`
`BEFORE THE PATENT TRIAL AND APPEAL BOARD
`
`LUPIN, LTD. and LUPIN PHARMACEUTICALS INC.,
`
`Petitioner
`
`v.
`
`SENJU PHARMACEUTICAL CO., LTD.
`
`Patent Owner
`
`Case IPR2015-01097
`
`Patent 8,754,131 B2
`
`DECLARATION OF ROBERT 0. WILLIAMS, III, PH.D
`
`Page 1 of 172
`
`SENJU EXHIBIT 2082
`LUPIN v SENJU
`IPR2015-01097
`
`
`
`TABLE OF CONTENTS
`
`I.
`
`II.
`
`INTRODUCTION ........................................................................................... 5
`
`BACKGROUND AND QUALIFICATIONS ................................................. 5
`
`III.
`
`INFORMATION CONSIDERED ................................................................... 8
`
`IV. LEGAL PRINCIPLES ..................................................................................... 9
`
`V.
`
`THE '131 PATENT ......................................................................................... 9
`
`A.
`
`B.
`
`C.
`
`Specification and Claims ....................................................................... 9
`
`Level of Skill in the Art.. .................................................................... .18
`
`Claim Construction ............................................................................. 20
`
`1.
`
`2.
`
`"Stable" and "Amount Sufficient to Stabilize" ......................... 20
`
`"Satisfies the preservative efficacy standard of US
`Pharmacopoeia as follows: viable cell counts of bacteria
`(S. aureus, P. aeruginosa) 24 hours and 7 days after
`inoculation decrease to not more than 1/1 0 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" ................. 22
`
`VI.
`
`SUMMARY OF OPINIONS ......................................................................... 24
`
`VII. THE STATE OF THE ART AS OF JANUARY 21, 2003 ........................... 30
`
`A.
`
`A Person of Ordinary Skill in the Art Would Not Have Pursued
`Bromfenac Formulations Over Other NSAID Formulations .............. 36
`
`1.
`
`2.
`
`No reason to pursue bromfenac formulations ........................... 36
`
`Design needs or market demands would not have
`supported the solution that Lupin proposes ............................. .40
`
`B.
`
`A Person of Ordinary Skill in the Art Would Not Have
`Considered Different Non-Ionic Surfactants Interchangeable ........... .49
`
`Page 2 of 172
`
`2
`
`
`
`1.
`
`2.
`
`No teaching of interchangeability of polysorbate 80 and
`tyloxapol in aqueous solutions ofNSAIDs .............................. 50
`
`No teaching of polysorbate 80 or tyloxapol as a stabilizer
`of aqueous ophthalmic preparations ofNSAIDs ...................... 57
`
`C.
`
`A Person of Ordinary Skill in the Art Would Not Have
`Considered Different NSAIDs Interchangeable .................................. 69
`
`VIII. THE TEACHINGS OF OGAWA AND SALLMANN WOULD NOT
`HAVE BEEN COMBINED WITH ANY REASONABLE
`EXPECTATION OF ARRIVING AT THE CLAIMED SUBJECT
`MATTEROFTHE '131 PATENT ............................................................... 71
`
`A.
`
`B.
`
`A Person of Ordinary Skill in the Art Would Have Had No
`Reason to Focus on Ogawa and its Bromfenac Formulations ............ 71
`
`At the Time of Invention, A Person of Ordinary Skill in the Art
`Would Not Have Combined Ogawa's Teachings With Those of
`Sallmann .............................................................................................. 75
`
`1.
`
`2.
`
`3.
`
`4.
`
`Ogawa and the problem it identifies with bromfenac ............... 75
`
`A person of ordinary skill in the art would not have
`looked to Sallmann or combined its teachings with those
`of0gawa ................................................................................... 80
`
`Dr. Lawrence's alleged motivation and expectation of
`success in fact would not have made the combination of
`Ogawa and Sallmann obvious to make ..................................... 91
`
`A person of ordinary skill in the art would not have
`modified Sallmann with the teachings of Ogawa ................... 1 06
`
`IX. OBJECTIVE EVIDENCE OF NON-OBVIOUSNESS OF THE '131
`PATENT CLAIMS ...................................................................................... 112
`
`A.
`
`B.
`
`A Unique, Non-Prior Art, Aspect ofthe '131 Patent Claims:
`The Use ofTyloxapol with Bromfenac ............................................ .112
`
`The Unexpectedly Superior Chemical Stabilizing Benefits of
`Tyloxapol Compared to Polysorbate 80 ........................................... .114
`
`Page 3 of 172
`
`3
`
`
`
`1.
`
`2.
`
`3.
`
`The '131 patent compares against the closest prior art for
`purposes of showing unexpected results ................................ .115
`
`A person of ordinary skill in the art would have had no
`expectation, based on polysorbate 80, oftyloxapol's
`effect on the chemical stability of bromfenac
`formulations ............................................................................ 117
`
`Tyloxapol's unexpectedly superior chemical stabilizing
`effect. ....................................................................................... 120
`
`C.
`
`D.
`
`Tyloxapol is Unexpectedly Better than Polysorbate 80 at
`Maintaining Preservative Efficacy .................................................... 129
`
`Tyloxapol's Unexpectedly Superior Stabilizing Effect Led to
`Actual Benefits for Patients ............................................................... 13 2
`
`E.
`
`Copying ofProlensa®by Generic Drug Companies ........................ .134
`
`X.
`
`SEPARATE PATENTABILITY OF INDIVIDUAL CLAIMS ................ .136
`
`A.
`
`B.
`
`C.
`
`Claims 4, 6, 10, 11, 16, 22 and 23: About 0.01 w/v% to About
`0.05 w/v% Tyloxapol; Claim 18: About 0.02 w/v% to About
`0.05 w/v% Tyloxapol; Claim 12: About 0.02 w/v% Tyloxapol .... 136
`
`Claims 7-12, 19-23 and 27: Greater Than About 90% of
`Bromfenac Remains After Storing at 60° C. for 4 Weeks ............... .143
`
`Claims 25-29: EP-Criteria B Standard for Preservative
`Efficacy .............................................................................................. 148
`
`XI. CONCLUSION ........................... ; ................................................................ 155
`
`XII. CLAIM CHART DEMONSTRATING THAT PROLENSA ®FALLS
`WITHIN THE SCOPE OF CERTAIN CLAIMS OF THE '131
`PATENT ............ -.......................................................................................... 159
`
`XIII. CHART DEMONSTRATING THAT LUPIN'S GENERIC
`BROMFENAC PRODUCT IS AN EXACT COPY OF PROLENSA ® ..... 171
`
`Page 4 of 172
`
`4
`
`
`
`I, Robert 0. 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 (IPR20 15-00903, IPR20 15-00902,
`
`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.
`
`Page 5 of 172
`
`5
`
`
`
`4.
`
`I have extensive expenence and expertise m 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 PharmaF orm, 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
`
`Page 6 of 172
`
`6
`
`
`
`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
`
`Page 7 of 172
`
`7
`
`
`
`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. 8,754,131 ("the' 131 patent"), the "Petition
`
`for Inter Partes Review of U.S. Patent No. 8,754,131" ("Petition") and the
`
`declarations of Dr. M. Jayne Lawrence (EX1 005), 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.
`
`Page 8 of 172
`
`8
`
`
`
`Lawrence's conclusions that the subject matter of the claims of the '131 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(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 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 '131 PATENT
`
`A.
`
`Specification and Claims
`
`14.
`
`I understand that Lupin has challenged claims 1-30 ofthe '131 patent,
`
`EX1 002, in this action. I further understand that the '131 patent has a priority date
`
`of January 21,2003.
`
`15. The '131 patent is directed, generally speaking, to stable aqueous
`
`liquid preparations comprising
`
`the non-steroidal anti-inflammatory drug
`
`("NSAID") 2-amino-3-( 4-bromobenzoy l)pheny !acetic acid ("bromfenac") or its
`
`Page 9 of 172
`
`9
`
`
`
`pharmacologically acceptable salt or hydrate thereof and the non-ionic surfactant
`
`tyloxapol. (EX1002.)
`
`16. The '131 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." (EX1 002 at 2:30-42.) 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 '131 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 '131 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.
`
`Page 10 of 172
`
`10
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`
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`18.
`
`The '131 patent claims are directed, generally speaking, to stable
`
`aqueous ophthalmic preparations comprising bromfenac and tyloxapol. (EX1002
`
`at 12:2-15:8.) The '131 patent has three independent claims (claims 1, 7, and 13)
`
`and 27 dependent claims. (I d.)
`
`19. Generally speaking, independent claim 1 of the ' 131 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 is present at a concentration
`
`from about 0.05 w/v% to about 0.2 w/v %, and wherein the second component is
`
`ty loxapol and is present in the liquid preparation in an amount sufficient to
`
`stabilize the first component. The stable aqueous liquid preparation of claim 1 is
`
`formulated for ophthalmic administration. (EX1002 at 12:2-14.)
`
`20. Generally speaking, dependent claim 2 of the '131 patent is directed to
`
`the aqueous liquid preparation of claim 1, further comprising a quaternary
`
`ammonium salt. (EX1002 at 12:15-16.)
`
`21. Generally speaking, dependent claim 3 of the ' 131 patent is directed to
`
`the aqueous liquid preparation of claim 1, wherein the first component is a
`
`bromfenac sodium salt. (EX1002 at 12:18.;20.)
`
`Page 11 of 172
`
`11
`
`
`
`22. Generally speaking, dependent claim 4 of the '131 patent is directed to
`
`the aqueous liquid preparation of claim 1, wherein the concentration oftyloxapol is
`
`from about 0.01 w/v% to about 0.05 w/v %. (EX1002 at 12:21-23.)
`
`23. Generally speaking, dependent claim 5 of the ' 131 patent is directed to
`
`the aqueous liquid preparation of claim 1, wherein the pH is from about 7.5 to
`
`about 8.5. (EX1002 at 12:24-25.)
`
`24. Generally speaking, dependent claim 6 of the '131 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. The stable aqueous
`
`liquid preparation of claim 6 is formulated for ophthalmic administration. In the
`
`stable aqueous liquid preparation of claim 6, the concentration of the 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 %. (EX1002 at 12:26-36.)
`
`25. Generally speaking, independent claim 7 of the '131 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
`
`Page 12 of 172
`
`12
`
`
`
`active ingredient contained in the preparation and is present at a concentration
`
`from about 0.05 w/v% to about 0.2 w/v %, and wherein the second component is
`
`ty loxapol. 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. (EX1002 at 12:37-51.)
`
`26. Generally speaking, dependent claim 8 of the '131 patent is directed to
`
`the aqueous liquid preparation of claim 7, further comprising a quaternary
`
`ammonium salt. (EX1002 at 12:52-53.)
`
`27. Generally speaking, dependent claim 9 ofthe '131 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. (EX1002 at 12:54-58.)
`
`28. Generally speaking, dependent claim 10 of the '131 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 %, wherein the first
`
`component is a bromfenac sodium salt, and wherein the concentration of the
`
`bromfenac sodium salt is from about 0.05 to about 0.1 w/v%. (EX1002 at 12:59-
`
`65.)
`
`Page 13 of 172
`
`13
`
`
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`2 9. Generally speaking, dependent claim 11 of the ' 13 1 patent is directed
`
`to the aqueous liquid preparation of claim 10, wherein the pH is from about 7.5 to
`
`about 8.5. (EX1002 at 12:66-67.)
`
`3 0. Generally speaking, dependent claim 12 of the ' 131 patent is directed
`
`to the stable aqueous liquid preparation of claim 7, wherein the stable aqueous
`
`liquid preparation consists essentially of (a) bromfenac or a pharmacologically
`
`acceptable salt or hydrate ofbromfenac, wherein the hydrate is at least one selected
`
`from a 112 hydrate, 1 hydrate and 3/2 hydrate, (b) tyloxapol, (c) boric acid, (d)
`
`sodium tetraborate, (e) EDTA sodium salt, (f) benzalkonium chloride, (g)
`
`polyvinylpyrrolidone, and (h) sodium sulfite. The concentration of the bromfenac
`
`sodium salt in the stable aqueous liquid preparation of claim 12 is from about 0.05
`
`w/v % to about 0.1 w/v % and the concentration of tyloxapol is about 0.02 w/v%.
`
`(EX1002 at 13:1-12.)
`
`31. Generally speaking, independent claim 13 of the ' 131 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 112 hydrate, 1
`
`hydrate and 3/2 hydrate, wherein the first component is the sole pharmaceutical
`
`active ingredient contained in the preparation and is present at a concentration
`
`from about 0.05 w/v% to about 0.2 w/v %, and wherein the second component is
`
`Page 14 of 172
`
`14
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`
`
`tyloxapol. The stable aqueous liquid preparation of claim 13 is formulated for
`
`ophthalmic administration and does not include mannitol. (EX1002 at 13:13-24.)
`
`32. Generally speaking, dependent claim 14 of the '131 patent is directed
`
`to the aqueous liquid preparation of claim 13, further comprising a quaternary
`
`ammonium salt. (EX1 002 at 13 :25-26.)
`
`3 3. Generally speaking, dependent claim 15 of the '131 patent is directed
`
`to the aqueous liquid preparation of claim 13, wherein the first component is a
`
`bromfenac sodium salt. (EX1002 at 13:27-29.)
`
`34. Generally speaking, dependent claim 16 of the '131 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
`
`the bromfenac sodium salt is from about 0.05 to about 0.1 w/v %.
`
`(EX1 002 at
`
`13:30-34.)
`
`3 5. Generally speaking, dependent claim 17 of the ' 131 patent is directed
`
`to the aqueous liquid preparation of claim 13, wherein the pH is from about 7.5 to
`
`about 8.5. (EX1002 at 13:35-36.)
`
`36. Generally speaking, dependent claim 18 of the '131 patent is directed
`
`to the stable aqueous liquid preparation of claim 13, wherein the stable aqueous
`
`liquid preparation consists essentially of (a) bromfenac or a pharmacologically
`
`acceptable salt or hydrate ofbromfenac, wherein the hydrate is at least one selected
`
`Page 15 of 172
`
`15
`
`
`
`from a 1/2 hydrate, 1 hydrate and 3/2 hydrate, (b) tyloxapol, (c) boric acid, (d)
`
`sodium tetraborate, (e) EDTA sodium salt, (f) benzalkonium chloride, (g)
`
`polyvinylpyrrolidone, and (h) sodium sulfite. The concentration of the bromfenac
`
`sodium salt in the stable aqueous liquid preparation of claim 18 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 %. (EX1002 at 13:37-48.)
`
`3 7. Generally speaking, dependent claim 19 of the ' 131 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. (EX1002 at 13:49-53.)
`
`3 8. Generally speaking, dependent claim 20 of the '131 patent is directed
`
`to the stable , liquid preparation of claim 19, further comprising a quaternary
`
`ammonium salt. (EX1002 at 13:54-55.)
`
`3 9. Generally speaking, dependent claim 21 of the ' 131 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. (EX1002 at 13:56-60.)
`
`Page 16 of 172
`
`16
`
`
`
`40. Generally speaking, dependent claim 22 of the ' 131 patent is directed
`
`to the stable aqueous liquid preparation of claim 21, 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
`
`bromfenac sodium salt is from about 0.05 to about 0.1 w/v%. (EX1002 at 13:61-
`
`67.)
`
`41. Generally speaking, dependent claim 23 of the ' 131 patent is directed
`
`to the aqueous liquid preparation of claim 22, wherein the pH is from about 7.5 to
`
`about 8.5. (EX1002 at 14:1-2.)
`
`42. Generally speaking, dependent claim 24 of the '131 patent is directed
`
`to the stable aqueous liquid preparation of claim 13, wherein the stable aqueous
`
`liquid preparation consists essentially of (a) bromfenac or a pharmacologically
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`acceptable salt or hydrate ofbromfenac, wherein the hydrate is at least one selected
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`from a 112 hydrate, 1 hydrate and 3/2 hydrate, (b) ty loxapol, (c) boric acid, (d)
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`sodium tetraborate, (e) EDTA sodium salt, (f) benzalkonium chloride, (g)
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`polyvinylpyrrolidone, and (h) sodium sulfite.
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`The stable aqueous
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`liquid
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`preparation of claim 24 is formulated for ophthalmic administration. The
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`concentration of the bromfenac sodium salt in the stable aqueous liquid preparation
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`of claim 24 is from about 0.05 w/v% to about 0.1 w/v %. (EX1002 at 14:3-14.)
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`Page 17 of 172
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`43. Generally speaking, dependent claims 25-29 of the '131 patent are
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`directed to the aqueous liquid preparations of claims 1, 4, 7, 9 and 13, respectively,
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`wherein the aqueous liquid preparation further satisfies the preservative efficacy
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`standard of EP-criteria B of the European Pharmacopoeia as follows: viable cell
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`counts of bacteria (S. aureus, P. aeruginosa) 24 hours and 7 days after inoculation
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`decrease to not more than 1/10 and not more than 1/1000, respectively, and
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`thereafter, the cell count levels off or decreases; and viable cell count of fungi (C.
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`albicans, A. niger) 14 days after inoculation decreases to not more than 1/10, and
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`thereafter, the cell count keeps the same level as that of 14 days after inoculation.
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`(EX1002 at 14:15 -15:4.)
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`44. Generally speaking, dependent claim 30 of the '131 patent is directed
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`to the aqueous liquid preparation of claim 1, further comprising one or more
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`additives selected from the group consisting of a preservative, buffer, thickener,
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`stabilizer, chelating agent, and pH controlling agent. (EX1002 at 15:5-8.)
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`B.
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`Level of Skill in the Art
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`45. Lupin and Dr. Lawrence state that a person of ordinary skill in the art
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`would be a "pharmaceutical scientist involved in the research and development of
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`pharmaceuticals, and would have a Ph. D. and several years of experience in the
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`field." (Petition at 6; EX1 005 at '1[21.) I disagree as this exaggerates the level of a
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`person of "ordinary skill" in the art. Instead, as of January 21, 2003, a person of
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`Page 18 of 172
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`ordinary skill in the art would more likely have at least a Bachelor's degree in
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`fields such as pharmaceutical chemistry, chemistry, or a related discipline with
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`about three to five years of work experience in this area, or a comparable level of
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`education and training. (Accord, EX2037, a declaration of Dr. Uday Kompella, a
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`petitioner's expert from related IPR2014-01043, offered in a litigation on a patent
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`involving ophthalmic formulations.) Alternatively, a person of ordinary skill in the
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`art could have a comparable level of overall experience in designing, evaluating
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`and/or administering pharmaceutical formulations obtained by some combination
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`of education such as, for example, a degree in medicine or Ph.D. degree, with work
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`expenence.
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`46.
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`I also agree with Dr. Paul Laskar, the expert for Lupin's IPR for
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`the '431 patent (IPR20 15--00903 ), which the '131 patent claims priority, that a
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`person of ordinary skill in the art as of January 21, 2003 would have been
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`"think[ing] along conventional wisdom in the art," thereby pursuing the clear and
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`objectively rational leads in the prior art, rather than arbitrary pathways not
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`tethered to the realities of rational drug discovery at the time of invention.
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`(EX2249 at ~ 18.) A person of ordinary skill in the art would have pursued these
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`rational leads to develop pharmaceutical products balancing efficacy, safety and
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`stability.
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`Page 19 of 172
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`C.
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`Claim Construction
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`1.
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`"Stable" and "Amount Sufficient to Stabilize"
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`4 7. All claims of the '131 patent contain the element "stable," and claims
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`1-6 further contain the element "amount sufficient to stabilize," either expressly or
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`through dependency.
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`In my opinion, the term "stable" as used in these claims
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`means having sufficient resistance
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`to degradation and having sufficient
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`preservative efficacy to be formulated and maintained for ophthalmic use. The
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`phrase "amount sufficient to stabilize" as used in these claims means an amount
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`sufficient to confer sufficient resistance to degradation to be formulated and
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`maintained for ophthalmic use.
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`48.
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`In the parallel District Court cases involving the '131 patent, I
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`submitted a declaration setting forth the basis for my interpretation of these terms.
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`(EX2125.) I understand that Chief Judge Simandle of the U.S. District Court for
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`the District of New Jersey agreed with my interpretation and exactly adopted the
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`meanings I provided above. (EX2065 at 5-6.)
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`49.
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`Judge Simandle's reasomng m this regard, supported by
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`the
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`specification and prosecution history, paralleled mme.
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`The
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`' 131 patent
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`specification clearly states that tyloxapol inhibits the change of the bromfenac (i.e.,
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`degradation) and inhibits the formulation's preservative efficacy from deteriorating
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`over time. (EX1002 at 2:30-42.) Experimental Examples 1 and 2 demonstrate the
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`Page 20 of 172
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`ability of tyloxapol to chemically stabilize bromfenac by inhibiting its degradation
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`under certain conditions. (!d. at 7: 1-8:48.) Experimental Example 3 provides the
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`results of a preservative efficacy test. (!d. at 8:51-10:49.) During prosecution of
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`the '431 patent, from which the '131 patent claims priority, the applicant relied on
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`and the Examiner credited the chemical stability test of Experimental Example 1
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`and the results shown in Table 1. (EX2245 at 7-8.)
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`50. As mentioned, Chief Judge Simandle adopted exactly my
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`interpretation of these claimed elements. (EX2065 at 5-6.) His opinion states that
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`"the phrase 'in an amount sufficient to stabilize said first component,' which refers
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`specifically to tyloxapol's effect on bromfenac, is explained by [Examples 1 and 2
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`of the '131 patent], which illustrate the concentration of tyloxapol that would
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`create an ophthlamically-acceptable solution which prevents the degradation of the
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`active ingredient bromfenac."
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`(Id. 19.) His opinion further states that "[t]he
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`specification also suggests that the term
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`'stable,' which . . . modifies the
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`composition as a whole, includes an additional dimension," and that "Example 3
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`demonstrates that in addition to being resistant to chemical degradation, the
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`tyloxapol compositions also satisfy preservative efficacy standards for ophthalmic
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`use." (!d. at 20.)
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`51. Thus, consistent with my interpretation, Chief Judge Simandle found
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`that the term "stable" used in the claims of the '131 patent incorporates the two
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`Page 21 of 172
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`21
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`concepts of chemical stability and preservative efficacy, and the phrase "amount
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`sufficient to stabilize" refers to tyloxapol's ability
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`to chemically stabilize
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`bromfenac.
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`2.
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`"Satisfies the preservative efficacy standard of US
`Pharmacopoeia as follows: viable cell counts of bacteria (S.
`aureus, P. aeruginosa) 24 hours and 7 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"
`
`52. Claims 25-29 of the
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`'131 patent use the phrase "satisfies the
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`preservative efficacy standard of US Pharmacopoeia as follows: viable cell counts
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`of bacteria (S. aureus, P. aeruginosa) 24 hours and 7 days after inoculation
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`decrease to not more than 1/10 and not more than 1