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.
`P etitioner,
`
`v.
`
`SENJU PHARMACEUTICAL CO., LTD., BAUSCH & LOMB, INC., and
`BAUSCH & LOMB PHARMA HOLDINGS CORP.
`Patent Owner.
`
`Case IPR20 15-00903
`Patent 8,129,431
`
`DECLARATION OF ROBERT 0. WILLIAMS, III, PH.D.
`
`PAGE 1 OF117
`
`SENJU EXHIBIT 2082
`INNOPHARMA v SENJU
`IPR20 15-00903
`
`

`
`TABLE OF CONTENTS
`
`1.
`
`11.
`
`Ill.
`
`1NTRODUCTION ............................................. .. .... .. ...................................... 5
`
`BACKGROUND AND QUALIFICATIONS ..... ...... ............................... ....... 5
`
`INFORMATION CONSIDERED ................................................................... 8
`
`IV. LEGAL PRINCIPLES ............................................. ........................................ 9
`
`V.
`
`THE ' 431 PATENT ......... ...................................... .......................................... 9
`
`A.
`
`B .
`
`Specification and Claims ....................................................................... 9
`
`Person of Ordinary Skill in the Art ..................................................... 15
`
`VI.
`
`SUMMARY OF OPINIONS ......................................................................... 16
`
`VII. THE STATE OF THE ART AS OF JANUARY21 , 2003 ........................... 22
`
`A.
`
`A Person of Ordinary Skill in the Art Would Not Have Pursued
`Bromfenac Formulations Over Other NSAID FormuJations .............. 26
`
`1.
`
`2.
`
`No reason to pursue bromfenac formulations ........................... 26
`
`Design needs or market demands would not have
`supported the solution that InnoPhanna proposes .................... 29
`
`B.
`
`A Person of Ordinary Skill in the Art Would Not Have
`Considered Different Non-Ionic Surfactants Interchangeable .. .......... 36
`
`1.
`
`2.
`
`No teaching of interchangeability of polysorbate 80 and
`tyloxapol in aqueous solutions ofNSAIDs .............................. 37
`
`No teaching of polysorbate 80 or tyloxapol as a stabilizer
`of aqueous ophthalmic preparatjons ofNSAlDs ..................... .42
`
`C.
`
`A Person of Ordinary Skill in the Art Would Not Have
`Considered Different NSAIDs Interchangeable .................................. 46
`
`VIII. THE TEACHINGS OF OGAWA, SALLMANN, AND FU WOULD
`NOT HAVE BEEN COMBINED WITH ANY REASONABLE
`EXPECTATION OF ARRIVING AT THE CLAIMED SUBJECT
`MATTER OF THE ' 431 PATENT .............................................................. .49
`
`PAGE 2 OF 117
`
`2
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`

`
`A.
`
`B.
`
`A Person of Ordinary Skill in the Art Would Have Had No
`Reason to Focus on Ogawa and its Bromfenac Fonnulations ........... .49
`
`At the Time of Invention, A Person of Ordinary Skill in the Art
`Would Not Have Combined Ogawa's Teachings With Those of
`Salhnann ..................................... ...... ................................................... 53
`
`1.
`
`2.
`
`3.
`
`4.
`
`Ogawa and the problem it identifies with bromfenac ............... 53
`
`A person of ordinary skill in the art would not have
`looked to Sallmann or combined its teachings with those
`of0gawa ..................................... ................... ........................... 57
`
`Dr. Laskar's alleged motivation and expectation of
`success in fact would not have made the combination of
`Ogawa and Sallmann obvious to make ......... ............................ 65
`
`A person of ordinary skill in the art would not have
`modified Sallmann with the teachings of Ogawa ..................... 70
`
`C.
`
`Dr. Laskar's Reliance on Fu is Similarly Scientifically
`Unsupportable and Does Not Remedy the Deficiencies in his
`Reliance on Ogawa and Sallmann ....................................................... 73
`
`1.
`
`2.
`
`Dr. Laskar's reliance on Fu for tyloxapol is unsupported .. ...... 75
`
`Fu does not suggest an amount of tyloxapol that could be
`used to stabilize bromfenac ....................................................... 79
`
`IX. OBJECTIVE EVIDENCE OF NON-OBVIOUSNESS OF THE '43 1
`PATENT CLAIMS ...................................................................... .................. 83
`
`A.
`
`B.
`
`A Unique, Non-Prior Art, Aspect of the '431 Patent Claims:
`The Use ofTyloxapol with Bromfenac ............................................... 83
`
`The Unexpectedly Superior Chemical Stabilizing Benefits of
`Tyloxapol Compared to Polysorbate 80 ................................ .............. 85
`
`1.
`
`2.
`
`The '431 patent compares against the closest prior art tor
`purposes of showing unexpected results ................................... 86
`
`A person of ordinary skill in the art would have had no
`expectation, based on polysorbate 80, of tyloxapol's
`
`PAGE 3 OF 117
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`3
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`

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`effect on the chemical stability of bromfenac
`formulations ............................. .......................... .. ..... ....... ......... 88
`
`3.
`
`Tyloxapol's unexpectedly superior chemical stabilizing
`effect. ...................................................... ................................... 90
`
`Tyloxapol is Unexpectedly Better than Polysorbate 80 at
`Maintaining Preservative Efficacy ...................................................... 99
`
`Tyloxapol's Unexpectedly Superior Stabilizing Effect Led to
`Actual Benefits for Patients ............................................................... I 01
`
`C.
`
`D.
`
`E.
`
`Copying ofProlensa® by Generic Drug Companies ......... .... .... ........ 104
`
`X.
`
`CONCLUSION ................................................... .............................. ........... 105
`
`XI. CLAIM CHART DEMONSTRATING THAT PROLENSA® FALLS
`vVITHrN THE SCOPE OF CERTAIN CLAIMS OF THE '43 1
`PATENT ........................................................... ................ ........................... 111
`
`XII.
`
`PAGE 4 O F 117
`
`4
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`

`
`I, Robert 0. Williams, Ill, Ph.D., under penalty of perjury, declare as follows:
`
`l.
`
`INTRODlJCTJON
`
`1.
`
`1 have been retained by Finnegan, Henderson, Farabow, Garrett &
`
`Dunner, LLP on behalf of Senju Pharmaceutical, Co., Ltd. in connection with two
`
`inter partes review ("IP R") proceedings (IPR20 15-00903 and IPR20 15-00902)
`
`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
`
`fonnulation 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 ofPhannacy in Austin,
`
`Texas, where J have been teaching and conducting research for twenty years. Also,
`
`I am the Division Head ofPhannaceutics.
`
`3.
`
`1 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 lhe University of Texas at Austin in
`
`1986. I am a licensed phannacist.
`
`PAGE 5 OF 117
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`5
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`4.
`
`I have extensive expenence and expertise m pharmaceutical
`
`fonnulation and the use of excipients in formulating various types of drug dosage
`
`fonns, 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 phannaceutical
`
`development since 1986.
`
`5.
`
`Prior to becoming a professor, I worked in the pharmaceutical
`
`industry for several companies including Rhone-Poulenc Rorer Pha1111aceuticals,
`
`Duramed Phannaceuticals 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-201 0 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, 1 have re levant industry
`
`experience in addition to my academic qualifications.
`
`6. My current research focuses on the development, fonnu1ation,
`
`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 phannaceuticaJ sciences. A
`
`PAGE 6 OF 117
`
`6
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`
`significant number of my papers are directed specificaJly to phannaceutical
`
`fommlation techniques and drug dosage forms. I have co-edited two books on the
`
`subject of phannaceutical 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 Medjcal and Biologjcal 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 Col1ege 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. 1 am a member
`
`of the Editorial Advisory Board for The Open Drug Delive1y 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
`
`PAGE 7 OF 117
`
`7
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`

`
`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, 1 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.
`
`Ill.
`
`INFORMATION CONSIDERED
`
`12. The opinions expressed in this declaration are based on my review of,
`
`among other materials, U.S. Patent No. 8, 129,431 ("the '431 patent"), the "Petition
`
`for Inter Partes Review of U.S. Patent No. 8,129,431" ("Petition") and the
`
`declarations of Dr. Paul A. Laskar (EX1 003), Stephen G. Davies, Ph.D. (EX21 05),
`
`and Shirou Sawa (EX2098). 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
`
`PAGE 8 OF 117
`
`8
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`

`
`Dr. Laskar's conclusions that the subject matter of the claims of the '431 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 skiJl in the art, and objective indicia of non(cid:173)
`
`obviousness, such as unexpected superior results, copying and commercial success.
`
`I understand that for an invention to be regarded as obvious, a person of ordinmy
`
`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 '431 PATENT
`
`A.
`
`Specification and Claims
`
`14.
`
`I understand that lnnoPharma has challenged claims 1-22 of the '431
`
`patent, EXlOOl, in this action.
`
`I further understand that the '43 1 patent has a
`
`priority date of January 21, 2003.
`
`15. The '431 patent is directed, generally speaking, to aqueous liquid
`
`preparations consisting essentially of the non-steroidal anti-inflammatory drug
`
`("NSAID") 2-amino-3-( 4-bromobenzoyl)phenylacetic acid ("bromfenac") or its
`
`PAGE 9 OF 117
`
`9
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`

`
`pharmacologically acceptable salt or hydrate thereof and the non-ionic surfactant
`
`tyloxapol. (EXlOOl.)
`
`16. The '43 1 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 furthennore, when the aqueous solution contains a preservative,
`
`deterioration in the preservative effect of said preservative can be inhibited for a
`
`long period of time." (EXlOOl at 2:34-47.) 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 '431 patent confirm with experimental proof.
`
`Similarly, this passage' s statement that " deterioration in the preservative ef~ect ...
`
`can be inhibited" refers to the ability of tyloxapol to control and stabilize a
`
`bromfenac fonnulation's microbial growth, which Experimental Example 3 and
`
`Tables 3- 1 to 3-3 confirm with experimental proof.
`
`17. Thus, the
`
`'43 1 patent specification describes aqueous solutions
`
`containing bromfenac and tyloxapol that are chemically stable, with controlled
`
`microbial growth, are safe and non-i1Titating to the eye, and are efficacious and
`
`suitable for ophthalmic administration.
`
`PAGE 10 OF 117
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`10
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`18. The '43 1 patent claims are directed, generally speaking, to aqueous
`
`ophthalmic preparations consisting essentially of bromfenac and
`
`tyloxapoL
`
`(EX1001 at 11:65- 14:22.) The ' 431 patent has two independent claims (claims 1
`
`and 18) and 20 dependent claims. (Id.)
`
`19. Generally speaking, independent claim 1 of the ' 431 patent is directed
`
`to an aqueous liquid preparation consisting essentially of bromfenac and tyloxapol,
`
`formulated for ophthalmic administration, and when a quaternary ammoruum
`
`compound is present, it is benzalkonium chloride ("BAC"). (EX I 00 l at 11:66-
`
`12:9.)
`
`20. Generally speaking, dependent claim 2 of the '431 patent is directed
`
`to the aqueous liquid preparation of claim 1, wherein the first component is a
`
`bromfenac sodium salt. (EXIOOl at 12:10-12.)
`
`21. Generally speaking, dependent claim 3 of the '431 patent is directed
`
`to the aqueous liquid preparation of claim 1, wherein the second component is
`
`tyloxapol and the pharmacologically acceptable salt of bromfenac is a sodium salt,
`
`the concentration of tyloxapol is from about 0.01 w/v % to abou.t 0.5 w/v %, the
`
`first component is a bromfenac sodium salt, and the concentration of the
`
`bromfenac sodium salt is from about 0.01 w/ v% to about 0.5 w/v %. (EXlOO l at
`
`12:13-23.)
`
`PAGE 11 OF 117
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`1 I
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`22. Generally speaking, dependent claim 4 of the '431 patent is directed
`
`to the aqueous liquid preparation of claim 3, wherein the concentration of
`
`tyloxapol is from about 0.01 w/v % to about 0.3 w/v % and the concentration of
`
`the bromfenac sodium salt is from abou t 0.05 to about 0.2 w/v %. (EX1001 at
`
`12:24-28.)
`
`23. Generally speaking, dependent claim 5 of the '431 patent is directed
`
`to the aqueous liquid preparation of claim 4, wherein the concentration of
`
`bromfenac sodium salt is about 0.1 w/v %. (EXlOOl at 12:29-33.)
`
`24. Generally speaking, dependent claim 6 of the '431 patent is directed
`
`to the aqueous liquid preparation of claim 4, wherein the concentration of
`
`tyloxapol is about 0.02 w/v %. (EX100l at 12:32-34.)
`
`25. Generally speaking, dependent claim 7 of the '43 1 patent is directed
`
`to the aqueous liquid preparation of claim 1, wherein the fonnulation further
`
`includes one or more additives selected from t he group consisting of a preservative,
`
`buffer, thickener, stabilizer, chelating agent, and pH controlling agent. (EX 1001 at
`
`12:35-39.)
`
`26. Generally speaking, dependent claim 8 of the '431 patent is directed
`
`to the aqueous liquid preparation of claim 7, wherein the preservative is BAC, the
`
`buffer is boric acid and/or sodium borate, the thickener is polyvinylpyrroJidone
`
`PAGE 12 OF 117
`
`12
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`("PVP"), the stabilizer is sodium sulfite, the chelating agent is sodium edetate, and
`
`the pH controlling agent is sodium hydroxide. (EXl 001 at 12 :40-46.)
`
`27. Generally speaking, dependent claim 9 of the '431 patent is directed
`
`to the aqueous liquid preparation of claim 8, wherein the pH is from about 7 to
`
`about 9. (EXIOOl at 12:47-48.)
`
`28. Generally speaking, dependent claim 10 of the '431 patent is directed
`
`to the aqueous liquid preparation of claim 8, wherein the pH is from about 7.5 to
`
`about 8.5. (EXl 001 at 12:49-50.)
`
`29. Generally speaking, dependent claim 11 of the '431 patent is directed
`
`to the aqueous liquid preparation of claim 4, where the concentration of bromfenac
`
`sodium salt is 0.2 w/v %. (EXIOO l at 12:51-53.)
`
`30. Generally speaking, dependent claim 12 of the '431 patent is directed
`
`to the aqueous liquid preparation of claim 4, where the concenb·ation of tyloxapol
`
`is about 0.3 w/v %. (EXIOOI at 12:54-55.)
`
`31. Generally speaking, dependent claim 13 of the '431 patent is directed
`
`to the aqueous liquid preparation of claim 12, wherein the fonnulation further
`
`includes one or more additives selected from the group consisting of a preservative,
`
`buffer, thickener, stabilizer, chelating agent, and pH controlling agent. (EX I 001 at
`
`12:56-60.)
`
`PAGE 13 OF 117
`
`13
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`32. Generally speaking, dependent claim 14 of the '431 patent is directed
`
`to the aqueous liquid preparation of claim 13, wherein said preservative is BAC,
`
`said buffer is boric acid and/or sodium borate, said thickener is PVP, said stabilizer
`
`is sodium sulfite, said chelating agent is sodium edetate, and said pH controlling
`
`agent is sodium hydroxide. (EX I 00 I at 1 2:6 1-67.)
`
`33. Generally speaking, dependent claim 15 of the '431 patent is directed
`
`to the aqueous liquid preparation of claim 11, wherein the concentration of
`
`tyloxapol is about 0.02 w/v %. (EXlOOl at 13: l-3.)
`
`34. Generally speaking, dependent claim 16 of the '43 1 patent is directed
`
`to the aqueous liquid preparation of claim J 5, wherein the fotmulation further
`
`includes one or more additives selected from the group consisting of a preservative,
`
`buffer, thickener, stabilizer, chelating agent, and pH controlling agent. (EXlOOl at
`
`13:4-8.)
`
`3 5. Generally speaking, dependent claim 17 of the '431 patent is directed
`
`to the aqueous liquid preparation of claim 16, wherein said preservative is BAC,
`
`said buffer is boric acid and/or sodium borate, said thickener is PVP, said stabilizer
`
`is sodium sulfite, said chelating agent is sodium edetate, and said pH controlling
`
`agent is sodium hydroxide. (EXJ 00 l at 13 :9-14.)
`
`36. Generally speaking, independent claim 18 of the
`
`'431 patent is
`
`directed to an aqueous liquid preparation consisting essential ly of bromfenac,
`
`PAGE 14 OF 117
`
`14
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`tyloxapol, boric acid, sodium tetra borate, EDT A sodium salt, BAC, PVP, and
`
`sodium sulfite, formulated for ophthalmic administration, wherein BAC is the only
`
`quaternary ammonium compound included. (EXlOOl at 13:15-14:9.)
`
`37. Generally speaking, dependent claim 19 of the '431 patent is directed
`
`to the aqueous liquid preparation of claim 18, wherein (a) is a bromfenac sodium
`
`salt. (EXlOOl at 14:10-12.)
`
`38. Generally speaking, dependent claim 20 of the '431 patent is directed
`
`to the aqueous liquid preparation of claim 19, where the concentration of
`
`bromfenac sodium salt is from about 0.01 to about 0.5% and the concentration of
`
`tyloxapol is about 0.02 w/v%. (EXlOOl at 14:13-16.)
`
`39. Generally speaking, dependent claim 21 of the '431 patent is directed
`
`to the aqueous liquid preparation of claim 20, wherein the concentration of
`
`bromfenac sodium salt is about 0.01 w/v %. (EX1001 at 14:17-19.)
`
`40. Generally speaking, dependent claim 22 of the '431 patent is directed
`
`to the aqueous liquid preparation of claim 20, wherein the concentration of
`
`bromfenac sodium salt is about 0.1 w/v %. (EXIOOl at 14:20-22.)
`
`B.
`
`Person of Ordinary Skill in the Art
`
`41. As of January 21, 2003, a person of ordinary skill m the art of
`
`the '431 patent would have at least a Bachelor's degree in fields such as
`
`pharmaceutical chemistry, chemistry, or a related discipline with about three to
`
`PAGE 15 OF 117
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`IS
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`

`
`five years of work experience in this area, or a comparable level of education and
`
`training.
`
`42.
`
`I agree with Dr. Laskar that a person of ordinary skill in the art as of
`
`January 21, 2003 would have been "think[ing] along conventional wisdom in the
`
`art," thereby pursuing clear and objectively rational leads in the prior art, rather
`
`than arbitrary pathways not tethered to the realities of rational drug discovery at the
`
`time of invention. (EX1003 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.
`
`VI. SUMMARY OF OPINIONS
`
`43.
`
`I understand that the Board has granted InnoPharma's petition to
`
`institute this IPR regarding the purported obviousness of claims 1-22 of the '431
`
`patent on the following grounds:
`
`Ground 1: Obviousness of claims 1-5, 7-14, and 18-19 over U.S. Patent
`
`No. 4,910,225 ("Ogawa") (EX1004) and U.S. Patent No. 6,107,343
`
`("Sallmann") (EXl 009)
`
`Ground 2: Obviousness of claims 6, 15-17, and 20-22 over Ogawa,
`
`SaJLmann, and Australian Patent No. AU-B-22042/88 ("Fu") (EX1011)
`
`44. As discussed further below, Ogawa taught the use of water soluble
`
`polymer and a sulfite, particularly sodium sulfite, a well-known antioxidant
`
`PAGE 16 OF 117
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`16
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`(EX2014 at 3:41 -55),
`
`to chemically stabilize bromfenac from degradation.
`
`(EXl 004 at Exp. Ex. 6.) From this, a person of ordinary skill in the art would have
`
`readily understood that oxidation caused bromfenac's degradation. (EX 1021 at 5.)
`
`A person of ordinary skill in the art wouJd neither have combined the teachings of
`
`Sallmann or Fu with those of Ogawa, nor have reasonably expected the teachings
`
`of Sallmarm or Fu to remedy bromfenac' s oxidative degradation problem.
`
`45. This is at least because Ogawa, Sallmann, and Fu relate to different
`
`active ingredjents and provide solutions to entirely unrelated problems: Ogawa
`
`involves the chemical stability of bromfenac, 1 whereas Fu involves the physical
`
`stability of ketorolac formulations, and SallmaiU1 is directed to establishing that
`
`diclofenac potassium is more effective therapeutically than diclofenac sodium. As
`
`such, a person of ordinary skill in the art would not have looked to Sallmann or Fu
`
`to solve bromfenac's oxidative degradation.
`
`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
`
`limits over a period of time. Physical stability, by contrast, looks to whether the
`
`formulation 's appearance (i.e., clarity or turbidity) changes within acceptable
`
`limits over time.
`
`PAGE 17 OF 117
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`17
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`46.
`
`Specifically, Sallmann is directed to formulations of diclofenac
`
`potassium, a structuraiiy dissimilar NSAID from bromfenac, and contains no
`
`teaching that diclofenac is susceptible to chemical degradation.
`
`(EXl 009 .)
`
`Similarly, Fu contains no teaching that its NSAID, ketorolac (also structurally
`
`dissimilar to bromfenac), is susceptible to chemical degradation.
`
`(EX1011.)
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`Instead, Fu is directed to physically stabilizing formulations of ketoroJac and
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`benzalkonium chloride (BAC) by preventing the formation of a precipitate.
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`(EXlOll at, e.g., 14:16-32, 15:12-17:20, 18:8-19:27.) There is no teaching in
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`Ogawa of the formation of any similar precipitate. Ogawa only teaches the
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`formation of a red insoluble oxidative degradation product- clearly not the
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`precipitant salt of an NSAID and BAC. (EX1004 at Exp. Exs. 4-6.) -
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`47. Thus, objectively viewing the art, a person of ordinary skill in the art
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`would not have been motivated to selectively pick solubilizers from Sallmann or
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`Fu to solve bromfenac' s oxidative degradation, when those solubilizers were used
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`for a completely unrelated purpose. Furthennore, a person of ordinary skill in the
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`art would not have expected that the solubilizers taught in Sallmann and Fu would
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`have prevented or impeded bromfenac' s oxidation. As their names suggest,
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`PAGE 18 OF 117
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`solubilizers typically solubilize poorly-soluble drugs, whereas antioxidants are
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`used to prevent oxidative degradation of drugs. Even Dr. Lawrence, who serves as
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`InnoPham1a' s expert in the district court litigation involving the '431 patent as
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`well as Lupin's expert in IPR2015-01099, has testified that solubility and stability
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`are "not synonymous at all." (EX2 140 at 43:22-44:12.) Moreover, a person of
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`ordinary skill in the art would have understood that surfactants like polysorbate 80
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`and tyloxapol would both cause degradation of bromfenac through generation of
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`hydroperoxides and would not have been inclined to switch them, particularly
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`when Ogawa touted its formulations' stabil ity as excellent. (EX21 05 at ~ 72.)
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`48. A person of ordinary skill in the art, moreover, would also have not
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`simply substituted Ogawa's polysorbate 80 for Sallmann 's tyloxapol merely
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`because both are nonionic surfactants. Indeed, even among polysorbates, there are
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`significant differences in properties. (/d. at ~ 81.) Polysorbate 80 and tyloxapol
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`are vastly structurally dissimilar with correspondingly different chemical and
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`physical properties, such that a person of ordinary skill in the art would not
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`consider them so readily interchangeable (id. at~~ 79-84), particularly in complex
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`and highly sensitive ophthahn ic fonnu lations where seemingly
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`insignificant
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`changes in the fonnulation's components could affect substantial changes in its
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`properties.
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`PAG E 19 OF 117
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`19
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`49.
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`In that regard, Ogawa touts its bromfenac formulations as having
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`excellent chemical stability. (EXl 004 at 1 0:49-57 .) A person of ordinary skill in
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`the art exercising common sense would not have blindly substituted polysorbate 80
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`with tyloxapol without considering how it might impact the chemical stability of
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`Ogawa's formulations. None of the art of record suggests using tyloxapol to
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`chemically stabilize an NSAID in an aqueous formulation. And in Ogawa,
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`polysorbate 80 does not function as a stabilizer for bromfenac.
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`(Id. at 8:3-9:7;
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`EX2095 at Exp. Exs. 4-6.) That role belongs to PVP and sodium sulfite. (ld. at
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`3:48-62.) Rather than substitute polysorbate 80 with tyloxapol, a person of
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`ordinary skill in the rut exercising common sense and engaging in rational drug
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`discovery would have more likely pursued improvements to PVP or sodium sulfite.
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`50. Additionally, a person of ordinary skill in the rut would not have been
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`motivated to substitute Sallmann's diclofenac potassium for Ogawa's bromfenac,
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`for doing so would have been contrary to the entire purpose of the Sallmann patent,
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`i.e.,
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`the use of diclofenac potassium.
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`Additionally, Sallmann's use of
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`cyclodextrins (EX1009 at Ex. 2), which were known to complex aryl groups
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`present in bromfenac (EX21 05 at ~ 96), could negatively impact chemical stability,
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`and therefore nm afoul of the "consisting essentially of' language in the '431
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`patent claims. I have been informed and understand that this phrase as it is used in
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`a patent claim means that the claim encompasses the recited clements and only
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`PAGE 20 OF 117
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`20
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`those non-recited elements that do not materially affect the basic and novel
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`properties of the claimed composition. As such, any non-recited element that
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`materially affects the basic and novel properties of the composition is excluded
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`from the claim's scope.
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`51 .
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`It was completely unexpected
`
`that
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`tyloxapol would stabilize
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`bromfenac against chemical degradation. It was similarly unexpected, as discussed
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`below, that it would do so in such a convincing manner compared to Ogawa's
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`polysorbate 80. Tyloxapol's unexpected stabilization benefits translated into
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`similarly unexpected benefits seen in the commercialized product Prolensa®, an
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`ophthalmic bromfenac (0.07%) solution covered by certain claims of the '431
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`patent. This stabilization benefit permjtted formulating Prolensa® at pH 7.8, a
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`comfortable and less irritating pH that is close to that of natural tears (EX2088 at
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`~ 66b;
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`, that led to enhanced ocular penetration and,
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`without a reduction in efficacy, allowed lowering of the amount ofbromfenac from
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`0.09% to 0.07%, which meant less drug contacting surgically compromised ocular
`
`tissue. (EX2030; EX2026; EX2Q27.) With these new benefits, Prolensa® garnered
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`significant acclaim in the medical community. (EX2Jl3 at 965; EX2 118 at 3 1;
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`EX2119 at 929.) Furthennore, it was marketed and commercialized, despite the
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`availability of generic bromfenac fonnulations (EX2028 at J ), and in fact,
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`lnnoPhanna and five other generic companies have sought to market exact copies
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`PAGE 21 OF 117
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`21
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`of Prolensa®, supporting the successful and non-obvious nature of the formulation.
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`(See infra at ,,~ I 81-82.) This objective evidence indicates that tyloxapol 's
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`unexpectedly superior stabilizing effect constitutes a material and substantial
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`difference more than in degree, producing a more comfortable, less i1ritating, more
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`efficacious formulation embodied
`
`in Prolensa®, which further supports and
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`enhances the nonobviousness of the claimed preparations.
`
`VII. THE STATE OF THE ART AS OF JANUARY 21, 2003
`
`52. As of the January 21, 2003 priority date of the '431 patent, drug
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`formulation was a difficult and unpredictable endeavor, and it remains so today.
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`The formulation of ophthalmic drugs is particularly complex, because when
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`formulating ophthalmic dosage forms such as the aqueous liquid preparations of
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`the '431 patent, stability is more challenging and critical than with other dosage
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`forms such as tablets or capsules.
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`In addition, the surface area of the eye is
`
`extremely small, and the residence time for an eye drop is quite short, which
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`increases the challenge in designing an aqueous dosage form that can pass through
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`the hydrophobic cornea membrane of the eye to reach the intended site of action.
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`Dr. Laskar himself has acknowledged these fonnulation challenges in swom
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`testimony
`
`in a patent infringement case involving the ophthalmic product
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`Combigan®.
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`(EX2135 at 989, 1020, l 022.)
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`PAGE 22 OF 117
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`53. Notwithstanding these formulation challenges, InnoPharma and Dr.
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`Laskar cite Ogawa, SalJmann and Fu, and advance a simple "swapping" theme,
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`which involves swapping tyloxapol in Sallmann's Example 2 for polysorbate 80 in
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`Ogawa's Example 6, or alternatively, swapping bromfenac in Ogawa's Example 6
`
`for diclofenac in Sallmann's Example 2. (Petition at 6-9.) InnoPhanna and Dr.
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`Laskar's contrived and overly simplistic swapping position is not tethered to the
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`realities of rational drug discovery at the time of invention, but is more indicative
`
`of already knowing the solution and working backwards to rationalize it. -
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`As such, Dr. Laskar' s analysis ignores 1) other
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`leads or approaches a person of ordinary skill in tl1e art at the time would have
`
`been motivated to and more likely to pursue; 2) the important structural and
`
`functional differences among non-ionic surfactants like tyloxapol and polysorbate
`
`80 and ethoxylated octylphenols in Fu; and 3) the important structural and
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`functional differences among NSAIDs
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`like bromfenac and diclofenac and
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`ketorolac in Fu, which Dr. Lask