevent a patient from emitting more than 16 Have you seen any others? that use method 1? A Fax: 314.644.1334 THE WITNESS: I am not sure. MIDWEST LITIGATION SERVICES Phone: 1.800.280.3376 Fax: 314.644.1334 www.ceMweatatigationvem You are not sure how Method -- MIDWEST LITIGATION SERVICES Phone: 1.800280.3376 Fez: 314.644.1334 Case 3:12-cv-01141-SMY-DGW Document 176-23 *SEALED* Filed 12/01/14 Page 28 of 57 Page ID #2761 Case: 16-3334 Document: 55-50 Filed: 02/08/2017 Pages: 57 (1455 of 1511) DAVID WALKER 2/18/2014 DAVID WALKER 2/18/2014 Page111 Page 109 1 then, and we'll see how long it takes -- No. 2 how long it lasts. Are you aware of any 3 take very long. a method 2 bottle would lead to streaming? 1 A 2 3 Q other coopanios that use -- or still Imo method 2? 4 The shushing didn't 4 MR. CORNFELD: I'm sorry? MR. STRAUSS: The shushing 5 A No. 5 6 Q Let me see if I understand how 6 didn't take very long. 7 long it lasts. the °hamster Plus worked. 7 10 A Yes. 10 11 Q But there was also a small 11 MR. STRAUSS: 13 made of a thin plastic membrane and easy to 13 14 press, correct? 14 17 18 a way to refer to it. It's where people 20 Q 21 should press on the bottle to get a drop 21 A I don't know. 22 dispensed. 22 Q Yes. Yes. Now, one of the thing. that 23 I know that phrase wan used in Q Scope. Similar to BY MR. CORNFELD: 20 23 Objection to the Relevance. Ocumeter Plus, is that the question? 19 I am not sure, but it would be A Foundation. THE WITNESS: 18 area, correct? 19 MR. STRAUSS: form. 17 And that woo called a target Q -- on an eye drop bottle? Q 16 of the walls of the bottle. 16 Objection. BY MR. CORNFELD: 15 There is a thinner part of one A 15 Did anyone else over use a Q similar method on a bottle -- 12 oo -called target are. on the bottle that was 12 Okay. BY MR. CORNFELD: 9 were pleated and rigid, correct? 9 MR. CORNFELD: 8 Most of the wall. of the bottle 8 We will see how They are quiet now. 24 the -- in the NDA for the °carter -- the 24 would happen with the Ocumeter Plus is 25 supplemental NDA for the Committer Flue, and 25 because there woo just this email amount of MICONESTLIIIGATONWSERNICES Phne:lson2est176 wwwmadmalhhodowano Fax: 314.644.1334 MIDWEST LITIGATION SERVICES Phone: 1.300.2803376 wwwiOdwanlidodboxem DAVID WALKER 2/102014 DAVID WALKER 2I02614 Page 112 Pere 110 1 maybe we will see it as we go on. 2 But you would agree that would 3 make sense to refer to that as a target area, 4 correct? displacement when the user would 2 target area, the uner would be unable to get all of the liquid out of the bottle, correct? 5 A Yes. 6 Q And -- so when a user would 6 press on that target area, the amount of 7 8 displacement would be smaller than it was in 8 9 the older 10 11 MR. STRAUSS: 4 kind 9 of bottle, correct? 10 Yes. A Correct. Q And that smaller amount of pre.. the 1 5 7 The foundation. form. speculation. THE WITNESS: Object to the It calls for I don't know that that's an issue. BY MR. CORNFELD: Q You never heard that there was 11 on issue with the Ocumeter Plus, that there 12 displacement would be just enough to allow 12 would .till be some liquid left in the bottle 13 one to he emitted, correct? 13 when the user could no longer get any out? drop MR. STRAUSS: 14 15 THE WITNESS: MR. STRAUSS: 17 18 15 Yes. 16 Rick, there's 17 18 somebody out in the hall. MR. CORNFELD: 19 I 20 it too. 21 probably should have said something here. It's coming through, and I 22 23 24 19 Yeah, I can hear You know, I was going to . Q Fax:314.644.1334 You -- did you ever hoar that assure that the patient would get out the amount that was on the label? MR. STRAUSS: Object to the form and foundation. 25 MIDWEST LITIGATION SERVICES Phone: 1800.2003376 BY MR. CORNFELD: 22 video. We just shushed I had not heard 21 24 wwwwWamodidgadoosmo THE WITNESS: of that. Merck had to overfill the bottle in order to 23 MR. STRAUSS: Objection to form and foundation. 20 would imagine it's coming through on the 25 MR. STRAUSS: 14 object to the form and foundation. 16 Fax: 314.644.1334 wwwankhymUMptlemsem THE WITNESS: Every liquid MIDWEST LITIGATION SERVICES Phone: 1.0003303376 Fax: 314.644.1334 Case 3:12-cv-01141-SMY-DGW Document 176-23 *SEALED* Filed 12/01/14 Page 29 of 57 Page ID #2762 Case: 16-3334 Document: 55-50 Filed: 02/08/2017 Pages: 57 (1456 of 1511) DAVID WALKER 318/2014 DAVID WALKER 21111/2014 Page 113 Page 115 product has overage included in the fill; 1 There was -- there was what is called a piercing point to do that. 2 any liquid-containing vial has an overage 2 3 included above and beyond the labeled 3 4 claim. 4 There's always -- there's Do you see that in the middle paragraph on Page 9246? 5 always liquid that remains in any bottle 7 you try to dispense from. 7 Q Did you ever learn that thin Yes. It refers to that process as activating the container, correct? BY MR. CORNFELD: 9 A Q 9 A Yes. Q That was done by use of what in 10 was a particular problem that Merck was 10 referred to as a -- kind of a spike, which 11 addressing with the FDA for the Odometer 11 they call a piercing point that was in the 12 Plus? 12 inner nap, correct? 13 A No. 13 A Yes. 14 Q Normally with -- with the prior 14 Q The -- the Ocumeter Plus had 15 kind of bottle, how much liquid would be left 15 16 on the bottom when the user couldn't get 16 A Yes. 17 anymore out? 17 Q And that -- and as you 18 MR. STRAUSS: Objection to the 19 form. Foundation. Relevance. 20 THE WITNESS: I don't know. I 21 hadn't seen any documentation to that 22 23 regard. 25 Q 18 indicated, that method with the piercing 19 point was also patented, correct? 20 A Yes. 21 Q Why was that method used? 22 BY MR. CORNFELD: 24 23 If you would go back to the 24 "Chemical and Pharmaceutical Manufacturing 25 www.mIdwestlItIgatIon.com both an inner cap and outer cap, correct? MIDWEST LITIGATION SERVICES Phone: 1.600.2803376 Fax: 314.644.1334 MR. STRAUSS: Objection to the form. Foundation. THE WITNESS: Method used for what? To open the bottle? To pierce the www.mldwesdhigadon.com MIDWEST LITIGATION SERVICES Phone: 1.800.280.3376 DAVID WALKER 2/18/2014 DAVID WALKER 7118/2014 Page 114 1 Page 116 and Control Documentation," that's headed tip? What is your-- 2 9235 -- or I'm sorry, the first page is Page 2 BY MR. CORNFELD: 3 9235, the document we were looking at before 3 Q 4 and go back to Page 9246. 4 A (Reviewing.) 6 7 second paragraph it says, "Refer to 1 for • 7 8 drawing of the existing container closure 8 9 system and the °comet.= Plus container enclosure system"? 11 A Yes. 12 Si And "1" means Attachment 1 to 13 this document, correct? 14 15 A (Reviewing.) Q There is • footnote on the Right. Rather than having a bottle with the opening already there when the You see at the end of the 10 patient opens the bottle. A By this means the bottle was hermetically sealed, and it allowed the 9 bottle to be filled from the wider opening of 10 the base rather than through a narrow opening 11 of the tip, because the tip and the bottle 12 were one. 13 With the previous Boston 14 rounds, you filled into the bottle and then 15 pushed the tip within the bottle. With the 16 previous page, Footnote 1, that explains 16 Ocumeter Plus, there was no opening in the 17 that. 17 bottle other than the bottom of the bottle to Do you see that? 18 fill through. (Reviewing.) 19 18 19 A 20 21 Yes. Q 22 By doing that then, did that Q 20 create a manufacturing benefit; it was easier All right. 21 to manufacture? We will look at those in a 22 A Yes. 23 Q Regular -- I shouldn't say 23 moment, but first, as long as we are on this 24 document, I want to ask you about what it 24 regular, but other types of eye drop bottles, 25 says about piercing the hole in the tip. 25 not the Ocumeter Plus, they maintain their www.mldwestlidptIoncorn MIDWEST LITIGATION SERVICES Phone: 11100.260.3376 Fax: 314.644.1334 Fax: 314.644.1334 www.nddwestlitlgatIon.com MIDWEST LITIGATION SERVICES Phone: 1.800.230.3376 Fax: 314.644.1334 Case 3:12-cv-01141-SMY-DGW Document 176-23 *SEALED* Filed 12/01/14 Page 30 of 57 Page ID #2763 =2014 57 Case:DAVID 16-3334 Document: 55-50 Filed: 02/08/2017DAVID WALKER Pages: (1457 of 1511) WALKER 24182014 Page 119 Page 117 1 seal by having something -- a seal put over 1 2 the cap, correct? 2 MR. STRAUSS: 3 That is more of a A 3 the seal is protecting the drug? Foundation. tamper evident feature to show that the cap 4 5 has never been removed from the bottle prior 5 6 to the patients getting the bottle. 6 MR. STRAUSS: 7 THE VIDEOGRAPHER: 9 MR. STRAUSS: 12 That's fine. This is what we get -- we asked the 13 Now they are 14 people to be quiet. 15 tormenting us electronically. fine. 16 As long as you don't hear it. 11 have a hundred percent container Closure 12 integrity testing performed because it was a 13 bottle closed by heat fusion and the 14 regulations in Europe require 100 percent 15 inspection of any container closed by heat 16 fusion. 17 I don't hear it, MR. CORNFELD: 17 That's The Ocumeter Plus bottle had to A 10 anything. 11 Don't they have to go through ca that type of testing too? 9 It's faint. I don't hear MR. CORNFELD: 10 integrity of a bottle. BY MR. CORNFELD: 8 clicking noise on the video? 8 Sterility testing is not a means of assuring closure 7 Can you hear this Calls for speculation. THE WITNESS: 4 Form. Objection. Do other eye drop bottles have Q 18 but I don't have the videotape. I just 18 to have that type of testing if they are 19 have, you know, the video conferencing. 19 not -Yes, there are -- there are A I was just Making 20 21 sure -- I just was making sure in between 21 other types of bottles that are formed by a 22 your questions, and the videographer said 22 manner called blow-field -- blow-fill-seal; 23 that is, where resin is extruded, blown into 24 the shape desired and then the medication is 25 filled into the -- that formed polymer shape MR. STRAUSS: 20 23 that it's not a problem. faint. 24 25 So we are fine. It's just I just wanted to make sure. ..„ „ ..„ wwwaoldwadMiplimunm MIDWEST LITIGATION SERVICES Pbum:IROOMITO6 Fee: 314.6441334 www.midweatlitigatioasom . ... MIDWEST LITIGATION SERVICES Phone: 1.800.286.3376 DAVID WALKER 2/10/2014 DAVID WALKER 2I3/74114 Page 120 Page 118 1 and then the opening through which the drives you crazy, we can -- I don't know, 2 filling occurred is sealed so now that take a break or something. 3 package has been closed by heat fusion and, 4 therefore, such blow-fill-seal products must MR. CORNFELD: 1 2 3 Well, if it No. No big deal. 4 MR. STRAUSS: 5 I was just making sure it wasn't 5 be 100 percent inspected for closure 6 something I could turn off. 6 integrity. 7 0 9 7 BY MR. CORNFELD: Q 8 All bottles need to go through Q A bottle Of the Ocumeter type, iS that a blow-filled type of bottle? A 9 testing to make sure that they stay -- that No, because those are discrete 10 the drug stays sterile inside during the 10 components, and they are not closed by heat 11 shipping process, correct? 11 fusion. MR. STRAUSS: 12 13 form. 14 Foundation. 12 Object to the 13 Scope. Q Did those bottles, the °coaster type of bottles, have to go through container Go ahead. 14 closure testing of the nature that you just THE WITNESS: described? We have to test 15 16 the sterility of the product within the 16 17 bottle after the bottle has been filled, 17 18 so that's that release. And we test the 18 19 sterility of the product through its 19 the Geometer Plus bottle, that the container expiree-dating period. 20 closure integrity -- that something would 21 happen to the container closure integrity All right. 22 during shipping? So wouldn't that indicate that 23 A No. Si But according to Kuma it is a 15 20 21 22 BY MR. CORNFELD: Q 23 24 even using other methods of sealing the 24 25 bottle, as long as they pass that teat, that 25 www.midwestIlligation.com MIDWEST LITIGATION SERVICES 1.11406M: 1.300.2303376 Fee: 314.6441334 Fax: 314.644.1334 A No, there's not a regulatory requirement for that. Q Is that a significant risk with risk with a bottle like the Connate= Plus www.moklwasIIMIggionAam MIDWEST LITIGATION SERVICES Flamm: 1.1002110.3376 Fax: 314.644.1334 Case 3:12-cv-01141-SMY-DGW Document 176-23 *SEALED* Filed 12/01/14 Page 31 of 57 Page ID #2764 Case: 16-3334 Document: 55-50 Filed: 02/08/2017 Pages: 57 (1458 of 1511) DAVIDIVALRER 2/18/2014 DAVID WALKER 1/182014 Page 121 Page 123 1 whore the -- where heat is used, so that that 1 2 testing has to be done? 3 4 2 integral bottle and tip, not discrete bottle Object to the 3 and tip like Ocumeter, and then there was the 4 plug that is heat-sealed against the bottle THE WITNESS: There is a risk 5 after filling. 6 to bottles and other forms closed by heat 6 7 fusion such as ampoules. For example, if 7 8 a drop during the filling process dripped 8 9 We had an MR. STRAUSS: form. 5 outer cap that fit together. from the filling needle onto one of the 9 Q Okay. so there are -- there are several component., and when a patient actually has the bottle, he can take them 10 surfaces that's supposed to be closed by 10 apart so there can be two pieces, so to 11 heat fusion, that liquid would inhibit 11 speak? 12 the heat fusion process, and you wouldn't 12 A Yes. 13 get a good seal formed. 13 Q Two caps that are put 14 Imagine trying to heat an 14 15 ampoule with a flame and water is in the 15 16 glass; the water is going to cool the 16 17 glass, come boiling out. 18 to allow the glass to close on itself. 19 20 It's not going BY MR. CORNFELD: Q together -- go ahead. A 17 the bottle and dispense medication to their 18 eye. 19 Would you take a look at Page The patient would have a cap to remove from the bottle, so they can invert 20 Q You see that it states that the inspection, referring to the inspection by 21 9247, please. 21 Betts, includes dimensional and visual 22 specifications and routine tests under 22 examination. 23 heading 2. 23 24 25 A wwwarldwedlitigsdourem Hero is another discussion of Do you see that? Do you see that? 24 A Yes. Yes. 25 Q And that's on Page 9247. www.rolderedlltIgationrom MIDWEST LITIGATION SERVICES Phone: 1.800.280.3376 MIDWEST LITIGATION SERVICES Phone: 1.800.280.3376 Fax 314.644.1334 DAVID WALKER 2/18/2014 DAVID WALKER 2/18/2014 Page 122 1 CI Is this, again, something that Page 124 1 Do you know what dimensions 2 I should ask Mr. Grossman about because he 2 3 would b. the person knowledgeable about this? 3 A No. 4 0 If you look at the 4 5 MR. STRADSS: 7 8 9 10 Object to the form. 6 5 THE WITNESS: I think it would depend on the particular question you had. second-to-last paragraph on Page 9247, you 6 see there is a reference to 7 assembled bottles. A All right. 9 The first senten sentence 10 11 gays, "Cash lot of individual parts, bottom 11 12 closure, inner cap, outer cap and bottle is 12 13 sampled, inspected and released by Betts." 14 Botts inspects? 8 BY MR. CORNFELD: Q Do you see that? inspection of the (Reviewing., It says visual testing includes flash, color-stained and misassembled parts. Q Be are not looking at the same -- I was looking at the second-to-last 13 paragraph on Page 9247. 14 of the final Ocumeter Plus assembled bottle. It states, "Each lot 15 A Yea. 15 is also sampled, inspected and released by 16 Q And there they do refer to the 16 netts.. 17 18 19 20 bottle having different components, correct? 17 A I see that. A Correct. 18 0 You see that? Q The difference differen is -- well, 19 A Yes 20 CI And -- okay. strike that. 21 You said this was all one 21 Earlier -- the earlier 22 system without different parts, so what does 22 23 this seen here when it'• referring to four 23 ago had to do with the individual parts, but 24 different COMponenta? 24 this is looking at the assembled bottles, 25 correct? 25 A www.mIdweatlillgallocrom Well, we had the inner and MIDWEST LITIGATION SERVICES Phone: 18001903376 Flu: 314.644.1334 Fax: 314.644.1334 inspection we were looking at just a moment wwwaddwesflitigedosrom MIDWEST LITIGATION SERVICES Phone: 1.8002803376 Fax: 314.644.1334 Case 3:12-cv-01141-SMY-DGW Document 176-23 *SEALED* Filed 12/01/14 Page 32 of 57 Page ID #2765 WALKER 2/180014 Case:DAVID 16-3334 Document: 55-50 Filed: 02/08/2017 Pages: 57 (1459 of 1511) DAVID WALKER 2/18/2014 Page 127 Page 125 BY MR. CORNFELD: A Yes. Q Do you know what dimensions ars 2 • What &lee? 3 looked at there, in that inspection of the 3 A There would have to be several 4 assembled bottles? 4 more. This isn't enough to adequately No. 5 describe the bottle. 2 A 5 specification. that Mick submitted to the functional testa that are done. Do you know what theme are? 8 A No. 9 Q The final paragraph on Page 8 9 10 Were any other. part of the Q It state. that there are FDA? MR. STRAUSS: Object to the form and foundation. 10 THE WITNESS: There would have 11 9247 states, "Each lot of Ocumeter Plus 11 12 assembled sterilised bottle. received at 12 to be more than this to provide a 13 Merck is subjected to an inspection." 13 dimensionally, sufficiently detailed 14 14 15 15 A Yes. 16 Q And there's AQL, Acceptance 18 19 20 A Q BY MR. CORNFELD: 16 What other dimensions would Q 17 have been provided to the rDA for the Do you see that? 18 Ocumeter Plus in the specification.? Yes. 19 All right. 20 Quality Level. 17 description of the bottle. Do you see that? So I am not sure which A 21 It states that the inspection 21 What other dimensions besides the three that are listed here? 22 by Merck was for conformance to the 22 specifications would have been submitted to 23 parameter. and specification., correct? 23 the FDA, but there are more specifications 24 A Yes. 24 required for the dimensions of the bottle to 25 51 And it says, "Routine 25 have the proper components molded by Betts. MIDWEST LITIGATION SERVICES Phone:1.800.280.3376 www.midwestlitigation.rom For: 314.644.1334 vewwiedwestlitigation.com MIDWEST LITIGATION SERVICES Phone: 1100.280.3376 DAVID WALKER 2/180014 DAVID WALKER 2/180014 Page 128 Page 126 inspection by Merck will include dimensional 2 checks such a. overall height, inner disinter 2 3 of the bottle at the base and outer diameter 3 4 of the bottom closure at the base." 4 A 6 7 8 9 Q Do you know if there are any tolerances would be required. those three? 9 Were there any other dimension. 10 submitted to the FDA for the Ocumeter Plus Are those the dimensions that 11 beside■ the overall height, the inner were part of the specifications for the 12 diameter of the bottle at the base, and the bottle? 13 outer diameter of the bottom closure at the 14 base? Q A Q Those three? 15 16 A Those would be part of the 16 17 specification. A I don't know what other dimensions were submitted to the FDA. Q Do you know if there were any 18 other dimensions that were submitted to the of the specifications for the Ocumeter Plus 19 FDA besides those three? bottle? 20 Q 18 Were any other dimensions part 21 MR. STRAUSS: Objection to the 21 22 Q included in the specifications that Merck No, I don't know. A 15 20 filling line and reliably seal with the Mirabel, the dimensional specifications and 14 19 To have the proper component 7 Yes. 17 A molded by Betts that would reliably fit our 6 other dimensions that are checked besides 11 13 Were any -- I'm sorry? Yes. 8 10 12 • heat-sealing process that was validated for Do you see that? 5 form. Foundation. THE WITNESS: There would be 23 If you would look at Page 9254. Q A (Reviewing.) Q Do you see Paragraph F refers 24 25 specification. 25 ram 314.694.1334 I don't know if others were 23 more than those as part of the MIDWEST LITIGATION SERVICES Phone: 1800.280.3376 A submitted. 22 24 rnyvuoldwestlitigation.cam Fax: 314.644.1334 to specifications and test method.? www.midweselltIgalloo.cae MIDWEST LITIGATION SERVICES Phone: 1.600.280.3376 Fax: 314.644.1334 Case 3:12-cv-01141-SMY-DGW Document 176-23 *SEALED* Filed 12/01/14 Page 33 of 57 Page ID #2766 WALKER 21182014 Case:DAVID 16-3334 Document: 55-50 Filed: 02/08/2017 DAVID WALKER Pages: 57 (1460 of 1511) 2784014 Page 129 1 2 3 A Yes. Q And it states that the 4 A Yes. Q Are the es the type of 8 i Ocumeter Plua on Page 9261 and following, correct? THE WITNESS: This is referring 9 form. 11 12 to the solution within the bottle. BY MR. CORNFELD: 14 I just want to make nu sure that I S 15 don't -- I shouldn't ask you about it) I 16 should ask Mr. Grossman. 17 A All right. 0 Nell, when we looked at the And first we have dimensions for the Ocumeter and then we have 10 the dimensions for the °ammeter Plus, 11 correct? 12 A Yes. 13 Q And the °coaster ha.page. for 14 each of the pa., rt including dimensions for 15 the Ocumeter tip on Page 9267 correct? A Yes. GI Let (Reviewing.) 18 Q (Reviewing.) Yes. 17 these. 19 A 16 He may be better than I for And Attachment 1 is the .at of 4 8 Objection to Q 5 7 MR. STRAUSS: Yes. dimensions for both the Ocumeter and the to the actual drug that would be within Mr. Gro..man . . area of knowledge? A 3 6 10 18 2 specifications that we talked about earlier 9 13 g specification. for COSOPT remain unchanged? 5 6 Page 131 1 19 me ask you just a couple of questions about this diagram. 20 earlier specification. and said these are 20 21 unchanged, you said you weren't familiar with 21 22 those and I should oink Mk. Grossman. 22 the diagram of the tip but the other part. of 23 still the cm? 23 the Ocumeter ae well, correct? 24 A Yes. 25 Si All right. wwwraldwo.Magadmurm Is that MIDWEST LITIGATION SERVICES MommlAUMMM21376 Far: 314.644.1334 I mean, there are lots -- there are lots of dimensions on actually not just 24 A Yes. 25 12 Are these dimensions in inches? www.addwestlltigadonrom MIDWEST LITIGATION SERVICES Phone: 1.000250.3376 DAVE/W.1.MM MADAM DAVID WALKER 276/2014 Page 130 1 Would you take a look at the -- 2 the big exhibit with the attachments, the one 3 that starts with Page 9259. 4 5 Page132 1 And you moo those are the attachments to the document we just MR. STRAUSS: 2 are you on, or which one are you asking 3 about? 4 been Rick, what page MR. CORNFELD: The Ocumeter 5 dimensions, specifically the tip on Page 9267. 6 looking at, which is the chemical and 6 V pharmaceutical manufacturing and control 7 MR. STRAUSS: Okay. 8 documentation in the supplemental NDA that 8 THE WITNESS: (Reviewing.) 9 Merck submitted to the sm. for the Ocumeter 9 Yes, they are in inches. 10 nu.? 10 11 MR. STRAUSS: Objection. To 12 the extent that is a question, I object 13 to it. But go ahead. 15 THE WITNESS: 16 17 (Reviewing.) It is a list of attachments. Q BY MR. CORNFELD: 4 12 that has a number 40 and a circle by it? 14 A Yes. 15 Q All right. 17 And these are the attachments to the document that we have been looking at, All right. Do you sea there's a dimension 16 BY MR. CORNFELD: 18 19 11 13 14 And that dimension is .062 die __ die., D-I-A, period, meaning diameter? 18 A Yes. 19 Q And that'. the dimension for 20 which is the chemical and manufacturing -- 20 the outer orifice of the dropper tip of the 21 ...au.. me, the chemical and pharmaceutical 21 °ammeter, correct? 22 manufacturing and control documentation 22 23 submitted by warck for -- as part of the 23 24 supplemental NDA for the Ocumeter Plus, 25 correct? wwwAddwesUldgathmAmm 24 A Fax:314.644.1334 (Reviewing.) There's also a diameter of .093 that's further out. 2 5CI MIDWEST LITIGATION SERVICES Phone: 1200.2503376 Fax: 314.644.1334 wwwaddweadidgadenrom Right. I wao going to get to MIDWEST LITIGATION SERVICES Phase: 1500215.3376 Fax: 314.644.1334 Case 3:12-cv-01141-SMY-DGW Document 176-23 *SEALED* Filed 12/01/14 Page 34 of 57 Page ID #2767 2/182014 57 Case:DAVID 16-3334 Document: 55-50 Filed: 02/08/2017DAVID WALKER Pages: (1461 of 1511) WALKER 2/182014 Page 135 Page 133 9267, was .093 inches, correct? that in a second. Okay. A 2 3 But the actual -- the hole 3 A Yes. Q And that dimension is by the number 39 in a circle, correct? 4 through which the drop comes, that • 4 5 .062 inches in diameter, correct, according 5 A Yes. 6 Q What does that number and the to the diagram on Page 9267? 6 8 A Yes. 7 Q All right. 8 And then, of course, if there 9 9 10 is a hole, there is a part of the tip that is 11 around the hole, correct? 11 MR. STRAUSS: Objection to the form. 13 to be something there. 15 Q 17 18 It's not a cylindrical hole at the very end, 13 but rather there's some depth. You see circled 42. depth of .010, so you have a larger diameter at the very end of the tip and it tapers a 17 little going inward on the tip. It's sort of a ring of plastic 18 19 the 40 mean? Is that to mean that -- why -- A Right. 20 21 Q -- that surrounds the hole? 21 Okay. Nave you seen that 22 24 25 But my question is what does Q 20 23 There is a 15 16 19 22 slope or a chamfer at the end of the tip. 12 All right. BY MR. CORNFELD: 16 Well, number 40 refers to -- if you see, there's a bit of a, I don't know, a 14 THE WITNESS: Yeah, there has 14 a circle, what do those nunhers refer to? A 10 12 number 40 that we just looked at, which is in why is that a 40? What does that refer to? referred to as -- that whole outer part with 23 A Well, I imagine -- the hole and the ring of plastic around it as 24 Q Is there a list somewhere? the platform? 25 www.midwestlitigstion.com MIDWEST LITIGATION SERVICES Phone: 1.808.280.3376 (Simultaneous Conversation.) MIDWEST LITIGATION SERVICES Fax: 314.644.1334 www.midweedklgatioarom Phone 1800180.3376 DAVID WALKER 2/18/2014 DAVID WALKER 2/18/2014 Page 136 Page 134 A 3 A I don't know. I never had to 4 Okay. 6 Q 7 Noll, the whole portion, that 7 tip of the dropper tip, correct? MR. STRAUSS: Object to the form. 11 14 Do you see that -- that starts 8 at Page 9269 with the title page and then 9 there's the series of diagram.? 10 A Yes. 11 Q Page 9270 is a diagram of the the part of the tip closest to a 13 separate and combined in the finished patient's eye when delivering medication. 14 container, correct? 15 A Yes. Okay. 16 Q Is the piercing point or spike And if I -- if we refer to that 17 BY MR. CORNFELD: Q 16 for the Oconeter Plus. various parts of the Ocuneter Plus, both THE WITNESS: That's -- that's 13 All right. 12 12 15 Q Now, let's look at the diagram ring with the hole in it, is the wary tippity 10 So, yes, I imagine there is a list elsewhere besides on this diagram. refer to it. 6 9 A 2 3 ring -- that ring of plastic as? 4 5 (Reporter Clarification.) I have not heard that term. What would you refer to the 2 17 shown in this diagram -- on this page? 18 whole area as the platform, will you 18 A Are you on Page 9270? 19 understand that that's what I am referring 19 Q Yes. 20 to? 20 A No, the piercing point is not Q All right. 21 A Yes. 21 22 Q Okay. 22 And the diameter of the 23 23 shown. Than the nest page, Page 9271, 24 platform on the Ocumetar, according to the 24 again shows the various parts of the two 25 diagram submitted to the FDA by Merck on Page 25 typos of Ocumeter Plus containers, one with a www.midwesthdrationsam Fax: 314.6441334 MIDWEST LITIGATION SERVICES Phone: 1.800.280.3376 Far: 314.644.1334 wwwwdehredlldration.00m MIDWEST LITIGATION SERVICES Phone: 1.800100.3376 Fax: 314.644.1334 Case 3:12-cv-01141-SMY-DGW Document 176-23 *SEALED* Filed 12/01/14 Page 35 of 57 Page ID #2768 Case: 16-3334 Document: 55-50 Filed: 02/08/2017 Pages: 57 (1462 of 1511) DAVID WALKER 2/11/2014 DAVID WALKER 2/18/2014 Page 137 Page 139 long plug and one with a abort plug. 2 Is that right? 3 A Is the -- is the spike shown on plug, correct? 7 the membrane at the top, the membrane which 9 What does the B refer to? 11 All right. 13 diagrams. 10 Yes. Q There i• -- there is a letter on the diagram in the top left corner of the is pierced by the spike? 12 But the spike itself is not shown? A A Correct. From the diagram that appears 12 to be the overall height of the bottle itself 13 from base to tip. 14 15 (Reviewing.) 9272, short plug, yes. The bottle on Page 9271 ahoy. 11 14 4 No. However, if you look at Q 9 that is the Ocumeter Plus with the short A A the bottle, the membrane is shown in the tip. 10 So if we look at Page 9272, 3 this page? 6 All right. 2 Yes. 4 5 • Q Does the B go to that table on 15 the left where there is a aeries of line. A, B, C, D, 9 end V in the left-hand column? 16 All right. 16 17 And on neither pages 9270 or 17 A I would expect so. 18 Q All right. 18 9271, are there any dimensions, correct? 19 (Reviewing.) A 20 19 No dimensions. 20 The B is in a column that's headed with the word. T -0-7 -IC -S. 21 All right. 21 22 Now, would you look at Page. 22 A Q 23 9272 -- if you can look at 9272 and 9273 23 24 together -- 24 25 A www.roldwestlItigatIon.com (Reviewing.) MIDWEST LITIGATION SERVICES Phone: 1.500.2803376 25 Few: 314.644.1334 Do you know what that means? No. All right. The B has some writing opposite that says, Datamyta -A-T -A-N-Y -T www.nddwesifingotion.com CGS, 2 MIDWEST LITIGATION SERVICES Phone: 1300.280.3376 DAVID WALKER 2/18/2014 Far: 314.644.1334 DAVID WALKER 2118/2014 Page 138 • Page 140 -- thee. are diagrams of the LG-48. 2 two versions of the bottle, one with the 2 3 short plug and one with the long plug, 3 4 correct? 5 4 MR. STRAUSS: Objection to form. 7 THE WITNESS: (Reviewing.) 8 Yes. 9 11 12 A 14 Q You see that a lot of thee. two 13 12 diagrams are in French? Yes. I don't speak or read French Can you translate any of this 21 23 A (Reviewing.) o Thews diagram. on Page 9272 or THE WITNESS: I am not sure what it means. BY MR. CORNFELD: Q and so I was guessing one meant minor and the 15 other meant major. MR. STRAUSS: It's interesting. BY MR. CORNFELD: 18 Q 19 A No. 20 Q And then there's a column 21 9273. I can't translate them; 24 however, I can tell from the drawings what 25 the circled letters are representing. www.roldweatIlagatlonnom MIDWEST LITIGATION SERVICES Phase: 1300.250.3376 Do you know what that means? 23 A No. 24 Q And the numbers below those 25 Fnx:314.644.1334 Do you have any idea? special IA-A-J-9-0-A. 22 A The next column is N-A-J-E-U-A, 14 17 on the page for ee? 20 form. 16 either. 18 22 MR. STRAUSS: Object to the 10 A 19 spelled M-I-N-B-U-A. 11 Q 17 6 I don't speak French. I don't 15 The other columns in the table -- there is a column headed with a word Bow is your French? 16 Q 5 9 read French. 13 No. Can we guess that mean. minor? BY MR. CORNFELD: 10 Do you know what that means? A word, in the top row, 2.5, 0.40 and 0.10, do www.ndavese0ItlentIon.com MIDWEST LITIGATION SERVICES Phone: 1.800.2803376 s Fax: 314.644.1334 Case 3:12-cv-01141-SMY-DGW Document 176-23 *SEALED* Filed 12/01/14 Page 36 of 57 Page ID #2769 2/10/2014 57 Case:DAVID 16-3334 Document: 55-50 Filed: 02/08/2017DAVID WALKER Pages: (1463 of 1511) WALKER 2/18/2014 Page 143 Page 141 A 2 3 2 3 A I see that as circled letter E. 4 Q All right. 6 Yes, that's where the short 7 plug enters the base of the bottle so they 27.75 millimeters plus or minus 5 (Reviewing.) A Where -- where is that? Na. Detail Y on Page 9272, can you tell me what that is? 4 0.10 as shown on Page 9272, correct? 7 can be sealed together by heat. 8 Thane are dimensions, and we 10 A Yes. Q What are those? A They are circled letter A, the 11 have already aeon one, shown on pages 9272 12 and 73, Correct? 12 13 A Yes. 13 14 Q And you pointed out that there 14 bottle with the cap. Circled letter F, the length of the short plug. is a dimension for the overall height, which 15 16 is 63.00 plus or minus 0.2 by the letter B on 16 17 Page 92727 17 21 19 on Page 9273 for the bottle with the long 20 thickness of the target area? plug, correct? 21 And the lama dimension is shown Q 22 A Yes. 23 Q What is the plus or minus mean? 23 That's the tolerance. That's 24 A 24 25 how much that overall height could vary, from www.mldweatiftlaatImuom MIDWEST LITIGATION SERVICES Phone: I Wm fax 3376 Feb 314.644.1334 It appears to be the wall A 22 25 That', the wall thickness in Q the pleated portion, or is it the well 19 20 Circled letter D, the wall thickness of the bottle. 18 Yes. A 18 Yes. Are there other dimensions on 10 11 15 A • the diagram on Page 9272? 9 All right. Q 9 Yes. A 1 you know what they refer to? thickness just above the base, so neither the pleated portion nor the target area. Are there any other dimensions Q besides what you just referred to on Page www.aiderestlidgedomeom MIDWEST LITIGATION SERVICES Phone: 1.800.280.3376 DAVID WALKER 2/18/2014 DAVID WALKER 2/18/2014 Page 144 Page 142 9273? 63.00 millimeters. Q 2 3 4 Okay. 2 That was going to be my next 3 4 question is what units thee, were in. 9 (Reviewing.) A Same type of dimensions: diameter plug, height of plug, height of assembled bottle with cap, wall thickness of These are millimeters? A Yes. 6 • All right. 7 The passage we looked at 8 8 9 earlier in Merck's submission to the FDA bottle. Q This time the height of the plug is different obviously because we are talking about the long plug, but it's shown by letter F; is that right? 10 referred to the dimension for the inner 10 11 diameter of the bottle at the base. 11 A Yes. 12 Q Is the spike or piercing point Is that shown on Page 9272 or 12 13 13 9273? A 14 Yes. A No. Q So there are no dimensions 15 Q Which dimension is that? 16 A Circled letter C. 16 Q So that's 27.78 plus or minus 17 18 18 0.12; is that right? A 19 Q Again, in mill/astern? 20 21 A Yes. 21 22 Q All right. 22 And is there dimension for the 23 24 outer diameter of the bottom closure of the 24 25 base? 25 www.oldweolitWation.com MIDWEST LITIGATION SERVICES Phone: 1.800.280.3376 presented of the piercing point, correct? MR. STRAUSS: Object to the form. THE WITNESS: 19 Yes. 20 23 shown on either 9272 or 9273? 14 15 17 Fax: 314.644.1334 Fax: 314.644.1334 There are no dimensions here for the piercing point. BY MR. CORNBELD: Q Do you know if Merck ever gave those dimensions to the FDA? A www.midwestfitigatIonaom (Reviewing.) I don't know. MIDWEST LITIGATION SERVICES Phone: 1.800.280_3376 Fax: 314.644.1334 Case 3:12-cv-01141-SMY-DGW Document 176-23 *SEALED* Filed 12/01/14 Page 37 of 57 Page ID #2770 WALKER 2/18/2014 Case:DAVID 16-3334 Document: 55-50 Filed: 02/08/2017 DAVID WALKER Pages: (1464 of 1511) 2/10/201457 Page 145 Q Page 147 The membrane that's -- that the we've called the inner orifice? 2 piercing point or spike pierces, thee. 2 3 dimensions are not shown in the diagrams in 3 opened, the membrane, there's an orifice 4 Attachment 1 of Merck submission to the FDA, 4 remaining. 5 correct? 6 form. 7 11 Q fluid to go from the bottle into the tip and then be emitted further out of that outer BY MR. CORNFELD: 10 So when the patient presses the target area, that causes a email amount of THE WITNESS, Not shown. 9 After the spike of the cap is 5 MR. STRAUSS: Object to the 7 A 9 And that membrane would orifice, correct? 10 constitute what we were referring to as the 11 A Eventually gravity forces pull on the drop to detach it from the tip. 12 platform, the outer -- the outer portion of 12 Surface tension can no longer hold the drop 13 the bottle after it's pierced, the hole in 13 on the tip. 14 the middle, in other words, that ring? 15 16 A 14 No, that would be more like the 15 inner orifice in the Ocumeter tip. 17 Q Q Rut just as the Ocumeter, when a person presses on -- strike that. 16 Doesn't the -- isn't the 17 Just as in the Ocumeter, when a patient is using the eye dropper and p 18 membrane the portion that separates the 18 on it, that first cavees a amall amount of 19 bottle -- excuse no, isn't the membrane when 19 medicine to go from the bottle into the tip through the inner orifice, correct? 20 it's pierced by the spike, doesn't that 20 21 create the hole through which the drop is 21 A Yes. 22 emitted from the bottle? 22 Q And then gravity will cause 23 A No, the tip already has a hole 23 that drop to drop from the tip into the eye 24 in it. If we look at the illustration on 24 through the outer orifice, correct? 25 9272 that has dimension B that goes to the 25 www.mldwestlidgedonsom A MIDWEST LITIGATION SERVICES Phone: 1800.280.3376 Far 314.644.1334 www.eddwestlidgetioncom Gravity will pull the drop from MIDWEST LITIGATION SERVICES Phone: 1.800.280.3376 DAVID WALKER 2/18/2014 DAVID WALKER 2/18/2014 Page 146 1 Page 148 top of the bottle without the cap, there is a the tip once the force of gravity exceeds the 2 hole there at that tip at the highest-most 2 3 region of the bottle there. That's already 3 4 open. The membrane is further down. surface tension holding the fluid to the tip. Q All right. 4 The difference between the 5 °Punster and the Ocumeter Plus being that fi The membrane is analogous to the inner 6 with the °punster Plus, the patient can only 7 orifice you were describing in the Ocumeter 7 get essentially one drop worth of medicine 9 there won't be that phenomenon of casing tip. 9 from the bottle into the tip and therefore Q Is there any diagram that Merck 10 submitted to the FDA that shows that 10 more than one drop to go out of the tip, 11 preexisting hole in the -- that preexisting 11 correct? 12 outer orifice in the Ohmmeter Pls.? 12 13 14 15 A It's illustrated on 9271 and on Q Okay. 13 9270. 16 So if we look at 9270, in the 14 You can answer. THE WITNESS: The deflection 16 from the target area limits how much 17 material could be dispensed each time left-hand diagram where it says bottle, at 18 the very top of that diagram of the bottle, 18 19 that shaded area represents an orifice? 19 20 Q 22 MR. STRAUSS: Object to the form of the question. 15 17 21 Fax: 314.644.1334 Open end of the tip. 20 Okay. 21 So to coopers the Ohmmeter Plus 22 it's pressed. BY MR. CORNFELD: Q All right. A. opposed to the °punster where there's not that -- 23 when it's actually used to the °punster, both 23 A With the Ocumeter -- 24 of those have a little teeny-tiny hole 24 Q Go ahead. 25 between the bottle and the tip, correct, what 25 A With the Ocumeter you can apply wwwiddenaMigotiolion MIDWEST LITIGATION SERVICES Phone: 1800.280.3376 Fu: 314.644.1334 www.reldwestatlgatiolveom MIDWEST LITIGATION SERVICES Phone: L800.280.3376 Fax: 314.644.1334 Case 3:12-cv-01141-SMY-DGW Document 176-23 *SEALED* Filed 12/01/14 Page 38 of 57 Page ID #2771 Case: 16-3334 Document: 55-50 Filed: 02/08/2017 Pages: 57 (1465 of 1511) DAVID WALKER 2/18/2014 DAVID WALKER 2/18/2014 Page 151 Page 149 MR. STRAUSS: Yeah, we can go a tremendous amount Of force and squeeze all the record. 4 4 restriction of the inner orifice in the 5 Ocumeter you can get more then on. drop to go The time is 1:25. (whereupon a Recess Commenced 6 out of the tip, correct? 6 THE VIDEOGRAPHER: Going off 3 So that even with the flow Q 3 off the record. 2 you wanted out each time. 2 A Yes, that would be possible. Q Whereat with the Ocumeter Plus, at 1:25 and Testimony Recommenced at 2:26.) THE VIDEOGRAPHER: Back on the 9 you have that same amount of flow restriction 9 10 but because of that target area being limited 10 record. This begins Tape Number 3 of 11 , you can only get one 11 where a person p 12 drop to go from the bottle to the tip, 12 13 correct? 13 the deposition. The time is 2:26. BY MR. CORNFELD: 14 A Correct. 14 15 Q All right. 15 I. the -- in the diagrams of 16 16 All right. Q Mr. Walker, I'd like to ask you about Attachment 7 in that list of 17 the Ocumeter Plus, is the dimension of the 17 18 outer orifice shown in the diagram that 18 attachments. it begins on Page 340. It's Merck submitted to the FDA? 19 MACK PRASCO Bates numbers Page 340 -- I'm 20 sorry, it'. 9340; 9340. 19 MR. STRAUSS: Object to the 20 21 22 23 THE WITNESS: (Reviewing.) 22 like to ask you about from this attachment It's not here. 23 starts on 9365. It's the user tact. 25 Q wwwmathnm106gadmumw Okay. I am there. 25 Is the amount of that plastic MIDWEST LITIGATION SERVICES Phone) 1.800.210.3376 (Reviewing.) A 24 BY MR. CORNFELD: 24 Actually, the part that I would 21 form. Foundation. Fax: 314.644.1334 www.aidwestlItIpaloo.eam MIDWEST LITIGATION SERVICES Phone: 1.6001903376 DAVID WALKER 2/18/2014 DAVID WAI KFR 2/18/2014 Page 152 Page 150 Okay. Q 1 ring around the outer orifice, what we have 2 been talking -- calling the platform or the 2 3 platform width, is that shown? 3 earlier in connection with the sutaisaion for the Ocumeter. 4 A No. 4 5 Q Did -- to your knowledge, did 5 6 Merck ever inform the FDA of what those 7 dimensions wore? 8 9 6 11 We talked about user tests Is this the same kind of user test? MR. STRAUSS: Object to the 7 form and foundation. MR. STRAUSS: Object to the 8 THE WITNESS: I don't know. 10 test. Drops were dispensed over a course MR. CORNFELD: Steve, I know 11 of several days during the testing THE WITNESS: It is a similar 9 form. 10 12 it's well into lunchtime where you are, 13 and it's into lunch where I am. Why 12 period. 13 BY MR. CORNFELD: Q Actually, it look. like there 14 don't we break for lunch. I probably 14 15 have no more than a couple of hours left. 15 were drops dispensed for more than several -- 16 it was 31 days on Page 9366, correct? MR. STRAUSS: Okay. When do 16 17 you want to come back? 17 A Correct. Q And on Page 9367 for that user 18 MR. CORNFELD: Should be -- 18 19 MR. STRAUSS: 1:15 central. 19 test, it was drop. dispensed for 62 days, 20 MR. CORNFELD: Yeah, let me 20 correct? 21 if I can ask -- ask you, sir, I don't 21 A Correct. know what the weather is like in 22 Q And that was two drops per day; Philadelphia and -- 23 22 23 THE VIDEOGRAPHER: Do you want 24 25 to go off the record for this? www.midwastlitimatIonsom Fax:314.644.1334 MIDWEST LITIGATION SERVICES Phone: 1500.230.3376 Esc 314.644.1334 is that right? 24 A Yes. 25 Q Now, the line that says wwwaddweanMpstonamm MIDWEST LITIGATION SERVICES Phone: Esoossoans Far: 314.644.1334 Case 3:12-cv-01141-SMY-DGW Document 176-23 *SEALED* Filed 12/01/14 Page 39 of 57 Page ID #2772 Case:DAVID 16-3334 Document: 55-50 Filed: 02/08/2017 DAVID WALKER Pages: 57 (1466 of 1511) WALKER 2/18/2014 2/18/2014 Page 153 Page 155 "reference," is that the specification that 2 must be adhered to? 3 A (Reviewing.) • A It might be material that was 4 6 7 form and foundation. 2 BY MR. CORNFELD: I am unsure. 4 Q Do you know approxinately when? What sloe night it 1.7 5 A I would expect it would be within about a year's time after the not subjected to this periodic regular 7 dispensing from the bottle. So that you have submission. That occurred, I thought was dated February 2nd. a comparison of material that just sat in the 10 THE WITNESS: No. 3 9 bottle and then material that was dispensed 10 11 from a bottle over this course of 31 or 11 12 62 days and then the material remaining in 12 Q Would you take -- I'm sorry, I didn't man to interrupt you. A I would have to go back to the -- something we examined earlier. 13 the bottle after the 31 and 62 days was 13 14 separately tested, so you could determine by 14 15 comparison whether any effect occurred during 15 was approved within one year's time of that 16 this simulated use period. 16 submission. Right. So we had a February 2, 2000, date. So I would expect Ocumeter Plus 17 All right. 17 18 The -- the parameter. that are 18 docunent with the Bates number beginning WRACK PRASCO 9700. 19 being tented are the one. in the column 19 20 headings; is that right? 20 21 22 MR. STRAUSS: Object to the foundation. 23 24 21 www.mldwesUltigatloricom Would you look specifically at So, for example, appearance, MIDWEST LITIGATION SERVICES Phone: 1.800.280.3376 A (Reviewing.) 24 Q Are you 25 A I am there. 23 BY MR. CORNFELD: Q I would like to show you the Page 9752. 22 THE WITNESS: Yes. 25 Q Fax: 314.644.1334 Okay. there? MIDWEST LITIGATION SERVICES Phone: 1.8001803376 www.mIdwestlItIgalion.com DAVID WALKER 2/111/2014 DAVID WALKER 2/18/2014 Page 154 Page 156 p0, freezing point and so forth; is that 2 3 • right? 2 Do you gee this as a table of manufacturing changes? Yes. 3 Ph. size of the drops Imo not 4 foundation. I don't see them listed here. 6 summary of manufacturing changes. 7 All right. 7 8 And for reference, we are A 4 5 6 9 MR. STRAUSS: Object to the tested in the user teat, correct? A THE WITNESS: It's titled a BY MR. CORNFELD: A21 right. ▪ talking about the user test that we. 9 And do you recognise thin as 10 submitted with the application to the FDA for 10 something that was aubmitted to the FDA as 11 the Ocumeter Plus and specifically on Bates 11 part of an annual report by Merck? 12 pages MACK MASCO 9366 and 9367, correct? 12 13 MR. STRAUSS: Object to the 13 THE WITNESS: Yes. 15 14 form. 16 BY MR. CORNFELD: 17 Q 18 23 29 17 MR. STRAUSS: Object to the form and foundation. 21 22 16 Can you tell me why drop sig. we. not tested? 19 20 Do you know when the FDA MR. STRAUSS: Object to the MIDWEST LITIGATION SERVICES Phone: 1.800.2803376 Q 19 Ocumeter Flu.? Do you zee that? A Yes. And do you sae the submission 23 type I.. 5-005, which would neon that it wan a 24 supplemental application, correct? 25 Fox: 314.644.1334 Would you see that the first line of this table on Page 9752 ref.rs to the 22 approved the Ocuneter Plus? www.mldwesIlitigotIoneom BY MR. CORNFELD: 18 21 BY MR. CORNFELD: 25 THE WITNESS: I had not seen this before. 20 THE WITNESS: No. g MR. STRAUSS: Object to the form and foundation. 14 15 Fax: 314.644.1334 A wwwroldwestlitigadoorom I don't know if that's what it MIDWEST LITIGATION SERVICES Phone: 1.8001803376 Fax: 314.644.1334 Case 3:12-cv-01141-SMY-DGW Document 176-23 *SEALED* Filed 12/01/14 Page 40 of 57 Page ID #2773 Case: 16-3334 Document: 55-50 Filed: 02/08/2017 Pages: 57 (1467 of 1511) DAVID WALKER 2/18/2014 DAVID WALKER 2/18/2014 Page 159 Page 157 make the change, but if we are making a stands for. change to a filling process, we are obligated You don't know that the "S" Q 2 stand. for supplemental? 3 4 4 Q Would you ma* that — do you 5 7 November 21, 2000? That wasn't my question, why But are you familiar with this -- this change that Merck made? Would you accept that as the Q date the FDA approved the Geometer Plus? 9 A No. 10 Q Nave you ever seen this 11 A Yes. 11 12 Q You can put that document 12 document before? 13 aside. 13 All right. you notified the FDA. Yes. A 10 Q No, I don't. 6 9 to notify the FDA. A sea that it says the approval date he 8 3 A No. Q what does in-process fill volume range as used on Page 9662 mean? 14 And I nest would like, to show 14 15 you the document with the Bates number MRCS 15 PRASCO 9660 through 9696. 16 operations, the weights of containers filled 17 are checked to make sure the proper amount 18 has been added to the container, and we will 16 Do you sea that this is on 17 18 application that Derck submitted to the FDA 19 on January 13, 20037 So frequently during filling A 19 have limits that if we fall below or go above 20 A Yes. 20 means we are no longer in specification and 21 Q And this was an epplication of 21 if we are changing either the specifications the type known as CBE-30. 22 Do you see that towards the 23 24 25 bottom of the page? Yes. A www.sildweadIdgationcom MIDWEST LITIGATION SERVICES Phone: 1.800280.3376 Fax: 314.644.1334 22 or those limits for which we have to take 23 action, then we are changing our process and 24 we would have to notify the FDA of that 25 change. www.sidwestlitiastion.eam MIDWEST LITIGATION SERVICES Plasm 1.800.2803376 DAVID WALKER 2/18/2014 DAVID WALKER 2/18/2014 Page 160 Page 158 fl If you would look at Page 9662. 3 4 5 2 Do you can that it says there 2 that the submission is for an update to the 3 in-process fill volume range for COSOPT in 4 (Reviewing.) I am there. Do you see -- okay. Do you see that this page is the beginning of • letter from Merck to the A CBE -30 means that that's 7 A 6 Yes. will you take a look at Page 9682, pleat., Q the Ocuseter Plus container? A FDA dated July 9, 2003? 8 something Derck is notifying the FDA about 8 9 30 days before it's actually going into 9 A Yes. 10 Q I am not sure if this is really 10 effect, correct? 12 foundation and the form. THE WITNESS: Yes. 13 14 15 11 N.R. STRAUSS: Object to the 11 BY MR. CORNFELD: Q part of this entire document or should be e 12 separate document because, ae I said, I 13 wasn't sure whether -- where each document 14 began and ended. But are you familiar with this 15 And this was submitted by Merck correspondence -- 16 more than two years after the FDA got -- 16 17 approved the (Munster Plus, correct? 17 A No. fl -- shown on page — •Down on 18 19 20 A Yes. 18 Q And do you know why Merck was 19 asking for a change or — strike that. Do you know why Merck was 21 Page 9602? 20 A No. 21 Q You haven't seen that. Okay. Do you Mae the first Sentence 22 notifying the FDA about a change in the 22 23 in-piecess fill volume range for COSOPT in 23 refers to the supplemental new drug 24 the OCumater Plus container.? 24 application dated January 13, 2003? 25 A www.sildwestlitigation.com 25 I don't know why we chose to MIDWEST LITIGATION SERVICES Phone: 18002603376 Fax: 314.644.1334 Fax: 314.644.1334 www.uddivestlitlgation.com Do you see that? MIDWEST LITIGATION SERVICES Phone: 1.000.200.3376 Fax: 314.644.1331 Case 3:12-cv-01141-SMY-DGW Document 176-23 *SEALED* Filed 12/01/14 Page 41 of 57 Page ID #2774 Case:DAVID 16-3334 Document: 55-50 Filed: 02/08/2017 DAVID WALKER Pages: 57 (1468 of 1511) WALKER 2/18/20/4 2/18/2014 Page 161 2 A Yes. Q And that', -- that'. the one we Page 163 for the number of drops per milliliter 2 dispensed. just looked at, correct? 4 A Row are you aware of that? (Reviewing.) 4 Yes. 6 7 A From having reviewed a different document. and then the letter to the FDA 6 Q All right. from Merck refer. to telephone conversatiOns Do you have any information as on June 23, 2003, and July 23, 2000 -- excuse to whether Dr. Shavnagri of the FDA .aid why 9 no, July 3, 2003 between Dr. Viepi Shavnagri 9 10 of the FDA, and me. Virginia Snyder of mere. 10 A No. 11 Research Laboratories, a divieion of Rezak. 11 Q Do you know whether it wee in 12 Do you see that? 13 A Yes. 14 Q Do you have any information 15 about those telephone conversations? 16 A 17 18 20 21 June -- in the June 23, 2003, meeting or the 13 July 3, 2003, meeting when he asked for 14 that -- not meeting, but telephone 15 conversation? No. 16 A No. 17 Q Either way, that was about two 18 and a half years after the FDA approved the A No. 19 Ocumeter Plus for use with COSOPT? Q Do you know He. Virginia Snyder 20 A Correct. 21 Q Prior to that time had Merck of Merck Research Laboratories? 22 12 Have you ever heard of them before you saw this just now? 19 he was inter...tad in thin information? A No. 23 Do you see according to this 22 ever told the FDA the number of drops per 23 milliliter that you would get out of the 24 document on Page 9682, Dr. Shavnagri, in 24 Ocumeter Plus or the drop aire of the drops 25 addition to requesting clarification of the 25 that came out of the Ocumeter Plus? www.midwestatligalleo.com MIDWEST LITIGATION SERVICES Phone: 1.800.280.3376 Fax: 314.644.1334 www.mIdwestUtIgadon.com MIDWEST LITIGATION SERVICES Phone: 1.800.200.3376 DAVID WALKER 2/18/2014 DAVID WALKER 2/18/2014 Page 162 Page 164 rationale through the change -- the MR. STRAUSS: Object to the 2 in-process fill volume., also asked for 2 3 information relating to drop delivery, 3 4 meaning drop. per milliliter of the new 4 BY MR. CORNFELD: 5 containers? Q You are not aware of that? 6 A I don't know if we ever 6 Do you see that? 7 A Yes. 8 Q Are you aware of the fact that 9 9 10 to the number of drops per milliliter of the 10 11 new container.? 11 A Yes. 12 13 You knew that they asked that? 13 14 MR. STRAUSS: Are you asking 14 15 16 him about this letter? BY MR. CORNFELD: 17 Q Did you know, acids from seeing 19 that information? 19 A 25 20 deposition, I was aware of this request. 23 22 What Sr. you -- are you aware www.enidwastlidgatIon.com I was aware that the FDA asked MIDWEST LITIGATION SERVICES Phone: 1.8002803376 If they never provided information, you're confirming that he MR. CORNFELD: He said he didn't know if they provided it. Are you saying that Merck never did provide it? 21 Okay. of? A MR. STRAUSS: Object to the form of the question. doesn't know the details of the 20 24 here and case to thi. depoeition, correct? 11 From preparations made for this Fax: 314.644.1334 If Merck ever did, you are not information they didn't provide? 18 Q Q aware of what that information is as you sit 16 thie letter just now, that the FDA asked for 21 THE WITNESS: I don't know. 15 18 22 form and foundation. provided such information. 8 the FDA asked Merck for information relating 12 Fax: 314.644.1334 MR. STRAUSS: No. You're asking a question again for approximately 23 the 200th time, following up on something 24 to which he says he doesn't know. So if 25 he doesn't know, then your follow-up weleondweatlitigatIon.com MIDWEST LITIGATION SERVICES Phone: 1.800.280.3376 Fax: 314.644.1334 Case 3:12-cv-01141-SMY-DGW Document 176-23 *SEALED* Filed 12/01/14 Page 42 of 57 Page ID #2775 Case:DAVID 16-3334 Document: 55-50 Filed: 02/08/2017 Pages: (1469 of 1511) 10612014 57 WALKER 2/180014 DAVID WALKER Page 167 Page 165 1 question asking details about what he 1 2 doesn't know don't make sense, but ask 2 your question. 3 3 best. MR. STRAUSS: Thank you. BY MR. CORNFELD: 5 When you nought information 0 5 I will do my MR. CORNFELD: 4 BY MR. CORNFELD: 4 me a letter. Would you turn to Page 9692, indicating that the FDA had asked for the 6 7 drop size, the number of drops per milliliter 7 8 in 2003 in preparation for this deposition, 8 A (Reviewing.) did you try to find out whether Merck had 9 0 And do you see that this is ever provided drop size information to the 10 also part of the submission that Merck made FDA before that time? 11 to the FDA that we have been looking at? 6 9 10 11 I had not tried to find that A 12 out. 13 12 A Yes. 13 Q And there is a section here called drop delivery? 14 And nobody called to your Q 14 Q please. 15 attention that Merck had provided information 15 A Yes. 16 on the size of its eye drops before 2003, 16 Q Is thin the document you 17 correct? 19 question. That calls for attorney-client 19 communication which he's not required to 21 answer. MR. CORNFELD: 24 Fair point. BY MR. CORNFELD: 25 0 Other than -- other than what MIDWEST LITIGATION SERVICES Pbum: 1.900.280.3376 wwwaddbmWfigibtogum DAVID WALKER If it is, it is. So in July of 2003 Merck stated Q 21 his attention is not your business. 23 MR. STRAUSS: BY MR. CORNFELD: 20 Whether -- whatever I called to Yes. A 18 20 22 indicated earlier that you would look at? 17 Don't answer that MR. STRAUSS: 18 22 to the FDA, quote, In response to the 23 agency's rampant, the number of drop. per 24 milliliter for each of the ophthalmic drug 25 products are provided in the following MIDWEST LITIGATION SERVICES Fax: 314.44.1334 Phone: 1.1100280.3376 www.niderestalzatlantom DAVID WALKER lasnom 2/18/2014 Page 168 Page 166 1 an attorney may have told you, has anyone 1 2 ever brought to your attention that Merck 2 3 either did or did not provide information on 3 A yes • its drop nines before July of 2003, brought 4 Q And for COSOPT, the number of information like that to the FDA? 5 9 5 A 6 7 Q 8 9 14 In that right? drops per milliliter is 29, correct? 6 A Approximately 29. 7 0 You see that for COSOPT it says 29 drops per milliliter? 8 You said you don't know what A You don't know if anything we. shared, correct? A 12 13 table." was shared. 10 11 I don't know what was shared with the FDA regarding drop size before 2003. I don't know if anything was shared. 0 I also see there is a 10 superscript that says, ^Approximate as 11 delivered from the Ocumeter Plus bottle." 12 It's not exactly 29. 13 It's approximately 29. Q 14 Now, does Merck have any It's not always 29. Man any other number for COSOPT 15 provided aside from approminately 29 drops per milliliter? 15 documentation of thew phone conthreatiOnn 16 with the FDA on June 23rd and July 3, 20037 16 17 I don't know. 17 A I don't know. 18 Q Nan any other number provided A MR. CORNFELD: 18 Steve, I would 19 like to request any such documentation 19 in thin submission to the FDA where it says 20 that exists. 20 29 drop. per milliliter? MR. STRAUSS: 21 Okay. A 21 I will So I would have to look through 22 respond to your request -- you know, I am 22 all of this document to see if there are 23 nut -- I'm not required to keep notes on 23 other references besides 29 for the drops per milliliter. 24 what you -- what comes to your mind while 24 25 we are in here, so I assume you will send 25 MIDWEST LITIGATION SERVICES www.roldwzathigationtom Plamm:12003S13376 Q . ..„„ Far:314.644.1334 Foe: 314.644.1334 . In preparation for this . mumzddmmandbabuzsm MIDWEST LITIGATION SERVICES Phone: 1.0002803376 Fax: 314.644.1334 Case 3:12-cv-01141-SMY-DGW Document 176-23 *SEALED* Filed 12/01/14 Page 43 of 57 Page ID #2776 WALKER 2/18/2014 Case:DAVID 16-3334 Document: 55-50 Filed: 02/08/2017 DAVID WALKER Pages: (1470 of 1511) 2/14/101457 Page 169 1 Page171 deposition, did you seal any number? 2 A 3 approximately 29. 1 No other number than 2 Ha. Merck ever had a program of Q measuring the drop sire. of COSOPT? 3 44 Q Noll, 29 with a footnote A I don't know. Q Did Merck ever measure the drop 5 .eying, "Approximately as delivered from the 5 aides of COSOPT or the -- do you understand 6 °mullet.= Plus container," correct? 6 when I .ay the drop tire. of COSOPT, that 7 A Correct. 7 includes the number of drops per milliliter 8 Q I. there • range given hero? 8 or whatever the quantity is, correct? 9 A No. 10 a Is there an amount of 11 9 10 variability provided here? 12 13 A No. Q I. there any definition of what MR. STRAUSS: Object to the form of the question. 11 You know, it you want to have 12 some compound definition regarding drop 13 size then you are going to have to ask 14 approximate moans, whether it's plus or minus 14 the question that way each time, because 15 one, whether it'. 29, 99 times out of • 100 15 that's not what it sounds like to me. 16 or whatever it means? 16 I am going to object to the question. 17 Is there any explanation? 17 18 A No. 18 19 0 How was thin result of 29 drops 19 measuring the number of drop. per milliliter or any other quantity for COSOPT? BY MR. CORNFELD: 4 20 per milliliter, approximate a. delivered from 20 21 the Ocumoter Plus container, how 18 that 21 A 22 result obtained? 22 Q 23 A 23 24 I am not sure of the experimental details that were used. 25 Are you aware of -- oven if you Q MIDWEST LITIGATION SERVICES Ptosm:IANOIAM.3376 Far: 314.644.1334 Has Merck ever had a program of I don't know. from this one measurement asurement of the drop size of COSOPT wham. it reported 24 approximately 29 drop. per milliliter to the 25 FDA in 2003, has M.rck at any other time ever . - „ - _ ,„ . „ „ -..- ...„ „... _ ......„ www.midweselltigationrom So wwwaddevesUMmdbosom MIDWEST LITIGATION SERVICES Phone: 1.800280.3376 DAVID WALKER 2/18(2914 DAVID WALKER 2!1en014 Page 170 1 don't know the detail., are you aware. of 2 anything about how this number was Obtained? 3 4 A know anything about it? A 8 Q Do you know who performed the A No. Q Do you know where it was test? 11 12 13 I don't know how they performed this test. 9 10 I would How about generalities, do you 0 Pege 172 1 have to speculate how they did that. 5 6 No, not the specifics. measured the number of drop. per milliliter 2 or the drop sine that come out of the 3 Ocumetor bottle for COSOPT? 9 A I don't know. 5 Q Do you know if any reword. 6 exist of the test that formed the bast. for 7 Merck'. statement to the FDA on Pogo 9692 8 regarding the number of drops per milliliter 9 of COSOPT? 10 11 A 13 14 A No. 14 Si Do you know when it was 15 performed? 16 I do not know if those records exist. 12 performed? 15 16 MR. CORNFELD: Steve, I will request those. MR. STRAUSS: okay. I will respond. BY MR. CORNFELD: 17 A No. 17 18 Q Do you know whether it was 18 per milliliter would convert to in term. of the six. of the drop? Q Did you calculate what 29 drop. 19 performed before or after the FDA made the 19 20 reque.t in Juno or July of 2003? 20 A Yes. 21 Q And what doe• that convort to? 22 A Approximately 34.4 microliters 23 per drop. 21 22 A No. 9 Did Merck have a general 23 program of mea.uring the drop sine. of 24 COSOPT? 25 A Fax: 314.644.1334 I don't know. 24 Q 25 rounding 34.45 up. I think I got 34.5, but I woe - . . www.mldwest.Htlfation.com NUDWESPIJIIGAIIENVSERWFS Phone: 1.800.280.3376 Fax: 314.644.1334 www.roldwedlitIsedoo.00m MIDWEST LITIGATION SERVICES Phone: 1.800.280.3376 Fax: 314.644.1334 Case 3:12-cv-01141-SMY-DGW Document 176-23 *SEALED* Filed 12/01/14 Page 44 of 57 Page ID #2777 Case: 16-3334 Document: 55-50 Filed: 02/08/2017 Pages: 57 (1471 of 1511) DAVID WALKER 2/182014 DAVID WALKER 2/18/2014 Page 175 Page 173 1Merck COSOPT and then in parenthesis Ocueeter 1 A Okay. 2 Q Okay. 2 But 34.4 or 34.5; i• that 3 3 4 Flue? Do you 4 right? nee that? A Yes. Q And if you saw this — if this S A Yes. 5 6 Q Are you aware of any other 6 jogs your memory, do you recall that they had 7 published an earlier paper whore they had the people who measured the drop else of 7 COSOPT around this time? 8 9 A No. 10 Q I would like to show you PL 13 with the Deventer Plus and they showed both ...ult. with the results from the Ocumeter (Reviewing.) 12 Plus being in parenthesis? Do you have it? 13 A Yes. 14 Q okay. 15 Q 14 15 (Reviewing.) A Okay. 0 I see that. Okay. And you nee that what they got 16 ewe this is a published Do you 16 17 they did this time was update that ...tilt 10 A 12 drop sire from the Ocumater in 1999 and what 9 11 437. 11 8 article by Fiscella and others entitled, 17 for the Ocumetor Plum for COSOPT was Cost Considerations for 18 29.2 drops per milliliter, correct? 18 "medical Therapy 19 Glaucoma"? Do you 20 nee that? 19 A Yes. 20 Q And that is approximately 29; 21 A Yes. 21 in other words, about the same or maybe even 22 Q And that wa. published in the 22 exactly the same as what Merck reported to of Ophthalmology in 2003, 23 the FDA, correct? 23 24 American Journal correct? A 25 www.roldweStlignstionrom Yes. MIDWEST LITIGATION SERVICES Phooe:1.800.280.3376 Fax: 314.644.1334 24 A Yes. 25 Q Now, isn't it the cm that by www.mldwestlittgadon.com MIDWEST LITIGATION SERVICES Phone: 1.800.2803376 DAVID WALKER 2/18/2014 DAVID WALKER 1/10/2014 Page 176 Page 174 2 3 4 you wore only getting 23.6 drop. per right around the time that 1 2011 guys were telling the FDA what you found 2 milliliter for COSOPT out of the ()curter in terms of the number of drops per 3 Plus? milliliter for COSOPT, correct? 4 1 Q you So 5 5 A Yes. 6 Q Rave you seen this paper -- MR. STRAUSS: THE WITNESS: 6 i. thin one of the erticle• you said you looked 7 about that. 8 at before this depo.ition? 8 BY MR. CORNFELD: A 10 11 Q 12 13 14 15 9 (Reviewing.) Q Q I don't know Mould you take a look at I may have seen this before. 10 PRASCO -- we looked at this document before, All right. 11 but PRASCO 1 through PRASCO 94. If you would look at Table 1 on 12 MR. STRAUSS: What is the -- 13 what is the top first page of the Yes. 14 document/ And you se• this is the table 15 page -- the Sates number page is 440. A Object to the form and foundation. 7 9 MR. CORNFELD: It looks like -- it looks like a photocopy of maybe the 16 of results of what thew. authors got when 16 11 they measured the number of drops per 17 box of medication. 18 milliliter that they would get for various 18 on the lower right, and it looks like 19 proneription ophthalmic medication.? It says PRASCO 00001 19 maybe there's a -- also a copy of a 20 A Yes. 20 portion of a label. 21 CI And you nee Merck COSOPT -- 21 ile listed towards the bottom? 22 23 A Yes. 23 24 '2 All 22 Merck's COSOPT 25 right. And you nee first they say MIDWEST LITIGATION SERVICES wwweedwmtnigatIoneom P6,00 1.000.2003376 Fax: 314.644.1334 F.e: 314.644.1334 MR. STRAUSS: It's a Prasco labeling document that Came to you? MR. CORNFELD: It's actually 24 the whole gamut -- the whole -- 25 everything that you produced to us for wwivaidwestlItigation.com MIDWEST LITIGATION SERVICES Phone: 1.800.280.3376 Fax: 314.644.1334 Case 3:12-cv-01141-SMY-DGW Document 176-23 *SEALED* Filed 12/01/14 Page 45 of 57 Page ID #2778 Case: 16-3334 Document: 55-50 Filed: 02/08/2017 Pages: 57 (1472 of 1511) DAVID WALKER 2/1812.014 DAVID WALKER 2/18/2014 Page 177 Page 179 Prasco, I think, on Friday -2 MR. STRAUSS: Okay. 3 MR. CORNFELD: -- maybe 4 report of a call from a ear of generic Thursday and I didn't have time to 2 Fresco -- excuse ma, generic COSOPT, we will 3 give her the initials MC. 4 separate them out, so I just had them all 6 included in one document. 1 Do you see her -- her name is under caller. And we will just refer to her 6 It would have been in the very by her initials. 7 Do you see that? back of the box. 9 MR. STRAUSS: Oh, here it is. 9 10 Yeah, we never had this out. That's why 10 11 we were looking for -- 11 12 A Yes. Q And this is dated September 20, 2011, correct? A (Reviewing.) MR. CORNFELO. I'm sorry. 12 September 28, 2011, yes. 13 MR. STRAUSS: We were looking 13 All right. 14 through the piles of what you have gone 14 15 through in such a highly regimented and 15 16 organized fashion, and we were unable to 16 17 discern said document because, in fact, 17 18 you had improperly instructed your 18 19 paralegal, who works for me as an 19 And the -- under event notice it states, Prase. -- strike that. Before I ask you anything further, have you ..an this document before? A No. MR. STRAUSS: I will just tell 20 associate, to search the wrong file. But 20 you, Rick, this is not a Merck document. 21 now we have corrected this. 21 It's a Prasco document. You have the 22 23 MR. CORNFELD: I apologize. You know, it's something I -- I couldn't 22 witness Kirk Seemann who his job is to 23 know these -- know these documents and 24 remember whether I, in my highly 24 manage the people that make them so, you 25 organized fashion that -- I, you know, 25 know - • MIDWEST LITIGATION SERVICES Phone, 1.800.280.3376 wwwheldvomMEgadawsom Fax: 314.644.1334 www.midwesUithottlonuom MIDWEST LITIGATION SERVICES Phone: 1.800.28E3376 DAVID WALKER 2/18/2014 DAVID WALKER 2/18/2014 Page 178 1 Page 180 heard just a tiny bit of sarcasm there. 2 3 MR. CORNFELD: I understand, I knew that there was something 2 in there that I was going to ask about 4 but I probably didn't have to but in 5 light of the answers, so... 6 4 6 7 MR. CORNFELD: It's an "All's 11 three minutes. 12 15 9 10 MR. STRAUSS: That's right. 13 14 MR. STRAUSS: Okay. BY MR. CORNFELD: Q well that ends well" situation as long as I don't go over time by about there's some questions I need to ask about the Merck end. MR. STRAUSS: No problem. We 10 but I won't have another Merck witness after I finish that deposition and got it now. 9 MR. CORNFELD: Which is unlikely. BY MR. CORNFELD: Okay. So do you ow* under event notice that this document on PRASCO 93 11 indication that Prasco received an e-mail from 12 • consumer who said, "I am using dortolamidm 13 hydrochloride-tinolol maleate ophthalmic 14 solution"? 15 Do you see that? 16 Okay. 16 A Yes. 17 Mr. Walker, do you now have in 17 Q And that's generic -- generic 18 front of you the document with the Bates 18 19 numbers PRASCO 1 through PRASCO 94? 19 A Yes. 20 0 And she say. she mime one drop 20 A Yeah. COSOPT, correct? 21 All right. 21 in each eye BID, and that means she uses it 22 Would you turn to Page 93. 22 twice a day, correct? 23 24 25 Do you have that there? A Q www.ondweatitigadmmwm Yes. Do you sae that this was a MIDWEST LITIGATION SERVICES Phone: 1.800.280.3376 Fax: 314.644.1334 23 A Yes. 24 Q And she say., "My pharmacy and 25 Fax: 314.644.1334 I disagree on how long a 10-milliliter bottle vnvw.nildwestlltIgation.com MIDWEST LITIGATION SERVICES Phone: 1.800.230.3376 Fax: 314.644.1334 Case 3:12-cv-01141-SMY-DGW Document 176-23 *SEALED* Filed 12/01/14 Page 46 of 57 Page ID #2779 Case: 16-3334 Document: 55-50 Filed: 02/08/2017 Pages: 57 (1473 of 1511) DAVID WALKER 2/16/2014 DAVID WALKER 2/1162014 Page 183 Page 181 1 should last." 1 2 A 3 4 Q Do you see that? 2 Yes. 3 And down under resolution 4 A No, I don't know what it stands Q All right. for. Nell, if you would assume that it stands for drops, have you ever seen 5 notes, we see the response that the Prasco 5 6 representative made to this consumer and the 6 equivalency charts that show 1 milliliter representatives stated, "Ne cannot determine 7 equal to 15 or 20 drops? 8 the exact number of drops per bottle 8 A No. 9 dispenser or the exact number of days of 9 Q Do you have any idea what she 7 10 might be referring to there? 10 therapy per bottle becalms usage may vary 11 with individual patients. 11 A No. 12 provide you with approximately how many days 12 Q All right. 13 of therapy a bottle should last based on the 13 14 recommended dose stated in the product 14 "Neither of those would equal 59 days, much less eight weeks. However, I can Anyway, she goes on to state, Thanks for your help." 15 insert. For the product insert for 15 16 dorsolsmide HCL tinolol maleate, ophthalmic 16 And then she signs her name. 17 solution in a 10-milliliter bottle, putting 17 Do you see that? 18 one drop in each eye two times daily, the 18 19 number of days of therapy would last 19 20 approximately 59 days." 20 the page, the Merck rep -- excuse me, the Do you see that? 21 Preece representative wrote back and stated, A Yes. 22 "Please allow me to clarify the previous Q And 59 days with one drop in 23 response you received from me. 24 each eye twice a day would mean 236 drops, 24 regarding the approximate number of days of 25 correct? 25 therapy, 21 22 23 www.mkbrestlidgetkairem MIDWEST LITIGATION SERVICES Phone: 1,000.2803376 Par: 314.644.1334 A Yes. Q And then in the next block on The answer which I sent to you earlier is MIDWEST LITIGATION SERVICES Phone: 190018033'76 wwwmidwestHdgmtblimm Fe:: 314.644.1334 DAVID WALKER 2082014 DAVID WALKER MMOMIs Page 184 Page 182 However, this information is not 1 A Yes. 1 2 Q And than -- do you see that the 2 found in the package insert. 3 to Prasco from Merck, the product 3 customer -- excuse me, the consumer wrote correct. it was supplied The information that is stated 4 back, MC, that same date stating, "Can you 4 manufacturer. 5 tell me where in the product insert you found 5 in the package insert relates to the 6 that information?" 6 recommended dose mentioned in previous Do you +me that -- 7 e-mail. A (Reviewing.) 8 the Confusing wording in our initial Q -- where it says, "On 9/28/11 9 correspondence." 7 8 9 10 11 12 13 11 A Yes. Yes, I see that. 12 Q And so far as thin page is Okay. 13 concerned that ended the correspondence with 14 this consummr, correct? consumer"? Q So she -- NC, the 14 Do you see that? 10 Prasco received a second e-mail from A my apologize" -- "my apologies for MR. STRAUSS: Object to the 15 consumer asked, "Can you toll me whore in the 15 16 private insert you found that information," 16 17 and the Prasco representative -- excuse me, 17 18 and the consumer wrote on and said, 18 19 "Generally the equivalency charts have 19 correspondence between consumers and 20 1 milliliter equal 15 SITS or 1 milliliter 20 Merck or consumers and Prasco. 21 equal Gres." 21 22 Do you see that? 22 foundation. THE WITNESS: Q Well, there's nothing else reported here, is there? 23 A Yes. 24 Q Do you recognize "OTT!" as an 24 A No. 25 Q All right. abbreviation for drops? www.roldwestlitigation.e6m MIDWEST LITIGATION SERVICES Mom 1.800.280.3376 Far 314.644.1334 I BY MR. cORNFELD) 23 25 I don't know. don't deal with this sort of www.mldwestIlligationtom MIDWEST LITIGATION SERVICES Phnom: 1.1100.260-3376 Fax: 314.644.1334 Case 3:12-cv-01141-SMY-DGW Document 176-23 *SEALED* Filed 12/01/14 Page 47 of 57 Page ID #2780 Case:DAVID 16-3334 Document: 55-50 Filed: 02/08/2017 DAVID WALKER Pages: 57 (1474 of 1511) WALKER 2A8/2.014 2/18/2014 841.185 1 2 10 milliliters would be the same as 3 23.6 drop. from 1 milliliter , correct? 4 A 6 Q 1 s2 3 4 in the bottle than it doss on the label, 5 correct? And that means the drops were a 6 lot bigger than they were when Merck told the 8 FDA in 2003 that you would get 29 drops 9 approximately out of 1 milliliter of COFOFT, i THE WITNESS: 14 It's part of the 8 with. Ail right. Q So then there's at least 10 Object to the 11 12 sure the patient get. 10 milliliter. at (Reviewing.) 13 least, correct? form and foundation. So we did previously say 15 We couldn't. testing and validation that we must to comply 10 MR. STRAUSS: 12 A 7 9 correct? 13 Merck doe. not shortchange Q customer., doss it, eir, by putting in le.. (Reviewing.) 7 11 BY MR. CORNFELD: Yes. 5 10 Page 187 Now, to get 236 drops out of 29 drops per milliliter in 2003. We are milliliters in a bottle, plus overage to make 14 A Correct. 15 Q And I don't know if you can do 16 saying 236 drops from a 10-m1 bottle. 16 this in your head or if you have a 17 And a 10-m1 bottle has an overage 17 calculator -- I did the calculation. 18 included in it. 18 ml. with 236 drop. convert. to a little over 19 42 -- I think 42.5 microliter.. 19 It's not just 10 mis. BY MR. CORNFELD: 20 Q So it might be 10.5? 20 21 A It could be more than 11. 21 22 Q Which would mean the drop. 23 gotten bigger, if you are dividing the drops 24 by 236? 25 A www.agdwastiltigadonsem s And it could be less than 10 MIDWEST LITIGATION SERVICES Phone: 1.000.2603376 Does that sound about right? A I'll make the calculation here. 23 5 I'm marry, it we. 42.4. 24 A 22 (Calculating.) (Calculating.) 25 Pam 314.644.1334 And 10 42.4. www.midwestlidgadenrers MIDWEST LITIGATION SERVICES Phone: 1.8002003376 DAVID WALKER 1/18/2014 DAVID WALKER 2/1E2014 Page 186 1 2 3 ml. It's certainly not 2 approximately 29, i. it? 4 5 Page 188 1 0 MR. STRAUSS: THE WITNESS: you familiar with this information that Merck 5 236 drops out of a 10-milliliter bottle? It doesn't state 6 7 8 drops are to be administered from the 8 9 bottle labeled as a 10-m1 bottle. 9 12 you are not familiar with this inquiry, are provided that the con.umer can expect to get It states how many BY MR. CORNFELD: Q And I take it since 4 a drop size here. 10 All right. Object to the 7 11 5 3 form of the question. 6 10 Rave you ...en anything in what Merck ever told the FDA that they A No, I wasn't familiar with Q And I animals then you are not this. familiar with the basis for saying that, what tests or measurement. were done? 11 A No. 12 0 But you would expect that if 13 shortchanged ...tomer. by putting le.. than 13 Merck i. providing this information, that 14 10 male in a 10-ml bottle? 14 there were some tests or measurements that Object to the 15 were done to back it up, correct? Actually, don't 16 15 MR. STRAUSS: 16 form of the question. 17 even answer that question. 18 absurd. 19 20 That's 17 If you -MR. CORNFELD: You're instructing him not to answer? 21 MR. STRAUSS: Yeah, that -- MR. STRAUSS: form of the question. 18 foundation. 19 calls for speculation. Object to the Lack of Asked and answered. 20 Go ahead. 21 THE WITNESS: And I would expect if 22 your question, that has he seen anything 22 we were providing information, there 23 in the Merck documents that says Merck 23 would be a basis for being able to 24 shortchanges customers, yeah, I am 24 25 telling him not to answer that question. 25 www.nedwestlidgalionrom MIDWEST LITIGATION SERVICES Phone: 1800.280.3376 Fax: 314.644.1334 Fax: 314.644.1334 provide that information. BY MR. CORNFELD: www.midweseldgetion.com MIDWEST LITIGATION SERVICES Phone: 1.800280.3376 Fee: 314.644.1334 Case 3:12-cv-01141-SMY-DGW Document 176-23 *SEALED* Filed 12/01/14 Page 48 of 57 Page ID #2781 1118/2014 57 WALKER 2/18/2014 Case:DAVID 16-3334 Document: 55-50 Filed: 02/08/2017DAVID WALKER Pages: (1475 of 1511) Page 191 Page 189 1 Can you provide me with any Q 1 A Yes. Which is 62 days -- mecums me, 2 help in suggesting what you think that basis 2 0 3 was? 3 62 drops? MR. STRAUSS: 4 Objection. for speculation. 6 Lack of foundation. 9 4 A Sixty-two drops. S B All right. And what this consumer MC was 6 7 doing was using four drops a day, and Franco, to be some way of showing that we can 8 based on what Merck told than, said to her dispense two drops twice per day from a 9 that it would last 59 days, correct? THE WITNESS: 7 8 Calls Asked and answered. 5 There would have MR. STRAUSS: 10 Object to the 10 bottle and provide 59 days, and in one 11 the documents we reviewed previously we 11 form of the question, the foundation of 12 showed in-use testing for the 5-ml bottle 12 the question. 13 that showed 62-day supply. 13 of BY MR. CORNFELD: 14 15 16 Q That was only -- A Two drops per day. Right. You're looking at stability testing. 15 connection, but that's my objection. You can answer his question. 16 Two I don't understand the 14 drops per day from a 5-ml bottle. So now if 17 18 I do four drops per day from a 10-m1 bottle, 18 stability of the product after drops were 19 I can supply 62 days based on that testing. 20 CI 21 22 24 dispensed for 31 days and 62 days. 20 doesn't say how many drops could come out It was 31 days from a 5-ml 21 22 that previous document. 25 Rang on a minute. Q I will look MIDWESTLITIGATIONSERVIDS Phonc1.800.2A*3376 wwwiskhrmnithmhoniom of the bottle. BY MR. CORNFELD, 23 We would have to go back to A It 19 I'm sorry. bottle, correct? 23 THE WITNESS: So this shows the 17 Far: 314.644.1334 Q Right. Right. My question 24 originally was, wouldn't Merck, have -- Of 25 they were saying that you could get 236 drop. wwwiddwenlidwadoniom MIDWEST LITIGATION SERVICES Pho05:1.9001803376 DAVID WALKER 228/2014 DAVID WALKER 220n014 Page 192 Page 190 1 it up. MR. STRAUSS: 2 3 What -- do you know what stack that was in? MR. CORNFELD) 4 I am looking for Yeah, it was Page 9340, in that huge 5 it. 6 stack. 7 MR. STRAUSS: 8 the stability testing? 9 10 The Attachment 7, 1 out of a 10-milliliter bottle, wouldn't they 2 have a basis with soma kind of measurement 3 that would have shown that. 4 saying, well, maybe they got that number of 5 drops from the user test, but actually they Yes. MR. STRAUSS: Okay. didn't because they didn't empty out the 7 bottle. A 10 11 thought you were --- I thought you were 11 12 just asking him about volume testing. 12 Right. I don't know where they got the 9 But I And you were 6 8 MR. CORNFELD: information of 59 days. (,) Okay. But certainly there should be a Hang on, Steve. 13 test somewhere that somebody did that would 14 provide a basis for the information that the So somewhere down 15 10-milliliter bottle would provide 236 drops, 16 there you get to this thing that says 16 correct? 17 Attachment 7. 17 MR. CORNFELD) 13 14 Actually, it's Page 9366. MR. STRAUSS: 15 THE WITNESS: 18 18 Hm-hm. Repeat the question, A Sorry. Q Certainly there should be a please. 19 (Reviewing.) 19 20 Yep. 20 test eomewhere that aonmone at Merck did to 21 provide the basis for saying as they said to All right. 22 Prance, that a 10-milliliter bottle would So you ego this was the user 23 provide 236 drops, correct? 21 22 BY MR. CORNFELD: Q 23 24 25 test where it was two drops per day for 24 31 day., correct? 25 vrr.mkhnnnidgaUossmn MIDWEST LITIGATION SERVICES Phomm:II001803376 For: 314.644.1334 Wm:314.6443334 A I would expect there's a foundation for that statement. wwwiddmnWdradmicom MIDWEST LITIGATION SERVICES Phone: 1.000.2803376 91x:314.64t11M Case 3:12-cv-01141-SMY-DGW Document 176-23 *SEALED* Filed 12/01/14 Page 49 of 57 Page ID #2782 Case: 16-3334 Document: 55-50 Filed: 02/08/2017 DAVID WALKER Pages: 57 (1476 of 1511) 2/182011 DAVID WALKER 2/182014 Page 193 1 2 familiar with this correspondence, you don't 3 know, or maybe you do know who at Merck would 4 have provided that information to Premco? 5 A 6 Q 1 2 A Yew, there was a response on the 28th about 59 days. 3 i All right. Q 4 No. 7 8 Page 195 I take it since you are not Q To have provided that 5 information on the same day the customer made If — strike that. 6 the request, would you expect that this is Do you know where at Merck a 1 information that already erieted at Merck? f ile that would Contain the supporting basis 8 99 for saying that a 10-milliliter bottle would MR. STRAUSS: form and foundation. Object to the Calls for 10 provide 236 drops, do you know where that 10 11 file would be? 11 But would you expect it? 12 THE WITNESS: 13 the data was somehow available. 12 A No. 13 9 Is there a department at merck, 14 and I don't mean to be technical about the 14 15 word "department," a department, an office, 15 16 division, anything, that would have been 16 17 responsible for doing that test and providing 17 18 that information? 19 A I would expect if the 20 information was collected there would be a 21 department that has that information 22 available. All right. 0 1 mean, they didn't suddenly do a test to answer her query, correct? 18 A No. 19 Q All right. 20 ± 21 They couldn't have done it that foot -- 22 A No. What department depant would that be? 23 4 -- correct? A I would think it is the people 24 A Correct. who prepare our regulatory filings would have 25 Q Okay. 24 MIDWEST LITIGATION SERVICES Phone; 1.800.280.3376 wwerroldweatlitigatIoncom Om 314.694.1339 oww.m1dwealillgatIon.00m MIDWEST LITIGATION SERVICES Phone: 1.800.280.3376 DAVID WALKER 2/182014 information. that 2 t Page 196 1 Does the department have a Q That's correct. 2 3nano? Okay. Do you have any idea whether 3 Merck ever told the FDA this information that 4 A Regulatory affairs. 4 • bottle would last 236 -- with 236 drops, 5 Q And sir, the exchange of e-mail 5 59 days? correspondence where the customer NC made her 66 MR. STRAUSS: 7 inquiry and was provided that information 7 8 about a bottle lasting 59 day., that all took 8 place on the same date, in September of 2011, 99 10 10 MR. STRAUSS: 12 Objection to the 11 (Reviewing.) 13 foundation. 13 12 THE WITNESS: THE WITNESS: FDA. Do you have knowledge about Q what Merck is obligated to tell the FDA? I see that there was 14 15 correspondence on the 28th and the 29th. 15 lot to the FDA. 16 knowledge. BY MR. CORNFELD: 17 Q 18 The initial inquiry was on the 17 28th, correct? 19 A Ye, 20 0 And while I don't see -- strike 21 /2 Merck is obligated to tell a I don't have all that Do you have any understanding as to whether Merck would have been obligated 19 to tell the FDA this information? 21 And the response to the A 18 20 that. 22 I don't know if BY MR. CORNFELD: 14 16 Object to the form of the question. that information was ever provided to the correct? 11 22 A No, I don't know if we are obligated to provide that. 4 Do you have any understanding 23 customer we, also on the 28th, the response 23 a. to whether Merck was obligated to tell the 24 that indicated a bottle should last 59 days, 24 FDA the dimensions of the outer orifice of 25 correct? 25 the Geometer Plus? ... MIDWEST LITIGATION SERVICES wwwroldsrateigatkonrom Phone: 1.180280.3376 Fars 314.644.1334 DAVID WALKER 2/18/2014 Page 194 1 I would expect BY MR. CORNFELD: Q 23 25 speculation. Fax1314.644.1339 www4Wdwestlidg050ncom MIDWEST LITIGATION SERVICES Phone: 1.800.280.3376 Fez: 314.644.1334 Case 3:12-cv-01141-SMY-DGW Document 176-23 *SEALED* Filed 12/01/14 Page 50 of 57 Page ID #2783 21182014 57 Case:DAVID 16-3334 Document: 55-50 Filed: 02/08/2017DAVID WALKER Pages: (1477 of 1511) WALKER :imam Page 199 Page 197 1 Did you ask if we were A 1 3 MR. STRAUSS: 4 4 Do you have any idea? 5 BY MR. CORNFELD: 6 8 you knew if they did provide it. 9 know if they mere obligated to? 6 001049. you up, Steve. MR. STRAUSS: 11 stuff, and we will keep it to the side. THE WITNESS: 13 13 (Reviewing.) 14 Plan? 14 15 A 16 required. MR. STRAUSS: 17 Rick, are you Sure. Thank you. BY MR. CORNFELD: 15 I don't know if that's Do you want to hand me the big pile of goes around the outer orifice of the Ocumeter Or the ring of plastic that Q All right. 10 12 12 This will wake MR. CORNFELD: 9 obligated to. 11 you the document with the first page PL 8 Or do you I do not know if we were A 10 Mk. Walker, I'd like to show Q 5 7 I think I already &eked you if Q 7 BY MR. CORNFELD: 3 Yea. Q The time is 3:39 p.m. 2 obligated to provide that dimension? 2 record. Do you wee that the document Q 16 with the Rates number PL 1049 through 1056 in 17 a published article entitled, "Coat Analysis 18 close to a stopping point to take a 18 of Glaucoma Medications," by Nathan R. 19 bathroom break? 19 Rylander and Stephen D. Vold, published in 20 What time is it? 21 MR. CORNFELD: 22 23 For that, MR. STRAUSS: 3:26. 25 ,....--,„. „ ..„... ..., (Reviewing.) A 24 What -- it's 25 Can we just take, like, 10 MIDWEST LITIGATION SERVICES Phone: 1.800.1803376 .ww.m.swidt wk.... Ophthalmology? Yes. 23 that long, but that's fine. 24 2008 in the American Journal of 21 22 I know we haven't been going always. 20 In this one of the articles you 5 looked at to prepare for thin deposition? LITIGATION SERVICES Foe 3166461334 wwwnedwadlltigadonoom MIDWEST Phone: 1.800.280.3376 DAVID WALKER 2/182014 DAVID WALKER 2.282014 Page 200 Page 198 1 3 6 3 so 2:40. MR. CORNFELD: don't have to ask. to. I mean, within reason, of course. 7 8 MR. CORNFELD: 9 within. 13 14 MR. CORNFELD: 16 17 MR. STRAUSS: (Reviewing.) Q And you .es that the lent item Ten minutes. 19 THE VIDEOGRAPHER: on that table in COSOPT7 A Yes. 11 Q You see that there in a column with a number of drops per milliliter? A (Reviewing.) Q And. Yes. Do you nee that for COSOPT they 16 All right. MR. CORNFELD: Yes. 10 15 on my iPhone. Going off the record. 21 A 14 I will start the stopwatch 18 20 there in a table? 6 13 Can we maybe get back a little sooner? Ten minutes. 5 12 That's 15 minutes by -- by my watch. 15 with the page with the Sates nunber 1051, 9 All right. Do you :me on the third page 4 8 And this is Thanks. 12 No. 5 7 2:40. Okay. MR. STRAUSS: 10 11 Listen, you Any time you'd like MR. STRAUSS: (Reviewing.) A 2 3:26 -- 3:27 -- 2:27 central, 4 5 1 quick minutes, that's fine. 2 17 report 22.33 plus or minus .78 as the nunber 18 of drop. per milliliter? 19 A Yes. 20 5 And that's five years after The time is 3:27. 21 Merck told the MA that 1 milliliter of (Whereupon a Recess Commenced 22 COSOPT would be approximately 29 drop., 23 at 3:27 and Testimony Recommenced at 23 correct? 24 3:39.) 24 22 THE VIDEODRAPHER: 25 En= 314.644.1334 A 25 Back on the (Reviewing.) MR. STRAUSS: Object to the ..„ . www.moldwestfitimation-com MIDWEST LITIGATION SERVICES Pham:1.80.2803376 Fu: 314.644.1334 wwweNdmwdlidgadeneam MIDWEST LITIGATION SERVICES Pboem1I00JI03376 Fax: 314.644.1334 Case 3:12-cv-01141-SMY-DGW Document 176-23 *SEALED* Filed 12/01/14 Page 51 of 57 Page ID #2784 Case:DAVID 16-3334 Document: 55-50 Filed: 02/08/2017 DAVID WALKER Pages: 57 (1478 of 1511) WALKER 2/18/2014 2/18/2014 Page 201 Page 203 form of the question. 2 per milliliter? THE WITNESS: The 3 4 2 correspondence regarding the 29 drops per 3 milliliter that Merck shared, when was 4 that? Is that 2007? MR. STRAUSS: Object to the form and foundation of the question. THE WITNESS: I don't know. BY MR. CORNFELD: MR. CORNFELD: 2003. 7 8 2007? 9 BY MR. CORNFELD: 10 7 22.33 drop. per milliliter? The record will show it, ao just accept mo that -- what I am telling you, 12 that it was from 2003. 13 14 A Okay, Q So approximately five year. 11 Q paper, I take it? 14 16 milliliter of 009OFT would be lees than 16 29 drape approximately or specifically 22.33 17 18 plus or minus .78, Correct? form. 21 they performed the test. 12 15 MR. STRAUSS: Object to the I gum.. you haven't read this A I also don't know how they performed the test. Q You read the paper to see what they said about -- 18 A There's not a standard -- 19 Q You haven't read -- A Pardon me. There's not a 20 THE WITNESS: (Reviewing.) No, because I don't know how A 13 17 20 Does Merck have any idea? 10 later, Dr. Rylander and Dr. VOld found that a 19 DO you have any idea why Dr. Rylander and Dr. Vold only got only 9 11 15 Q THE WITNESS: Was it 2003 or 21 standard way for measuring drops obtained per 22 MR. STRAUSS: And foundation. 22 milliliter out of a bottle. There's not a 23 THE WITNESS: They show a lower 23 regulatory protocol to follow. There is not 24 number. They don't describe how the 24 a USP method for making this measurement. 25 drops were dispensed. And we don't know 25 There is no agreed-upon method. wee.mldwestatMadonrom MIDWEST LITIGATION SERVICES Phone: 1300280.3376 Fax: 314.644,1334 MIDWEST LITIGATION SERVICES Phone: 1.800.2103376 www.roideestlidgaboa.com DAVID WALKER 2/111/2014 DAVID WALKER 2/18/2014 Page 202 Page 204 from the document we reviewed earlier Q Whatever method Dr. Rylander 2 about Merck measuring 29 drops per 2 did -- did you understand the American 3 milliliter, how those drops were 3 Journal of Ophthalmology is a peer-reviewed 4 dispensed, the angle of orientation, the 4 journal for ophthalmologists, for eye environment, how the bottle was squeezed. 5 doctors? There are many variables that could affect the number of drops per 8 9 11 6 A Yes. 7 Q And whatever method Merck used, milliliter obtained. it thought it wan sufficiently reliable to BY MR. CORNFELD: 10 9 What Merck told the -- I'm .orry. 12 What Merck told the FDA was tell the FDA approximately 29 drop. per 10 milliliter, no ifs, ands or buts, no caveat. 11 about how they did it, just 29 drop. per 12 milliliter, Correct? 13 simply in response to how many drop. do you 13 A Correct. 14 get from 1 milliliter. Merck said 29, and it 14 Q And whatever -- and whatever 15 didn't add any caveats about the angle or how 15 16 hard you logueere or anything like that. It 16 sufficiently reliable in his mind and in that 17 max just approximately 29. 17 of the peer reviewer. at the American Journal 18 19 A Dr. Rylander, however they did it, it wan Correct? 18 of Ophthalmology that they could report this Correct. 19 result, correct? 20 All right. 20 A He reported this. 21 And here it'. 22.33, correct? 21 Q Yes. And so hi. method wa. 22 A 23 24 25 (Reviewing.) Correct. Q Was Merck aware of this finding by Dr. Rylander and Dr. Vold of 22.33 drop. eme.reideestlidgation.com MIDWEST LITIGATION SERVICES Phone: 1.800.2803376 Fax: 314.644.1334 22 sufficiently reliable -- I should may 23 "their," because there are two doctor. who 24 did this study. 25 Fax: 314.644.1334 www.nideestildgation.com It we. sufficiently reliable to MIDWEST LITIGATION SERVICES Phone: 1.800280.3376 Fax: 314.644.1334 Case 3:12-cv-01141-SMY-DGW Document 176-23 *SEALED* Filed 12/01/14 Page 52 of 57 Page ID #2785 Case: 16-3334 Document: 55-50 Filed: 02/08/2017 Pages: 57 (1479 of 1511) DAVID WALKER 2/18/2014 DAVID WALKER 2118(2014 Page 207 Page 205 No, November 27, 2012. them and to the peer reviewers at the 2 American Journal of Ophthalmology that they 2 3 could report this result, correct? 3 Yes. I see that. 4 MR. STRAUSS: Objection. Okay. I Misheard you. A Q Okay. All right. And if you would THE WITNESS: I don't know. I 5 6 don't know if the peer reviewer saw the 6 turn to the second page, specifically Page 10035, do you see the -- one of those changes method used. 7 BY MR. CORNFELD: 8 Certainly it was sufficiently Q 9 10 8 on November 27, 2012, to the COSOPT label was 9 related to instructions for use? reliable that they -- whatever method we. 10 A Yes. Q And do you see that Merck told used was sufficiently reliable that the 11 12 journal felt they could publish it and Dr. 12 13 Rylander and Dr. Vold could report it, 13 revised the instructions for a new section of 14 correct? 14 the COSOPT label to include instructions for 15 patients to preen a finger into the corner of 16 their eye by the nose for two minute. to help 17 keep COSOPT in their eye? 11 MR. STRAUSS: Objection. Lack 15 of foundation. Calls for speculation. 16 THE WITNESS: I don't know. 17 18 BY MR. CORNFELD: 18 the FDA on November 27, 2012, that it had Do you see that? 19 A Yes. American Journal of Ophthalmology believed 20 Q Are you familiar with this 21 that this paper was reliable when it 21 22 published it? 22 A No. 23 Q Mould you look at Page 10049. 19 20 You don't know whether the Q MR. STRAUSS: That's not the 23 24 same question. Is that a new question? MR. CORNFELD: Go ahead. 25 www.wldwes0ffigatIon.eow MIDWEST LITIGATION SERVICES Phone: 1.800.280.3376 Fax: 314.644.1334 change in the instruction, for use? 24 A (Reviewing.) 25 Q And this -- I know this page is wxoldwastlitIgatIonsom MIDWEST LITIGATION SERVICES Phone: 1.1100180.3376 DAVID WALKER 2/18/2014 DAVID WALKER 2/18/2014 Page 208 Page 206 in the middle of a discussion. 1 MR. STRAUSS: Go ahead. 2 THE WITNESS: They accepted the 2 If you go back a couple of page., can you confirm that these are the 3 results that were tabulated here, and 3 4 they allowed its publication. 4 5 Q 7 6 So they thought it was reliable A Yes. 9 Q Would you take out A 8 MACK page are you on, Rick? MR. CORNFELD: Well, the 9 PRASCO Page 100034 through 56. (Reviewing.) MR. STRAUSS: I'm sorry, what 7 to be able to do that, correct? 8 10 instructions for use that Merck provides for COSOPT? BY MR. CORNFELD: 6 10 instructions for use start on Page 10047, 11 A (Reviewing.) 11 and the specific thing I want to ask 12 Q And if you look at the first 12 about is on 10049. THE WITNESS: (Reviewing.) page, which is Page 10034, do you see that 13 14 there is a list of label changes here that 14 15 Merck is reporting to the FDA in an annual 15 Q report? 16 A Yes. Q Okay. 13 16 17 A Yes. 17 18 Q Including label changes that it 18 19 informed the FDA about on Novenber 27, 2012, 19 20 correct? BY MR. CORNFELD: Do you see that? If we look at 10049, do you see paragraph 10 there? 20 A Yes. (Reviewing.) 21 Q And this has that instruction, 22 November 27, 2004 [SIC]. 22 after tieing COSOPT, press a finger into the 23 (Reviewing.) 23 corner of your eye by the nose as shown, 24 Where do you see the date 24 referring to a diagram there; this helps keep 25 COSOPT in your eye. 21 25 A November 7, 2004? www.mlawestangatIon.com Fee: 319.694.1334 MIDWEST LITIGATION SERVICES Phone: 1800.280.3376 Fee: 314.644.1334 law w.midwestlltigetlopeow MIDWEST LITIGATION SERVICES Phone: 1800.200_3376 Fax: 314.644.1334 Case 3:12-cv-01141-SMY-DGW Document 176-23 *SEALED* Filed 12/01/14 Page 53 of 57 Page ID #2786 Case:DAVID 16-3334 Document: 55-50 Filed: 02/08/2017 DAVID WALKER Pages: 57 (1480 of 1511) WALKER 2A8/2014 2/18/2014 Pete 209 1 Page 211 Do you see that? 1 Do you know many patient. that 2 A Yes. 2 use COSOPT or generic COSOPT have been using 3 Q So this is the new instruction 3 that drug for many years, correct? 4 that werck told the rDA that it was adding 4 5 for COSOPT in November of 2012, correct? S 6 A Yes. 7 Q Nov, to follow this 6 8 instruction -- are you familiar with what Werck was thinking when it added this 12 A medication for a long time. an indication that doesn't go away. MR. STRAUSS: I am also -- I mean, he already said he's not familiar Glaucoma is By MR. CORNFELD: 11 Q All right. 12 13 I would expect 9 10 I am not sure why they added this. 14 THE WITNESS: 8 i instruction? 11 Object to the that many glaucoma patients use 9 10 MR. STRAUSS: form and foundation. And so when they first start 13 using glaucoma medication or when they start 14 using COSOPT or COSOPT generic, they would 15 with this revision. He is not familiar 15 get the patient instructions and hopefully 16 with this document. Additionally, these 16 they would read them, correct? 17 instructions are outside of the class 1/ A That's our intention. 18 period, so I think it's beyond the 18 Q All right. 19 discovery order from the judge, you know, 19 20 and beyond the topic. 20 21 MR. CORNFELD: Our class -- our But you wouldn't expect they would re-read the patient instruction with 21 each time they refill the bottle if they are 22 class period goes up till class 22 already familiar with how to use it and they 23 certification. 23 have been using it and they have been using 24 it effectively, correct? 24 MR. STRAUSS: 25 No, your class period goes three years from -- you have 25 MR. STRAUSS: Object to the . - „..„. imov.midweelleigationsom MIDWEST LITIGATION SERVICES Phone: 1.800.2803376 Fax/ 314.644.1334 MIDWEST LITIGATION SERVICES Phone: 1.800.280.3376 www.soldwestlitIgation.com DAVID WALKER 2/18/2014 Far 314.644.1334 DAVID WALKER 2/18/2014 Page210 1 a defined class period. 2 MR. CORNFELD: Yeah, we are Page 2I2 1 form and foundation. 2 speculation. 3 going to move for class certification up 3 4 to the date of certification. 4 5 MR. STRAUSS: 6 That will be a change in what you currently have. 7 MR. CORNFELD: 8 I don't think 9 ahead. I do. But go instructions, the pharmacist would inform the patient and draw that to their attention. BY MR. CORNFELD: 9 What other questions you have for I would think if 5 8 MR. STRAUSS: 10 THE WITNESS: there is a labeling change or change in 6 7 so. Calls for Did Merck do anything to Q 10 specifically inform the pharmacist that there was a change in the instructions? 11 him about a document he doesn't know and 11 12 has never seen? 12 A I don't know. 13 Q I mean, the package insert had 13 BY MR. CORNFELD: 14 SI Do you have any idea whether 14 the instructions, and that's contained in the 15 there are any studies that show a glaucoma 15 container -- in the carton that the patient 16 medication like COSOPT is lees effective if 16 buys, correct? 17 you don't follow this instruction than if you 17 A Yes. 18 do? 18 Q And the patient opens it up, 19 A I am not aware of any such 19 sees there's some instructions, they know how 20 to use COSOPT, and they go ahead and use Are you aware of any studies 21 COSOPT ae they have been using it before, 22 that show that COSOPT is, ineffective if you 22 correct? 23 don't follow this instruction? 23 20 21 studies. Q 24 A I am not aware of such studies. 24 25 Q Did -- strike that. 25 wawaddwealithjadoacom MIDWEST LITIGATION SERVICES Phone: 1.800.2803376 Far/ 310.644.1334 MR. STRAUSS: Objection. Calls for speculation. wee.midweallitheitioncom THE WITNESS: I am not sure how MIDWEST LITIGATION SERVICES Phone: 1.800.280.3376 Fox: 314.644.1334 Case 3:12-cv-01141-SMY-DGW Document 176-23 *SEALED* Filed 12/01/14 Page 54 of 57 Page ID #2787 Case: 16-3334 Document: 55-50 Filed: 02/08/2017 Pages: (1481 of 1511) 211112014 57 2118D014 DAVID WALKER DAVID WALKER Page 215 Page213 1 use all their medications, ail patients pa 1 to expect of all our patients. 2 whether they are reading the instructions 2 3 or not. 3 4 BY MR. CORNFELD: 4 5 You certainly wouldn't expect Q 6 everybody to read those instructions every 7 time, would you? hope that they would read their 13 instructions each time they use -- THE WITNESS: instructions to inform patients. BY MR. CORNFELD: 13 Did -- strike that. Q You indicated earlier that you 14 Every -- every time they would I don't know what Merck did with regards to the change in 12 BY MR. CORNFELD: Object to the foundation. 11 It would be my THE WITNESS: 12 Q new instruction, to the attention of patients? 10 11 15 5 6 9 Object to form and foundation. 14 Did Merck do anything other MR. STRAUSS: MR. STRAUSS: 9 10 Q than re-write the instruction, to call theme I It would be my -- A 8 BY MR, CORNFELD: 15 had read some literature to prepare for today's deposition, correct? 16 take out thin night- or ten-page net of 16 17 instructions with tiny print and re-read it 17 A Yes. 18 each time when they have been using the drug 18 Q That was literature provided to 19 and using it effectively and their glaucoma 19 20 J. under control? 20 A Yes. 21 Q Had you seen any of that 22 23 That's not a MR. STRAUSS, 21 question, so -- it's interesting. BY MR. CORNFELD: 24 That's what you would -- that' • Si what you would expect? . ...,„...... „ „ . 25 Photw:LIOUNLIN6 DAVID WALKER 22 literature before you knew your deposition 23 was going to be taken? 24 A No. 25 Q Do you know if Merck had seen . „ „ ..„ MIDWESTLMGATIONSERVICES MIDWESTL41GATIONSERVICES www.midwestlitigationrom you by your attorney? Far: 314.644.1334 Far: 314.644.1334 Phone: 1.100280.3376 wws,WMwmUMptionrom DAVID WALKER 2//82314 1454014 Page 216 Page 214 MR. STRAUSS: 1 2 Object to the 1 any of that literature before this case wan 2 filed? There's a 3 form and foundation. THE WITNESS: 3 A That's is a very difficult I Can't speak for what difference between what we want the 4 question to answer. S patients to do and what we can expect 5 everyone at Merck has read. 6 them to do. 6 7 BY MR. CORNFELD: 7 8 Q 4 MR. STRAUSS: 9 10 form and foundation. 11 speculation. 13 14 17 18 21 22 23 There is no way for me to know Do you know if anyone at Merck Q was aware of it? 14 A I have no way of knowing what people know at Merck. Q So that's a "no," you don't 15 know if anyone at merck was aware of that sitting here as the -- you're only -- the 16 literature? only Merck representative I have to depose 17 today. 18 I do not know whether anyone at Merck had 19 read those articles previously. Q I'm asking you. MR. STRAUSS: 19 20 A what everyone at Merck has read. 11 13 BY MR. CORNFELD: Do you have any knowledge that 10 12 It's not up to me. 15 16 9 Object to the Calls for THE WITNESS: 12 8 Can you expect them to do that? Q Merck was aware of any of that literature? You are It doesn't mean 20 you can ask him any question you want. BY MR. CORNFELD: Q Do you expect -- is that something that you would expect them to do? A Q That is correct. That is a no. And not knowing that, I take it 21 you don't know how anyone at Merck might have 22 interpreted that literature or what their 23 opinion about that literature we., correct? 24 MR. STRAUSS: Same objection. 24 25 THE WITNESS: I don't know what 25 A I have no way of knowing anyone's interpretation of those articles. . wedvaoldwastlidgationse.n Phoebe: 1.800480.3376 ... ..„ MIDWEST LITIGATION SERVICES MIDWEST LITIGATION SERVICES Far: 314.644.1334 www.addwesdidgetloacom Phone: 1.1002803376 Fax: 314.644.1134 Case 3:12-cv-01141-SMY-DGW Document 176-23 *SEALED* Filed 12/01/14 Page 55 of 57 Page ID #2788 2/102014 57 WALKER ananmut Case:DAVE/ 16-3334 Document: 55-50 Filed: 02/08/2017DAVID WALKER Pages: (1482 of 1511) Page 219 Page 217 1 MR. CORNFELD: 2 Let's take a break. 3 but I just want to take a look at some 4 things. MR. STRAUSS: 6 THE VIDEOGRAPHER: 3 to know -- and I haven't seen any -- been 4 provided with any document. about that. Set has -- has Merck 5 Okey-doke. Going off All right. Has Merck -- what I simply want 2 I may be finished, 5 Q 1 All right. 6 investigated using something -- either 7 changing the Connotes Plus or using seem 8 The time is 3:58. 8 other method to deliver eye drops such as 9 (Whereupon a Recess Commenced 9 10 at 3:58 Testimony Recommenced at 4:05.) 10 7 the record. 11 12 THE VIDEOGRAPHER: Back on the The time is 4:05. 14 BY MR. CORNFELD: 15 Q A 11 record. 13 glaucoma drop. since the Ocumeter Plum went on the market? Since the Oeumeter Plus went on We did hear presentations from 12 different companies that were in the startup 13 phase who were trying to propose alternative 14 means of delivering medications topically, 15 that is, to the front of the eye, not 16 the market, has Merck investigated using -- 16 implants, that were not of a dropper bottle 17 using a method to deliver eye drops other 17 design. 18 than with the Ocumeter Plus that was then on 18 19 the market? 19 Are you aware of whether there 20 are any eye dropper. on the market today that 20 21 22 A That was - that later came to (2 All right. 21 are capable or said to be capable of Q No. 22 delivering drops that are smaller than I didn't understand the 23 existing drops? market? Pardon me. 23 A 24 question. 25 4 wwwsnidwen.Opokournm 24 No. Okay. 25 NODWKSTLITIGATIONSERVICES Phone: 1.000.280.3376 Fax: 314.644.1334 A I don't know the specific size of any eye droppers, and I haven't heard of www.midwestiMgOkosom MIDWEST LITIGATION SERVICES Fbno:LIMOSM163376 DAVID WALKER 1782014 DAVIDIVALKER 2/182014 Page 218 1 Page 220 Since the Ocuneter Plus went on 1 eye droppers that are being claimed to deliver smaller drop sikes. 2 the market in the year 2000, has werck 2 3 investigated -- investigated using a 3 4 different method to deliver eye drops? 4 34 or so that COSOPT was when Merck told the 5 A 4 say a drop sine leas than the We have examined in a very 5 FDA about it in 2003 or le.. than -- less 6 limited manner other technologies for the 6 than that, are you aware of any eye droppers 7 delivery of eye drops, but these were all 7 that are on the market that are said to be 6 very much in the -- in their infancy. 8 capable of delivering smaller drops than 9 that? 9 were not fully developed. 10 approved. 11 9 They They were not 10 The alternative method. -- I 11 No, I am not aware of eye droppersAcapable of delivering smaller drops. 12 mean, I see people write about, for *sample, 12 13 implants, things like that. 13 what your role is here today, I think I 14 understand, but you are not here as Merck's 14 15 16 Are those things with -- other than through an eye drop dispenser? A i So medications that are Q And just so that I understand 15 spokesman to talk about medical issue., 16 ophthalmological issues such as the eye's capacity to absorb medication? 17 delivered to the back of the eye are 17 18 implants. 18 A 19 implanted in the cornea. 19 in that capacity. There are eye screws that are There's something That's correct. I am not here 20 called ILUVIEN, which has been approved in 20 21 Europe for delivering medication to the back 21 22 of the eye for macular degeneration. 22 A Correct. 23 9 whether large or small or what 23 24 25 9 Are these methods other than through an eye drop dispenser? A vemmideesdidgadenxem Fez: 314.644.1334 24 Yes. MIDWEST LITIGATION SERVICES Phew: 1$00.2803376 25 Fax:314.644.1334 Q You are not here to talk about the effectiveness of eye drops, correct? have you, correct? A www.mkboothitipMkorem Correct. MIDWEST LITIGATION SERVICES Phone: 1.800.280.3376 Fax: 314.644.1334 Case 3:12-cv-01141-SMY-DGW Document 176-23 *SEALED* Filed 12/01/14 Page 56 of 57 Page ID #2789 unam Document: 55-50 Case: 16-3334 Filed: 02/08/2017 Pages: 57 (1483 of 1511) DAVID WALKER DAVID WALKER 2/102014 Page221 1 Q are not Merck's spokes epokman van Page 223 1 I, S. Arielle Santos, C.S.R., a 2 to talk about possible aide effects from eye 2 Registered Professional Reporter, Certified 3 drops , correct? 3 Shorthand Reporter, Certified LiveNote Reporter do hereby certify: 4 A Correct. 4 5 0 You are not Merck.. spokesman 5 That prior to being examined, the witness 6 to talk about how largo eye drops should be, 6 named in the forgoing deposition, was by me 7 correct? 7 duly sworn to testify the truth, the whole 8 A Correct. 8 truth, and nothing but the truth. 9 Q You are not -- I guess Steve is 9 10 going to object. That said deposition was taken before me at If you are not aware of 10 the time and place set forth and was taken 11 this, you are not aware of that, but X am 11 down by me in shorthand and thereafter 12 going to ask it anyway. 12 reduced to computerized transcription under 13 my direction and supervision, and I hereby 13 You are not Marck's spokesman 14 on whether there are benefits from having eye 14 certify the foregoing deposition is a full, 15 drops larger than any given size, correct? 15 true and correct transcript of my shorthand 16 notes so taken. 16 17 18 A I am not aware of benefits as a function of eye drop size. 17 So in other he words, you are Q 18 I further certify that I am neither counsel for nor related to any party to said action 19 not -- whether there are or not, you are not 19 nor in anywise interested in the outcome 20 Merck's spokesman on that subject, correct? 20 thereof. 21 A Correct. MR. CORNFELD: 22 21 That's all the 22 23 questions that I have. Thank you. 23 24 MR. STRAUSS: All right. 24 25 Thanks a lot. MIDWEST LITIGATION SERVICES Phone: 1.800.280.3376 verrer.mhbreartatigation.com S. Arielle Santos, RPR, CSR, CLR 25 Pax: 314.644.1334 MIDWEST LITIGATION SERVICES Phone: 1.800.280.3376 www.nddereetlidgation.com DAVID WALKER 2/18/2014 DAVID Fa: 314.644.1334 AJJWA 2/18/2014 Page222 1 We have the same start time 2 tomorrow morning, so I guess if people 3 are calling in the same way, if they just 4 make sure they do it -- you know, 5 coordinate it so that, you know, 6 everybody is up and rolling. Page 224 1 2 February 25, 2014 3 BRYAN CAVE LLP One Metropolitan Square 211 North Broadway, Suite 3600 St. Louis, Missouri 63102-2750 IN RE: CHARLENE EIKE, et al., on Behalf of themselves and all Others similarly situated vs. ALLERGAN, INC., et al 4 5 7 We will be good to go at - - Es hopefully on time tomorrow, 9:30 a.m. 9 Eastern. THE VIDEOGRAPHER: 10 6 7 Dear STEPHEN G. STRAUSS 8 Please find enclosed your copies of the deposition of DAVID WALKER taken on February 18, 2014 in the above-referenced case. Also enclosed is the original signature page and errata sheets. Going off 9 11 MIDWEST LITIGATION SERVICES the record. 10 This marks the end of Tape 12 13 11 Number 3 in the de position. 14 The time is 4:12 p.m. 12 15 MR. STRAUSS: 13 16 We will read and sign. Please have the witness read your copy of the transcript, indicate any changes and/or corrections desired on the errata sheets, and sign the signature page before a notary public. 14 Please return the errata sheets and notarized signature page to JOHN G. SIMON for filing prior to trial date. 15 Sincerely, 11 19 (Signature having not been waived, 16 20 the Videotaped deposition of 21 DAVID WALKER was Concluded at 18 19 22 4:12 p.m.) 20 17 Arielle santos Enclosures 21 23 22 23 29 24 25 25 www.mIdeestlitlyaboo.com MIDWEST LITIGATION SERVICES none: 1.800.280.3376 Fax: 314.644.1334 www.midwestlffigaboncom MIDWEST LITIGATION SERVICES Phone: 1.800160.3376 Fax: 314.644.1334 Case 3:12-cv-01141-SMY-DGW Document 176-23 *SEALED* Filed 12/01/14 Page 57 of 57 Page ID #2790 Case:RAWL/WALKER 16-3334 Document: 55-50 Filed: 02/08/2017 Pages: 57 (1484 of 1511) =VAN Page 225 ERRATA SHEET 1 2 Witness Name: DAVID WALKER 3 Case Name: CHARLENE EIKE, et al., on Behalf of 4 themselves and all Others similarly 5 situated vs. ALLERGAN, INC., et al 6 Date Taken: FEBRUARY 18, 2014 8 Page it 9 Should read: 10 Line Reason for change. 11 Line 12 Page t 13 Should read- 14 Reason for change- 15 16 Page t 17 Should read - Line t Reason for change. 18 Line 1 Page 1 19 Should read: Reason for change. 20 21 Page t 22 Should read: 23 Reason for change. Line t 24 25 Witness Signature. www4oldwestlitigetion.com MIDWEST LITIGATION SERVICES Phone: 1.800.280.3376 Fs= 314344.1334 DAVID WALKER 2/18/2014 Page 226 1 STATE OF 2 3 COUNTY OF 4 5 6 I, DAVID WALKER, do hereby certify: That I have read the foregoing deposition; 7 That I have made such changes in form 8 and/or substance to the within deposition as might 9 be necessary to render the same true and correct; 10 11 12 13 14 15 That having made such changes thereon, I hereby subscribe my name to the deposition. I declare under penalty of perjury that the foregoing is true and correct. Executed this day of 20_ , at 16 17 18 19 20 DAVID WALKER 21 22 23 24 NOTARY PUBLIC My Commission Expires: 25 www.mithrestlitigadoncam MIDWEST LITIGATION SERVICES Phone: 1.800.280.3376 Fax: 314.6441334 Case 3:12-cv-01141-SMY-DGW Document 176-49 *SEALED* Filed 12/01/14 Page 1 of 7 Case: 16-3334 Document:Page 55-51ID #3451 Filed: 02/08/2017 Pages: 7 (1485 of 1511) Redacted Redacted Redacted Redacted Redacted CE-000042 Redacted Redacted Redacted Redacted Redacted Redacted Redacted Redacted Redacted Redacted Redacted Case 3:12-cv-01141-SMY-DGW Document 176-49 *SEALED* Filed 12/01/14 Page 2 of 7 Case: 16-3334 Document:Page 55-51ID #3452 Filed: 02/08/2017 Pages: 7 (1486 of 1511) 00043 Redacted Redacted Redacted Redacted Redacted Redacted Redacted Redacted Redacted Redacted Case 3:12-cv-01141-SMY-DGW Document 176-49 *SEALED* Filed 12/01/14 Page 3 of 7 Case: 16-3334 Document:Page 55-51ID #3453 Filed: 02/08/2017 Pages: 7 (1487 of 1511) 00044 Redacted Redacted Redacted Redacted Redacted Redacted Redacted Case 3:12-cv-01141-SMY-DGW Document 176-49 *SEALED* Filed 12/01/14 Page 4 of 7 Case: 16-3334 Document:Page 55-51ID #3454 Filed: 02/08/2017 Pages: 7 (1488 of 1511) CE-000045 Redacted Redacted Redacted Redacted Case 3:12-cv-01141-SMY-DGW Document 176-49 *SEALED* Filed 12/01/14 Page 5 of 7 Case: 16-3334 Document:Page 55-51ID #3455 Filed: 02/08/2017 Pages: 7 (1489 of 1511) CE-000046 Redacted Redacted Redacted Redacted Redacted Case 3:12-cv-01141-SMY-DGW Document 176-49 *SEALED* Filed 12/01/14 Page 6 of 7 Case: 16-3334 Document:Page 55-51ID #3456 Filed: 02/08/2017 Pages: 7 (1490 of 1511) E-000047 Redacted Case 3:12-cv-01141-SMY-DGW Document 176-49 *SEALED* Filed 12/01/14 Page 7 of 7 Case: 16-3334 Document:Page 55-51ID #3457 Filed: 02/08/2017 Pages: 7 (1491 of 1511) CE-000048 Case 3:12-cv-01141-SMY-DGW Document 176-24 *SEALED* Filed 12/01/14 Page 1 of 2 Case: 16-3334 Document:Page 55-52ID #2791 Filed: 02/08/2017 Pages: 2 (1492 of 1511) Adverse Events Page 1 of 1 PRASCO Source: phone call Entered Sy: Lbrinkmart ;7;0.114 Mail Date Entered: 9/26/2011 Event ID: 2.4.4 Caller: Name; Address: Phone: Category: IBLEgith pa. Naas . IL O47:965:3916 Company: Osco Pharmacy # 3446 Title: AEb Phone 2: E Company Representative IS Distributor M Health Professional ri Study 17 Other ri Consumer l Foreign E Literature C! User Facility Patient: IR same as Caner Name: Address: Ftione: Age: Phone 2: Gender. Email: Weight (ibs): Pharmacy: Is Same as Caller Wholesaler Account #: Event: Expected Quantity: Partner Notification: 9/26/2011 General Inquiry: M DtszolamIde HaMmolot Mal - 2(0.S%-10 ml (66993490401 Product: Expiration Date: Lot Number: needed helo aettino draw to disowns Description: Brand) Plant: 1201 Partner: Event Notes Entered Entered By patient & RPh could not get drops to dispense. 9/26/2011 f.brinionan Patient was ist time user of thliproduct. Resolution Notes Entered Entered By FO asked RPh to replace cap &tighten arrows --then remove by turning cap in opposite direction as Indicated by arrows on the top. RPh was then able to get drops to dispense. FB also explained to RPh re: how arrows should align when bottle Is dosed. RPh stated that she would relay this info to the patient. 9/26/2011 Lbrinknian Prasco sent copy of this Inquiry to Merdc. P1 Closed? IU Adverse Event? Closed Date• 9./.2(4011.15111224 Admin: Resolution: Order Wpm JDE Address #: Complaint; Order .11,0e: JOE Address #: Partner Assigned Complaint #: • JOE Order it; Customer PO: JDE Order #: Customer PO; Pre-Pald Envelope: 522515 Partner narking #: The Admin Notes section is empty. Attachments: Export as PDF: Revision History: View Revision Entered Entered By P I 9/26/2011 2:25 PM Ebrinkmen ,P 2 9/26/2011 3:51 PM Ebrinkrnan Generate Complaints Imams des Resort Generate Resolution-Cortiolatnt Folder Report Confidential-Subject to Protective Order Produced by Prasco, LLC in Case 3:12-cv-1141-DRH-DGW (S.D.ILL.) Prasco 000092 Case 3:12-cv-01141-SMY-DGW Document 176-24 *SEALED* Filed 12/01/14 Page 2 of 2 Case: 16-3334 Document:Page 55-52ID #2792 Filed: 02/08/2017 Pages: of 1511) Page21 of(1493 2 Adverse Events A P RASCO F.WC !WEI Source: Email Entered By: f.brinkrnan Date Entered: 9/28/2011, Event ID: au Caller: Chapman, Marcella Company: 112 Northsh-cirw Dr. Morton, IL61550 • 309-263-2886 Phone 2: Name: Address: Phone: Category: Email: ff. Company Representative E Distributor IT Health Professional IN Study I Patient: Title: Consumer IW Foreign II Literature mchao112(amtco.com E Other 1-1 . User Facility l Same as Caller Gender: Age: Weight (Ibs): Pharmacy: m7 _- Same as Caller Company: Name: Address: Phone: Phone 2: Email: Wholesaler Account #: Event: Partner Notification: 9/28/2011, General Inquiry: Product: Lot Number: Description: ffi porzolamide HCITTirnolol Expected Quantity: -2/0.5%. 10 mL (66993-190-201 Expiration Date: Branch Plant: Partner. 1200 how Iona sholud bottle last? Event Notes Entered Entered By Prasco rec'd the following email from consumer: I am using dorzolamide hydrochloride-timolol maleate ophthalmic solution 1 drop each eye BID. My pharmacy and I disagree on how long a 10m1 bottle should last. 9/28/2011 f.brinkman Resolution Notes Entered Entered By FB responded: Good Afternoon, Thank you for contacting Prasco regarding DorzolamIde Hydrochlorlde-Timolol Maleate ophthalmic solution. We appreciate your Interest in our product . We cannot determine the exact number of drops per bottle dispenser or the exact number of days of therapy per bottle because ' usage may vary with individual patients. However, I can provide you with approximately how many days of therapy a bottle should last based on the recommended dose stated in the product insert. Per the product insert for Dorzolamlde HCI-Timolol Maleate ophthalmic solution In a 10 mL bottle, putting one (1) drop in each eye two (2) times dally, the number of days of therapy should last approximately 59 days (. 8 weeks). If your prescription does not match the information provided, you will need to follow up with the physician or pharmacist that prescribed your eye drops. 9/28/2011 f.brinkman • • sent copy of inquiry record to Merck. 9/28/2011 f.brinkman re-opened/closed: added Merck's complaint #. 9/28/2011 f.brinkman on 9.28.11, Prasco rec'd a 2nd email from consumer. Email stated: Can you tell me where In the product insert you found that Information? Generally, the equvalenvy charts habe 1m1 =15 gtts or 1m1 . 20gtts. Neither of those would equal 59 days much less 8 weeks. 9/29/2011 f.brinkman Thank you for your help. . Marcella Chapman FB responded on 9.28.11: Ms. Chapman, Please allow me to clarify the previous response you received from me. The answer regarding the approximate # of days of therapy which I sent to you earlier, is correct. However, this information Is not found In the package Insert It was supplied to Prasco from Merck, the product manufacturer. 9/29/2011 f.brinkman • The Information that is stated in the package Insert relates to the recommended dose (mentioned in previous email). My apologies for the confusing wording In our Initial correspondence. Confidential-Subject to. Protective Order Produced b Prasco, LLC in Case 3:12-cv-1141-DRH-DGW S.D.ILL. Prasco 000093 Case 3:12-cv-01141-SMY-DGW Document 176-50 *SEALED* Filed 12/01/14 Page 1 of 5 SF-000029 Case: 16-3334 Document:Page 55-53ID #3458 Filed: 02/08/2017 Pages: 5 (1494 of 1511) Redacted Redacted Redacted Redacted Case 3:12-cv-01141-SMY-DGW Document 176-50 *SEALED* Filed 12/01/14 Page 2 of 5 SF-000038 Case: 16-3334 Document:Page 55-53ID #3459 Filed: 02/08/2017 Pages: 5 (1495 of 1511) Redacted Redacted Redacted Redacted Case 3:12-cv-01141-SMY-DGW Document 176-50 *SEALED* Filed 12/01/14 Page 3 of 5 SF-000049 Case: 16-3334 Document:Page 55-53ID #3460 Filed: 02/08/2017 Pages: 5 (1496 of 1511) Redacted Redacted Redacted Redacted Case 3:12-cv-01141-SMY-DGW Document 176-50 *SEALED* Filed 12/01/14 Page 4 of 5 SF-000050 Case: 16-3334 Document:Page 55-53ID #3461 Filed: 02/08/2017 Pages: 5 (1497 of 1511) Redacted Redacted Redacted Redacted Case 3:12-cv-01141-SMY-DGW Document 176-50 *SEALED* Filed 12/01/14 Page 5 of 5 SF-000051 Case: 16-3334 Document:Page 55-53ID #3462 Filed: 02/08/2017 Pages: 5 (1498 of 1511) Case 3:12-cv-01141-SMY-DGW Document 176-25 *SEALED* Dorzolamide HC1 and Timolol Maleate Ophthalmic Solution Filed 12/01/14 Page 1 of 2 Page ID #2793 Case: 16-3334 Document: 55-54 Filed: 02/08/2017 Pages: 2 (1499 of 1511) After completion of in-process analytical testing, the solution is aseptically filled into Alcon's DROP-TAINER® packaging system which consists of either gamma or ethylene oxide sterilized bottles and plugs, and gamma sterilized closures. How are the manufacturing steps (unit operations) related to the drug product quality? For this simple dosage form, validated processes are required to assure the sterility assurance level and overall quality for the sterile finished drug product. In-process controls have been established to ensure that adequate controls and validated parameters are in place for the manufacturing processes as presented in Module 3, Section 3.2.P.3.4. How were the critical process parameters identified, monitored, and/or controlled? For this simple dosage form, the critical parameters were identified as those associated with sterility assurance for this sterile finished drug product. The critical sterility assurance parameters monitored during the manufacturing process include sterilizing filter integrity testing, validated sterilization cycle parameters, bulk product bioburden, pre-sterilization bulk product holding time and environmental monitoring. What is the scale-up experience with the unit operations in this process? The primary stability batch (exhibit batch) was produced in the Alcon ASPEX Manufacturing Facility within the production scale batch size range using standard production equipment. 2.3.P.2.4 Container Closure System What specific container closure attributes are necessary to ensure product performance? Dorzolamide-Timolol Ophthalmic Solution will be packaged in Alcon's standard DROPTAINER® packaging system. The package system selected is appropriately sized for the desired label claim and is easy to squeeze due to its shape and resin characteristics. This system consists of a low density polyethylene (LDPE) bottle and dispensing plug and a polypropylene (PP) closure. A white DROP-TAINER with blue closure was selected to 2.3 Introduction to the Quality Overall Summary , Page 20 AD_DORZ-TIM_EIKE001234 Case 3:12-cv-01141-SMY-DGW Document 176-25 *SEALED* Dorzolamide HC1 and Timolol Maleate Ophthalmic Solution Filed 12/01/14 Page 2 of 2 Page ID #2794 Case: 16-3334 Document: 55-54 Filed: 02/08/2017 Pages: 2 (1500 of 1511) resemble the container of COSOPT. Consistent with the COSOPT labeling, the opaque (white) bottle also provides protection from light. The bottle and plug are sterilized by either ethylene oxide or gamma irradiation, and the closure by gamma irradiation. The resins used in the packaging components for Dorzolamide-Timolol Ophthalmic Solution have been previously approved for use in numerous ophthalmic products marketed by Alcon and have been subjected to USP physicochemical and toxicological testing in accordance with the USP. All USP testing results are acceptable. Performance studies included drop-size studies to confirm consistency of the drug product delivery and container/closure and sterility stability testing to confirm maintenance of sterility. 2.3.P.2.5 Microbiological Attributes The microbiological attributes include preservative effectiveness, sterility and container/closure integrity. Dorzolamide-Timolol Ophthalmic Solution meets USP <51> Antimicrobial Effectiveness Test requirements initially. Data also show efficacy of a formulation containing 80% of label benzalkonium chloride. A sterility test based on the USP direct transfer test has been validated for the product and USP requirements are met initially. Stability lot samples will continue to be evaluated for sterility until the desired expiration period is reached. In addition to routine sterility testing, the product packaging has been subjected to microbial ingress testing which demonstrate that these container/closure systems provide highly effective barriers for the maintenance of product sterility. 2.3.P.3. MANUFACTURE Who manufactures the drug product? Dorzolamide-Timolol Ophthalmic Solution will be manufactured and tested by: Alcon Research, Ltd. (subsidiary of Alcon Laboratories, Inc.) ASPEX (Alcon Sterile Products Expansion) Manufacturing Facility 6201 South Freeway Fort Worth, TX 76134-2099 (Drug Establishment Registration Number 1610287) 2.3 Introduction to the Quality Overall Summary , Page 21 AD_DORZ-TIM_EIKE001235 Redacted Redacted Redacted Redacted Case 3:12-cv-01141-SMY-DGW Document 176-51 *SEALED* Filed 12/01/14 Page 1 of 11 Page ID #3463 Case: 16-3334 Document: 55-55 Filed: 02/08/2017 Pages: 11 (1501 of 1511) JP-000122 Redacted Redacted Redacted Redacted Redacted Redacted Case 3:12-cv-01141-SMY-DGW Document 176-51 *SEALED* Filed 12/01/14 Page 2 of 11 Page ID #3464 Case: 16-3334 Document: 55-55 Filed: 02/08/2017 Pages: 11 (1502 of 1511) JP-000123 Redacted Redacted Redacted Redacted Redacted Case 3:12-cv-01141-SMY-DGW Document 176-51 *SEALED* Filed 12/01/14 Page 3 of 11 Page ID #3465 Case: 16-3334 Document: 55-55 Filed: 02/08/2017 Pages: 11 (1503 of 1511) JP-000124 Redacted Redacted Redacted Case 3:12-cv-01141-SMY-DGW Document 176-51 *SEALED* Filed 12/01/14 Page 4 of 11 Page ID #3466 Case: 16-3334 Document: 55-55 Filed: 02/08/2017 Pages: 11 (1504 of 1511) JP-000125 Redacted Redacted Redacted Case 3:12-cv-01141-SMY-DGW Document 176-51 *SEALED* Filed 12/01/14 Page 5 of 11 Page ID #3467 Case: 16-3334 Document: 55-55 Filed: 02/08/2017 Pages: 11 (1505 of 1511) JP-000126 Redacted Redacted Redacted Redacted Case 3:12-cv-01141-SMY-DGW Document 176-51 *SEALED* Filed 12/01/14 Page 6 of 11 Page ID #3468 Case: 16-3334 Document: 55-55 Filed: 02/08/2017 Pages: 11 (1506 of 1511) JP-000127 Redacted Redacted Redacted Redacted Case 3:12-cv-01141-SMY-DGW Document 176-51 *SEALED* Filed 12/01/14 Page 7 of 11 Page ID #3469 Case: 16-3334 Document: 55-55 Filed: 02/08/2017 Pages: 11 (1507 of 1511) JP-000128 Redacted Redacted Redacted Case 3:12-cv-01141-SMY-DGW Document 176-51 *SEALED* Filed 12/01/14 Page 8 of 11 Page ID #3470 Case: 16-3334 Document: 55-55 Filed: 02/08/2017 Pages: 11 (1508 of 1511) JP-000129 Redacted Redacted Redacted Redacted Case 3:12-cv-01141-SMY-DGW Document 176-51 *SEALED* Filed 12/01/14 Page 9 of 11 Page ID #3471 Case: 16-3334 Document: 55-55 Filed: 02/08/2017 Pages: 11 (1509 of 1511) JP-000130 Redacted Redacted Redacted Redacted Case 3:12-cv-01141-SMY-DGW Document 176-51 *SEALED* Filed 12/01/14 Page 10 of 11 Page ID #3472 Case: 16-3334 Document: 55-55 Filed: 02/08/2017 Pages: 11 (1510 of 1511) JP-000132 Redacted Redacted Redacted Case 3:12-cv-01141-SMY-DGW Document 176-51 *SEALED* Filed 12/01/14 Page 11 of 11 Page ID #3473 Case: 16-3334 Document: 55-55 Filed: 02/08/2017 Pages: 11 (1511 of 1511) JP-000133