UNITED STATES PATENT AND TRADEMARK OFFICE
`
`
`
`BEFORE THE PATENT TRIAL AND APPEAL BOARD
`
`
`
`LUPIN, LTD. and LUPIN PHARMACEUTICALS INC.,
`
`Petitioner
`
`
`v.
`
`
`SENJU PHARMACEUTICAL CO., LTD.
`
`Patent Owner
`
`__________________
`
`Case IPR2015-01105
`
`Patent 8,871,813 B2
`
`__________________
`
`DECLARATION OF ROBERT O. WILLIAMS, III, PH.D
`
`
`
`
`1
`
`
`
`
`
`
`
`
`
`
`
`SENJU EXHIBIT 2082
`LUPIN v SENJU
`IPR2015-01105
`
`PAGE 1 OF 158
`
`

`
`
`
`TABLE OF CONTENTS
`
`I.
`
`II.
`
`INTRODUCTION ........................................................................................... 5
`
`BACKGROUND AND QUALIFICATIONS ................................................. 5
`
`III.
`
`INFORMATION CONSIDERED ................................................................... 8
`
`IV. LEGAL PRINCIPLES ..................................................................................... 9
`
`V.
`
`THE ’813 PATENT ......................................................................................... 9
`
`A.
`
`B.
`
`C.
`
`Specification and Claims ....................................................................... 9
`
`Level of Skill in the Art ....................................................................... 18
`
`Claim Construction for “Stable” and “Amount Sufficient to
`Stabilize” ............................................................................................. 19
`
`VI. SUMMARY OF OPINIONS ......................................................................... 21
`
`VII. THE STATE OF THE ART AS OF JANUARY 21, 2003 ........................... 27
`
`A. A Person of Ordinary Skill in the Art Would Not Have Pursued
`Bromfenac Formulations Over Other NSAID Formulations .............. 33
`
`1.
`
`2.
`
`No reason to pursue bromfenac formulations ........................... 33
`
`Design needs or market demands would not have
`supported the solution that Lupin proposes .............................. 37
`
`B. A Person of Ordinary Skill in the Art Would Not Have
`Considered Different Non-Ionic Surfactants Interchangeable ............ 46
`
`1.
`
`2.
`
`No teaching of interchangeability of polysorbate 80 and
`tyloxapol in aqueous solutions of NSAIDs .............................. 47
`
`No teaching of polysorbate 80 or tyloxapol as a stabilizer
`of aqueous ophthalmic preparations of NSAIDs ...................... 54
`
`C. A Person of Ordinary Skill in the Art Would Not Have
`Considered Different NSAIDs Interchangeable.................................. 66
`
`
`
`2
`
`PAGE 2 OF 158
`
`

`
`
`
`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 ’813 PATENT ............................................................... 68
`
`A. A Person of Ordinary Skill in the Art Would Have Had No
`Reason to Focus on Ogawa and its Bromfenac Formulations ............ 69
`
`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 .............................................................................................. 72
`
`1.
`
`2.
`
`3.
`
`4.
`
`Ogawa and the problem it identifies with bromfenac ............... 72
`
`A person of ordinary skill in the art would not have
`looked to Sallmann or combined its teachings with those
`of Ogawa ................................................................................... 76
`
`Dr. Lawrence’s alleged motivation and expectation of
`success in fact would not have made the combination of
`Ogawa and Sallmann obvious to make ..................................... 88
`
`A person of ordinary skill in the art would not have
`modified Sallmann with the teachings of Ogawa ...................103
`
`IX. OBJECTIVE EVIDENCE OF NON-OBVIOUSNESS OF THE ’813
`PATENT CLAIMS ......................................................................................109
`
`A. A Unique, Non-Prior Art, Aspect of the ’813 Patent Claims:
`The Use of Tyloxapol with Bromfenac .............................................109
`
`B.
`
`The Unexpectedly Superior Chemical Stabilizing Benefits of
`Tyloxapol Compared to Polysorbate 80 ............................................111
`
`1.
`
`2.
`
`The ’813 patent compares against the closest prior art for
`purposes of showing unexpected results .................................112
`
`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 ............................................................................114
`
`
`
`3
`
`PAGE 3 OF 158
`
`

`
`
`
`3.
`
`Tyloxapol’s unexpectedly superior chemical stabilizing
`effect ........................................................................................117
`
`C.
`
`D.
`
`E.
`
`Tyloxapol is Unexpectedly Better than Polysorbate 80 at
`Maintaining Preservative Efficacy ....................................................126
`
`Tyloxapol’s Unexpectedly Superior Stabilizing Effect Led to
`Actual Benefits for Patients ...............................................................129
`Copying of Prolensa® by Generic Drug Companies .........................131
`
`X.
`
`SEPARATE PATENTABILITY OF INDIVIDUAL CLAIMS .................133
`
`A.
`
`B.
`
`Claims 4, 6, 10, 11, 16, 21 and 22: About 0.01 w/v % to About
`0.05 w/v % Tyloxapol .......................................................................133
`
`Claims 7-12, 19-22 and 25: Greater Than About 90% of
`Bromfenac Remains After Storing at 60° C. for 4 Weeks ................140
`
`XI. CONCLUSION ............................................................................................145
`XII. CLAIM CHART DEMONSTRATING THAT PROLENSA® FALLS
`WITHIN THE SCOPE OF CERTAIN CLAIMS OF THE ’813
`PATENT ......................................................................................................150
`
`XIII. CHART DEMONSTRATING THAT LUPIN’S GENERIC
`BROMFENAC PRODUCT IS AN EXACT COPY OF PROLENSA® .....157
`
`
`
`
`
`
`
`4
`
`PAGE 4 OF 158
`
`

`
`
`
`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 &
`
`Dunner, LLP on behalf of Senju Pharmaceutical, Co., Ltd. in connection with six
`
`inter partes review (“IPR”) proceedings (IPR2015-00903, IPR2015-00902,
`
`IPR2015-01097, IPR2015-01099, IPR2015-01100 and IPR2015-01105) before the
`
`United States Patent and Trademark Office (“PTO”) Patent Trial and Appeal Board
`
`(“Board”) as an expert in the field of the design, evaluation, and formulation of
`
`drug products. My qualifications in these areas, as well as other areas, are
`
`established below and by my curriculum vitae, which is attached as EX2115.
`
`II. BACKGROUND AND QUALIFICATIONS
`2.
`I am currently the Johnson & Johnson Centennial Chair of
`
`Pharmaceutics at the University of Texas at Austin College of Pharmacy in Austin,
`
`Texas, where I have been teaching and conducting research for twenty years. Also,
`
`I am the Division Head of Pharmaceutics.
`
`3.
`
`I received a B.S. degree in biology from Texas A&M University in
`
`1979, a B.S. degree in pharmacy from the University of Texas at Austin in 1981,
`
`and a Ph.D. degree in pharmaceutics from the University of Texas at Austin in
`
`1986. I am a licensed pharmacist.
`
`
`
`5
`
`PAGE 5 OF 158
`
`

`
`
`
`4.
`
`I have extensive experience and expertise
`
`in pharmaceutical
`
`formulation and the use of excipients in formulating various types of drug dosage
`
`forms, including aqueous liquid preparations. I have experience with ophthalmic
`
`dosage forms including solutions. I am an expert in the field of pharmaceutical
`
`development, and I have worked almost exclusively in the field of pharmaceutical
`
`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
`
`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
`
`the Chief Scientist from 2009 to 2013 and founder of Enavail, a particle
`
`engineering contract services company. Accordingly, I have relevant industry
`
`experience in addition to my academic qualifications.
`
`6. My current research focuses on the development, formulation,
`
`optimization and delivery of drugs by a variety of technologies, including aqueous
`
`liquid preparations. I have extensive research experience and have authored
`
`numerous publications in this area.
`
`7.
`
`I have authored or co-authored over 400 published papers, abstracts
`
`and book chapters related to my work in the pharmaceutical sciences. A
`
`
`
`6
`
`PAGE 6 OF 158
`
`

`
`
`
`significant number of my papers are directed specifically to pharmaceutical
`
`formulation techniques and drug dosage forms. I have co-edited two books on the
`
`subject of pharmaceutical formulation and drug delivery. I am a co-inventor on
`
`over 35 patents and/or patent applications that deal with drug formulation
`
`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
`
`example, I was elected as a fellow to the American Association of Pharmaceutical
`
`Scientists and the American Institute of Medical and Biological Engineering. I
`
`have also received the William J. Sheffield Outstanding Alumnus Award and was
`
`named a Dean’s Fellow at the University of Texas at Austin College of Pharmacy.
`
`9.
`
`I am currently the Editor-in-Chief for AAPS PharmSciTech, a joint
`
`publication of the American Association of Pharmaceutical Scientists and Springer
`
`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
`
`of the Editorial Advisory Board for Elsivier’s Journal of Drug Delivery Science
`
`and Technology. I also have served or currently serve as a reviewer for many
`
`scientific
`
`journals,
`
`including
`
`International
`
`Journal of Pharmaceutics,
`
`Pharmaceutical Research, European
`
`Journal
`
`of Pharmaceutics
`
`and
`
`Biopharmaceutics, Journal of the Controlled Release Society, Journal of Drug
`
`
`
`7
`
`PAGE 7 OF 158
`
`

`
`
`
`Delivery Science and Technology, Pharmaceutical Development and Technology,
`
`International Journal of Pharmaceutical Compounding, Journal of Membrane
`
`Science, AAPS PharmSciTech, Journal of Pharmaceutical Sciences, Journal of
`
`Pharmaceutical and Biomedical Analysis and Toxicology Letters.
`
`10.
`
`In addition to my research and teaching duties at the University of
`
`Texas at Austin, I have consulted for pharmaceutical, chemical and biotechnology
`
`companies. I have consulted for both innovator pharmaceutical companies and
`
`generic pharmaceutical companies. Most of these consulting activities have dealt
`
`specifically with drug formulation issues.
`
`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. 8,871,813 (“the ’813 patent”), the “Petition
`
`for Inter Partes Review of U.S. Patent No. 8,871,813” (“Petition”) and the
`
`declarations of Dr. M. Jayne Lawrence (EX1005), Stephen G. Davies, Ph.D.
`
`(EX2105), Shirou Sawa (EX2098), Dr. Adam C. Myers (EX2126) and Dr. Daryl S.
`
`Paulson (EX2128). I also based my opinions on my professional and academic
`
`experience in the area of pharmaceutical formulation. I reserve the right to testify
`
`about these materials and experience. As I discuss below, I disagree with Dr.
`
`
`
`8
`
`PAGE 8 OF 158
`
`

`
`Lawrence’s conclusions that the subject matter of the claims of the ’813 patent
`
`
`
`would have been obvious.
`
`IV. LEGAL PRINCIPLES
`
`13.
`
`I understand that an obviousness analysis involves a review of the
`
`scope and content of the prior art, the differences between the prior art and the
`
`claims at issue, the level of ordinary skill in the art, and objective indicia of non-
`
`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
`
`more prior art references in a manner that would result in the claimed subject
`
`matter with a reasonable expectation of success.
`
`V. THE ’813 PATENT
`
`A.
`14.
`
`Specification and Claims
`
`I understand that Lupin has challenged claims 1-27 of the ’813 patent,
`
`EX1003, in this action. I further understand that the ’813 patent has a priority date
`
`of January 21, 2003.
`
`15. The ’813 patent is directed, generally speaking, to stable aqueous
`
`liquid preparations comprising
`
`the non-steroidal anti-inflammatory drug
`
`(“NSAID”) 2-amino-3-(4-bromobenzoyl)phenylacetic acid (“bromfenac”) or its
`
`
`
`9
`
`PAGE 9 OF 158
`
`

`
`
`
`pharmacologically acceptable salt or hydrate thereof and the non-ionic surfactant
`
`tyloxapol. (EX1003.)
`
`16. The ’813 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,
`
`deterioration in the preservative effect of said preservative can be inhibited for a
`
`long period of time.” (EX1003 at 2:24-35.) This passage’s statement that the
`
`“change of the [bromfenac] over time can be inhibited” refers to the ability of
`
`tyloxapol to stabilize bromfenac from chemical degradation, which Experimental
`
`Examples 1-2 and Tables 1-2 of the ’813 patent confirm with experimental proof.
`
`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
`
`bromfenac formulation’s microbial growth, which Experimental Example 3 and
`
`Tables 3-1 to 3-3 confirm with experimental proof.
`
`17. Thus, the ’813 patent specification describes stable aqueous solutions
`
`containing bromfenac and tyloxapol that are chemically stable, with controlled
`
`microbial growth, are safe and non-irritating to the eye, and are efficacious and
`
`suitable for ophthalmic administration.
`
`
`
`10
`
`PAGE 10 OF 158
`
`

`
`
`
`18. The ’813 patent claims are directed, generally speaking, to stable
`
`aqueous ophthalmic preparations comprising bromfenac and tyloxapol. (EX1003
`
`at 11:30-14:24.) The ’813 patent has three independent claims (claims 1, 7 and 13)
`
`and 24 dependent claims. (Id.)
`
`19. Generally speaking, independent claim 1 of the ’813 patent is directed
`
`to a stable aqueous liquid preparation consisting essentially of (a) a first
`
`component, (b) a second component, wherein the first component is 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, (c) boric acid,
`
`(d) sodium tetraborate, and (e) water. The first component is the sole
`
`pharmaceutical active ingredient in the stable aqueous liquid preparation of claim 1
`
`and is present at a concentration from about 0.05 w/v % to about 0.2 w/v %. The
`
`second component is tyloxapol and is present in the stable aqueous liquid
`
`preparation of claim 1 in an amount sufficient to stabilize the first component. The
`
`stable aqueous liquid preparation of claim 1 is formulated for ophthalmic
`
`administration. (EX1003 at 11:30-42.)
`
`20. Generally speaking, dependent claim 2 of the ’813 patent is directed to
`
`the aqueous liquid preparation of claim 1, wherein the aqueous liquid preparation
`
`further consists of sodium sulfite. (EX1003 at 11:43-45.)
`
`
`
`11
`
`PAGE 11 OF 158
`
`

`
`
`
`21. Generally speaking, dependent claim 3 of the ’813 patent is directed to
`
`the aqueous liquid preparation of claim 1, wherein the first component is a
`
`bromfenac sodium salt. (EX1003 at 11:46-48.)
`
`22. Generally speaking, dependent claim 4 of the ’813 patent is directed to
`
`the aqueous liquid preparation of claim 1, wherein the concentration of tyloxapol is
`
`from about 0.01 w/v % to about 0.05 w/v %. (EX1003 at 11:49-51.)
`
`23. Generally speaking, dependent claim 5 of the ’813 patent is directed to
`
`the aqueous liquid preparation of claim 1, wherein the pH is from about 7.5 to
`
`about 8.5. (EX1003 at 11:52-54.)
`
`24. Generally speaking, dependent claim 6 of the ’813 patent is directed to
`
`the stable aqueous liquid preparation of claim 1, wherein it consists of: (a)
`
`bromfenac sodium salt; (b) tyloxapol; (c) boric acid; (d) sodium tetraborate; (e)
`
`EDTA sodium salt; (f) polyvinylpyrrolidone; (g) sodium sulfte; and (h) water,
`
`wherein the liquid preparation is formulated for ophthalmic administration,
`
`wherein the concentration of bromfenac sodium salt is from about 0.02 w/v % to
`
`about 0.1 w’v %, and the concentration of tyloxapol is from about 0.01 w/v % to
`
`about 0.05 w/v %. (EX1003 at 11:55-63.)
`
`25. Generally speaking, independent claim 7 of the ’813 patent is directed
`
`to a stable aqueous liquid preparation consisting essentially of (a) a first
`
`component, (b) a second component, wherein the first component is bromfenac or
`
`
`
`12
`
`PAGE 12 OF 158
`
`

`
`
`
`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, (c) boric acid,
`
`(d) sodium tetraborate, and (e) water. The first component is the sole
`
`pharmaceutical active ingredient in the stable aqueous liquid preparation of claim 7
`
`and is present at a concentration from about 0.05 w/v % to about 0.2 w/v %. The
`
`second component is tyloxapol. The stable aqueous liquid preparation of claim 7
`
`is formulated for ophthalmic administration and is characterized in that greater
`
`than about 90% of the original amount of the first component remains in the
`
`preparation after storage at about 60° C. for 4 weeks. (EX1003 at 11:64 –12:12.)
`
`26. Generally speaking, dependent claim 8 of the ’813 patent is directed to
`
`the stable aqueous liquid preparation of claim 7, wherein the aqueous liquid
`
`preparation further consists of sodium sulfite. (EX1003 at 12:12-14.)
`
`27. Generally speaking, dependent claim 9 of the ’813 patent is directed to
`
`the stable aqueous liquid preparation of claim 7, wherein the stable aqueous liquid
`
`preparation is characterized in that greater than about 92% of the original amount
`
`of the first component remains in the preparation after storage at about 60° C. for 4
`
`weeks. (EX1003 at 12:15-19.)
`
`28. Generally speaking, dependent claim 10 of the ’813 patent is directed
`
`to the aqueous liquid preparation of claim 7, wherein the concentration of
`
`tyloxapol is from about 0.01 w/v% to about 0.05 w/v %, the first component is a
`
`
`
`13
`
`PAGE 13 OF 158
`
`

`
`
`
`bromfenac sodium salt, and the concentration of bromfenac sodium salt is from
`
`about 0.05 w/v % to about 0.1 w/v %. (EX1003 at 12:20-26.)
`
`29. Generally speaking, dependent claim 11 of the ’813 patent is directed
`
`to the aqueous liquid preparation of claim 10, wherein the pH is from about 7.5 to
`
`about 8.5. (EX1003 at 12:27-28.)
`
`30. Generally speaking, dependent claim 12 of the ’813 patent is directed
`
`to the stable aqueous liquid preparation of claim 1, wherein it consists of: (a)
`
`bromfenac or a pharmacologically acceptable salt thereof or a hydrate thereof,
`
`wherein the hydrate is 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)
`
`polyvinylpyrrolidone; (g) sodium sulfte; and (h) water, wherein the concentration
`
`of bromfenac sodium salt is from about 0.05 w/v % to about 0.1 w/v %, and the
`
`concentration of tyloxapol is about 0.02 w/v %. (EX1003 at 12:29-38.)
`
`31. Generally speaking, independent claim 13 of the ’813 patent is directed
`
`to a stable aqueous liquid preparation consisting essentially of (a) a first
`
`component, (b) a second component, wherein the first component is 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, (c) boric acid,
`
`(d) sodium tetraborate, and (e) water. The first component is the sole
`
`pharmaceutical active ingredient in the stable aqueous liquid preparation of claim
`
`
`
`14
`
`PAGE 14 OF 158
`
`

`
`
`
`13 and is present at a concentration from about 0.05 w/v % to about 0.2 w/v %.
`
`The second component is tyloxapol. The stable aqueous liquid preparation of
`
`claim 13 is formulated for ophthalmic administration and does not include
`
`mannitol. (EX1003 at 12:39-50.)
`
`32. Generally speaking, dependent claim 14 of the ’813 patent is directedto
`
`the aqueous liquid preparation of claim 13, wherein the aqueous liquid preparation
`
`further consists of sodium sulfite. (EX1003 at 12:51-53.)
`
`33. Generally speaking, dependent claim 15 of the ’813 patent is directedto
`
`the aqueous liquid preparation of claim 13, wherein the first component is a
`
`bromfenac sodium salt. (EX1003 at 12:54-56.)
`
`34. Generally speaking, dependent claim 16 of the ’813 patent is directed
`
`to the aqueous liquid preparation of claim 13, wherein the concentration of
`
`tyloxapol is from about 0.01 w/v % to about 0.05 w/v % and the concentration of
`
`bromfenac sodium salt is from about 0.05 to about 0.1 w/v%. (EX1003 at 12:57-
`
`61.)
`
`35. Generally speaking, dependent claim 17 of the ’813 patent is directed
`
`to the aqueous liquid preparation of claim 13, wherein the pH is from about 7.5 to
`
`about 8.5. (EX1003 at 12:62-63.)
`
`36. Generally speaking, dependent claim 18 of the ’813 patent is directed
`
`to the stable aqueous liquid preparation of claim 13, wherein it consists of: (a)
`
`
`
`15
`
`PAGE 15 OF 158
`
`

`
`
`
`bromfenac or a pharmacologically acceptable salt thereof or a hydrate thereof,
`
`wherein the hydrate is 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)
`
`polyvinylpyrrolidone; (g) sodium sulfte; and (h) water, wherein the concentration
`
`of bromfenac sodium salt is from about 0.02 w/v % to about 0.1 w/v %, and the
`
`concentration of tyloxapol is from about 0.02 w/v % to about 0.05 w/v%.
`
`(EX1003 at 12:64 – 13:6.)
`
`37. Generally speaking, dependent claim 19 of the ’813 patent is directed
`
`to the stable aqueous liquid preparation of claim 13, wherein the stable aqueous
`
`liquid preparation is characterized in that greater than about 90% of the original
`
`amount of the first component remains in the preparation after storage at about 60°
`
`C. for 4 weeks. (EX1003 at 13:7-11.)
`
`38. Generally speaking, dependent claim 20 of the ’813 patent is directed
`
`to the stable aqueous liquid preparation of claim 19, wherein the stable aqueous
`
`liquid preparation is characterized in that greater than about 92% of the original
`
`amount of the first component remains in the preparation after storage at about 60°
`
`C. for 4 weeks. (EX1003 at 13:12-15.)
`
`39. Generally speaking, dependent claim 21 of the ’813 patent is directed
`
`to the stable aqueous liquid preparation of claim 20, wherein the concentration of
`
`tyloxapol is from about 0.01 w/v % to about 0.05 w/v %, wherein the first
`
`
`
`16
`
`PAGE 16 OF 158
`
`

`
`
`
`component is a bromfenac sodium salt, and the concentration of bromfenac sodium
`
`salt is from about 0.05 w/v % to about 0.1 w/v%. (EX1003 at 13:16-21.)
`
`40. Generally speaking, dependent claim 22 of the ’813 patent is directed
`
`to the aqueous liquid preparation of claim 21, wherein the pH is from about 7.5 to
`
`about 8.5. (EX1003 at 13:22-24.)
`
`41. Generally speaking, dependent claim 23 of the ’813 patent is directed
`
`to the stable aqueous liquid preparation of claim 13, wherein it consists of: (a)
`
`bromfenac or a pharmacologically acceptable salt thereof or a hydrate thereof,
`
`wherein the hydrate is 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)
`
`polyvinylpyrrolidone; (g) sodium sulfte; and (h) water, wherein the liquid
`
`preparation is formulated for ophthalmic administration, and wherein the
`
`concentration of bromfenac sodium salt is from about 0.05 w/v % to about 0.1
`
`w/v %. (EX1003 at 14:1-12.)
`
`42. Generally speaking, dependent claim 24 of the ’813 patent is directed
`
`to the aqueous liquid preparation of claim 1, wherein the aqueous liquid
`
`preparation does not include any preservative. (EX1003 at 14:13-14.)
`
`43. Generally speaking, dependent claim 25 of the ’813 patent is directed
`
`to the aqueous liquid preparation of claim 7, wherein the aqueous liquid
`
`preparation does not include any preservative. (EX1003 at 14:15-16.)
`
`
`
`17
`
`PAGE 17 OF 158
`
`

`
`
`
`44. Generally speaking, dependent claim 26 of the ’813 patent is directed
`
`to the aqueous liquid preparation of claim 13, wherein the aqueous liquid
`
`preparation does not include any preservative. (EX1003 at 14:17-18.)
`
`45. Generally speaking, dependent claim 27 of the ’813 patent is directed
`
`to the aqueous liquid preparation of claim 1, further consisting of one or more
`
`additives selected from the group consisting of buffers, thickeners, stabilizers,
`
`chelating agents, and pH controlling agents. (EX1003 at 14:19-23.)
`
`B.
`Level of Skill in the Art
`46. Lupin and Dr. Lawrence state that a person of ordinary skill in the art
`
`would be a “pharmaceutical scientist involved in the research and development of
`
`pharmaceuticals, and would have a Ph. D. and several years of experience in the
`
`field.” (Petition at 6; EX1005 at ¶ 21.) I disagree as this exaggerates the level of a
`
`person of “ordinary skill” in the art. Instead, as of January 21, 2003, a person of
`
`ordinary skill in the art would more likely have at least a Bachelor’s degree in
`
`fields such as pharmaceutical chemistry, chemistry, or a related discipline with
`
`about three to five years of work experience in this area, or a comparable level of
`
`education and training. (Accord, EX2037, a declaration of Dr. Uday Kompella, a
`
`petitioner’s expert from related IPR2014-01043, offered in a litigation on a patent
`
`involving ophthalmic formulations.) Alternatively, a person of ordinary skill in the
`
`art could have a comparable level of overall experience in designing, evaluating
`
`
`
`18
`
`PAGE 18 OF 158
`
`

`
`
`
`and/or administering pharmaceutical formulations obtained by some combination
`
`of education such as, for example, a degree in medicine or Ph.D. degree, with work
`
`experience.
`
`47.
`
`I also agree with Dr. Paul Laskar, the expert for Lupin’s IPR for
`
`the ’431 patent (IPR2015-00903), which the ’813 patent claims priority, 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 the clear and
`
`objectively rational leads in the prior art, rather than arbitrary pathways not
`
`tethered to the realities of rational drug discovery at the time of invention.
`
`(EX2249 at ¶ 18.) A person of ordinary skill in the art would have pursued these
`
`rational leads to develop pharmaceutical products balancing efficacy, safety and
`
`stability.
`
`C. Claim Construction for “Stable” and “Amount Sufficient to
`Stabilize”
`48. All claims of the ’813 patent contain the element “stable,” and claims
`
`1-6 further contain the element “amount sufficient to stabilize,” either expressly or
`
`through dependency. In my opinion, the term “stable” as used in these claims
`
`means having sufficient resistance
`
`to degradation and having sufficient
`
`preservative efficacy to be formulated and maintained for ophthalmic use. The
`
`phrase “amount sufficient to stabilize” as used in these claims means an amount
`
`
`
`19
`
`PAGE 19 OF 158
`
`

`
`
`
`sufficient to confer sufficient resistance to degradation to be formulated and
`
`maintained for ophthalmic use.
`
`49.
`
`In the parallel District Court cases involving the ’813 patent, I
`
`submitted a declaration setting forth the basis for my interpretation of these terms.
`
`(EX2125.) I understand that Chief Judge Simandle of the U.S. District Court for
`
`the District of New Jersey agreed with my interpretation and exactly adopted the
`
`meanings I provided above. (EX2065 at 5-6.)
`
`50.
`
`Judge Simandle’s reasoning in this regard, supported by the
`
`specification and prosecution history, paralleled mine. The ’813 patent
`
`specification clearly states that tyloxapol inhibits the change of the bromfenac (i.e.,
`
`degradation) and inhibits the formulation’s preservative efficacy from deteriorating
`
`over time. (EX1003 at 2:24-35.) Experimental Examples 1 and 2 demonstrate the
`
`ability of tyloxapol to chemically stabilize bromfenac by inhibiting its degradation
`
`under certain conditions. (Id. at 6:34-8:5.) Experimental Example 3 provides the
`
`results of a preservative efficacy test. (Id. at 8:7-9:50.) During prosecution of
`
`the ’431 patent, from which the ’813 patent claims priority, the applicant relied on
`
`and the Examiner credited the chemical stability test of Experimental Example 1
`
`and the results shown in Table 1. (EX2245 at 7-8.)
`
`51. As mentioned, Chief Judge Simandle adopted exactly my
`
`interpretation of these claimed elements. (EX2065 at 5-6.) His opinion states that
`
`
`
`20
`
`PAGE 20 OF 158
`
`

`
`
`
`“the phrase ‘in an amount sufficient to stabilize said first component,’ which refers
`
`specifically to tyloxapol’s effect on bromfenac, is explained by [Examples 1 and 2
`
`of the ’813 patent], which illustrate the concentration of tyloxapol that would
`
`create an ophthlamically-acceptable solution which prevents the degradation of the
`
`active ingredient bromfenac.” (Id. 19.) His opinion further states that “[t]he
`
`specification also suggests that the term ‘stable,’ which . . . modifies the
`
`composition as a whole, includes an additional dimension,” and that “Example 3
`
`demonstrates that in addition to being resistant to chemical degradation, the
`
`tyloxapol compositions also satisfy preservative efficacy standards for ophthalmic
`
`use.” (Id. at 20.)
`
`52. Thus, consistent with my interpretation, Chief Judge Simandle found
`
`that the term “stable” used in the claims of the ’813 patent incorporates the two
`
`concepts of chemical stability and preservative efficacy, and the phrase “amount
`
`sufficient to stabilize” refers to tyloxapol’s ability to chemically stabilize
`
`bromfenac.
`
`VI. SUMMARY OF OPINIONS
`53.
`I understand that the Board has granted Lupin’s petition to institute
`
`this IPR regarding the purported obviousness of claims 1-27 of the ’813 patent on
`
`the following ground: Obviousness of claims 1-27 over U.S. Patent No. 5,891,913
`
`(“Sallmann”) (EX1021) and U.S. Patent No. 4,910,225 (“Ogawa”) (EX1010).
`
`
`
`21
`
`PAGE 21 OF 158
`
`

`
`
`
`54. As discussed further below, Sallmann is directed to formulations of
`
`the potassium salt of diclofenac. Sallmann’s invention is the use of diclofenac
`
`potassium as superior to diclofenac sodium for treating ocular inflammation, with
`
`improved ocular penetration, ocular tolerance, onset of action and duration of
`
`action in the eye. (EX1021 at 1:48-59.) Dr. Lawrence, moreover, stated during
`
`her cross examination that “in terms of ocular penetration and tolerance, that
`
`[Sallmann] believe[s] diclofenac potassium is better than diclofenac sodium, so
`
`those are specific things I agree that [Sallmann] claim[s] is better.” (EX2316 at
`
`296:19-297:15.) Sallmann obtained this patent despite the known existence of
`
`diclofenac sodium for treating ocular inflammation. In view of Sallmann’s
`
`teaching, a person of ordinary skill in the art would not have been motivated to
`
`substitute Sallmann’s diclofenac potassium for Ogawa’s bromfenac, for doing so
`
`would have been contrary to the entire purpose of the Sallmann patent.
`
`55.
`
` Additionally, Sallmann’s use of cyclodextrins (EX1021 at Ex. 2),
`
`which were known to complex aryl groups present in bromfenac (EX2105 at ¶ 96),
`
`could negatively impact chemical stability, and therefore run afoul of the
`
`“consisting essentially of” language in the claims of the ’813 patent. I have been
`
`informed and understand that this phrase as it