UNITED STATES PATENT AND TRADEMARK OFFICE
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`BEFORE THE PATENT TRIAL AND APPEAL BOARD
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`LUPIN, LTD. and LUPIN PHARMACEUTICALS INC.,
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`Petitioner
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`v.
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`SENJU PHARMACEUTICAL CO., LTD.
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`Patent Owner
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`__________________
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`Case IPR2015-01100
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`Patent 8,927,606 B2
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`__________________
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`DECLARATION OF ROBERT O. WILLIAMS, III, PH.D
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`1
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`SENJU EXHIBIT 2082
`LUPIN v SENJU
`IPR2015-01100
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`PAGE 1 OF 171
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`TABLE OF CONTENTS
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`I.
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`II.
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`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 ’606 PATENT ......................................................................................... 9
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`A.
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`B.
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`C.
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`Specification and Claims ....................................................................... 9
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`Level of Skill in the Art ....................................................................... 18
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`Claim Construction for “Stable” and “Amount Sufficient to
`Stabilize” ............................................................................................. 19
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`VI. SUMMARY OF OPINIONS ......................................................................... 22
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`VII. THE STATE OF THE ART AS OF JANUARY 21, 2003 ........................... 28
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`A. A Person of Ordinary Skill in the Art Would Not Have Pursued
`Bromfenac Formulations Over Other NSAID Formulations .............. 33
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`1.
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`2.
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`No reason to pursue bromfenac formulations ........................... 33
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`Design needs or market demands would not have
`supported the solution that Lupin proposes .............................. 37
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`B. A Person of Ordinary Skill in the Art Would Not Have
`Considered Different Non-Ionic Surfactants Interchangeable ............ 47
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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 .............................. 48
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`No teaching of polysorbate 80 or tyloxapol as a stabilizer
`of aqueous ophthalmic preparations of NSAIDs ...................... 55
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`C. A Person of Ordinary Skill in the Art Would Not Have
`Considered Different NSAIDs Interchangeable.................................. 67
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`VIII. THE TEACHINGS OF OGAWA AND SALLMANN WOULD NOT
`HAVE BEEN COMBINED WITH ANY REASONABLE
`EXPECTATION OF ARRIVING AT THE CLAIMED SUBJECT
`MATTER OF THE ’606 PATENT ............................................................... 69
`
`A. A Person of Ordinary Skill in the Art Would Have Had No
`Reason to Focus on Ogawa and its Bromfenac Formulations ............ 70
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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 .............................................................................................. 73
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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 ............... 73
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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 ................................................................................... 78
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`Dr. Lawrence’s alleged motivation and expectation of
`success in fact would not have made the combination of
`Ogawa and Sallmann obvious to make ..................................... 89
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`A person of ordinary skill in the art would not have
`modified Sallmann with the teachings of Ogawa ...................104
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`IX. OBJECTIVE EVIDENCE OF NON-OBVIOUSNESS OF THE ’606
`PATENT CLAIMS ......................................................................................110
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`A. A Unique, Non-Prior Art, Aspect of the ’606 Patent Claims:
`The Use of Tyloxapol with Bromfenac .............................................110
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`B.
`
`The Unexpectedly Superior Chemical Stabilizing Benefits of
`Tyloxapol Compared to Polysorbate 80 ............................................112
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`1.
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`2.
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`The ’606 patent compares against the closest prior art for
`purposes of showing unexpected results .................................113
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`A person of ordinary skill in the art would have had no
`expectation, based on polysorbate 80, of tyloxapol’s
`effect on the chemical stability of bromfenac
`formulations ............................................................................116
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`3
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`3.
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`Tyloxapol’s unexpectedly superior chemical stabilizing
`effect ........................................................................................119
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`C.
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`D.
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`E.
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`Tyloxapol is Unexpectedly Better than Polysorbate 80 at
`Maintaining Preservative Efficacy ....................................................127
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`Tyloxapol’s Unexpectedly Superior Stabilizing Effect Led to
`Actual Benefits for Patients ...............................................................130
`Copying of Prolensa® by Generic Drug Companies .........................132
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`X.
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`SEPARATE PATENTABILITY OF INDIVIDUAL CLAIMS .................134
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`A.
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`B.
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`C.
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`Claims 5-8, 15-16, 23 and 27: About 0.01 w/v % to About 0.05
`w/v % Tyloxapol ...............................................................................134
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`Claims 11-18, 26 and 29: Greater Than About 90% of
`Bromfenac Remains After Storing at 60° C. for 4 Weeks ................141
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`Claims 28-30: EP-Criteria B Standard for Preservative
`Efficacy..............................................................................................146
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`XI. CONCLUSION ............................................................................................152
`XII. CLAIM CHART DEMONSTRATING THAT PROLENSA® FALLS
`WITHIN THE SCOPE OF CERTAIN CLAIMS OF THE ’606
`PATENT ......................................................................................................157
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`XIII. CHART DEMONSTRATING THAT LUPIN’S GENERIC
`BROMFENAC PRODUCT IS AN EXACT COPY OF PROLENSA® .....170
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`4
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`PAGE 4 OF 171
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`I, Robert O. Williams, III, Ph.D., under penalty of perjury, declare as follows:
`I.
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`INTRODUCTION
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`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 six
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`inter partes review (“IPR”) proceedings (IPR2015-00903, IPR2015-00902,
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`IPR2015-01097, IPR2015-01099, IPR2015-01100 and IPR2015-01105) before the
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`United States Patent and Trademark Office (“PTO”) Patent Trial and Appeal Board
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`(“Board”) as an expert in the field of the design, evaluation, and formulation of
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`drug products. My qualifications in these areas, as well as other areas, are
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`established below and by my curriculum vitae, which is attached as EX2115.
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`II. BACKGROUND AND QUALIFICATIONS
`2.
`I am currently the Johnson & Johnson Centennial Chair of
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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.
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`5.
`
`Prior to becoming a professor, I worked in the pharmaceutical
`
`industry for several companies including Rhone-Poulenc Rorer Pharmaceuticals,
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`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
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`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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`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.
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`8.
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`Over the course of my career, I have earned numerous prestigious
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`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
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`Pharmacy (an Informa Healthcare publication) from 2000 to 2014. I am a member
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`of the Editorial Advisory Board for Elsivier’s Journal of Drug Delivery Science
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`and Technology. I also have served or currently serve as a reviewer for many
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`scientific
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`journals,
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`including
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`International
`
`Journal of Pharmaceutics,
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`Pharmaceutical Research, European
`
`Journal
`
`of Pharmaceutics
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`and
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`Biopharmaceutics, Journal of the Controlled Release Society, Journal of Drug
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`
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`7
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`Delivery Science and Technology, Pharmaceutical Development and Technology,
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`International Journal of Pharmaceutical Compounding, Journal of Membrane
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`Science, AAPS PharmSciTech, Journal of Pharmaceutical Sciences, Journal of
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`Pharmaceutical and Biomedical Analysis and Toxicology Letters.
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`10.
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`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
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`believe I am qualified to give the opinion set out herein.
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`III.
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`INFORMATION CONSIDERED
`12. The opinions expressed in this declaration are based on my review of,
`
`among other materials, U.S. Patent No. 8,927,606 (“the ’606 patent”), the “Petition
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`for Inter Partes Review of U.S. Patent No. 8,927,606” (“Petition”) and the
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`declarations of Dr. M. Jayne Lawrence (EX1005), Stephen G. Davies, Ph.D.
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`(EX2105), Shirou Sawa (EX2098), Dr. Adam C. Myers (EX2126) and Dr. Daryl S.
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`Paulson (EX2128). I also based my opinions on my professional and academic
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`experience in the area of pharmaceutical formulation. I reserve the right to testify
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`about these materials and experience. As I discuss below, I disagree with Dr.
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`Lawrence’s conclusions that the subject matter of the claims of the ’606 patent
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`would have been obvious.
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`IV. LEGAL PRINCIPLES
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`13.
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`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.
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`I understand that for an invention to be regarded as obvious, a person of ordinary
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`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 ’606 PATENT
`
`A.
`14.
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`Specification and Claims
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`I understand that Lupin has challenged claims 1-30 of the ’606 patent,
`
`EX1004, in this action. I further understand that the ’606 patent has a priority date
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`of January 21, 2003.
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`15. The ’606 patent is directed, generally speaking, to methods of
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`administering stable aqueous liquid preparations comprising the non-steroidal anti-
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`inflammatory drug (“NSAID”) 2-amino-3-(4-bromobenzoyl)phenylacetic acid
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`(“bromfenac”) or its pharmacologically acceptable salt or hydrate thereof and the
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`non-ionic surfactant tyloxapol. (EX1004.)
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`16. The ’606 patent specification states that “the inventors of the present
`
`invention have found that, by adding, for example, [tyloxapol] to an aqueous liquid
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`preparation of [bromfenac], the aqueous solution becomes stable within a pH range
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`giving no irritation to eyes, and change of the [bromfenac] over time can be
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`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.” (EX1004 at 2:26-38.) 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 ’606 patent confirm with experimental proof.
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`Similarly, this passage’s statement that “deterioration in the preservative effect . . .
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`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,
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`the
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`’606 patent
`
`specification describes methods of
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`administering stable aqueous solutions containing bromfenac and tyloxapol that are
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`chemically stable, with controlled microbial growth, are safe and non-irritating to
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`the eye, and are efficacious and suitable for ophthalmic administration.
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`18. The ’606 patent claims are directed, generally speaking, to stable
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`aqueous ophthalmic preparations comprising bromfenac and tyloxapol. (EX1004
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`at 11:17-14:32.) The ’606 patent has three independent claims (claims 1, 11, and
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`19) and 27 dependent claims. (Id.)
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`19. Generally speaking, independent claim 1 of the ’606 patent is directed
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`to a method for treating an inflammatory disease of an eye, comprising
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`administering to the eye a stable aqueous liquid preparation that comprises two
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`components, wherein the first component is bromfenac or a pharmacologically
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`acceptable salt or hydrate of bromfenac, wherein the hydrate is at least one selected
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`from a 1/2 hydrate, 1 hydrate and 3/2 hydrate, wherein the first component is the
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`sole pharmaceutical active ingredient contained in the preparation, and wherein the
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`second component is tyloxapol and is present in the aqueous liquid preparation in
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`an amount sufficient to stabilize the first component. The stable aqueous liquid
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`preparation of the method of claim 1 is formulated for ophthalmic administration
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`and is administered to the eye at a dose and a frequency effective to treat the
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`inflammatory disease. (EX1004 at 11:17-31.)
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`20. Generally speaking, dependent claim 2 of the ’606 patent is directed
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`to the method of claim 1, wherein the inflammatory disease is a disease of an
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`anterior or posterior segment of the eye. (EX1004 at 11:32-34.)
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`11
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`21. Generally speaking, dependent claim 3 of the ’606 patent is directed
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`to the method of claim 2, wherein the disease is postoperative inflammation.
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`(EX1004 at 11:35-36.)
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`22. Generally speaking, dependent claim 4 of the ’606 patent is directed
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`to the method of claim 1, wherein the first component is a bromfenac sodium salt.
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`(EX1004 at 11:37-39.)
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`23. Generally speaking, dependent claim 5 of the ’606 patent is directed
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`to the method of claim 1, wherein the concentration of tyloxapol is from about 0.01
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`w/v % to about 0.05 w/v %, the first component is a bromfenac sodium salt, and
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`the concentration of bromfenac sodium salt is from about 0.01 to about 0.2 w/v%.
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`(EX1004 at 11:40-45.)
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`24. Generally speaking, dependent claim 6 of the ’606 patent is directed
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`wherein the concentration of bromfenac sodium salt is from about 0.02 w/v % to
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`about 0.1 w/v %. (EX1004 at 11:46-48.)
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`25. Generally speaking, dependent claim 7 of the ’606 patent is directed
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`to the method of claim 5, wherein the aqueous liquid preparation further comprises
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`a quaternary ammonium salt. (EX1004 at 11:49-51.)
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`26. Generally speaking, dependent claim 8 of the ’606 patent is directed,
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`to the method of claim 5, wherein the concentration of the bromfenac sodium salt
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`is about 0.1 w/v %. (EX1004 at 11:52-54.)
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`27. Generally speaking, dependent claim 9 of the ’606 patent is directed
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`to the method of claim 1, wherein the stable aqueous liquid preparation consists
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`essentially of (a) bromfenac sodium salt, (d) sodium tetraborate, (e) EDTA sodium
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`salt, (f) benzalkonium chloride, (g) polyvinylpyrrolidone, and (h) sodium sulfite.
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`The stable aqueous liquid preparation of the method of claim 9 is formulated for
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`ophthalmic administration, and the concentration of the bromfenac sodium salt in
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`the stable aqueous liquid preparation of the method of claim 9 is from about 0.02
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`w/v % to about 0.1 w/v %. (EX1004 at 11:55-63.)
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`28. Generally speaking, dependent claim 10 of the ’606 patent is directed
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`to the method of claim 1, wherein the dose comprises one or two drops. (EX1004
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`at 11:64-65.)
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`29. Generally speaking, independent claim 11 of the ’606 patent is
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`directed to a method for treating an inflammatory disease of an eye comprising
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`administering to the eye a stable aqueous liquid preparation that comprises two
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`components, wherein the first component is bromfenac or a pharmacologically
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`acceptable salt or hydrate of bromfenac, wherein the hydrate is at least one selected
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`from a 1/2 hydrate, 1 hydrate and 3/2 hydrate, wherein the first component is the
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`sole pharmaceutical active ingredient contained in the preparation, and wherein the
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`second component is tyloxapol. The stable aqueous liquid preparation of the
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`method of claim 11 is formulated for ophthalmic administration, is characterized in
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`that greater than about 90% of the original amount of the first component remains
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`in the preparation after storage at about 60° C. for 4 weeks, and is administered to
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`the eye at a dose and a frequency effective to treat the inflammatory disease.
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`(EX1004 at 11:66 – 12:15.)
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`30. Generally speaking, dependent claim 12 of the ’606 patent is directed
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`to the method of claim 11, wherein the stable aqueous liquid preparation of the
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`method of claim 12 is characterized in that greater than about 92% of the original
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`amount of the first component remains in the preparation after storage at about 60°
`
`C. for 4 weeks. (EX1004 at 12:16-20.)
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`31. Generally speaking, dependent claim 13 of the ’606 patent is directed
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`to the method of claim 11, wherein the inflammatory disease is a disease of an
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`anterior or posterior segment of said eye. (EX1004 at 12:21-23.)
`
`32. Generally speaking, dependent claim 14 of the ’606 patent is directed
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`to the method of claim 13, wherein the disease is postoperative inflammation.
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`(EX1004 at 12:24-25.)
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`33. Generally speaking, dependent claim 15 of the ’606 patent is directed
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`to the method of claim 11, wherein the concentration of tyloxapol is from about
`
`0.01 w/v % to about 0.05 w/v %, the first component is a bromfenac sodium salt,
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`and the concentration of bromfenac sodium salt is from about 0.01 to about 0.2
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`w/v%. (EX1004 at 12:26-31.)
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`34. Generally speaking, dependent claim 16 of the ’606 patent is directed
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`to the method of claim 15, wherein the concentration of bromfenac sodium salt is
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`from about 0.02 to about 0.1 w/v%. (EX1004 at 12:32-34.)
`
`35. Generally speaking, dependent claim 17 of the ’606 patent is directed
`
`to the method of claim 11, wherein the stable aqueous liquid preparation further
`
`comprises a quaternary ammonium salt. (EX1004 at 12:35-36.)
`
`36. Generally speaking, dependent claim 18 of the ’606 patent is directed
`
`to the method of claim 11, wherein the stable aqueous liquid preparation consists
`
`essentially of (a) bromfenac or a pharmacologically acceptable salt or hydrate of
`
`bromfenac, wherein the hydrate is at least one selected from a 1/2 hydrate, 1
`
`hydrate and 3/2 hydrate, (b) tyloxapol, (c) boric acid, (d) sodium tetraborate, (e)
`
`EDTA sodium salt, (f) benzalkonium chloride, (g) polyvinylpyrrolidone, and (h)
`
`sodium sulfite. The concentration of bromfenac sodium salt in the stable aqueous
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`liquid preparation of the method of claim 18 is from about 0.02 w/v % to about 0.1
`
`w/v %. (EX1004 at 12:37-47.)
`
`37. Generally speaking, independent claim 19 of the ’606 patent is
`
`directed to a method for treating an inflammatory disease of an eye comprising
`
`administering to the eye a stable aqueous liquid preparation that comprises two
`
`components, wherein the first component is bromfenac or a pharmacologically
`
`acceptable salt or hydrate of bromfenac, wherein the hydrate is at least one selected
`
`
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`from a 1/2 hydrate, 1 hydrate and 3/2 hydrate, wherein the first component is the
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`sole pharmaceutical active ingredient contained in the preparation, and wherein the
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`second component is tyloxapol. The stable liquid preparation of the method of
`
`claim 19 is formulated for ophthalmic administration, does not include mannitol,
`
`and is administered at a dose and a frequency effective to treat the inflammatory
`
`disease. (EX1004 at 12:48-62.)
`
`38. Generally speaking, dependent claim 20 of the ’606 patent is directed
`
`to the method of claim 19, wherein the inflammatory disease is a disease of an
`
`anterior or posterior segment of said eye. (EX1004 at 12:63-65.)
`
`39. Generally speaking, dependent claim 21 of the ’606 patent is directed
`
`to the method of claim 20, wherein the disease is postoperative inflammation.
`
`(EX1004 at 12:66-67.)
`
`40. Generally speaking, dependent claim 22 of the ’606 patent is directed
`
`to the method of claim 19, wherein the first component is a bromfenac sodium salt.
`
`(EX1004 at 13:1-3.)
`
`41. Generally speaking, dependent claim 23 of the ’606 patent is directed
`
`to the method of claim 22, wherein the concentration of tyloxapol is from about
`
`0.01 w/v % to about 0.05 w/v %, and the concentration of the bromfenac sodium
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`salt is from about 0.05 to about 0.2 w/v %. (EX1004 at 13:4-8.)
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`16
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`42. Generally speaking, dependent claim 24 of the ’606 patent is directed
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`to the method of claim 22, wherein the concentration of the bromfenac sodium salt
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`is from about 0.02 to about 0.1 w/v %. (EX1004 at 13:9-11.)
`
`43. Generally speaking, dependent claim 25 of the ’606 patent is directed
`
`to the method of claim 20, wherein the stable aqueous liquid preparation consists
`
`essentially of (a) bromfenac or a pharmacologically acceptable salt or hydrate of
`
`bromfenac, wherein the hydrate is at least one selected from a 1/2 hydrate, 1
`
`hydrate and 3/2 hydrate, (b) tyloxapol, (c) boric acid, (d) sodium tetraborate, (e)
`
`EDTA sodium salt, (f) benzalkonium chloride, (g) polyvinylpyrrolidone, and (h)
`
`sodium sulfite. The concentration of bromfenac sodium salt in the stable aqueous
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`liquid preparation of the method of claim 25 is from about 0.02 w/v % to about 0.1
`
`w/v %. (EX1004 at 13:12-22.)
`
`44. Generally speaking, dependent claim 26 of the ’606 patent is directed
`
`to the method of claim 20, wherein the stable aqueous liquid preparation of the
`
`method of claim 26 is characterized in that greater than about 90% of the original
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`amount of the first component remains in the preparation after storage at about 60°
`
`C. for 4 weeks. (EX1004 at 13:23-27.)
`
`45. Generally speaking, dependent claim 27 of the ’606 patent is directed
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`to the method of claim 20, wherein the concentration of tyloxapol is from about
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`0.01 w/v % to about 0.05 w/v %, the first component is a bromfenac sodium salt,
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`and the concentration of bromfenac sodium salt in is from about 0.02 to about 0.1
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`w/v%. (EX1004 at 13:28-33.)
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`46. Generally speaking, dependent claims 28-30 of the ’606 patent are
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`directed to the methods of claims 1, 11 and 19, respectively, wherein the aqueous
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`liquid preparation satisfies the preservative efficacy standard of EP-criteria B of
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`the European Pharmacopoeia as follows: viable cell counts of bacteria (S. aureus,
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`P. aeruginosa) 24 hours and 7 days after inoculation decrease to not more than
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`1/10 and not more than 1/1000, respectively, and thereafter, the cell count levels
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`off or decreases; and viable cell count of fungi (C. albicans, A. niger) 14 days after
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`inoculation decreases to not more than 1/10, and thereafter, the cell count keeps the
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`same level as that of 14 days after inoculation. (EX1004 at 14:1-31.)
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`B.
`Level of Skill in the Art
`47. Lupin and Dr. Lawrence state that a person of ordinary skill in the art
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`would be a “pharmaceutical scientist involved in the research and development of
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`pharmaceuticals, and would have a Ph. D. and several years of experience in the
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`field.” (Petition at 6; EX1005 at ¶ 21.) I disagree as this exaggerates the level of a
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`person of “ordinary skill” in the art. Instead, as of January 21, 2003, a person of
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`ordinary skill in the art would more likely have at least a Bachelor’s degree in
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`fields such as pharmaceutical chemistry, chemistry, or a related discipline with
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`about three to five years of work experience in this area, or a comparable level of
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`education and training. (Accord, EX2037, a declaration of Dr. Uday Kompella, a
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`petitioner’s expert from related IPR2014-01041, offered in a litigation on a patent
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`involving ophthalmic formulations.) Alternatively, a person of ordinary skill in the
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`art could have a comparable level of overall experience in designing, evaluating
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`and/or administering pharmaceutical formulations obtained by some combination
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`of education such as, for example, a degree in medicine or Ph.D. degree, with work
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`experience.
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`48.
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`I also agree with Dr. Paul Laskar, the expert for Lupin’s IPR for
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`the ’431 patent (IPR2015-00903), which the ’606 patent claims priority, that a
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`person of ordinary skill in the art as of January 21, 2003 would have been
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`“think[ing] along conventional wisdom in the art,” thereby pursuing the clear and
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`objectively rational leads in the prior art, rather than arbitrary pathways not
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`tethered to the realities of rational drug discovery at the time of invention.
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`(EX2249 at ¶ 18.) A person of ordinary skill in the art would have pursued these
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`rational leads to develop pharmaceutical products balancing efficacy, safety and
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`stability.
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`C. Claim Construction for “Stable” and “Amount Sufficient to
`Stabilize”
`49. All claims of the ’606 patent contain the element “stable,” and claims
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`1-10 further contain the element “amount sufficient to stabilize,” either expressly
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`or through dependency. In my opinion, the term “stable” as used in these claims
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`means having sufficient resistance
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`to degradation and having sufficient
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`preservative efficacy to be formulated and maintained for ophthalmic use. The
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`phrase “amount sufficient to stabilize” as used in these claims means an amount
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`sufficient to confer sufficient resistance to degradation to be formulated and
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`maintained for ophthalmic use.
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`50.
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`In the parallel District Court cases involving the ’606 patent, I
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`submitted a declaration setting forth the basis for my interpretation of these terms.
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`(EX2125.) I understand that Chief Judge Simandle of the U.S. District Court for
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`the District of New Jersey agreed with my interpretation and exactly adopted the
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`meanings I provided above. (EX2065 at 5-6.)
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`51.
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`Judge Simandle’s reasoning in this regard, supported by the
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`specification and prosecution history, paralleled mine. The ’606 patent
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`specification clearly states that tyloxapol inhibits the change of the bromfenac (i.e.,
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`degradation) and inhibits the formulation’s preservative efficacy from deteriorating
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`over time. (EX1004 at 2:26-38.) Experimental Examples 1 and 2 demonstrate the
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`ability of tyloxapol to chemically stabilize bromfenac by inhibiting its degradation
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`under certain conditions. (Id. at 6:46-8:529.) Experimental Example 3 provides
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`the results of a preservative efficacy test. (Id. at 8:30-9:49.) During prosecution of
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`the ’431 patent, from which the ’606 patent claims priority, the applicant relied on
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`and the Examiner credited the chemical stability test of Experimental Example 1
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`and the results shown in Table 1. (EX2245 at 7-8.)
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`52. As mentioned, Chief Judge Simandle adopted exactly my
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`interpretation of these claimed elements. (EX2065 at 5-6.) His opinion states that
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`“the phrase ‘in an amount sufficient to stabilize said first component,’ which refers
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`specifically to tyloxapol’s effect on bromfenac, is explained by [Examples 1 and 2
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`of the ’606 patent], which illustrate the concentration of tyloxapol that would
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`create an ophthlamically-acceptable solution which prevents the degradation of the
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`active ingredient bromfenac.” (Id. 19.) His opinion further states that “[t]he
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`specification also suggests that the term ‘stable,’ which . . . modifies the
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`composition as a whole, includes an additional dimension,” and that “Example 3
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`demonstrates that in addition to being resistant to chemical degradation, the
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`tyloxapol compositions also satisfy preservative efficacy standards for ophthalmic
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`use.” (Id. at 20.)
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`53. Thus, consistent with my interpretation, Chief Judge Simandle found
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`that the term “stable” used in the claims of the ’606 patent incorporates the two
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`concepts of chemical stability and preservative efficacy, and the phrase “amount
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`sufficient to stabilize” refers to tyloxapol’s ability to chemically stabilize
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`bromfenac.
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`VI. SUMMARY OF OPINIONS
`54.
`I understand that the Board has granted Lupin’s petition to institute
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`this IPR regarding the purported obviousness of claims 1-30 of the ’606 patent on
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`the following ground: Obviousness of claims 1-30 over U.S. Patent No. 5,891,913
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`(“Sallmann”) (EX1021) and U.S. Patent No. 4,910,225 (“Ogawa”) (EX1010).
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`55. As discussed further below, Sallmann is directed to formulations of
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`the potassium salt of diclofenac. Sallmann’s invention is the use of diclofenac
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`potassium as superior to diclofenac sodium for treating ocular inflammation, with
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`improved ocular penetration, ocular tolerance, onset of action and duration of
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`action in the eye. (EX1021 at 1:48-59.) Dr. Lawrence, moreover, stated during
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`her cross examination that “in terms of ocular penetration and tolerance, that
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`[Sallmann] believe[s] diclofenac potassium is better than diclofenac sodium, so
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`those are specific things I agree that [Sallmann] claim[s] is better.” (EX2316 at
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`296:19-297:15.) Sallmann obtained this patent despite the known existence of
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`diclofenac sodium for treating ocular inflammation. In view of Sallmann’s
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`teaching, a person of ordinary skill in the art would not have been motivated to
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`substitute Sallmann’s diclofenac potassium for Ogawa’s bromfenac, for doing so
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`would have been contrary to the entire purpose of the Sallmann patent.
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`56.
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` Additionally, Sallmann’s use of cyclodextrins (EX1021 at Ex. 2),