UNITED STATES PATENT AND TRADEMARK OFFICE
`
`
`
`BEFORE THE PATENT TRIAL AND APPEAL BOARD
`
`
`
`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 IPR2015-00902
`Patent 8,669,290
`
`
`
`DECLARATION OF ROBERT O. WILLIAMS, III, PH.D
`
`
`
`
`1
`
`
`
`
`
`
`
`
`
`SENJU EXHIBIT 2082
`INNOPHARMA v SENJU
`IPR2015-00902
`
`PAGE 1 OF 126
`
`
`
`

`
`
`
`TABLE OF CONTENTS
`
`I.
`
`II.
`
`INTRODUCTION ........................................................................................... 5
`
`BACKGROUND AND QUALIFICATIONS ................................................. 5
`
`III.
`
`INFORMATION CONSIDERED ................................................................... 8
`
`IV. LEGAL PRINCIPLES ..................................................................................... 9
`
`V.
`
`THE ’290 PATENT ......................................................................................... 9
`
`A.
`
`B.
`
`C.
`
`Specification and Claims ....................................................................... 9
`
`Level of Skill in the Arti ..................................................................... 18
`
`Claim Construction for “Stable” and “Amount Sufficient to
`Stabilize” ............................................................................................. 18
`
`VI. SUMMARY OF OPINIONS ......................................................................... 21
`
`VII. THE STATE OF THE ART AS OF JANUARY 21, 2003 ........................... 26
`
`A. A Person of Ordinary Skill in the Art Would Not Have Pursued
`Bromfenac Formulations Over Other NSAID Formulations .............. 29
`
`1.
`
`2.
`
`No reason to pursue bromfenac formulations ........................... 29
`
`Design needs or market demands would not have
`supported the solution that InnoPharma proposes .................... 33
`
`B. A Person of Ordinary Skill in the Art Would Not Have
`Considered Different Non-Ionic Surfactants Interchangeable ............ 40
`
`1.
`
`2.
`
`No teaching of interchangeability of polysorbate 80 and
`tyloxapol in aqueous solutions of NSAIDs .............................. 41
`
`No teaching of polysorbate 80 or tyloxapol as a stabilizer
`of aqueous ophthalmic preparations of NSAIDs ...................... 45
`
`C. A Person of Ordinary Skill in the Art Would Not Have
`Considered Different NSAIDs Interchangeable.................................. 51
`
`
`
`2
`
`PAGE 2 OF 126
`
`
`
`

`
`
`
`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 ’290 PATENT ............................................................... 53
`
`A. A Person of Ordinary Skill in the Art Would Have Had No
`Reason to Focus on Ogawa and its Bromfenac Formulations ............ 53
`
`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 .............................................................................................. 57
`
`1.
`
`2.
`
`3.
`
`4.
`
`Ogawa and the problem it identifies with bromfenac ............... 57
`
`A person of ordinary skill in the art would not have
`looked to Sallmann or combined its teachings with those
`of Ogawa ................................................................................... 62
`
`Dr. Laskar’s alleged motivation and expectation of
`success in fact would not have made the combination of
`Ogawa and Sallmann obvious to make ..................................... 70
`
`A person of ordinary skill in the art would not have
`modified Sallmann with the teachings of Ogawa ..................... 74
`
`IX. OBJECTIVE EVIDENCE OF NON-OBVIOUSNESS OF THE ’290
`PATENT CLAIMS ........................................................................................ 77
`
`A. A Unique, Non-Prior Art, Aspect of the ’290 Patent Claims:
`The Use of Tyloxapol with Bromfenac ............................................... 77
`
`B.
`
`The Unexpectedly Superior Chemical Stabilizing Benefits of
`Tyloxapol Compared to Polysorbate 80 .............................................. 79
`
`1.
`
`2.
`
`The ’290 patent compares against the closest prior art for
`purposes of showing unexpected results ................................... 80
`
`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 .............................................................................. 82
`
`
`
`3
`
`PAGE 3 OF 126
`
`
`
`

`
`3.
`
`Tyloxapol’s unexpectedly superior chemical stabilizing
`effect ........................................................................................ ..84
`
`C.
`
`D.
`
`Tyloxapol is Unexpectedly Better than Polysorbate 80 at
`Maintaining Preservative Efficacy .................................................... ..92
`
`Tyloxapol’s Unexpectedly Superior Stabilizing Effect Led to
`Actual Benefits for Patients ............................................................... ..94
`
`E.
`
`Copying of Prolensa® by Generic Drug Companies ......................... ..97
`
`SEPARATE PATENTABILITY OF INDIVIDUAL CLAIMS ................. _.98
`
`A.
`
`Claims 4-5, 1 1-12, 17-18 and 23-24: About 0.01 W/V % to
`
`About 0.05 w/V % Tyloxapol ............................................................ ..98
`
`B.
`
`Claims 8-13, 20-25, 27, 29 and 30: Greater Than About 90% of
`
`Bromfenac Remains After Storing at 60° C. for 4 Weeks .............. .. 103
`
`C.
`
`Claims 26-30: EP—Criteria B Standard for Preservative
`
`Efficacy............................................................................................ .. 1 04
`
`CONCLUSION .......................................................................................... ..106
`
`CLAIM CHART DEMONSTRATING THAT PROLENSA® FALLS
`
`VVITHIN THE SCOPE OF CERTAIN CLAIMS OF THE ’290
`
`PATENT .................................................................................................... ..1 1 1
`
`"mi—
`
`PAGE 4 OF 126
`
`

`
`
`
`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 two
`
`inter partes review (“IPR”) proceedings (IPR2015-00903 and IPR2015-00902)
`
`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
`I am currently the Johnson & Johnson Centennial Chair of
`2.
`
`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 126
`
`
`
`

`
`
`
`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 126
`
`
`
`

`
`
`
`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 The Open Drug Delivery Journal. 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, Drug Delivery Science and Technology, Pharmaceutical
`
`
`
`7
`
`PAGE 7 OF 126
`
`
`
`

`
`
`
`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. 8,669,290 (“the ’290 patent”), the “Petition
`
`for Inter Partes Review of U.S. Patent No. 8,669,290” (“Petition”) and the
`
`declarations of Dr. Paul A. Laskar (EX1003), 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. Laskar’s
`
`
`
`8
`
`PAGE 8 OF 126
`
`
`
`

`
`conclusions that the subject matter of the claims of the ’290 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 ’290 PATENT
`
`A.
`14.
`
`Specification and Claims
`
`I understand that InnoPharma has challenged claims 1-30 of the ’290
`
`patent, EX1001, in this action. I further understand that the ’290 patent has a
`
`priority date of January 21, 2003.
`
`15. The ’290 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 126
`
`
`
`

`
`
`
`pharmacologically acceptable salt or hydrate thereof and the non-ionic surfactant
`
`tyloxapol. (EX1001.)
`
`16. The ’290 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.” (EX1001 at 2:35-47.) 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 ’290 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 ’290 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 126
`
`
`
`

`
`
`
`18. The ’290 patent claims are directed, generally speaking, to stable
`
`aqueous ophthalmic preparations comprising bromfenac and tyloxapol. (EX1001
`
`at 12:2-15:8.) The ’290 patent has three independent claims (claims 1, 8, and 14)
`
`and 27 dependent claims. (Id.)
`
`19. Generally speaking, independent claim 1 of the ’290 patent is directed
`
`to a stable aqueous liquid preparation comprising bromfenac and tyloxapol, which
`
`is present in an amount sufficient to stabilize bromfenac, formulated for
`
`ophthalmic administration, wherein bromfenac is the sole pharmaceutical active
`
`ingredient in the preparation and tyloxapol is present in an amount sufficient to
`
`stabilize bromfenac. (EX1001 at 12:2-12.)
`
`20. Generally speaking, dependent claim 2 of the ’290 patent is directed to
`
`the aqueous liquid preparation of claim 1, further comprising a quaternary
`
`ammonium salt. (EX1001 at 12:13-14.)
`
`21. Generally speaking, dependent claim 3 of the ’290 patent is directed to
`
`the aqueous liquid preparation of claim 1, wherein the first component is a
`
`bromfenac sodium salt. (EX1001 at 12:15-17.)
`
`22. Generally speaking, dependent claim 4 of the ’290 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 %, wherein the first component is a
`
`
`
`11
`
`PAGE 11 OF 126
`
`
`
`

`
`
`
`bromfenac sodium salt, and wherein the concentration of the bromfenac sodium
`
`salt is from about 0.01 to about 0.2 w/v%. (EX1001 at 12:18-25.)
`
`23. Generally speaking, dependent claim 5 of the ’290 patent is directed to
`
`the aqueous liquid preparation of claim 4, wherein the concentration of the
`
`bromfenac sodium salt is about 0.1 w/v %. (EX1001 at 12:26-28.)
`
`24. Generally speaking, dependent claim 6 of the ’290 patent is directed to
`
`the aqueous liquid preparation of claim 1, wherein the pH is from about 7.5 to
`
`about 8.5. (EX1001 at 12:29-30.)
`
`25. Generally speaking, dependent claim 7 of the ’290 patent is directed to
`
`the stable aqueous liquid preparation of claim 1, wherein the stable aqueous liquid
`
`preparation consists essentially of (a) bromfenac sodium salt, (b) tyloxapol, (c)
`
`boric acid, (d) sodium tetraborate, (e) EDTA sodium salt, (f) benzalkonium
`
`chloride, (g) polyvinylpyrrolidone, and (h) sodium sulfite, wherein the stable
`
`aqueous liquid preparation is formulated for ophthalmic administration, and
`
`wherein the concentration of the bromfenac sodium salt is from about 0.02 w/v %
`
`to about 0.1 w/v %. (EX1001 at 12:31-40.)
`
`26. Generally speaking, independent claim 8 of the ’290 patent is directed
`
`to a stable aqueous liquid preparation comprising two components, wherein the
`
`first component is bromfenac or a pharmacologically acceptable salt or hydrate of
`
`bromfenac, where the hydrate is at least one selected from a 1/2 hydrate, 1 hydrate
`
`
`
`12
`
`PAGE 12 OF 126
`
`
`
`

`
`
`
`and 3/2 hydrate, wherein the first component is the sole pharmaceutical active
`
`ingredient contained in the preparation, and wherein the second component is
`
`tyloxapol. The stable aqueous liquid preparation of claim 8 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. (EX1001 at 12:41-53.)
`
`27. Generally speaking, dependent claim 9 of the ’290 patent is directed to
`
`the aqueous liquid preparation of claim 8, further comprising a quaternary
`
`ammonium salt. (EX1001 at 12:54-55.)
`
`28. Generally speaking, dependent claim 10 of the ’290 patent is directed
`
`to the stable aqueous liquid preparation of claim 8, 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. (EX1001 at 12:56-60.)
`
`29. Generally speaking, dependent claim 11 of the ’290 patent is directed
`
`to the aqueous liquid preparation of claim 8, wherein the concentration of
`
`tyloxapol is from about 0.01 w/v % to about 0.05 w/v %, wherein the first
`
`component is a bromfenac sodium salt, and wherein the concentration of the
`
`bromfenac sodium salt is from about 0.01 to about 0.2 w/v%. (EX1001 at 12:61-
`
`67.)
`
`
`
`13
`
`PAGE 13 OF 126
`
`
`
`

`
`
`
`30. Generally speaking, dependent claim 12 of the ’290 patent is directed
`
`to the aqueous liquid preparation of claim 11, wherein the pH is from about 7.5 to
`
`about 8.5. (EX1001 at 13:1-2.)
`
`31. Generally speaking, dependent claim 13 of the ’290 patent is directed
`
`to the stable aqueous liquid preparation of claim 8, wherein the stable aqueous
`
`liquid preparation consists essentially of (a) bromfenac or a pharmacologically
`
`acceptable salt or hydrate of bromfenac, where 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, wherein the concentration of the
`
`bromfenac sodium salt is from about 0.02 w/v % to about 0.1 w/v %. (EX1001 at
`
`13:3-13.)
`
`32. Generally speaking, independent claim 14 of the ’290 patent is directed
`
`to a stable aqueous liquid preparation comprising 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 from a 1/2 hydrate, 1
`
`hydrate and 3/2 hydrate, wherein the first component is the sole pharmaceutical
`
`active ingredient contained in the preparation, and wherein the second component
`
`is tyloxapol. The stable aqueous liquid preparation of claim 14 is formulated for
`
`ophthalmic administration and does not include mannitol. (EX1001 at 13:14-25.)
`
`
`
`14
`
`PAGE 14 OF 126
`
`
`
`

`
`
`
`33. Generally speaking, dependent claim 15 of the ’290 patent is directed
`
`to the aqueous liquid preparation of claim 14, further comprising a quaternary
`
`ammonium salt. (EX1001 at 13:26-27.)
`
`34. Generally speaking, dependent claim 16 of the ’290 patent is directed
`
`to the aqueous liquid preparation of claim 14, wherein the first component is a
`
`bromfenac sodium salt. (EX1001 at 13:28-30.)
`
`35. Generally speaking, dependent claim 17 of the ’290 patent is directed
`
`to the aqueous liquid preparation of claim 16, wherein the concentration of
`
`tyloxapol is from about 0.01 w/v % to about 0.05 w/v %, and wherein the
`
`concentration of bromfenac sodium salt is from about 0.05 to about 0.2 w/v %.
`
`(EX1001 at 13:31-35.)
`
`36. Generally speaking, dependent claim 18 of the ’290 patent is directed
`
`to the aqueous liquid preparation of claim 17, wherein the pH is from about 7.5 to
`
`about 8.5. (EX1001 at 13:36-37.)
`
`37. Generally speaking, dependent claim 19 of the ’290 patent is directed
`
`to the stable aqueous liquid preparation of claim 14, wherein the stable aqueous
`
`liquid preparation consists essentially of (a) bromfenac or a pharmacologically
`
`acceptable salt or hydrate of bromfenac, where 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)
`
`
`
`15
`
`PAGE 15 OF 126
`
`
`
`

`
`
`
`polyvinylpyrrolidone, and (h) sodium sulfite, wherein the concentration of the
`
`bromfenac sodium salt is from about 0.02 w/v % to about 0.1 w/v %. (EX1001 at
`
`38-48.)
`
`38. Generally speaking, dependent claim 20 of the ’290 patent is directed
`
`to the stable aqueous liquid preparation of claim 14, 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. (EX1001 at 13:49-53.)
`
`39. Generally speaking, dependent claim 21 of the ’290 patent is directed
`
`to the aqueous liquid preparation of claim 20, further comprising a quaternary
`
`ammonium salt. (EX1001 at 13:54-55.)
`
`40. Generally speaking, dependent claim 22 of the ’290 patent is directed
`
`to the stable aqueous liquid preparation of claim 20, 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. (EX1001 at 13:56-60.)
`
`41. Generally speaking, dependent claim 23 of the ’290 patent is directed
`
`to the 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
`
`component is a bromfenac sodium salt, and wherein the concentration of the
`
`
`
`16
`
`PAGE 16 OF 126
`
`
`
`

`
`
`
`bromfenac sodium salt is from about 0.01 to about 0.2 w/v%. (EX1001 at 13:61-
`
`67.)
`
`42. Generally speaking, dependent claim 24 of the ’290 patent is directed
`
`to the stable aqueous liquid preparation of claim 23, wherein the pH is from about
`
`7.5 to about 8.5. (EX1001 at 14:1-2.)
`
`43. Generally speaking, dependent claim 25 of the ’290 patent is directed
`
`to the stable aqueous liquid preparation 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 stable aqueous liquid
`
`preparation of claim 25 is formulated for ophthalmic administration and the
`
`concentration of the bromfenac sodium salt in the stable aqueous liquid preparation
`
`of claim 25 is from about 0.02 w/v % to about 0.1 w/v %. (EX1001 at 14:3-14.)
`
`44. Generally speaking, dependent claims 26-30 of the ’290 patent are
`
`directed to the aqueous liquid preparations of claims 1, 8, 14, 20, and 22,
`
`respectively, wherein
`
`the aqueous
`
`liquid preparation further satisfies
`
`the
`
`preservative efficacy standard of EP-criteria B of the European Pharmacopoeia as
`
`follows: viable cell counts of bacteria (S. aureus, P. aeruginosa) 24 hours and 7
`
`
`
`17
`
`PAGE 17 OF 126
`
`
`
`

`
`
`
`days after inoculation decrease to not more than 1/10 and not more than 1/1000,
`
`respectively, and thereafter, the cell count levels off or decreases; and viable cell
`
`count of fungi (C. albicans, A. niger) 14 days after inoculation decreases to not
`
`more than 1/10, and thereafter, the cell count keeps the same level as that of 14
`
`days after inoculation. (EX1001 at 14:15-15:8.)
`
`Level of Skill in the Arti
`
`B.
`45. As of January 21, 2003, a person of ordinary skill in the art would
`
`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.
`
`46.
`
`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 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. (EX1003 at ¶ 20.) The person of ordinary skill 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”
`
`47. All claims of the ’290 patent contain the element “stable,” and claims
`
`1-7 further contain the element “amount sufficient to stabilize,” either expressly or
`
`
`
`18
`
`PAGE 18 OF 126
`
`
`
`

`
`
`
`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
`
`sufficient to confer sufficient resistance to degradation to be formulated and
`
`maintained for ophthalmic use.
`
`48.
`
`In the parallel District Court cases involving the ’290 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.)
`
`49.
`
`Judge Simandle’s reasoning in this regard, supported by the
`
`specification and prosecution history, paralleled mine. The ’290 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. (EX1001 at 2:35-47.) Experimental Examples 1 and 2 demonstrate the
`
`ability of tyloxapol to chemically stabilize bromfenac by inhibiting its degradation
`
`under certain conditions. (Id. at 7:7-8:52.) Experimental Example 3 provides the
`
`results of a preservative efficacy test. (Id. at 8:53-10:48.) During prosecution of
`
`the ’431 patent, to which the ’290 patent claims priority, the applicant relied on
`
`
`
`19
`
`PAGE 19 OF 126
`
`
`
`

`
`
`
`and the Examiner credited the chemical stability test of Experimental Example 1
`
`and the results shown in Table 1. (EX2245 at 7-8.)
`
`50. As mentioned, Chief Judge Simandle adopted exactly my
`
`interpretation of these claimed elements. (EX2065 at 5-6.) His opinion states that
`
`“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 ’290 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.)
`
`51. Thus, consistent with my interpretation, Chief Judge Simandle found
`
`that the term “stable” used in the claims of the ’290 patent incorporates the two
`
`dimensions of chemical stability and preservative efficacy, and the phrase “amount
`
`sufficient to stablize” refers to tyloxapol’s ability to chemically stabilize
`
`bromfenac.
`
`
`
`20
`
`PAGE 20 OF 126
`
`
`
`

`
`
`
`VI. SUMMARY OF OPINIONS
`I understand that the Board has granted InnoPharma’s petition to
`52.
`
`institute this IPR regarding the purported obviousness of claims 1-30 of the ’290
`
`patent on the following ground: Obviousness of claims 1-30 over U.S. Patent No.
`
`4,910,225 (“Ogawa”) (EX1004) and U.S. Patent No. 6,107,343 (“Sallmann”)
`
`(EX1009).
`
`53. As discussed further below, Ogawa taught the use of water soluble
`
`polymer and a sulfite, particularly sodium sulfite, a well-known antioxidant
`
`(EX2014 at 3:41-55), to chemically stabilize bromfenac from degradation.
`
`(EX1004 at Exp. Ex. 6.) From this, a person of ordinary skill in the art would have
`
`readily understood that oxidation caused bromfenac’s degradation. (EX1021 at 5.)
`
`A person of ordinary skill in the art would neither have combined the teachings of
`
`Sallmann with those of Ogawa, nor have reasonably expected the teachings of
`
`Sallmann to remedy bromfenac’s oxidative degradation problem.
`
`54. This is at least because Ogawa and Sallmann relate to different active
`
`ingredients and provide solutions to entirely unrelated problems: Ogawa involves
`
`the chemical stability of bromfenac,1 whereas Fu involves the physical stability of
`
`
`1 To a person of ordinary skill in the art, chemical stability looks to whether a
`
`formulation’s active ingredient does not change (i.e., degrade) within acceptable
`
`
`
`
`
`21
`
`PAGE 21 OF 126
`
`
`
`

`
`
`
`ketorolac formulations and Sallmann is directed to establishing that diclofenac
`
`potassium is more effective than diclofenac sodium. As such, a person of ordinary
`
`skill in the art would not have looked to Sallmann to solve bromfenac’s oxidative
`
`degradation. Specifically, Sallmann is directed to formulations of diclofenac
`
`potassium, a structurally dissimilar NSAID from bromfenac, and contains no
`
`teaching that diclofenac is susceptible to chemical degradation. (EX1009.)
`
`55. Thus, objectively viewing the art, a person of ordinary skill in the art
`
`would not have been motivated to selectively pick solubilizers from Sallmann to
`
`solve bromfenac’s oxidative degradation, when those solubilizers were used for a
`
`completely unrelated purpose. Furthermore, a person of ordinary skill in the art
`
`would not have expected that the solubilizers taught in Sallmann would have
`
`prevented or impeded bromfenac’s oxidation. As their names suggest, solubilizers
`
`typically solubilize poorly-soluble drugs, whereas antioxidants are used to prevent
`
`oxidative degradation of drugs. Even Dr. Lawrence, who serves as InnoPharma’s
`
`expert in the district court litigation involving the ’290 patent as well as Lupin’s
`
`expert in IPR2015-01099, has testified that solubility and stability are “not
`
`
`limits over a period of time. Physical stability, by contrast, looks to whether the
`
`formulation’s appearance (i.e., clarity or turbidity) changes withi