UNITED STATES PATENT AND TRADEMARK OFFICE
`
`BEFORE THE PATENT TRIAL AND APPEAL BOARD
`
`LUPIN LTD. and LUPIN PHARMACEUTICALS INC.
`
`Petitioner,
`
`V.
`
`SENJU PHARMACEUTICAL CO., LTD.,
`Patent Owner.
`
`Case IPR2015-01099
`
`Patent 8,669,290
`
`DECLARATION OF STEPHEN G. DAVIES, D.Phil.
`
`Page 1 of 58
`
`SENJU EXHIBIT 2105
`
`LUPIN v SENJU
`IPR2015-01099
`
`

`
`Table of Contents
`
`I.
`
`BACKGROUND AND QUALIFICATIONS .............................................. .. 2
`
`II.
`
`INFORMATION CONSIDERED ................................................................ .. 4
`
`III.
`
`LEGAL PRINCIPLES .................................................................................. .. 5
`
`IV.
`
`THE ’290 PATENT ..........................................
`
`.......................................... .. 6
`
`V.
`
`SUMMARY OF OPINIONS ...................................................................... .. 13
`
`VI.
`
`STATEMENT OF OPINIONS EXPRESSED AND BASES AND
`
`REASONS THEREFOR ............................................................................. .. 15
`
`A.
`
`The Level of Skill in the Art ............................................................. .. 15
`
`B.
`
`Bromfenac is Structurally and Chemically Dissirnilar to
`Diclofenac, Ketorolac and Pranlukast .............................................. .. 16
`
`C.
`
`D.
`
`1.
`
`2.
`
`3.
`
`Comparison of Bromfenac and Diclofenac ............................ .. 17
`
`Comparison of Bromfenac and Ketorolac .............................. .. 24
`
`Comparison of Bromfenac and Pranlukast ............................ .. 28
`
`Dr. Lawrence Has Not Established That a Precipitate Will Form
`between an NSAID such as Bromfenac and BAC ........................... .. 33
`
`Non-ionic Surfactants are Structurally and Chemically Diverse
`and Not Interchangeable ................................................................... .. 37
`
`1.
`
`2.
`
`Comparison of Polysorbate 80 and Tyloxapol ....................... .. 37
`
`Comparison of Octoxynol 9, Octoxynol 40 and
`Tyloxapol ................................................................................ .. 42
`
`E.
`
`Cyclodextrins May Impact the Stability of the Claimed
`Bromfenac Formulations .................................................................. .. 48
`
`VII. NON—OBVIOUSNESS OF THE CLAIMS OF THE ’290 PATENT ........ .. 49
`
`VIII. CONCLUSION ........................................................................................... .. 51
`
`Page 2 of 58
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`1
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`

`
`1, Stephen G. Davies, under penalty of perjury, declare as follows:
`
`1.
`
`I have been retained by Finnegan, Henderson, Farabow, Garrett &
`
`Dunner, LLP on behalf of Senju Pharmaceutical, Co., Ltd. in connection with this
`
`action as an expert in organic chemistry and medicinal chemistry.
`
`I.
`
`BACKGROUND AND QUALIFICATIONS
`
`2.
`
`I am the Waynflete Professor of Chemistry at the University of Oxford,
`
`Oxford, England.
`
`I have been employed teaching chemistry at Oxford since 1980.
`
`From 2006 to 2011, I was Chairman of the Department of Chemistry.
`
`In this
`
`position,
`
`I had full
`
`responsibility for all
`
`teaching,
`
`research,
`
`financial and
`
`managerial matters in one of the largest chemistry departments in the world.
`
`I
`
`have also supervised more than 100 graduate students and 100 post-doctoral
`
`fellows in the area of organic, organometallic and medicinal chemistry.
`
`3.
`
`In 1973, I earned a B.A. in Chemistry from the University of Oxford.
`
`In 1975, I earned a D. Phil. in Chemistry from the University of Oxford. In 1980, I
`
`received a D. Se. in Chemistry from the University of Paris.
`
`4.
`
`Over the course of my career, I have been a committee member of
`
`many professional organizations, a list of which can be found in my curriculum
`
`vitae, attached as Exhibit 2049.
`
`5.
`
`I have authored over 550 publications and have given scores of
`
`research lectures. My research interests include synthetic organic and medicinal
`
`Page 3 of 58
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`

`
`chemistry, and in particular,
`
`the preparation of enantiomerically pure organic
`
`compounds,
`
`including
`
`the
`
`asymmetric
`
`and
`
`stereoselective
`
`synthesis
`
`of
`
`enantiomerically pure organic compounds for potential therapeutic use. A list of
`
`my publications may be found attached as Exhibit 2050.
`
`6.
`
`I have also held several editorial appointments.
`
`I am the Founding
`
`Editor and Editor of Organic Series of “Oxford Chemistry Primers” and “Oxford
`
`Chemistry Masters,” an Executive Editorial Board Member of “Tetrahedron,” the
`
`Founding Editor and Editor—in—chief of “Tetrahedron: Asymmetry,” and the Editor
`
`of the “On Chemistry” Books.
`
`7.
`
`Over
`
`the course of my career,
`
`I have received several awards,
`
`including the Hickinbottom Fellowship (1984), Pfizer Award for Chemistry (1985),
`
`1984 Corday Morgan Medal, Royal Society of Chemistry (1986), Royal Society of
`
`Chemistry Award ior Organometallic Chemistry (1987), Pfizer Award for
`
`Chemistry (1988), Royal Society of Chemistry Bader Award (1989), Tilden
`
`Lecture Award, Royal Society of Chemistry (1996), Royal Society of Chemistry
`
`Award in Stereochemistry (1997), Prize Lectureship of the Society of Synthetic
`
`Organic Chemistry, Japan (1998), Distinguished Technopreneur Award, Singapore
`
`(2008), and Royal Society of Chemistry Perkin Prize for Organic Chemistry
`
`(2011).
`
`Page 4 of 58
`
`

`
`8.
`
`I am also the founder of numerous companies including ones focused
`
`on the preparation of compounds for potential pharmaceutical use. Along with
`
`several others, I founded Oxford Asymmetry, Ltd.
`
`in 1992, which became a
`
`division of Oxford Asymmetry International plc, with a mission to provide
`
`pharmaceutical companies with enantiomerically pure compounds of interest on
`
`any desired scale, from small amounts for biological evaluation and research, to
`
`commercial quantities. Currently, I am the Founder and Non—executive Chairman
`
`of Scilnk Ltd.
`
`I am also the Non—executive Director of Isis Innovation Ltd.
`
`I am
`
`also the Founder and Non—executive Director of OxStem Ltd.
`
`I am also the
`
`Founder and Non—executive Director of Summit Therapeutics plc, which develops
`
`pharmaceutical compounds and has two such compounds currently undergoing
`
`Phase II/III clinical trials.
`
`9.
`
`On the basis of my education and the experience described above, I
`
`believe I am qualified to give the opinion set out herein.
`
`II.
`
`INFORMATION CONSIDERED
`
`10. The opinions expressed in this declaration are based on my review of
`
`U.S. Patent No. 8,669,290 (“the ’29O patent”),
`
`the “Petition for Inter Partes
`
`Review of U.S. Patent No. 8,669,290” (“Petition”) and Exhibits to the Petition,
`
`including the declaration of Dr. Jayne Lawrence (EX1005).
`
`I have also reviewed
`
`the transcript of Dr. Lawrence’s cross examination (EX2316).
`
`I have also
`
`Page 5 of 58
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`

`
`reviewed the transcript of Dr. Laskar’s cross examination in IPR20l5—OO902
`
`involving the ’290 patent and IPR20l5-00903] (EX21 14).
`
`I have further reviewed
`
`the transcript of the deposition of Dr. Jayne Lawrence, who also serves as Lupin’s
`
`expert in the district court litigation involving the ’290 patent (EX2l40).
`
`I also
`
`base this opinion on my professional and academic experience in the areas of
`
`organic chemistry and medicinal chemistry.
`
`I reserve the right to testify about
`
`these materials and experience.
`
`As I discuss below,
`
`I disagree with Dr.
`
`Lawrence’s conclusions that the claims of the ’290 patent are invalid based on
`
`obviousness.
`
`III. LEGAL PRINCIPLES
`
`11.
`
`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
`
`claimed subject matter, the level of ordinary skill in the art, and objective indicia of
`
`non-obviousness, such as unexpected results, acclaim 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.
`
`1 I understand that Dr. Laskar is InnoPharma and Lupin’s expert in IPR20l5-
`
`00903 regarding U.S. Patent No. 8,129,431.
`
`5
`
`Page 6 of 58
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`

`
`IV. THE ’290 PATENT
`
`12.
`
`I understand that Lupin has challenged claims 1-30 of the ’290 patent,
`
`EX100l, in this proceeding.
`
`I further understand that the ’29O patent has a priority
`
`date of January 21, 2003.
`
`13. 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 a
`
`pharmacologically acceptable salt or hydrate thereof, and the non-ionic surfactant
`
`tyloxapol.
`
`(EX100l at Abstract; claims 1-30.)
`
`The ’290 patent has three
`
`independent claims (claims 1, 8 and 14) and 27 dependent claims (claims 2-7, 9-13
`
`and 15-30).
`
`14.
`
`Independent claim 1 of the ’290 patent is directed, generally speaking,
`
`to a stable aqueous liquid preparation comprising two components, where 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
`
`and 3/2 hydrate, where the first component is the sole pharmaceutical active
`
`ingredient contained in the preparation, and where the second component
`
`is
`
`tyloxapol 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. (EXl00l at claim 1.)
`
`Page 7 of 58
`
`

`
`15. Dependent claim 2 of the ’290 patent is directed, generally speaking, to
`
`the aqueous liquid preparation of claim 1,
`
`further comprising a quaternary
`
`ammonium salt. (EX1001 at claim 2.)
`
`16. Dependent claim 3 of the ’290 patent is directed, generally speaking, to
`
`the aqueous liquid preparation of claim 1, where the first component
`
`is a
`
`bromfenac sodium salt. (EX1001 at claim 3.)
`
`17. Dependent claim 4 of the ’290 patent is directed, generally speaking, to
`
`the aqueous liquid preparation of claim 1, where the concentration of tyloxapol is
`
`from about 0.01 w/v% to about 0.05 w/V %, where the first component is a
`
`bromfenac sodium salt, and where the concentration of the bromfenac sodium salt
`
`is from about 0.01 to about 0.2 w/v%. (EX1001 at claim 4.)
`
`18. Dependent claim 5 of the ’290 patent is directed, generally speaking, to
`
`the aqueous liquid preparation of claim 4, where the concentration of the
`
`bromfenac sodium salt is about 0.1 w/v %. (EX1001 at claim 5.)
`
`19. Dependent claim 6 of the ’290 patent is directed, generally speaking, to
`
`the aqueous liquid preparation of claim 1, where the pH is from about 7.5 to about
`
`8.5. (EX1001 at claim 6.)
`
`20. Dependent claim 7 of the ’290 patent is directed, generally speaking, to
`
`the stable aqueous liquid preparation of claim 1, where the stable aqueous liquid
`
`preparation consists ‘essentially of (a) bromfenac sodium salt, (b) tyloxapol, (c)
`
`Page 8 of 58
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`

`
`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 7 is formulated for ophthalmic administration. The
`
`concentration of the bromfenac sodium salt in the stable aqueous liquid preparation
`
`of claim 7 is from about 0.02 w/V % to about 0.1 W/V %. (EX1001 at claim 7.)
`
`21.
`
`Independent claim 8 of the ’290 patent is directed, generally speaking,
`
`to a stable aqueous liquid preparation comprising two components, where 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
`
`and 3/2 hydrate, where the first component is the sole pharmaceutical active
`
`ingredient contained in the preparation, and where 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.
`
`(EXIOO l at claim 8.)
`
`22. Dependent claim 9 of the ’29O patent is directed, generally speaking, to
`
`the aqueous liquid preparation of claim 8,
`
`further comprising a quaternary
`
`ammonium salt. (EXl001 at claim 9.)
`
`23. Dependent claim 10 of the ’290 patent is directed, generally speaking,
`
`to the stable aqueous liquid preparation of claim 8, where the stable aqueous liquid
`
`Page 9 of 58
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`

`
`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. (EXlO01 at claim 10.)
`
`24. Dependent claim 11 of the ’290 patent is directed, generally speaking,
`
`to the aqueous liquid preparation of claim 8, where the concentration of tyloxapol
`
`is from about 0.01 w/v % to about 0.05 w/v %, where the first component is a
`
`bromfenac sodium salt, and where the concentration of the bromfenac sodium salt
`
`is from about 0.01 to about 0.2 w/v%. (EX1001 at claim 11.)
`
`25. Dependent claim 12 of the ’290 patent is directed, generally speaking,
`
`to the aqueous liquid preparation of claim 11, where the pH is from about 7.5 to
`
`about 8.5. (EX1001 at claim 12.)
`
`26. Dependent claim 13 of the ’290 patent is directed, generally speaking,
`
`to the stable aqueous liquid preparation of claim 8, where 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,
`
`((1) sodium
`
`tetraborate,
`
`(e)
`
`EDTA sodium salt,
`
`(1)
`
`benzalkonium chloride,
`
`(g)
`
`polyvinylpyrrolidone, and (h) sodium sulfite. The concentration of the bromfenac
`
`sodium salt in the stable aqueous liquid preparation of claim 13 is from about 0.02
`
`w/v % to about 0.1 w/v %. (EXl00l at claim 13.)
`
`Page 10 of 58
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`

`
`27.
`
`Independent claim 14 of the ’290 patent is directed, generally speaking,
`
`to a stable aqueous liquid preparation comprising two components, where 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, l hydrate
`
`and 3/2 hydrate, where the first component is the sole pharmaceutical active
`
`ingredient contained in the preparation, and where the second component
`
`is
`
`tyloxapol. The stable aqueous liquid preparation of claim 14 is formulated for
`
`ophthalmic administration and does not include mannitol. (EXl001 at claim 14.)
`
`28. Dependent claim 15 of the ’290 patent is directed, generally speaking,
`
`to the aqueous liquid preparation of claim 14, further comprising a quaternary
`
`ammonium salt. (EX100l at claim 15.)
`
`29. Dependent claim 16 of the ’290 patent is directed, generally speaking,
`
`to the aqueous liquid preparation of claim 14, where the first component is a
`
`bromfenac sodium salt. (EXl001 at claim 16.)
`
`30. Dependent claim 17 of the ’290 patent is directed, generally speaking,
`
`to the aqueous liquid preparation of claim 16, where the concentration of tyloxapol
`
`is from about 0.01 w/v % to about 0.05 w/v % and the concentration of bromfenac
`
`sodium salt is from about 0.05 to about 0.2 w/v %. (EX100l at claim 17.)
`
`Page 11 of 58
`
`10
`
`

`
`31. Dependent claim 18 of the ’290 patent is directed, generally speaking,
`
`to the aqueous liquid preparation of claim 17, where the pH is from about 7.5 to
`
`about 8.5. (EX1001 at claim 18.)
`
`32. Dependent claim 19 of the ’290 patent is directed, generally speaking,
`
`to the stable aqueous liquid preparation of claim 14, where 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,
`
`((1)
`
`sodium tetraborate,
`
`(e) EDTA sodium salt,
`
`(f) benzalkonium chloride,
`
`(g)
`
`polyvinylpyrrolidone, and (h) sodium sulfite. The concentration of the brornfenac
`
`sodium salt in the stable aqueous liquid preparation of claim 19 is from about 0.02
`
`w/v % to about 0.1 w/V %. (EX1001 at claim 19.)
`
`33. Dependent claim 20 of the ’290 patent is directed, generally speaking,
`
`to the stable aqueous liquid preparation of claim 14, where 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 claim 20.)
`
`34. Dependent claim 21 of the ’290 patent is directed, generally speaking,
`
`to the aqueous liquid preparation of claim 20, further comprising a quaternary
`
`ammonium salt. (EX1001 at claim 21.)
`
`Page 12 of 58
`
`11
`
`

`
`35. Dependent claim 22 of the ’290 patent is directed, generally speaking,
`
`to the stable aqueous liquid preparation of claim 20, where 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. (EXl00l at claim 22.)
`
`36. Dependent claim 23 of the ’290 patent is directed, generally speaking,
`
`to the aqueous liquid preparation of claim 20, where the concentration of tyloxapol
`
`is from about 0.01 W/v % to about 0.05 w/v %, where the first component is a
`
`bromfenac sodium salt, and where the concentration of the bromfenac sodium salt
`
`is from about 0.01 to about 0.2 w/v%. (EX100l at claim 23.)
`
`37. Dependent claim 24 of the ’290 patent is directed, generally speaking,
`
`to the stable aqueous liquid preparation of claim 23, where the pH is from about
`
`7.5 to about 8.5. (EXl001 at claim 24.)
`
`38. Dependent claim 25 of the ’290 patent is directed, generally speaking,
`
`to the stable aqueous liquid preparation of claim 20, where 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,
`
`(0 benzalkonium chloride,
`
`(g)
`
`polyvinylpyrrolidone, and (h)
`
`sodium sulfite.
`
`The stable aqueous
`
`liquid
`
`Page 13 of 58
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`12
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`

`
`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 claim 25.)
`
`39. Dependent claims 26-30 of the ’290 patent are directed, generally
`
`speaking,
`
`to the aqueous liquid preparations of claims 1, 8, 14, 20, and 22,
`
`respectively, where 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 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 claims 26-30.)
`
`V.
`
`SUMMARY OF OPINIONS
`
`40.
`
`I understand that the Board has granted Lupin’s petition to institute this
`
`IPR regarding the purported obviousness of claims 1-30 of the ’290 patent on the
`
`following ground:
`
`9 Obviousness of claims 1-30 over U.S. Patent No. 5,891,913
`
`(“Sallmann”)
`
`(EX102l)
`
`in View of U.S. Patent No. 4,910,225
`
`(“Ogawa”) (EXl0l0)
`
`13
`
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`
`41. As discussed further below, it is my opinion that a person of ordinary
`
`skill in the art would have had no reason to combine the disclosures of Sallmann
`
`and Ogawa as Dr. Lawrence contends, to arrive at the claimed preparations of
`
`the ’290 patent. Ogawa teaches the use of sodium sulfite, a well—known
`
`antioxidant (EX2036 at 5), to chemically stabilize bromfenac from degradation and
`
`prevent the formation of red insoluble matters. (EXl0l0 at Experimental Example
`
`6.)2 Indeed, colored degradation products are typical of oxidation reactions.
`
`(EX2l04 at 525, 530-31.) A person of ordinary skill in the art would have readily
`
`understood,
`
`therefore, that oxidation caused bromfenac’s degradation and that
`
`Ogawa solved this problem using sodium sulfite.3 (See EX2036 at 5.) _
`
`2
`
`_ _ _
`
`3 There is no evidence in Ogawa that sodium edetate impacts bromfenac’s
`
`chemical stability.
`
`(See, e.g., EXIOIO.) Dr. Lawrence states that “[c]helating
`
`agents are added to complex with alkaline earth and heavy-metal ions that are
`
`known to cause toxicity in the eye as well as ensuring preservative efficacy and
`
`chemical stability.” (EXIOOS at ‘][‘][ 184, 241.) I disagree. Chelating agents such as
`
`sodium edetate are highly oxidized and thus unlikely to act as anti-oxidants. Thus,
`
`chelating agents would not be expected to impact the chemical stability of a drug,
`
`Page 15 of 58
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`14
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`

`
`— There is no teaching in Osawa of the
`
`formation of any salt or any “complex” between bromfenac and BAC, contrary to
`
`Dr. Lawrence’s argument.
`
`(EXIOOS at ‘I 83.) Rather, Ogawa discloses only the
`
`precipitation of a red insoluble oxidative degradation product.
`
`(EX1010 at
`
`Experimental Examples 4-6.)
`
`42. Sallmann is directed to formulations of diclofenac potassium in
`
`particular and contains no teaching that diclofenac is susceptible to chemical
`
`degradation. (EX1021 at 1:1 - 3226.) Thus, as discussed further below, a person of
`
`ordinary skill in the art would not have been motivated to combine Ogawa and
`
`Sallmann, because these references relate to different active ingredients and
`
`provide different solutions to entirely unrelated problems.
`
`VI.
`
`STATEMENT OF OPINIONS EXPRESSED AND BASES AND
`
`REASONS THEREFOR
`
`A.
`
`The Level of Skill in the Art
`
`43. As of January 21, 2003, a person of ordinary skill in the art would have
`
`at least a Bachelor’s degree in a field such as chemistry, chemical engineering,
`
`like bromfenac, that degrades by oxidation. Indeed, Experimental Examples 4-d
`
`demonstrate that disodium edetate had no effect on bromfenac’s oxidation.
`
`(’225
`
`patent at Experimental Examples 4-6.)
`
`15
`
`Page 16 of 58
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`

`
`pharmaceutical sciences or a related discipline with about three to five years of
`
`work experience in this area, or a comparable level of education and training.
`
`B.
`
`Bromfenac is Structurally and Chemically Dissimilar to
`Diclofenac, Ketorolac and Pranlukast
`
`44. Dr. Lawrence states that “bromfenac has certain structural similarities
`
`with other NSAIDs, including diclofenac, ketorolac, and flurbiprofen. Each of
`
`these NSAIDS has a carboxylic acid group (—COOH) on an aryl ring.”4 (EX1005 at
`
`‘][ 95.) The physical, chemical, and biological properties of molecules containing
`
`multiple functional groups do not depend solely on the characteristics of one of
`
`those functional groups. Rather, these properties depend on complex interactions
`
`between all the functional groups present in the molecule and their disposition
`
`relative to each other. As discussed further below, it is a gross oversimplification
`
`4 Dr. Lawrence mischaracterizes the chemical structure of bromfenac,
`
`diclofenac, ketorolac, and flurbiprofen. She incorrectly states that bromfenac,
`
`diclofenac, ketorolac, and flurbiprofen each have “a carboxylic acid group (-
`
`COOH) on an aryl ring.” (EX1005 at ‘[1 95.)
`
`In fact, the carboxylic acid group in
`
`these molecules is on a side—chain and not directly attached to the aryl group. This
`
`is an important structural difference that would impact the biological, chemical,
`
`and physical properties of the molecules.
`
`16
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`Page 17 of 58
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`to suggest that all carboxylic acids will behave similarly or will have similar
`
`properties.
`
`1.
`
`Comparison of Bromfenac and Diclofenac
`
`45. Ogawa is directed to bromfenac formulations.
`
`(EX1010 at 2:45 -
`
`3:15.) Sallmann is directed to diclofenac potassium formulations.
`
`(EX1021 at 1:1
`
`— 3:26.) Dr. Lawrence states that a person of ordinary skill in the art would have
`
`had a reason to combine the disclosures of Ogawa and Sallmann. In particular, Dr.
`
`Lawrence states
`
`that “[d]iclofenac and bromfenac are both NSAIDs and
`
`structurally similar.
`
`In my view, and as discussed above, it would have been
`
`obvious to substitute bromfenac for diclofenac in a formulation containing
`
`tyloxapol and have an expectation that the formulation would maintain required
`
`stability.” (EXl0O5 at ‘]I 257.)
`
`I disagree. As discussed below, bromfenac and
`
`diclofenac are structurally and chemically dissimilar in numerous important
`
`respects.
`
`46. As shown in Table 1 below, bromfenac is a derivative of amfenac,
`
`whereas diclofenac is not.
`
`In fact, bromfenac and diclofenac have completely
`
`different base structures.
`
`Page 18 of 58
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`17
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`
`
`hm otmcum omlcnotonac
`
`'“°'°'°"'°
`
`Table 1.
`
`47. Table 2 below depicts the chemical structures of bromfenac and
`
`diclofenac .
`
`diclofenac
`
`Table 2.
`
`48. Bromfenac and diclofenac differ significantly in their structure and
`
`three-dimensional shape.
`
`Page 19 of 58
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`18
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` Important differences
`
`in structure between bromfenac and diclofenac include:
`
`0
`
`0
`
`0
`
`0
`
`Bromfenac and diclofenac are derivatives of different base
`
`structures, as noted above.
`
`Bromfcstac is :1 primary amine (NH2 group), whereas diclofenac
`is a secondary amine (NI-I group).5
`
`Bromfenac has a 4—bromobenznvl group attached adjacent to
`the NH; group, whereas diclofenac has a 2,5-dichlorophenyl
`group attached directly to the NH group.
`
`Bromfenac has a carbonyl (C=O) group, whereas diclofenac
`does not.6
`
`A person of ordinary skill in the art would expect these differences to lead to
`
`significantly different functional and chemical properties, as discussed below. I
`
`I I
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`Page 20 of 58
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`49. For example, the electron density distribution will vary significantly
`
`between bromfenac and diclofenac based on their different chemical structures,
`
`leading to different hydrogen bonding abilities. Specifically, a person of ordinary
`
`skill in the art would expect the different amino groups in bromfenac (NH2) and
`
`diclofenac (NH) to have different basicities and different hydrogen bonding
`
`abilities.
`
`(EX2l0l at 919.) Moreover, in bromfenac, the aniline fragment bears
`
`only one (benzoyl) electron withdrawing substituent whereas in diclofenac the
`
`aniline fragment bears three (aryl and 2 chlorine atoms) electron withdrawing
`
`substituents, as shown highlighted below.
`
`bromfenac
`
`50. A person of ordinary skill in the art would also expect the different
`
`distributions of heteroatoms;
`
`i.e., atoms other than carbon,
`
`in bromfenac and
`
`diclofenac to lead to different hydrogen bonding abilities. A person of ordinary
`
`skill in the art would expect different hydrogen bonding abilities to result in
`
`different lipophilicities and solubilities in water.
`
`(EX2l56 at 43-49; EX2040 at 8-
`
`9.)
`
`Page 21 of 58
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`20
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`51.
`
`In fact, bromfenac contains more strong hydrogen bonding sites than
`
`diclofenac, particularly its carbonyl group, as shown in red below:
`
`diclofenac
`
`bromfenac
`
`52. The ability to form strong hydrogen bonds impacts solvation and how
`
`solvated the molecule is in an aqueous solution. Specifically, solvation occurs by
`
`intermolecular interactions, including hydrogen bonding. Because bromfenac has
`
`more strong hydrogen bonding sites than diclofenac, a person of ordinary skill in
`
`the art would expect the bromfenac ion to be better solvated than the diclofenac ion.
`
`A better solvated ion is more likely to stay in solution and less likely to form
`
`insoluble salts or precipitates (EX2072 at 403-04), such as the “complex” that Dr.
`
`Lawrence alleges is formed between NSAIDS and BAC. (EXl005 at ‘l[ 83.)
`
`53. Furthermore, a person of ordinary skill
`
`in the art would expect
`
`bromfenac’s single bromine on its aromatic ring versus dic1ofenac’s two chlorines
`
`on its aromatic ring to impact the polarity of the two molecules. Polarity also
`
`impacts solvation. (EX2099 at 170-71.) Because a person of ordinary skill in the
`
`Page 22 of 58
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`21
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`art would expect bromfenac to have more polar regions than diclofenac, he or she
`
`would also expect bromfenac to be less likely to form insoluble salts or precipitates.
`
`(Id.)
`
`54. Bromfenac and diclofenac also have significantly different
`
`three-
`
`dimensional structures, as shown below.
`
`In bromfenac, the brominated aromatic
`
`ring is approximately in the same plane as the rest of the molecule.
`
`In diclofenac,
`
`the nitrogen is very sterically hindered, due to the presence of the dual chlorine
`
`atoms, and the chlorinated phenyl group is approximately at a right angle to the
`
`plane of the rest of the molecule. Differences in three-dimensional structure
`
`impact molecular interactions in the solid state. (EX2246 at 660.) In solution such
`
`differences also affect the pharmacological properties of molecules, as well as the
`
`solubility of their various salts, as set forth in Lipinski’s rules.
`
`(EX2l56 at 37-38,
`
`43-49; EX2040 at 8-9.)
`
`h.
`
`‘\
`
`~ z zfz‘ .5 ‘gig
`
`.{.m_,
`..
`
`K
`
`3D Structures of bromfenac (left) and diclofenac (right). For bromfenac the 3D co-ordinates
`were generated using MM2 refinement within the Chem3D package; for diclofenac the 3D co-
`
`Page 23 of 58
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`22
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`

`
`ordinates were obtained from X-ray crystal structure data downloaded from the Cambridge
`crystallographic Database.
`
`55. Furthermore, I disagree with Dr. Lawrence’s statement that “[o]ther
`
`references disclosed that polysorbate
`
`80 and tyloxapol
`
`could be used
`
`interchangeably in formulations and/or
`
`that
`
`tyloxapol was preferred over
`
`polysorbate 80,” citing EXIO67, EX1068, EX1039, EXIO69, EX1070, EX1071,
`
`and EXlO72.
`
`(EX1005 at ‘][ 136.) Almost all of the references cited by Dr.
`
`Lawrence are directed to suspensions or emulsions, which are different from
`
`solutions such as the aqueous liquid preparations of the ’290 patent. (See EXl067,
`
`EX1068, EXIO69, EXl070 and EX1071.) EX1039 is directed to tobramycin and
`
`diclofenac formulations, not bromfenac formulations.
`
`(EX1039 at 2:38-59.)
`
`EXl072 is directed to the physiological activity of multitudes of non-ionic
`
`surfactants and contains no disclosure regarding the use of non-ionic surfactants in
`
`ophthalmic formulations.
`
`(EX 1072). None of these references provides any
`
`evidence whatsoever that bromfenac needs to be or can be solubilized by
`
`polysorbate 80 or tyloxapol.
`
`56.
`
`In fact, as discussed above, because of bromfenac’s hydrogen bonding
`
`ability, a person of ordinary skill in the art would have no reason to assume,
`
`without testing, that bromfenac would form a precipitate with BAC requiring a
`
`solubilizer to prevent.
`
`In addition, the sodium salt of bromfenac is freely water-
`
`soluble (EX2248 at 29, left column; EX2140 at 33:1-9), and thus any solubilizing
`
`Page 24 of 58
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`23
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`effect of polysorbate 80 or tyloxapol would not be required to dissolve or
`
`solubilize bromfenac sodium.
`
`Indeed, Dr. Lawrence unequivocally stated, in a
`
`peer-reviewed prior art publication that “it is
`
`no use trying to increase the aqueous solubility of a water-soluble hydrophilic drug
`
`in an aqueous-based surfactant system.” (EX2l39 at 423;_.) I
`
`agree with Dr. Lawrence that a person of ordinary skill in the art would have had
`
`no reason to try to solubilize an already water-soluble hydrophilic drug such as the
`
`sodium salt of bromfenac by using an aqueous-based surfactant such as tyloxapol.
`
`2.
`
`Comparison of Bromfenac and Ketorolac
`
`57.
`
`I further disagree with Dr. Lawrence’s opinion that “EP ’984 taught
`
`that non-ionic surfactants in the ethoxylated octylphenol class, such as Octoxynol 9
`
`and Octoxynol 40 can stabilize an aqueous NSAID formulation containing BAC,
`
`even in the absence of PVP or a sulfite.” (EXl005 at ‘I 85.) EP 0 306 984 Al
`
`(“Fu”)
`
`discloses
`
`formulations
`
`containing
`
`the
`
`specific NSAID ketorolac
`
`tromethamine, not NSAIDs generally, with Octoxynol 40, not Octoxynol 9 as Dr.
`
`Lawrence contends.
`
`(EX1014 at 6-9.) As discussed below, bromfenac and
`
`ketorolac are structurally and chemically dissimilar in numerous respects. Table 3
`
`below depicts the chemical structures of bromfenac and ketorolac.
`
`Page 25 of 58
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`24
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`O
`
`NH2
`
`0
`
`O D 0
`
`Br
`
`W 0
`
`bromfenac
`
`ketorolac
`
`Table 3.
`
`58. Bromfenac and ketorolac differ significantly in their structure and
`
`three-dimensional shape.
`
`— _ Important differences in
`
`structure between bromfenac and ketorolac include:
`
`0
`
`0
`
`0
`
`I
`
`-
`
`Unlike bromfenac, ketorolac is not a derivative of amfenac.
`
`Bromfenac is a primary amine (NH; group), whereas ketorolac
`is a tertiary amine (NR3 group).
`
`Bromfenac has a 4-bromo