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 16L 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 16L 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 16L 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 16L 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 16L 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 16L 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 16L 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 16L 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 16L 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 16L 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 16L 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