UNITED STATES PATENT AND TRADEMARK OFFICE
`
`BEFORE THE PATENT TRIAL AND APPEAL BOARD
`
`LUPIN LTD. and LUPIN PHARMACEUTICALS INC.
`
`Petitioner,
`
`V.
`
`SENJU PHARMACEUTICAL C0,, LTD.,
`Patent Owner.
`
`Case IPR2015-01100
`
`Patent 8,927,606
`
`DECLARATION OF STEPHEN G. DAVIES, D.Phil.
`
`Page 1 of 59
`
`SENJU EXHIBIT 2105
`
`LUPIN v SENJU
`IPR2015-01100
`
`

`
`Table of Contents
`
`I.
`
`BACKGROUND AND QUALIFICATIONS .............................................. .. 2
`
`II.
`
`INFORMATION CONSIDERED ................................................................ .. 4
`
`III.
`
`LEGAL PRINCIPLES .................................................................................. .. 5
`
`IV.
`
`THE ’606 PATENT ...................................................................................... .. 6
`
`V.
`
`SUMMARY OF OPINIONS ...................................................................... .. 14
`
`VI.
`
`STATEMENT OF OPINIONS EXPRESSED AND BASES AND
`
`REASONS THEREFOR ............................................................................. .. 16
`
`A.
`
`The Level of Skill in the Art ............................................................. .- 16
`
`B.
`
`Bromfenac is Structurally and Chemically Dissimilar to
`Diclofenac, Ketorolac and Pranlukast .............................................. .. 16
`
`C.
`
`D.
`
`1.
`
`2.
`
`3.
`
`Comparison of Bromfenac and Diclofenac ............................ .. 17
`
`Comparison of Bromfenac and Ketorolac .............................. .. 25
`
`Comparison of Bromfenac and Pranlukast ............................ .. 29
`
`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 ................................................................... .. 38
`
`1.
`
`2.
`
`Comparison of Polysorbate 80 and Tyloxapol ....................... .. 38
`
`Comparison of Octoxynol 9, Octoxynol 40 and
`Tyloxapol................................................................................ .. 43
`
`E.
`
`Cyclodextrins May Impact the Stability of the Claimed
`Bromfenac Formulations .................................................................. .. 49
`
`VII. NON-OBVIOUSNESS OF THE CLAIMS OF THE ’606 PATENT ........ .. 50
`
`VIII. CONCLUSION ........................................................................................... .. 52
`
`Page 2 of 59
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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—doctora1
`
`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. Sc. 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 59
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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 for 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 59
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`

`
`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. 8,927,606 (“the ’606 patent”),
`
`the “Petition for Inter Partes
`
`Review of U.S. Patent No. 8,669,606” (“Petition”) and Exhibits to the Petition,
`
`including the declaration of Dr. Jayne Lawrence (EXl005).
`
`I have also reviewed
`
`the transcript of Dr. Lawrence’s cross examination (EX23l6).
`
`I have also
`
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`
`reviewed the transcript of Dr. Laskar’s cross examination in IPR20l5-00902 and
`
`IPR20l5-00903 (EX2114) '
`
`.
`
`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 ’606 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 ’606 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 IPR2015-00902
`regarding U.S. Patent No. 8,669,290 (“the ’290 patent”) and IPR2015-00903
`regarding U.S. Patent No. 8,129,431 (“the ’431 patent”).
`
`5
`
`Page 6 of 59
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`

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`IV. THE ’606 PATENT
`
`1.
`
`I understand that Lupin has challenged claims 1-30 of the ’606 patent,
`
`EX1004, in this proceeding. 1 further understand that the ’606 patent has a priority
`
`date of January 21, 2003.
`
`2.
`
`The ’606 patent is directed, generally speaking, to methods for treating
`
`an inflammatory disease of an eye, the method comprising administering to said
`
`eye a stable aqueous liquid preparations comprising the non-steroidal anti-
`
`inflammatory drug (“NSAID”) 2-amino-3-(4—bromobenzoyl)phenylacetic acid
`
`(“bromfenac”), or a pharrnacologically acceptable salt or hydrate thereof, and the
`
`non-ionic surfactant tyloxapol.
`
`(EX1004 at Abstract; claims 1-30.) The ’606
`
`patent has three independent claims (claims 1, 11 and 19) and 27 dependent claims
`
`(claims 2-10, 12-18 and 20-30).
`
`3.
`
`Independent claim 1 of the ’606 patent is directed, generally speaking,
`
`to a method for
`
`treating an inflammatory disease of an eye, comprising
`
`administering to the eye a stable aqueous liquid preparation that comprises two
`
`components, wherein the first component is brornfenac or a pharmacologically
`
`acceptable salt or hydrate of bromfenac, wherein the hydrate is at least one selected
`
`from a 1/2 hydrate, 1 hydrate and 3/2 hydrate, wherein the first component is the
`
`sole pharmaceutical active ingredient contained in the preparation, and wherein the
`
`second component is tyloxapol and is present in the aqueous liquid preparation in
`
`Page 7 of 59
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`an amount sufficient to stabilize the first component. The stable aqueous liquid
`
`preparation of the method of claim 1 is formulated for ophthalmic administration
`
`and is administered to the eye at a dose and a frequency effective to treat the
`
`inflammatory disease. (EX1004 at claim 1.)
`
`4.
`
`Dependent claim 2 of the ’606 patent is directed, generally speaking, to
`
`the method of claim 1, wherein the inflammatory disease is a disease of an anterior
`
`or posterior segment of the eye. (EX1004 at claim 2.)
`
`5.
`
`Dependent claim 3 of the ’606 patent is directed, generally speaking, to
`
`the method of claim 2, wherein the disease is postoperative inflammation.
`
`(EX1004 at claim 3.)
`
`6.
`
`Dependent claim 4 of the ’606 patent is directed, generally speaking, to
`
`the method of claim 1, wherein the first component is a bromfenac sodium salt.
`
`(EX1004 at claim 4.)
`
`7.
`
`Dependent claim 5 of the ’606 patent is directed, generally speaking, to
`
`the method of claim 1, wherein the concentration of tyloxapol is from about 0.01
`
`w/V % to about 0.05 w/v %, the first component is a bromfenac sodium salt, and
`
`the concentration of bromfenac sodium salt is from about 0.01 to about 0.2 w/v%.
`
`(EX1004 at claim 5.)
`
`Page 8 of 59
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`
`8.
`
`Dependent claim 6 of the ’606 patent is directed, generally speaking, to
`
`the method of claim 5, wherein the concentration of bromfenac sodium salt is from
`
`about 0.02 w/V % to about 0.1 w/v %. (EX1004 at claim 6.)
`
`9.
`
`Dependent claim 7 of the ’606 patent is directed, generally speaking, to
`
`the method of claim 5, wherein the aqueous liquid preparation further comprises a
`
`quaternary ammonium salt. (EX1004 at claim 7.)
`
`l0. Dependent claim 8 of the ’606 patent is directed, generally speaking, to
`
`the method of claim 5, wherein the concentration of bromfenac sodium salt is
`
`about 0.1 w/v %. (EX1004 at claim 8.)
`
`11. Dependent claim 9 of the ’606 patent is directed, generally speaking, to
`
`the method of claim 1, wherein the stable aqueous liquid preparation consists
`
`essentially of (a) bromfenac sodium salt, (d) sodium tetraborate, (e) EDTA sodium
`
`salt, (f) benzalkonium chloride, (g) polyvinylpyrrolidone, and (h) sodium sulfite.
`
`The stable aqueous liquid preparation "of the method of claim 9 is formulated for
`
`ophthalmic administration, and the concentration of the bromfenac sodium salt in
`
`the stable aqueous liquid preparation of the method of claim 9 is from about 0.02
`
`w/v % to about 0.1 w/v %. (EX1004 at claim 9.)
`
`12. Dependent claim 10 of the ’606 patent is directed, generally speaking,
`
`to the method of claim 1, wherein the dose comprises one or two drops.
`
`(EX1004
`
`at claim 10.)
`
`Page 9 of 59
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`
`13.
`
`Independent claim 11 of the ’606 patent is directed, generally speaking,
`
`to a method for
`
`treating an inflammatory disease of an eye comprising
`
`administering to the eye a stable aqueous liquid preparation that comprises two
`
`components, wherein the first component is bromfenac or a pharmacologically
`
`acceptable salt or hydrate of bromfenac, wherein the hydrate is at least one selected
`
`from a 1/2 hydrate, 1 hydrate and 3/2 hydrate, wherein the first component is the
`
`sole pharmaceutical active ingredient contained in the preparation, and wherein the
`
`second component is tyloxapol. The stable aqueous liquid preparation of the
`
`method of claim 11 is formulated for ophthalmic administration, 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, and is administered to
`
`the eye at a dose and a frequency effective to treat the inflammatory disease.
`
`(EXIOO4 at claim 1 1.)
`
`14. Dependent claim 12 of the ’606 patent is directed, generally speaking,
`
`to the method of claim 11, wherein the stable aqueous liquid preparation of the
`
`method of claim 12 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.
`
`(EXIOO4 at claim 12.)
`
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`15. Dependent claim 13 of the ’606 patent is directed, generally speaking,
`
`to the method of claim 11, wherein the inflammatory disease is a disease of an
`
`anterior or posterior segment of said eye. (EXIOO4 at claim 13.)
`
`16. Dependent claim 14 of the ’606 patent is directed, generally speaking,
`
`to the method of claim 13, wherein the disease is postoperative inflammation.
`
`(EXIOO4 at claim 14.)
`
`17. Dependent claim 15 of the ’606 patent is directed, generally speaking,
`
`to the method of claim 11, wherein the concentration of tyloxapol is from about
`
`0.01 w/v % to about 0.05 w/v %, the first component is a bromfenac sodium salt,
`
`and the concentration of bromfenac sodium salt is from about 0.01 to about 0.2
`
`w/v%.
`
`(EX1004 at claim 15.)
`
`18. Dependent claim 16 of the ’606 patent is directed, generally speaking,
`
`to the method of claim 15, wherein the concentration of bromfenac sodium salt is
`
`from about 0.02 to about 0.1 w/v%. (EXl004 at claim 16.)
`
`19. Dependent claim 17 of the ’606 patent is directed, generally speaking,
`
`to the method of claim 11, wherein the stable aqueous liquid preparation further
`
`comprises a quaternary ammonium salt. (EX1004 at claim 17.)
`
`20. Dependent claim 18 of the ’606 patent is directed, generally speaking,
`
`to the method of claim 11, wherein the stable aqueous liquid preparation consists
`
`essentially of (a) bromfenac or a pharmacologically acceptable salt or hydrate of
`
`Page 11 of 59
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`10
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`
`bromfenac, wherein the hydrate is at least one selected from a 1/2 hydrate,
`
`1
`
`hydrate and 3/2 hydrate, (b) tyloxapol, (c) boric acid, (d) sodium tetraborate, (e)
`
`EDTA sodium salt, (f) benzalkonium chloride, (g) polyvinylpyrrolidone, and (h)
`
`sodium sulfite. The concentration of bromfenac sodium salt in the stable aqueous
`
`liquid preparation of the method of claim 18 is from about 0.02 w/v % to about 0.1
`
`w/v %. (EX1004 at claim 18.)
`
`21.
`
`Independent claim 19 of the ’606 patent is directed, generally speaking,
`
`to a method for
`
`treating an inflammatory disease of an eye comprising
`
`administering to the eye a stable aqueous liquid preparation that comprises 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, l hydrate and 3/2 hydrate, wherein the first component is the
`
`sole pharmaceutical active ingredient contained in the preparation, and wherein the
`
`second component is tyloxapol. The stable liquid preparation of the method of
`
`claim 19 is formulated for ophthalmic administration, does not include mannitol,
`
`and is administered at a dose and a frequency effective to treat the inflammatory
`
`disease. (EX1004 at claim 19.)
`
`22. Dependent claim 20 of the ’606 patent is directed, generally speaking,
`
`to the method of claim 19, wherein the inflammatory disease is a disease of an
`
`anterior or posterior segment of said eye. (EX 1004 at claim 20.)
`
`Page 12 of 59
`
`11
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`

`
`23. Dependent claim 21 of the ’606 patent is directed, generally speaking,
`
`to the method of claim 20, wherein the disease is postoperative inflammation.
`
`(EX1004 at claim 21.)
`
`24. Dependent claim 22 of the ’606 patent is directed, generally speaking,
`
`to the method of claim 19, wherein the first component is a bron1fenac sodium salt.
`
`(EX1004 at claim 22.)
`
`25. Dependent claim 23 of the ’606 patent is directed, generally speaking,
`
`to the method of claim 22, 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 0.2 w/v %. (EX1004 at claim 23.)
`
`26. Dependent claim 24 of the ’606 patent is directed, generally speaking,
`
`to the method of claim 22, wherein the concentration of the bromfenac sodium salt
`
`is from about 0.02 to about 0.1 w/V %. (EX1004 at claim 24.)
`
`27. Dependent claim 25 of the ’606 patent is directed, generally speaking,
`
`to the method of claim 20, wherein the stable aqueous liquid preparation consists
`
`essentially of (a) bromfenac or a pharmacologically acceptable salt or hydrate of
`
`bromfenac, wherein the hydrate is at least one selected from a 1/2 hydrate,
`
`1
`
`hydrate and 3/2 hydrate, (b) tyloxapol, (c) boric acid, ((1) sodium tetraborate, (e)
`
`EDTA sodium salt, (f) benzalkonium chloride, (g) polyvinylpyrrolidone, and (h)
`
`sodium sulfite. The concentration of bromfenac sodium salt in the stable aqueous
`
`Page 13 of 59
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`12
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`

`
`liquid preparation of the method of claim 25 is from about 0.02 w/V % to about 0.1
`
`w/V %. (EX1004 at claim 25.)
`
`28. Dependent claim 26 of the ’606 patent is directed, generally speaking,
`
`to the method of claim 20, wherein the stable aqueous liquid preparation of the
`
`method of claim 26 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. (EX1004 at claim 26.)
`
`29. Dependent claim 27 of the ’606 patent is directed, generally speaking,
`
`to the method of claim 20, wherein the concentration of tyloxapol is from about
`
`0.01 w/v % to about 0.05 w/v %, the first component is a bromfenac sodium salt,
`
`and the concentration of bromfenac sodium salt in is from about 0.02 to about 0.1
`
`w/v%. (EX1004 at claim 27.)
`
`30. Dependent claims 28-30 of the ’606 patent are directed, generally
`
`speaking, to the methods of claims 1, 11 and 19, respectively, wherein the aqueous
`
`liquid preparation 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
`
`Page 14 of 59
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`13
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`
`inoculation decreases to not more than 1/10, and thereafter, the cell count keeps the
`
`same level as that of 14 days after inoculation. (EX1004 at claims 28-30.)
`
`V.
`
`SUMMARY OF OPINIONS
`
`31.
`
`I understand that the Board has granted Lupin’s petition to institute this
`
`IPR regarding the purported obviousness of claims 1-30 of the ’606 patent on the
`
`following ground:
`
`0 Obviousness of claims 1-30 over U.S. Patent No. 5,891,913
`
`(“Sallmarm”)
`
`(EXl02l) in view of U.S. Patent No. 4,910,225
`
`(“Ogawa”) (EXIOIO)
`
`32. 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 ’606 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. (EX10l0 at Experimental Example
`
`6.)2 Indeed, colored degradation products are typical of oxidation reactions.
`
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`(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.) _
`
`— There is no teaching in Ogawa of the
`
`formation of any salt or any “complex” between bromfenac and BAC, contrary to
`
`Dr. Lawrence’s argument.
`
`(EXl005 at ‘I! 83.) Rather, Ogawa discloses only the
`
`precipitation of a red insoluble oxidative degradation product.
`
`(EXl0lO at
`
`Experimental Examples 4-6.)
`
`3 There is no evidence in Ogawa that sodium edetate impacts bromfenac’s
`
`chemical stability. (See, e.g., EX1010.) 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.” (EXl005 at‘]H 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,
`
`like bromfenac, that degrades by oxidation.
`
`Indeed, Experimental Examples 4-6
`
`demonstrate that disodium edetate had no effect on bromfenac’s oxidation.
`
`(‘Z25
`
`patent at Experimental Examples 4-6.)
`
`15
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`
`33. Sallmann is directed to formulations of diclofenac potassium in
`
`particular and contains no teaching that diclofenac is susceptible to chemical
`
`degradation. (EX102l at 1:1 - 3:26.) 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
`
`34. 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,
`
`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
`
`35. Dr. Lawrence states that “brornfenac 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
`
`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 c-arboxylic acid group (-
`
`Page 17 of 59
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`
`‘][ 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
`
`to suggest that all carboxylic acids will behave similarly or will have similar
`
`properties.
`
`1.
`
`Comparison of Bromfenac and Diclofenac
`
`36. Ogawa is directed to bromfenac formulations.
`
`(EXl010 at 2:45 —
`
`3:15.) Sallmann is directed to diclofenac potassium formulations. (EXl021 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
`
`COOH) on an aryl ring.” (EXl0O5 at ‘][ 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.
`
`17
`
`Page 18 of 59
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`

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`stability.” (EX1005 at ‘][‘][ 257, 600.)
`
`I disagree. As discussed below, bromfenac
`
`and diclofenac are structurally and chemically dissimilar in numerous important
`
`respects.
`
`37. 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.
`
`0
`
`NH;
`
`0
`
`Nr-I2
`
`“H
`
`»
`
`OH
`
`D
`
`Br
`
`r r/
`
`on
`
`0
`
`amfenac
`(bane structure of bromtenac)
`
`bromfenac
`
`/ I
`‘*
`
`NH
`\
`| /
`
`,
`
`OH
`
`c!
`
`/ I
`R‘
`Cl
`
`NH
`\\
`l /
`
`UH
`
`0
`
`base structure of dlclofenac
`
`d'°'°f°"‘°
`
`Table 1.
`
`38. Table 2 below depicts the chemical structures of bromfenac and
`
`diclofenac.
`
`Page 19 of 59
`
`18
`
`

`
`diclofenac
`
`0
`
`NH2
`
`O O
`
`Br
`
`bromfenac
`
`Cl
`
`NH
`
`OH
`
`O
`
`c:
`
`on
`
`0
`
`Table 2.
`
`39. Bromfenac and diclofenac differ significantly in their structure and
`
`three-dimensional shape.
`
`Important differences
`
`in structure between bromfenac and diclofenac include:
`
`0
`
`0
`
`-
`
`Bromfenac and diclofenac are derivatives of different base
`
`structures, as noted above.
`
`Bromfenac is a primary amine (NH; group). Whereas diclofenac
`is a secondary amine (NI-1 gr0up).5
`'
`
`Bromfenac has a 4-bromobenzoyl group attached adjacent to
`the NH; group, whereas diclofenac has a 2,5-dichlorophenyl
`group attached directly to the NH group.
`
`‘
`
`Page 20 of 59
`
`19
`
`

`
`0
`
`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
`
`40. For example, the electron density distribution will vary significantly
`
`between brornfenac 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 brornfenac (NH2) and
`
`diclofenac (NH)
`
`to have different basicities and different hydrogen bonding
`
`abilities.
`
`(EX2101 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.
`
`0‘.
`
`[Q 0
`
`Page 21 of 59
`
`

`
`
`
`41. 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; EX204O at 8-
`
`9-)
`
`42.
`
`In fact, bromfenac contains more strong hydrogen bonding sites than
`
`diclofenac, particularly its carbonyl group, as shown in red below:
`
`bromfenac
`
`43. The ability to form strong hydrogen bonds impacts solvation and how
`
`solvated the molecule is in an aqueous solution. Specifically, solvation occurs by
`
`21
`
`Page 22 of 59
`
`

`
`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. (EXl0O5 at ‘l[ 83.)
`
`44. Furthermore, a person of ordinary skill
`
`in the art would expect
`
`bromfenac’s single bromine on its aromatic ring versus diclofenac’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
`
`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)
`
`45. Brornfenac 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
`
`Page 23 of 59
`
`22
`
`

`
`differences also affect the pharmacological properties of molecules, as well as the
`
`solubility of their various salts, as set forth in Lipinski’s rules.
`
`(EX2156 at 37-38,
`
`43-49; EX2040 at 8-9.)
`
`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-
`ordinates were obtained from X-ray crystal structure data downloaded from the Cambridge
`crystallographic Database.
`
`46. 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.”
`
`(EXl005 at ‘][ 514; see also EXl005 at ‘]I 136 (citing EX1067,
`
`EXl068, EX1039, EX1069, EX1070, EX1071, and EX1072).) 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 ’606
`
`patent.
`
`(See EX1067, EXl068, EXIO69, EXl07O and EX1071.) EX1039 is
`
`directed to tobramycin and diclofenac formulations, not bromfenac formulations.
`
`Page 24 of 59
`
`23
`
`

`
`(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.
`
`(EXl072). None of these
`
`references provides any evidence whatsoever that bromfenac needs to be or can be
`
`solubilized by polysorbate 80 or tyloxapol.
`
`47.
`
`In fact, as discussed above, because of brornfenac’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
`
`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.
`
`Page 25 of 59
`
`24
`
`

`
`2.
`
`Comparison of Bromfenac and Ketorolac
`
`48.
`
`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.” (EX1005 at ‘][ 85.) EP 0 306 984 A1
`
`(“Fu”)
`
`discloses
`
`formulations
`
`containing
`
`the
`
`specific NSAID ketorolac
`
`trometharnine, not NSAIDs generally, with Octoxynol 40, not Octoxynol 9 as Dr.
`
`Lawrence contends.
`
`(EX10l4 at 6-9.) As discussed below, bromfenac and
`
`ketorolac are structurally and chemically dissimilar in numerous respects. Table 3
`
`below depicts the