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 IPR20 15-01097
`Patent 8,154,131
`
`DECLARATION OF STEPHEN G. DAVIES, D.Phil.
`
`Page 1 of 59
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`SENJU EXHIBIT 2105
`LUPIN v SENJU
`IPR2015-01097
`
`

`
`Table of Contents
`
`I.
`
`II.
`
`BACKGROUND AND QUALIFICATIONS ................................................ 2
`
`INFORMATION CONSIDERED .................................................................. 4
`
`III. LEGAL PRINCIPLES ...................................................... .............................. 5
`
`IV. THE ' 131 PATENT ........................................................................................ 6
`
`V.
`
`SUMMARY OF OPINIONS ........................................................................ 14
`
`VI.
`
`STATEMENT OF OPINIONS EXPRESSED AND BASES AND
`REASONS THEREFOR ............................................................................... t 7
`
`A.
`
`B.
`
`The Level of Skill in the Art ............................................................... 17
`
`Bromfenac is Structurally and Chemically Dissimilar to
`Diclofenac, Ketorolac and Pranlukast ................................................ 17
`
`1.
`
`2.
`
`3.
`
`Comparison of B romfenac and Diclofenac .............................. 18
`
`Comparison of Bromfenac and Ketorolac ................................ 26
`
`Comparison of Bromfenac and Pranlukast .............................. 30
`
`C. Dr. Lawrence Has Not Established That a Precipitate Will Form
`between an NSAID such as Bromfenac and BAC ............................. 34
`
`D.
`
`Non-ionic Surfactants are Structurally and Chemically Diverse
`and Not Interchangeable .......................................... : .......................... 39
`
`1.
`
`2.
`
`Comparison of Polysorbate 80 and Tyloxapol.. ....................... 39
`
`Comparison of Octoxynol 9, Octoxynol 40 and
`Tyloxapol. ................................................................................. 44
`
`E.
`
`Cyclodextrins May Impact the Stability of the Claimed
`Bromfenac Formulations .................................................................... 50
`
`VII. NON-OBVIOUSNESS OF THE CLAIMS OF THE '131 PATENT .......... 51
`
`VIII. CONCLUSION ......................................................... .' ................................... 53
`
`Page 2 of 59
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`1
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`I, 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. 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 gtven scores of
`
`research lectures. My research interests include synthetic organic and medicinal
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`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 pic, 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.
`
`l am also the
`
`Founder and Non-executive Director of Summit Therapeutics pic, which develops
`
`pharmaceutical compounds and bas 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. 8,754,131 (''the '131 patent"), the "Petition for Inter Partes
`Review of U.S. Patent No. 8,754,13 e· ("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 59
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`reviewed the transcript of Dr. Laskar's cross examination in IPR20l5-00902 and
`
`IPR2015-00903 (EX2114) 1
`
`•
`
`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 ' 131 patent (EX2140). 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 '131 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 in
`
`IPR2015-00902 regarding U.S. Patent No. 8,669,290 ("the '290 patent") and
`
`1PR2015-00903 regarding U.S. Patent No. 8,129,431 ("the '431 patent").
`
`Page 6 of 59
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`IV. THE '131 PATENT
`
`12.
`
`I understand that Lupin has challenged claims 1-30 of the '13 1 patent,
`
`EX 1002, in this proceeding. I further understand that the '131 patent has a priority
`
`date of January 21, 2003.
`
`13. The '131 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.
`
`(EX1002 at Abstract; claims 1-30.) The '131 patent has three
`
`independent claims (claims 1, 7 and 13) and 27 dependent claims (claims 2-6, 8-12
`
`and 14-30).
`
`14.
`
`Independent claim 1 of the ' 131 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 is present at a concentration from about
`
`0.05 w/v % to about 0.2 w/v %, and where the second component is tyloxapol and
`
`is present in the liquid preparation in an amount sufficient to stabilize the first
`
`Page 7 of 59
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`component. The stable aqueous liquid preparation of claim 1 is formulated for
`
`ophthalmic administration. (EXl 002 at claim 1.)
`
`15. Dependent claim 2 of the '131 patent is directed, generally speaking, to
`
`the aqueous liquid preparation of claim 1, further comprising a quaternary
`
`ammonium salt. (EX1002 at claim 2.)
`
`16. Dependent claim 3 of the' 131 patent is directed, generally speaking, to
`
`the aqueous liquid preparation of claim 1, where the first component is a
`
`bromfenac sodium salt. (EX1002 at claim 3.)
`
`17. Dependent claim 4 of the '131 patent is directed, generally speaking, to
`
`the aqueous liquid preparation of claim 1, wherein the concentration of ty1oxapol is
`
`from about 0.01 w/v% to about 0.05 w/v %. (EX1002 at claim 4.)
`
`18. Dependent claim 5 of the' 131 patent is directed, generally speaking, to
`
`the aqueous liquid preparation of claim 1, wherein the pH is from about 7.5 to
`
`about 8.5. (EX1002 at claim 5.)
`
`19. Dependent claim 6 of the ' 131 patent is directed, generally speaking, 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
`
`Page 8 of 59
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`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 claim 6.)
`
`20.
`
`Independent claim 7 of the '131 patent is directed, generally speaking,
`
`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
`
`tyloxapol. 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 claim 7.)
`
`21. Dependent claim 8 of the' 131 patent is directed, generally speaking, to
`
`the aqueous liquid preparation of claim 7, further comprising a quaternary
`
`ammonium salt. (EX1002 at claim 8.)
`
`22. Dependent claim 9 of the '131 patent is directed, generally speaking, 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
`
`Page 9 of 59
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`of the first component remains in the preparation after storage at about 60° C. for 4
`
`weeks. (EX1002 at claim 9.)
`
`23. Dependent claim 10 of the '131 patent is directed, generally speaking,
`
`to the aqueous liquid preparation of claim 7, wherein the ~oncentration 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 claim
`
`10.)
`
`24. Dependent claim 11 of the '131 patent is directed, generally speaking,
`
`to the aqueous liquid preparation of claim 10, wherein the pH is from about 7.5 to
`
`about 8.5. (EX1002 at claim 11.)
`
`25 . Dependent claim 12 of the '131 patent is directed, generally speaking,
`
`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 of bromfenac, wherein the hydrate is at least one selected
`
`from a 1/2 hydrate, 1 hydrate and 3/2 hydrate, (b) tyloxapol, (c) boric acid, (d)
`
`sodium tetraborate, (e) EDTA sodium salt, (f) benzalkonium chloride, (g)
`
`polyvinylpyrrolidone, and (h) sodium sulfite. The concentration of the bromfenac
`
`sodium salt in the stable aqueous liquid preparation of claim 12 is from about 0.05
`
`Page 10 of 59
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`w/v % to about 0.1 w/v % and the concentration of tyloxapol is about 0.02 w/v%.
`
`(EX1002 at claim 12.)
`
`26.
`
`Independent claim 13 of the '131 patent is directed, generaUy speaking,
`
`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
`
`tyloxapol. The stable aqueous liquid preparation of claim 13 is formulated for
`
`ophthalmic administration and does not include mannitol. (EX1002 at claim 13.)
`
`27. Dependent claim 14 of the '131 patent is directed, generally speaking,
`
`to the aqueous liquid preparation of claim 13, further comprising a quaternary
`
`ammonium salt. (EX1002 at claim 14.)
`
`28. Dependent claim 15 of the '131 patent is directed, generally speaking,
`
`to the aqueous liquid preparation of claim 13, wherein the first component is a
`
`bromfenac sodium salt. (EX1002 at claim 15.)
`
`29. Dependent claim 16 of the ' 131 patent is directed, generally speaking,
`
`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
`
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`the bromfenac sodium salt is from about 0.05 to about 0.1 w/v %. (EX1002 at
`
`claim 16.)
`
`30. Dependent claim 17 of the '131 patent is directed, generally speaking,
`
`to the aqueous liquid preparation of claim 13, wherein the pH is from about 7.5 to
`
`about 8.5. (EX1002 at claim 17.)
`
`31. Dependent claim 18 of the '131 patent is directed, generally speaking,
`
`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 of bromfenac, wherein the hydrate is at least one selected
`
`from a 1/2 hydrate, l 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 claim 18.)
`
`32. Dependent claim 19 of the '131 patent is directed, generally speaking,
`
`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 claim 19.)
`
`Page 12 of 59
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`33. Dependent claim 20 of the '131 patent is directed, generally speaking,
`
`to the stable aqueous liquid preparation of claim 19, further comprising a
`
`quaternary ammonium salt. (EX1002 at claim 20.)
`
`34. Dependent claim 21 of the '131 patent is directed, generally speaking,
`
`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 claim 21.)
`
`35. Dependent claim 22 of the '131 patent is directed, generally speaking,
`
`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 claim
`
`22.)
`
`36. Dependent claim 23 of the ' 131 patent is directed, generally speaking,
`
`to the aqueous liquid preparation of claim 22, wherein the pH is from about 7.5 to
`
`about 8.5. (EX1002 at claim 23.)
`
`37. Dependent claim 24 of the '131 patent is directed, generally speaking,
`
`to the stable aqueous liquid preparation of claim 13, wherein the stable aqueous
`
`liquid preparation consists essentially of (a) bromfenac or a pharmacologically
`
`Page 13 of 59
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`acceptable salt or hydrate of bromfenac, wherein the hydrate is at least one selected
`
`from a 1/2 hydrate, 1 hydrate and 3/2 hydrate, (b) tyloxapol, (c) boric acid, (d)
`
`sodium tetraborate, (e) EDTA sodium salt, (f) benzalkonium chloride, (g)
`
`polyvinylpyrrolidone, and (h) sodium sulfite.
`
`The stable aqueous liquid
`
`preparation of claim 24 is formulated for ophthalmic administration. The
`
`concentration of the bromfenac sodium salt in the stable aqueous liquid preparation
`
`of claim 24 is from about 0.05 w/v% to about 0.1 w/v %. (EX1002 at claim 24.)
`
`38. Dependent claims 25-29 of the '131 patent are directed, generally
`
`speaking, to the aqueous liquid preparations of claims 1, 4, 7, 9 and 13,
`
`respectively, wherein
`
`the aqueous
`
`liquid preparation further satisfies
`
`the
`
`preservative efficacy standard of EP-criteria B of the European Pharmacopoeia as
`
`follows: viable cell counts of bacteria (S. aureus, P. aeruginosa) 24 hours and 7
`
`days after inoculation decrease to not more than 1/1 0 and not more than 111000,
`
`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 1110, and thereafter, the cell count keeps the same level as that of 14
`
`days after inoculation. (EX1002 at claim 25-29.)
`
`39. Dependent claim 30 of the ' 131 patent is directed, generally speaking,
`
`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,
`
`stabilizer, chelating agent, and pH controlling agent. (EX1002 at claim 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 '131 patent on the
`
`following ground:
`
`• Obviousness of claims 1-30 over U.S. Patent No. 5,891 ,9 13
`
`("Sallmann") (EX1021) in view of U.S. Patent No. 4,910,225
`
`("Ogawa") (EX 101 0)
`
`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 '131 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. (EX1010 at Experimental Example
`
`6.) 2
`
`Indeed, colored degradation products are typical of oxidation reactions.
`
`(EX21 04 at 525, 530-31.) A person of ordinary skill in the art would have readily
`
`2
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`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. (EX1005 at 1 83.) Rather, Ogawa discloses only the
`
`precipitation of a red insoluble oxidative degradation product.
`
`(EXJOIO 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
`
`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." (EX1005 at «)[1 184, 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 Exampl~ 4-6
`
`demonstrate that disodium edetate had no effect on bromfenac's oxidation. ('225
`
`patent at Experimental Examples 4-6.)
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`degradation. (EX1021 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.
`
`43. Moreover, as discussed further below, even if Dr. Lawrence were
`
`correct that a person of ordinary skill in the art would have been motivated to
`
`combine Ogawa and Sallmann, which she is not, these references do not disclose
`
`any formulation containing 0.02 w/v% tyloxapol, which is required in claim 12 of
`
`the '131 patent.
`
`Fu discloses formulations
`
`containing 0.02% Octoxynol 40 (EX 1014 at Example 2), but, as discussed below,
`
`Octoxynol 40 and tyloxapol are entirely different compounds with different
`
`structures and different properties, and thus are not interchangeable.
`
`Fu's
`
`disclosure of 0.02 w/v% Octoxynol 40 therefore does not in any way teach or
`
`suggest 0.02 w/v% tyloxapol.
`
`44. Nor does Sallmann disclose any formulation containing 0.02 w/v%
`
`tyloxapoJ. The tyloxapol concentration disclosed in Sallmann's Example 2 is 0. I
`
`w/v% (EX1021 at 8:1 -15), which is five times greater than 0.02 w/v% tyloxapol,
`
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`as set forth in claim 12 of the '1 31 patent. Thus, even if Dr. Lawrence were
`
`correct that a person of ordinary skill in the art would have combined Ogawa and
`
`Sallman, which she is not, this combination would not have led a person of
`
`ordinary skill in the art to make any formulation containing 0.02 w/v% tyloxapol.
`
`VI. STATEMENT OF OPINIONS EXPRESSED AND BASES AND
`REASONS THEREFOR
`
`A.
`
`The Level of Skill in the Art
`
`45. 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 thi s area, or a comparable level of education and training.
`
`B.
`
`Bromfenac is Structurally and Chemically Dissimilar to
`Diclofenac, Ketorolac and Pranlukast
`
`46. 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
`
`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 <(95.) In fact, the carboxylic acid group in
`
`these molecules is on a side-chain and not directly attached to the aryl group. This
`
`Page 18 of 59
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`17
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`1[ 95.) The physical, chemical, and biological properties of molecules containing
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`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 wilJ have similar
`
`properties.
`
`1.
`
`Comparison of Bromfenac and Diclofenac
`
`47. Ogawa is directed to bromfenac formulations.
`
`(EXIOIO 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." (EX1005 at <).1[ 257, 374.) I disagree. As discussed below, bromfenac
`
`is an important structural difference that would impact the biological, chemical,
`
`and physical properties of the molecules.
`
`18
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`Page 19 of 59
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`

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`and diclofenac are structurally and chemically dissimilar in numerous important
`
`respects.
`
`48. 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.
`
`amfenac
`(baee atructura of bromfenac)
`
`-
`
`beat atructure of dlclofenac
`
`Table 1.
`
`bromfenac
`
`(I(C'
`Y NH
`CI~(QTI
`Uh
`
`diclofenac
`
`49. Table 2 below depicts the chemical structures of bromfenac and
`
`diclofenac.
`
`Page 20 of 59
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`19
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`

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`0
`
`OH
`
`ycCI
`
`I
`
`NH
`
`Cl
`
`OH
`
`bromfenac
`
`diclofenac
`
`Br
`
`Table 2.
`
`50. Bromfenac and diclofenac differ significantly in their structure and
`
`three-dimensional shape.
`
`Important differences
`
`in structure between bromfenac and diclofenac include:
`
`•
`
`•
`
`•
`
`Bromfenac and diclofenac are derivatives of different base
`structures, ac; noted above.
`
`Bromfenac is a primary amine (NH2 group), whereas dicJofenac
`is a secondary amine (NH group).5
`
`Bromfenac has a 4-bromobenzoyl group attached adjacent to
`the NH2 group, whereas diclofenac has a 2,5-dichlorophenyl
`group attached directly to the NH group.
`
`5
`
`-
`
`Page 21 of 59
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`20
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`

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`•
`
`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.
`
`-
`
`51. For example, the electron density distribution will vary significantly
`
`between bromfcnac 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. (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
`
`substitucnts, as shown highlighted below.
`
`6 ------
`
`Page 22 of 59
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`21
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`- I
`
`

`
`Br
`
`NH
`
`OH ~OH vg
`
`bromfenac:
`
`dlclofenac
`
`52. 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. (EX2156 at 43-49; EX2040 at 8-
`
`9.)
`
`53.
`
`In fact, bromfenac contains more strong hydrogen bonding sites than
`
`diclofenac, particularly its carbonyl group, as shown in red below:
`
`Br
`
`bromfenac
`
`dlclofenac
`
`54. The ability to form strong hydrogen bonds impacts solvation and how
`
`solvated the molecule is in an aqueous solution. Specifically, solvation occurs by
`22
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`Page 23 of 59
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`

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`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. (EX1005 at183.)
`
`55. 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 brornfenac to be less likely to form insoluble salts or precipitates.
`
`(/d.)
`
`56. Bromfenac and diclofenac also have significantly different three(cid:173)
`
`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 24 of 59
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`23
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`
`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 30 co-ordinates
`were generated using MM2 refinement within the Chem3D package; for diclofenac the 3D co(cid:173)
`ordinates were obtained from X-ray crystal structure data downloaded from the Cambridge
`crystallographic Database.
`
`57. Furthermore, I disagree with Dr. Lawrence's statement that "[o]ther
`
`prior art references disclosed that polysorbate 80 and tyloxapol could be used
`
`interchangeably in formulations and/or that
`
`tyloxapol was preferred over
`
`polysorbate 80." (EX1005 at 1 291; see also EX1005 at 1 136 (citing EX1067,
`
`EXI068, EX1039, EX1069, EX1070, EX1071, and EX1072).) Almost all of the
`
`references cited by Dr. Lawrence are directed to suspensions or emulsjons, which
`
`are different from solutions such as the aqueous liquid preparations of the '131
`
`patent. (See EX1067, EX1068, EX1069, EX1070 and EX107l.) EX1039 is
`
`directed to tobramycin and diclofenac formulations, not bromfenac formulations.
`
`Page 25 of 59
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`24
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`(EX1039 at 2:38-59.) EX1072 is directed to the physiological activity of
`
`m