UNITED STATES PATENT AND TRADEMARK OFFICE
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`
`
`BEFORE THE PATENT TRIAL AND APPEAL BOARD
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`
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`INNOPHARMA LICENSING, INC., INNOPHARMA LICENSING LLC,
`INNOPHARMA INC., INNOPHARMA LLC,
`MYLAN PHARMACEUTICALS INC., and MYLAN INC.
`Petitioner,
`
`v.
`
`SENJU PHARMACEUTICAL CO., LTD., BAUSCH & LOMB, INC., and
`BAUSCH & LOMB PHARMA HOLDINGS CORP.
`Patent Owner.
`
`
`Case IPR2015-00903
`Patent 8,129,431
`
`
`
`DECLARATION OF ROBERT O. WILLIAMS, III, PH.D.
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`1
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`SENJU EXHIBIT 2082
`INNOPHARMA v SENJU
`IPR2015-00903
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`PAGE 1 OF 117
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`TABLE OF CONTENTS
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`I.
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`II.
`
`INTRODUCTION ........................................................................................... 5
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`BACKGROUND AND QUALIFICATIONS ................................................. 5
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`III.
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`INFORMATION CONSIDERED ................................................................... 8
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`IV. LEGAL PRINCIPLES ..................................................................................... 9
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`V.
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`THE ’431 PATENT ......................................................................................... 9
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`A.
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`B.
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`Specification and Claims ....................................................................... 9
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`Person of Ordinary Skill in the Art ..................................................... 15
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`VI. SUMMARY OF OPINIONS ......................................................................... 16
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`VII. THE STATE OF THE ART AS OF JANUARY 21, 2003 ........................... 22
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`A. A Person of Ordinary Skill in the Art Would Not Have Pursued
`Bromfenac Formulations Over Other NSAID Formulations .............. 26
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`1.
`
`2.
`
`No reason to pursue bromfenac formulations ........................... 26
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`Design needs or market demands would not have
`supported the solution that InnoPharma proposes .................... 29
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`B. A Person of Ordinary Skill in the Art Would Not Have
`Considered Different Non-Ionic Surfactants Interchangeable ............ 36
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`1.
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`2.
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`No teaching of interchangeability of polysorbate 80 and
`tyloxapol in aqueous solutions of NSAIDs .............................. 37
`
`No teaching of polysorbate 80 or tyloxapol as a stabilizer
`of aqueous ophthalmic preparations of NSAIDs ...................... 42
`
`C. A Person of Ordinary Skill in the Art Would Not Have
`Considered Different NSAIDs Interchangeable.................................. 46
`
`VIII. THE TEACHINGS OF OGAWA, SALLMANN, AND FU WOULD
`NOT HAVE BEEN COMBINED WITH ANY REASONABLE
`EXPECTATION OF ARRIVING AT THE CLAIMED SUBJECT
`MATTER OF THE ’431 PATENT ............................................................... 49
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`A. A Person of Ordinary Skill in the Art Would Have Had No
`Reason to Focus on Ogawa and its Bromfenac Formulations ............ 49
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`B. At the Time of Invention, A Person of Ordinary Skill in the Art
`Would Not Have Combined Ogawa’s Teachings With Those of
`Sallmann .............................................................................................. 53
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`1.
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`2.
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`3.
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`4.
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`Ogawa and the problem it identifies with bromfenac ............... 53
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`A person of ordinary skill in the art would not have
`looked to Sallmann or combined its teachings with those
`of Ogawa ................................................................................... 57
`
`Dr. Laskar’s alleged motivation and expectation of
`success in fact would not have made the combination of
`Ogawa and Sallmann obvious to make ..................................... 65
`
`A person of ordinary skill in the art would not have
`modified Sallmann with the teachings of Ogawa ..................... 70
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`C. Dr. Laskar’s Reliance on Fu is Similarly Scientifically
`Unsupportable and Does Not Remedy the Deficiencies in his
`Reliance on Ogawa and Sallmann ....................................................... 73
`
`1.
`
`2.
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`Dr. Laskar’s reliance on Fu for tyloxapol is unsupported ........ 75
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`Fu does not suggest an amount of tyloxapol that could be
`used to stabilize bromfenac ....................................................... 79
`
`IX. OBJECTIVE EVIDENCE OF NON-OBVIOUSNESS OF THE ’431
`PATENT CLAIMS ........................................................................................ 83
`
`A. A Unique, Non-Prior Art, Aspect of the ’431 Patent Claims:
`The Use of Tyloxapol with Bromfenac ............................................... 83
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`B.
`
`The Unexpectedly Superior Chemical Stabilizing Benefits of
`Tyloxapol Compared to Polysorbate 80 .............................................. 85
`
`1.
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`2.
`
`The ’431 patent compares against the closest prior art for
`purposes of showing unexpected results ................................... 86
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`A person of ordinary skill in the art would have had no
`expectation, based on polysorbate 80, of tyloxapol’s
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`effect on the chemical stability of bromfenac
`formulations .............................................................................. 88
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`3.
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`Tyloxapol’s unexpectedly superior chemical stabilizing
`effect .......................................................................................... 90
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`C.
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`Tyloxapol is Unexpectedly Better than Polysorbate 80 at
`Maintaining Preservative Efficacy ...................................................... 99
`
`E.
`
`D.
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`Tyloxapol’s Unexpectedly Superior Stabilizing Effect Led to
`Actual Benefits for Patients ...............................................................101
`Copying of Prolensa® by Generic Drug Companies .........................104
`CONCLUSION ............................................................................................105
`X.
`XI. CLAIM CHART DEMONSTRATING THAT PROLENSA® FALLS
`WITHIN THE SCOPE OF CERTAIN CLAIMS OF THE ’431
`PATENT ......................................................................................................111
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`4
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`XII.
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`PAGE 4 OF 117
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`I, Robert O. Williams, III, Ph.D., under penalty of perjury, declare as follows:
`I.
`
`INTRODUCTION
`
`1.
`
`I have been retained by Finnegan, Henderson, Farabow, Garrett &
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`Dunner, LLP on behalf of Senju Pharmaceutical, Co., Ltd. in connection with two
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`inter partes review (“IPR”) proceedings (IPR2015-00903 and IPR2015-00902)
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`before the United States Patent and Trademark Office (“PTO”) Patent Trial and
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`Appeal Board (“Board”) as an expert in the field of the design, evaluation, and
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`formulation of drug products. My qualifications in these areas, as well as other
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`areas, are established below and by my curriculum vitae, which is attached as
`
`EX2115.
`
`II. BACKGROUND AND QUALIFICATIONS
`I am currently the Johnson & Johnson Centennial Chair of
`2.
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`Pharmaceutics at the University of Texas at Austin College of Pharmacy in Austin,
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`Texas, where I have been teaching and conducting research for twenty years. Also,
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`I am the Division Head of Pharmaceutics.
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`3.
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`I received a B.S. degree in biology from Texas A&M University in
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`1979, a B.S. degree in pharmacy from the University of Texas at Austin in 1981,
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`and a Ph.D. degree in pharmaceutics from the University of Texas at Austin in
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`1986. I am a licensed pharmacist.
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`5
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`4.
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`I have extensive experience and expertise
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`in pharmaceutical
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`formulation and the use of excipients in formulating various types of drug dosage
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`forms, including aqueous liquid preparations. I have experience with ophthalmic
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`dosage forms including solutions. I am an expert in the field of pharmaceutical
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`development, and I have worked almost exclusively in the field of pharmaceutical
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`development since 1986.
`
`5.
`
`Prior to becoming a professor, I worked in the pharmaceutical
`
`industry for several companies including Rhone-Poulenc Rorer Pharmaceuticals,
`
`Duramed Pharmaceuticals and Eli Lilly and Company. Additionally, from 1996 to
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`2007 I was co-founder and President of PharmaForm, a contract pharmaceutical
`
`laboratory, and from 2007 to mid-2010 I was a director of Akela Pharma. I was
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`the Chief Scientist from 2009 to 2013 and founder of Enavail, a particle
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`engineering contract services company. Accordingly, I have relevant industry
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`experience in addition to my academic qualifications.
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`6. My current research focuses on the development, formulation,
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`optimization and delivery of drugs by a variety of technologies, including aqueous
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`liquid preparations. I have extensive research experience and have authored
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`numerous publications in this area.
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`7.
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`I have authored or co-authored over 400 published papers, abstracts
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`and book chapters related to my work in the pharmaceutical sciences. A
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`6
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`significant number of my papers are directed specifically to pharmaceutical
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`formulation techniques and drug dosage forms. I have co-edited two books on the
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`subject of pharmaceutical formulation and drug delivery. I am a co-inventor on
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`over 35 patents and/or patent applications that deal with drug formulation
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`technology.
`
`8.
`
`Over the course of my career, I have earned numerous prestigious
`
`professional awards and honors, which are described on my curriculum vitae. For
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`example, I was elected as a fellow to the American Association of Pharmaceutical
`
`Scientists and the American Institute of Medical and Biological Engineering. I
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`have also received the William J. Sheffield Outstanding Alumnus Award and was
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`named a Dean’s Fellow at the University of Texas at Austin College of Pharmacy.
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`9.
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`I am currently the Editor-in-Chief for AAPS PharmSciTech, a joint
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`publication of the American Association of Pharmaceutical Scientists and Springer
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`Publishing. I was the Editor-in-Chief for Drug Development and Industrial
`
`Pharmacy (an Informa Healthcare publication) from 2000 to 2014. I am a member
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`of the Editorial Advisory Board for The Open Drug Delivery Journal. I also have
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`served or currently serve as a reviewer for many scientific journals, including
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`International Journal of Pharmaceutics, Pharmaceutical Research, European
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`Journal of Pharmaceutics and Biopharmaceutics, Journal of the Controlled
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`Release Society, Drug Delivery Science and Technology, Pharmaceutical
`
`
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`7
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`Development and Technology,
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`International Journal of Pharmaceutical
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`Compounding, Journal of Membrane Science, AAPS PharmSciTech, Journal of
`
`Pharmaceutical Sciences, Journal of Pharmaceutical and Biomedical Analysis and
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`Toxicology Letters.
`
`10.
`
`In addition to my research and teaching duties at the University of
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`Texas at Austin, I have consulted for pharmaceutical, chemical and biotechnology
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`companies. I have consulted for both innovator pharmaceutical companies and
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`generic pharmaceutical companies. Most of these consulting activities have dealt
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`specifically with drug formulation issues.
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`11. On the basis of my education and the experience described above, I
`
`believe I am qualified to give the opinion set out herein.
`
`III.
`
`INFORMATION CONSIDERED
`
`12. The opinions expressed in this declaration are based on my review of,
`
`among other materials, U.S. Patent No. 8,129,431 (“the ’431 patent”), the “Petition
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`for Inter Partes Review of U.S. Patent No. 8,129,431” (“Petition”) and the
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`declarations of Dr. Paul A. Laskar (EX1003), Stephen G. Davies, Ph.D. (EX2105),
`
`and Shirou Sawa (EX2098). I also based my opinions on my professional and
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`academic experience in the area of pharmaceutical formulation. I reserve the right
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`to testify about these materials and experience. As I discuss below, I disagree with
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`8
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`Dr. Laskar’s conclusions that the subject matter of the claims of the ’431 patent
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`
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`would have been obvious.
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`IV. LEGAL PRINCIPLES
`
`13.
`
`I understand that an obviousness analysis involves a review of the
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`scope and content of the prior art, the differences between the prior art and the
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`claims at issue, the level of ordinary skill in the art, and objective indicia of non-
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`obviousness, such as unexpected superior results, copying and commercial success.
`
`I understand that for an invention to be regarded as obvious, a person of ordinary
`
`skill in the art must have had a reason to modify the prior art or to combine one or
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`more prior art references in a manner that would result in the claimed subject
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`matter with a reasonable expectation of success.
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`V. THE ’431 PATENT
`
`A.
`14.
`
`Specification and Claims
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`I understand that InnoPharma has challenged claims 1-22 of the ’431
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`patent, EX1001, in this action. I further understand that the ’431 patent has a
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`priority date of January 21, 2003.
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`15. The ’431 patent is directed, generally speaking, to aqueous liquid
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`preparations consisting essentially of the non-steroidal anti-inflammatory drug
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`(“NSAID”) 2-amino-3-(4-bromobenzoyl)phenylacetic acid (“bromfenac”) or its
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`9
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`pharmacologically acceptable salt or hydrate thereof and the non-ionic surfactant
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`tyloxapol. (EX1001.)
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`16. The ’431 patent specification states that “the inventors of the present
`
`invention have found that, by adding, for example, [tyloxapol] to an aqueous liquid
`
`preparation of [bromfenac], the aqueous solution becomes stable within a pH range
`
`giving no irritation to eyes, and change of the [bromfenac] over time can be
`
`inhibited, and furthermore, when the aqueous solution contains a preservative,
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`deterioration in the preservative effect of said preservative can be inhibited for a
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`long period of time.” (EX1001 at 2:34-47.) This passage’s statement that the
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`“change of the [bromfenac] over time can be inhibited” refers to the ability of
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`tyloxapol to stabilize bromfenac from chemical degradation, which Experimental
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`Examples 1-2 and Tables 1-2 of the ’431 patent confirm with experimental proof.
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`Similarly, this passage’s statement that “deterioration in the preservative effect . . .
`
`can be inhibited” refers to the ability of tyloxapol to control and stabilize a
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`bromfenac formulation’s microbial growth, which Experimental Example 3 and
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`Tables 3-1 to 3-3 confirm with experimental proof.
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`17. Thus, the ’431 patent specification describes aqueous solutions
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`containing bromfenac and tyloxapol that are chemically stable, with controlled
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`microbial growth, are safe and non-irritating to the eye, and are efficacious and
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`suitable for ophthalmic administration.
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`18. The ’431 patent claims are directed, generally speaking, to aqueous
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`ophthalmic preparations consisting essentially of bromfenac and tyloxapol.
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`(EX1001 at 11:65-14:22.) The ’431 patent has two independent claims (claims 1
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`and 18) and 20 dependent claims. (Id.)
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`19. Generally speaking, independent claim 1 of the ’431 patent is directed
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`to an aqueous liquid preparation consisting essentially of bromfenac and tyloxapol,
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`formulated for ophthalmic administration, and when a quaternary ammonium
`
`compound is present, it is benzalkonium chloride (“BAC”). (EX1001 at 11:66-
`
`12:9.)
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`20. Generally speaking, dependent claim 2 of the ’431 patent is directed
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`to the aqueous liquid preparation of claim 1, wherein the first component is a
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`bromfenac sodium salt. (EX1001 at 12:10-12.)
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`21. Generally speaking, dependent claim 3 of the ’431 patent is directed
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`to the aqueous liquid preparation of claim 1, wherein the second component is
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`tyloxapol and the pharmacologically acceptable salt of bromfenac is a sodium salt,
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`the concentration of tyloxapol is from about 0.01 w/v % to about 0.5 w/v %, the
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`first component is a bromfenac sodium salt, and the concentration of the
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`bromfenac sodium salt is from about 0.01 w/v % to about 0.5 w/v %. (EX1001 at
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`12:13-23.)
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`11
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`22. Generally speaking, dependent claim 4 of the ’431 patent is directed
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`to the aqueous liquid preparation of claim 3, wherein the concentration of
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`tyloxapol is from about 0.01 w/v % to about 0.3 w/v % and the concentration of
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`the bromfenac sodium salt is from about 0.05 to about 0.2 w/v %. (EX1001 at
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`12:24-28.)
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`23. Generally speaking, dependent claim 5 of the ’431 patent is directed
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`to the aqueous liquid preparation of claim 4, wherein the concentration of
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`bromfenac sodium salt is about 0.1 w/v %. (EX1001 at 12:29-33.)
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`24. Generally speaking, dependent claim 6 of the ’431 patent is directed
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`to the aqueous liquid preparation of claim 4, wherein the concentration of
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`tyloxapol is about 0.02 w/v %. (EX1001 at 12:32-34.)
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`25. Generally speaking, dependent claim 7 of the ’431 patent is directed
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`to the aqueous liquid preparation of claim 1, wherein the formulation further
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`includes one or more additives selected from the group consisting of a preservative,
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`buffer, thickener, stabilizer, chelating agent, and pH controlling agent. (EX1001 at
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`12:35-39.)
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`26. Generally speaking, dependent claim 8 of the ’431 patent is directed
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`to the aqueous liquid preparation of claim 7, wherein the preservative is BAC, the
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`buffer is boric acid and/or sodium borate, the thickener is polyvinylpyrrolidone
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`12
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`(“PVP”), the stabilizer is sodium sulfite, the chelating agent is sodium edetate, and
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`the pH controlling agent is sodium hydroxide. (EX1001 at 12:40-46.)
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`27. Generally speaking, dependent claim 9 of the ’431 patent is directed
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`to the aqueous liquid preparation of claim 8, wherein the pH is from about 7 to
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`about 9. (EX1001 at 12:47-48.)
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`28. Generally speaking, dependent claim 10 of the ’431 patent is directed
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`to the aqueous liquid preparation of claim 8, wherein the pH is from about 7.5 to
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`about 8.5. (EX1001 at 12:49-50.)
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`29. Generally speaking, dependent claim 11 of the ’431 patent is directed
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`to the aqueous liquid preparation of claim 4, where the concentration of bromfenac
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`sodium salt is 0.2 w/v %. (EX1001 at 12:51-53.)
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`30. Generally speaking, dependent claim 12 of the ’431 patent is directed
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`to the aqueous liquid preparation of claim 4, where the concentration of tyloxapol
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`is about 0.3 w/v %. (EX1001 at 12:54-55.)
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`31. Generally speaking, dependent claim 13 of the ’431 patent is directed
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`to the aqueous liquid preparation of claim 12, wherein the formulation further
`
`includes one or more additives selected from the group consisting of a preservative,
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`buffer, thickener, stabilizer, chelating agent, and pH controlling agent. (EX1001 at
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`12:56-60.)
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`13
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`32. Generally speaking, dependent claim 14 of the ’431 patent is directed
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`to the aqueous liquid preparation of claim 13, wherein said preservative is BAC,
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`said buffer is boric acid and/or sodium borate, said thickener is PVP, said stabilizer
`
`is sodium sulfite, said chelating agent is sodium edetate, and said pH controlling
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`agent is sodium hydroxide. (EX1001 at 12:61-67.)
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`33. Generally speaking, dependent claim 15 of the ’431 patent is directed
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`to the aqueous liquid preparation of claim 11, wherein the concentration of
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`tyloxapol is about 0.02 w/v %. (EX1001 at 13:1-3.)
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`34. Generally speaking, dependent claim 16 of the ’431 patent is directed
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`to the aqueous liquid preparation of claim 15, wherein the formulation further
`
`includes one or more additives selected from the group consisting of a preservative,
`
`buffer, thickener, stabilizer, chelating agent, and pH controlling agent. (EX1001 at
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`13:4-8.)
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`35. Generally speaking, dependent claim 17 of the ’431 patent is directed
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`to the aqueous liquid preparation of claim 16, wherein said preservative is BAC,
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`said buffer is boric acid and/or sodium borate, said thickener is PVP, said stabilizer
`
`is sodium sulfite, said chelating agent is sodium edetate, and said pH controlling
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`agent is sodium hydroxide. (EX1001 at 13:9-14.)
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`36. Generally speaking, independent claim 18 of the ’431 patent is
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`directed to an aqueous liquid preparation consisting essentially of bromfenac,
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`14
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`tyloxapol, boric acid, sodium tetraborate, EDTA sodium salt, BAC, PVP, and
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`sodium sulfite, formulated for ophthalmic administration, wherein BAC is the only
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`quaternary ammonium compound included. (EX1001 at 13:15-14:9.)
`
`37. Generally speaking, dependent claim 19 of the ’431 patent is directed
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`to the aqueous liquid preparation of claim 18, wherein (a) is a bromfenac sodium
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`salt. (EX1001 at 14:10-12.)
`
`38. Generally speaking, dependent claim 20 of the ’431 patent is directed
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`to the aqueous liquid preparation of claim 19, where the concentration of
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`bromfenac sodium salt is from about 0.01 to about 0.5% and the concentration of
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`tyloxapol is about 0.02 w/v%. (EX1001 at 14:13-16.)
`
`39. Generally speaking, dependent claim 21 of the ’431 patent is directed
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`to the aqueous liquid preparation of claim 20, wherein the concentration of
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`bromfenac sodium salt is about 0.01 w/v %. (EX1001 at 14:17-19.)
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`40. Generally speaking, dependent claim 22 of the ’431 patent is directed
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`to the aqueous liquid preparation of claim 20, wherein the concentration of
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`bromfenac sodium salt is about 0.1 w/v %. (EX1001 at 14:20-22.)
`
`Person of Ordinary Skill in the Art
`
`B.
`41. As of January 21, 2003, a person of ordinary skill in the art of
`
`the ’431 patent would have at least a Bachelor’s degree in fields such as
`
`pharmaceutical chemistry, chemistry, or a related discipline with about three to
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`five years of work experience in this area, or a comparable level of education and
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`training.
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`42.
`
`I agree with Dr. Laskar that a person of ordinary skill in the art as of
`
`January 21, 2003 would have been “think[ing] along conventional wisdom in the
`
`art,” thereby pursuing clear and objectively rational leads in the prior art, rather
`
`than arbitrary pathways not tethered to the realities of rational drug discovery at the
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`time of invention. (EX1003 at ¶ 18.) A person of ordinary skill in the art would
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`have pursued these rational leads to develop pharmaceutical products balancing
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`efficacy, safety and stability.
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`VI. SUMMARY OF OPINIONS
`I understand that the Board has granted InnoPharma’s petition to
`43.
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`institute this IPR regarding the purported obviousness of claims 1-22 of the ’431
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`patent on the following grounds:
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`
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`
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`Ground 1: Obviousness of claims 1-5, 7-14, and 18-19 over U.S. Patent
`
`No. 4,910,225 (“Ogawa”) (EX1004) and U.S. Patent No. 6,107,343
`
`(“Sallmann”) (EX1009)
`
`Ground 2: Obviousness of claims 6, 15-17, and 20-22 over Ogawa,
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`Sallmann, and Australian Patent No. AU-B-22042/88 (“Fu”) (EX1011)
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`44. As discussed further below, Ogawa taught the use of water soluble
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`polymer and a sulfite, particularly sodium sulfite, a well-known antioxidant
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`(EX2014 at 3:41-55), to chemically stabilize bromfenac from degradation.
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`(EX1004 at Exp. Ex. 6.) From this, a person of ordinary skill in the art would have
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`readily understood that oxidation caused bromfenac’s degradation. (EX1021 at 5.)
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`A person of ordinary skill in the art would neither have combined the teachings of
`
`Sallmann or Fu with those of Ogawa, nor have reasonably expected the teachings
`
`of Sallmann or Fu to remedy bromfenac’s oxidative degradation problem.
`
`45. This is at least because Ogawa, Sallmann, and Fu relate to different
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`active ingredients and provide solutions to entirely unrelated problems: Ogawa
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`involves the chemical stability of bromfenac,1 whereas Fu involves the physical
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`stability of ketorolac formulations, and Sallmann is directed to establishing that
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`diclofenac potassium is more effective therapeutically than diclofenac sodium. As
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`such, a person of ordinary skill in the art would not have looked to Sallmann or Fu
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`to solve bromfenac’s oxidative degradation.
`
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`1 To a person of ordinary skill in the art, chemical stability looks to whether a
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`formulation’s active ingredient does not change (i.e., degrade) within acceptable
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`limits over a period of time. Physical stability, by contrast, looks to whether the
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`formulation’s appearance (i.e., clarity or turbidity) changes within acceptable
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`limits over time.
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`46. Specifically, Sallmann is directed to formulations of diclofenac
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`potassium, a structurally dissimilar NSAID from bromfenac, and contains no
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`teaching that diclofenac is susceptible to chemical degradation. (EX1009.)
`
`Similarly, Fu contains no teaching that its NSAID, ketorolac (also structurally
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`dissimilar to bromfenac), is susceptible to chemical degradation. (EX1011.)
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`Instead, Fu is directed to physically stabilizing formulations of ketorolac and
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`benzalkonium chloride (BAC) by preventing the formation of a precipitate.
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`(EX1011 at, e.g., 14:16-32, 15:12-17:20, 18:8-19:27.) There is no teaching in
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`Ogawa of the formation of any similar precipitate. Ogawa only teaches the
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`formation of a red insoluble oxidative degradation product—clearly not the
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`precipitant salt of an NSAID and BAC. (EX1004 at Exp. Exs. 4-6.) Dr. Laskar
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`agrees, having testified that the appearance of red insoluble matters in Ogawa
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`“would suggest that there’s been some chemical degradation – change to
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`bromfenac.” (EX2114 at 228:16-24.)
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`47. Thus, objectively viewing the art, a person of ordinary skill in the art
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`would not have been motivated to selectively pick solubilizers from Sallmann or
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`Fu to solve bromfenac’s oxidative degradation, when those solubilizers were used
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`for a completely unrelated purpose. Furthermore, a person of ordinary skill in the
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`art would not have expected that the solubilizers taught in Sallmann and Fu would
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`have prevented or impeded bromfenac’s oxidation. As their names suggest,
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`solubilizers typically solubilize poorly-soluble drugs, whereas antioxidants are
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`used to prevent oxidative degradation of drugs. Even Dr. Lawrence, who serves as
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`InnoPharma’s expert in the district court litigation involving the ’431 patent as
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`well as Lupin’s expert in IPR2015-01099, has testified that solubility and stability
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`are “not synonymous at all.” (EX2140 at 43:22-44:12.) Moreover, a person of
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`ordinary skill in the art would have understood that surfactants like polysorbate 80
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`and tyloxapol would both cause degradation of bromfenac through generation of
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`hydroperoxides and would not have been inclined to switch them, particularly
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`when Ogawa touted its formulations’ stability as excellent. (EX2105 at ¶ 72.)
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`48. A person of ordinary skill in the art, moreover, would also have not
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`simply substituted Ogawa’s polysorbate 80 for Sallmann’s tyloxapol merely
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`because both are nonionic surfactants. Indeed, even among polysorbates, there are
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`significant differences in properties. (Id. at ¶ 81.) Polysorbate 80 and tyloxapol
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`are vastly structurally dissimilar with correspondingly different chemical and
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`physical properties, such that a person of ordinary skill in the art would not
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`consider them so readily interchangeable (id. at ¶¶ 79-84), particularly in complex
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`and highly sensitive ophthalmic formulations where seemingly insignificant
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`changes in the formulation’s components could affect substantial changes in its
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`properties.
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`49.
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`In that regard, Ogawa touts its bromfenac formulations as having
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`excellent chemical stability. (EX1004 at 10:49-57.) A person of ordinary skill in
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`the art exercising common sense would not have blindly substituted polysorbate 80
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`with tyloxapol without considering how it might impact the chemical stability of
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`Ogawa’s formulations. None of the art of record suggests using tyloxapol to
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`chemically stabilize an NSAID in an aqueous formulation. And in Ogawa,
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`polysorbate 80 does not function as a stabilizer for bromfenac. (Id. at 8:3-9:7;
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`EX2095 at Exp. Exs. 4-6.) That role belongs to PVP and sodium sulfite. (Id. at
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`3:48-62.) Rather than substitute polysorbate 80 with tyloxapol, a person of
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`ordinary skill in the art exercising common sense and engaging in rational drug
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`discovery would have more likely pursued improvements to PVP or sodium sulfite.
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`50. Additionally, a person of ordinary skill in the art would not have been
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`motivated to substitute Sallmann’s diclofenac potassium for Ogawa’s bromfenac,
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`for doing so would have been contrary to the entire purpose of the Sallmann patent,
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`i.e.,
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`the use of diclofenac potassium.
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` Additionally, Sallmann’s use of
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`cyclodextrins (EX1009 at Ex. 2), which were known to complex aryl groups
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`present in bromfenac (EX2105 at ¶ 96), could negatively impact chemical stability,
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`and therefore run afoul of the “consisting essentially of” language in the ’431
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`patent claims. I have been informed and understand that this phrase as it is used in
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`a patent claim means that the claim encompasses the recited elements and only
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`those non-recited elements that do not materially affect the basic and novel
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`properties of the claimed composition. As such, any non-recited element that
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`materially affects the basic and novel properties of the composition is excluded
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`from the claim’s scope.
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`51.
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`It was completely unexpected
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`that
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`tyloxapol would stabilize
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`bromfenac against chemical degradation. It was similarly unexpected, as discussed
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`below, that it would do so in such a convincing manner compared to Ogawa’s
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`polysorbate 80. Tyloxapol’s unexpected stabilization benefits translated into
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`similarly unexpected benefits seen in the commercialized product Prolensa®, an
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`ophthalmic bromfenac (0.07%) solution covered by certain claims of the ’431
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`patent. This stabilization benefit permitted formulating Prolensa® at pH 7.8, a
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`comfortable and less irritating pH that is close to that of natural tears (EX2088 at
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`¶ 66b; EX2114 at 170:23-171:3), that led to enhanced ocular penetration and,
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`without a reduction in efficacy, allowed lowering of the amount of bromfenac from
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`0.09% to 0.07%, which meant less drug contacting surgically compromised ocular
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`tissue. (EX2030; EX2026; EX2027.) With these new benefits, Prolensa® garnered
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`significant acclaim in the medical community. (EX2113 at 965; EX2118 at 31;
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`EX2119 at 929.) Furthermore, it was marketed and commercialized, despite the
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`availability of generic bromfenac formulations (EX2028 at 1), and in fact,
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`InnoPharma and five other generic companies have sought to market exact copies
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`of Prolensa®, supporting the successful and non-obvious nature of the formulation.
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`(See infra at ¶¶ 181-82.) This objective evidence indicates that tyloxapol’s
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`unexpectedly superior stabilizing effect constitutes a material and substantial
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`difference more than in degree, producing a more comfortable, less irritating, more
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`efficacious formulation embodied in Prolensa®, which further supports and
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`enhances the nonobviousness of the claimed preparations.
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`VII. THE STATE OF THE ART AS OF JANUARY 21, 2003
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`52. As of the January 21, 2003 priority date of the ’431 patent, drug
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`formulation was a difficult and unpredictable endeavor, and it remains so today.
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`The formulation of ophthalmic drugs is particularly complex, because when
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`formulating ophthalmic dosage forms such as the aqueous liquid preparations of
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`the ’431 patent, stability is more challenging and critical than with other dosage
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`forms such as tablets or capsules. In addition, the surface area of the eye is
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`extremely small, and the residence time for an eye drop is quite short, which
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`increases the challenge in designing an aqueous dosage form that can pass through
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`the hydrophobic cornea membrane of the eye to reach the intended site of action.
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`Dr. Laskar himself has acknowledged these formulation challenges in sworn
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`testimony in a patent infringement case involving the ophthalmic product
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`Combigan®. (EX2135 at 989, 1020, 1022.)
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`53. Notwithstanding these formulation challenges, InnoPharma and Dr.
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`Laskar cite Ogawa, Sallmann and Fu, and advance a simple “swapping” theme,
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`which involves swapping tyloxapol in Sallmann’s Example 2 for polysorbate 80 in
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`Ogawa’s Example 6, or alternatively, swapping bromfenac in Ogawa’s Example 6
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`for diclofenac in Sallmann’s Example 2. (Petition at 6-9.) InnoPharma and Dr.
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`Laskar’s contrived and overly simplistic swapping position is not tethered to the
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`realities of rational drug discovery at the time of invention, but is more indicative
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`of already knowing the solution and working backwards to rationalize it. In fact,
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`Dr. Laskar admitted on cross examination that he focused on tyloxapol and
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`benzalkoniu