UN1TED STATES PATENT AND TRADEMARK OFFICE
`
`BEFORE THE PATENT TRIAL AND APPEAL BOARD
`
`INNOPHARMA LICENSING, INC., INNOPHARMA LICENSING LLC,
`INNOPHARMA INC., INNOPHARMA LLC,
`MYLAN PHARMACEUTICALS INC., and MYLAN INC.
`Petitioner,
`
`v.
`
`SENJU PHARMACEUTICAL CO., LTD., BAUSCH & LOMB, INC .• and
`BAUSCH & LOMB PHARMA HOLDINGS CORP.
`Patent Owner.
`
`Case IPR20 14-00902
`Patent 8,669,290
`
`DECLARATION OF STEPHEN G. DAVIES, D.Phil.
`
`PAGE 1 OF 56
`
`SENJU EXHIBIT 2105
`INNOPHARMA v SENJU
`IPR20 15-00902
`
`

`
`Table of Contents
`
`I.
`
`BACKGROUND AND QUALIFICATIONS ................................................. 2
`
`II.
`
`INFORMATION CONSIDERED ................................................................... 4
`
`ill. LEG"AL PRINCIPLES ..................................................................................... 5
`
`IV. THE '290 PATENT ......................................................................................... 5
`
`V.
`
`SUMMARY OF OPINIONS ......................................................................... I3
`
`VI. STATEMENT OF OPINIONS EXPRESSED AND BASES AND
`REASONS THEREFOR ............................................................................... 15
`
`A.
`
`B.
`
`The Level of Skill in the Att ............................................................... I 5
`
`Bromfenac is Structurally and Chemically Dissimilar to
`Diclofenac, Ketorolac and Pranlukast.. ............................................... 15
`
`1.
`
`2.
`
`3.
`
`Comparison of Bromfenac and Diclofenac .............................. 15
`
`Comparison of Bromfenac and Ketorolac ................................ 23
`
`Comparison ofBromfenac and Pranlukast ............................... 27
`
`C.
`
`Dr. Laskar Has Not Established That a Precipitate Will Form
`between an NSAID such as Bromfenac and BAC .............................. 33
`
`D. Non-ionic Surfactants are Structurally and ChernicaJly Diverse
`and Not Interchangeable ...................................................................... 37
`
`1.
`
`2.
`
`Comparison of PoJysorbate 80 and Tyloxapol ......................... 37
`
`Comparison of Octoxynol 9, Octoxynol 40 and
`Tyloxapol .................................................................................. 40
`
`E.
`
`Cyclodextrins May Impact the Stability of the Claimed
`Bromfenac Formulations .................................................................... .46
`
`VII. NON-OBVIOUSNESS OF THE CLAIMS OF THE '290 PATENT .......... .47
`
`VIII. CONCLUSION .............................................................................................. 49
`
`PAGE20F56
`
`

`
`I, Stephen G. Davies, under penalty of perjury, declare as follows:
`
`l.
`
`1 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 Depru.1ment of Chemistry.
`
`In this
`
`position, I had full responsibility for all teaching, research, financial and
`
`managerial matters in one of the lru.·gest chemistry departments in the world. I
`
`have also supervised more than 100 graduate students and 100 post-doctoraJ
`
`fellows in the area of organic, organometallic and medicinal chemistry.
`
`3.
`
`In 1973, I eaJ.ned a B .A. in Chemistry from the University of Oxford.
`
`In 1975, I eamed a D. Phil. in Chemistry from the University of Oxford. In 1980, 1
`
`received a D. Sc. in Chemistly from the University of Paris.
`
`4. Over the course of my career, 1 have been a comn1ittee 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 g1ven scores of
`
`research lectures. My research interests include synthetic organic and medicinal
`
`PAGE 3 OF 56
`
`

`
`chemistry, and in particular, the preparation of enantiomerically pure orgamc
`
`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 Seties 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 OrganometalJic Chemistry (1987), Pfizer Award for
`
`Chemistry ( 1988), Royal Society of Chemistry Bader A ward (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 Technoprenew- Award, Singapore
`
`(2008), and Royal Society of Chemistry Perkin Prize for Organic Chemistry
`
`(2011).
`
`PAGE 40F 56
`
`

`
`8.
`
`I am also the founder of numerous companies including ones focused
`
`on the preparation of compOLmds 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
`
`phannaceutical companies with enantiomerically pure compounds of interest on
`
`any desired scale, from small amounts for biological evaluation and research, to
`
`commercial quantities. CuiTently, I am the Founder and Non-executive Chairman
`
`of Sciink 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 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 '290 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. Paul A. Laskar (EX1003). I have also reviewed
`
`the transcript of Dr. Laskar' s cross examination (EX2114 ).
`
`1 have fmther
`
`PAGES OF 56
`
`

`
`reviewed the transcript of the deposition of Dr. Jayne Lawrence, who serves as
`
`lnnoPharma's expert in the district court litigation involving the '290 patent
`
`(EX2 I 40). 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. Laskar'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 rui 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.
`
`IV. THE '290 PATENT
`
`12.
`
`I understand that InnoPharma has challenged claims 1-30 of U.S.
`
`Patent No. 8,669,290 ("the '290 patent"), EXI 001 , in this proceeding. I finiher
`
`understand that the '290 patent has a priority date of January 2 1, 2003.
`
`PAGE6 OF 56
`
`

`
`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 swfactant
`
`tyloxapol.
`
`(EXlOOI 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 phrumacologically acceptable salt or hydrate of
`
`bromfenac, where the hydrate is at least one selected from a 112 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
`
`formuJated for ophthalmic administration. (EX l 00 l at claim 1.)
`
`15. Dependent cJaim 2 of the '290 patent is directed, generally speaking, to
`
`the aqueous liquid preparation of claim
`
`l, further comprising a quaternary
`
`ammonium salt. (EX1 001 at claim 2.)
`
`PAGE 70F 56
`
`

`
`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.)
`
`1 7. Dependent claim 4 of the '290 patent is directed, generally spealcing, to
`
`the aqueous liquid preparation of claim l , 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 %. (EX100 1 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. (EXlOOl 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)
`
`boric add, (d) sodium tetraborate, (e) EDTA sodium salt, (f) benzalkonium
`
`chloride, (g) polyvinylpyrrolidone, and (h) sodiwn sulfite. The stable aqueous
`
`liquid preparation of claim 7 is fmmulated for ophthalmic administration. The
`
`PAGE 8 OF 56
`
`

`
`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 %. (EXl 001 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 I /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 fmmulated 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. (EXl 001 at claim 8.)
`
`22. Dependent claim 9 of the '290 patent is directed, generally speaking, to
`
`the aqueous liquid preparation of claim 8, further comprising a quaternary
`
`ammoniwn salt. (EXIOOI at claim 9.)
`
`23. Dependent claim 1 0 of the '290 patent is directed, generally speaking,
`
`to the stable aqueous liquid preparation of claim 8, where the stable aqueous liquid
`
`preparation is characterized in that greater than about 92% of the original amount
`
`of the fiTst component remains in the preparation after storage at about 60° C. for 4
`
`weeks. (EXl 00 l at claim 1 0.)
`
`PAGE 9 OF 56
`
`

`
`24. Dependent claim 11 of the '290 patent is directed, generally speaking,
`
`to the aqueous I iquid preparation of claim 8, where the concentTation 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 phannacologicaJly acceptable
`
`salt or hydrate of bromfenac, where the hydrate is at least one selected from a I /2
`
`hydrate, 1 hydrate and 3/2 hydrate, (b) tyloxapol, (c) boric acid, (d) sodium
`
`tetraborate,
`
`(e) EDTA
`
`sodium
`
`saJt,
`
`(f)
`
`benzalkonium
`
`chloride,
`
`(g)
`
`polyvinylpyrrolidone, and (h) sodium sulfite. The concentration of the bromfenac
`
`sodium salt in the stable aqueous liquid prepru·ation of claim 13 is from about 0.02
`
`w/v% to about 0.1 w/v %. (EX1001 at claim 13.)
`
`27.
`
`Independent claim 14 of the '290 patent is directed, generally speaking,
`
`to a stable aqueous liquid prepru·ation comprising two components, where the first
`
`component is bromfenac or a pharmacologically acceptable salt or hydrate of
`
`PAGE 10 OF 56
`
`

`
`bromfenac, where the hydrate is at least one selected from a 1/2 hydrate, 1 hydrate
`
`and 3/2 hydrate, where the flrst component is the sole pharmaceutical active
`
`ingredjent 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. (EX1 001 at claim 1 4.)
`
`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. (EXlOOl 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. (EXJ 001 at claim 16.)
`
`30. Dependent claim 17 of the '290 patent is directed, generally speaking,
`
`to the aqueous liquid preparation of claim l 6, where the concentration oftyloxapol
`
`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 %. (EXl 001 at claim 17.)
`
`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
`
`PAGE 11 OF 56
`
`

`
`liquid preparation consists essentially of (a) bromfenac or a phannacologically
`
`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, (f) benzalkonium chloride, (g)
`
`polyvinylpyrrolidone, and (h) sodium sulfite. The concentration of the bromfenac
`
`sodium salt in the stable aqueous liquid preparation of claim 19 is from about 0.02
`
`w/v% to about 0.1 w/v %. (EXJ 001 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. (EXl 001 at claim 21.)
`
`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. (EXlOOl at claim 22.)
`
`PAGE 12 OF 56
`
`

`
`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%. (EXlOOl 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. (EXl 001 at claim 24.)
`
`38. Dependent claim 25 of the '290 patent is diTected, 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 tetra borate, (e) EDT A sodium salt, (f) benzalkonium chloride, (g)
`
`polyvinylpyrrolidone, and (h) sodium sulfite.
`
`The stable aqueous
`
`liquid
`
`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 %. (EXl 001 at claim 25.)
`
`39. Dependent claims 26-30 of the '290 patent are directed, generally
`
`speaking, to the aqueous liquid preparations of claims I, 8, 14, 20, and 22,
`
`PAGE 13 OF 56
`
`

`
`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 111 000, 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. (EXl 001 at claims 26-30.)
`
`V.
`
`SUMMARY OF OPINIONS
`
`40.
`
`I understand that the Board has granted InnoPharma's petition to
`
`institute this IPR regardi ng the purported obviousness of claims 1-30 of the '290
`
`patent on the following ground:
`
`• Obviousness of claims 1-30 over U.S. Patent No. 4,910,225
`
`("Ogawa") (EX1004) and U.S. Patent No. 6,107,343 ("Sallmann")
`
`(EX1009)
`
`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 Ogawa and
`
`Sallmann as Dr. Laskar contends, to arrive at the claimed preparations of the '290
`
`patent. Ogawa teaches the use of sodium sulfite, a well-known antioxidant
`
`(EX20 14 at 3 :41-55), to chemically stabilize bromfenac from degradation and
`
`PAGE 14 OF 56
`
`

`
`prevent the formation of red insoluble matters. (EXl 004 at Experimental Example
`
`6.) 1
`
`Indeed, colored degradation products are typical of oxidation reactions.
`
`(EX2104 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. (See EX1021 at 5.) There is no
`
`teaching in Ogawa of the formation of any salt or any "complex" between
`
`bromfenac and BAC, contrary to Dr. Laskar's argument. (EX I 003 at~ 29.) -
`
`-
`
`Rather, Ogawa discloses only the precipitation of a red insoluble oxidative
`
`degradation product. (EXl 004 at Experimental Examples 4-6.)
`
`42. Sallmann is directed to formulations of diclofenac potassium in
`
`particular and contains no teaching that dicJofenac is susceptible to chemical
`
`degradation. (EX1009 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.
`
`PAGE 15 OF 56
`
`

`
`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,
`
`pharmaceutical sciences or a related discipline with about three to five years of
`
`work experience in this area, or a compru·able level of education and training.
`
`B.
`
`Bromfenac is Structurally and Chemically Dissimilar to
`Diclofenac, Ketorolac and Pranlukast
`
`1.
`
`Comparison of Bromfenac and Diclofenac
`
`44. Ogawa is directed to bromfenac formu lations.
`
`(EXl 004 at 2:45 -
`
`3 :1 5.) Sallmam1 is directed to diclofeoac potassium formulations. (EX1009 at I :1
`
`- 3:26.) Dr. Laskar argues that a person of ordinary skill in the at1 would have had
`
`a reason to combine the disclosures of Ogawa and Sallmann. In particular, Dr.
`
`Laskar argues that "a POSA would have known that substituting bromfenac for
`
`diclofenac would have yielded predictable results because both are NSAIDs with
`
`similar physical and pharmacological properties," citing EXl 002. (EXl 003 at ~
`
`67-68.)
`
`I disagree. Although EX1002 correctly identifies bromfenac as a
`
`derivative of amfenac, it incorrectly identifies diclofenac as a di-chloro derivative
`
`of amfenac, when in fact amfenac and diclofenac have completely different base
`
`struch1res, as shown in Table 1 below. (EX1002 at 2.)
`
`PAGE 16 OF 56
`
`

`
`d&YOH d&rOH
`
`-...;;::
`
`h
`
`-...;;::
`
`Br
`
`amf1mac
`(base structure of bromfenac)
`
`bromt.n01c
`
`Q
`NH CrrOH
`
`-...;;::
`
`h
`
`~(
`6rroo
`
`-...;;::
`
`h
`
`base structure of diclofenac
`
`dlclofenac
`
`Table 1.
`
`Furthermore, EX1002 contains no information regarding the physical
`
`properties of bromfenac and diclofenac.
`
`I therefore disagree with Dr. Laskar's
`
`unsupported opinion because, as discussed below, bromfenac and diclofenac are
`
`structurally and chemically dissimilar in numerous important respects.
`
`45. Table 2 below depicts the cherrucal structures of bromfenac and
`
`diclofenac.
`
`Br
`
`Table 2.
`
`OH
`
`OH
`
`bromfenac
`
`diclofenac
`
`PAGE 17 OF 56
`
`16
`
`

`
`46. 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, as noted above.
`
`Bromfenac is a primary amine (NH2 group), whereas diclofenac
`is a secondary amine (NH group).
`
`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.
`
`Bromfenac has a carbonyl (C=O) group, whereas diclofenac
`does not.
`
`A person of ordinary skiJI in the art would expect these differences to lead to
`
`significantly different functional and chemical properties, as discussed below. II
`
`II
`47. For example, the electron density distribution will vary significantly
`
`between bromfenac and diclofenac based on their different chemical stmctures,
`
`leading to different hydrogen bonding abilities. Specifically, a person of ordinary
`
`PAGE 18 OF 56
`
`

`
`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
`
`substituents, as shown highlighted below.
`
`OH
`
`Br
`
`bromfenac
`
`diclofenac
`
`48. 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. (EX2036 at 43-49; EX2040 at 8-
`
`9.)
`
`49.
`
`PAGE 190F56
`
`18
`
`

`
`Bromfenac is described as freely soluble in water in a reference
`
`that Dr. Laskar cites regarding the Bronuck bromfenac sodium ophthalmic solution,
`
`which is formulated at a pH of 8.0-8.6. (EX2039 at 27, right column and 29, left
`
`column.) Moreover, bromfenac's solubility would not be expected to be pH(cid:173)
`
`dependent at moderate pH levels, such as those specified in the '290 patent,
`
`because bromfenac would be expected to be almost entirely in its carboxylate salt
`
`form at pH 6 and higher, as shown in Appendix A. Indeed, InnoPharma's district
`
`comt expert Dr. Lawrence candidly admits that the sodium saJt of bromfenac is a
`
`water-soluble hydrophilic drug. (EX2140 at 33:7-9.)
`
`50.
`
`PAGE200F56
`
`

`
`51.
`
`In fact, bromfenac contains more strong hydrogen bonding sites than
`
`diclofenac, particularly its carbonyl group, as shown in red below:
`
`Br
`
`bromfenac
`
`diclofenac
`
`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.
`
`Laskar alleges is fonned between bromfenac and BAC. (EX1003 at ~ 29.)
`
`53. Furthem1ore, 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
`
`PAGE21 OF 56
`
`20
`
`

`
`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.
`
`(/d.)
`
`54. Bromfenac and diclofenac also have significantly different three-
`
`dimensional sttuctures, as shown below. In bromfenac, the brominated aromatic
`
`ring is approximately in the same plane as the rest of the molecule. ln 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 i_nteractions in the solid state. (EX2037 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. (EX2036 at 37-38,
`
`43-49; EX2040 at 8-9.)
`
`30 Structures ofbromfenac (left) and diclofenac (right). For bromfenac the 30 co-ordinates
`were generated using MM2 refinement within the Chem30 package; for diclofenac the 30 co-
`
`PAGE 22 OF 56
`
`

`
`ordinates were obtained from X-ray crystal structure data downloaded from the Cambridge
`crystallographic Database.
`
`55. Fw1hermore, I disagree with Dr. Laskar's statement that "[a] POSA
`
`would have known
`
`that substituting
`
`tyloxapol for polysorbate 80 would
`
`successfully, and predictably, result in a stable ophthalmic formula6on of
`
`bromfenac because ... tyloxapol and polysorbate 80 had previously been used
`
`interchangeably as non-ionic surfactants in ophthalmic formulations," citing
`
`EX1021 and EX1022. (EX1003 at~ 62 (citations omjtted).) EXl 021 is directed to
`
`emulsions, which are different from solutions such as the aqueous liquid
`
`preparations of the '290 patent.
`
`(EX1021 at 1:5-11.) EX1022 is directed to
`
`tobramycin and diclofenac formulations, not bromfenac formulations. (EXI 022 at
`
`2 :38-59.) Neither EXl 021 nor EXI 022 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
`
`solubili zer to prevent. In addition, the sodium salt of bromfenac is freely water-
`
`soluble (EX2039 at 29, left column; EX2 140 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, InnoPharma's district court expert Dr.
`
`Lawrence unequivocally stated, in a peer-reviewed prior art publication, that "it is
`
`PAGE230F56
`
`

`
`no use trying to increase the aqueous solubility of a water-soluble hydrophilic drug
`
`in an aqueous-based surfactant system."
`
`(EX2139 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 ofBromfenac and Ketorolac
`
`57.
`
`I further disagree with Dr. Laskar's opinion that "a POSA would have
`
`further reason to expect to be able to successfully fonnu]ate an aqueous liquid
`
`ophthalmic preparation of bromfenac containing tyloxapol and BAC because Fu
`
`indicates that stable aqueous preparations of NSAIDs can be made using a
`
`surfactant (Octoxynol 9) that is closely related to (and known to be interchangeable
`
`with) tyloxapol."
`
`(EX I 003 at ~ 70.) Fu discloses formulations containing the
`
`specific NSAID ketorolac tromethamine, not NSAIDs generally, with Octoxynol
`
`40, not Octoxynol 9 as Dr. Laskar contends. (EXlOll at 17-19.) 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 24 OF 56
`
`

`
`OH
`
`OH
`
`bromfenac
`
`ketorolac
`
`Br
`
`Table 3.
`
`58. Bromfenac and ketorolac differ significantly m their structure and
`
`three-dimensional shape.
`
`Important differences m
`
`structure between bromfenac and ketorolac include:
`
`•
`
`•
`
`•
`
`•
`
`•
`
`Unlike bromfenac, ketorolac is not a derivative of amfenac.
`
`Bromfenac is a primary amine (NH2 group), whereas ketorolac
`is a tertiary amine (NR3 group).
`
`Bromfenac has a 4-bromobenzoyl group attached adjacent to
`the NH2 group, whereas ketorolac has a simple benzoyl group
`on the aromatic pyrrole group.
`
`Ketorolac has a pyrrole, whereas bromfenac does not.
`
`Bromfenac is an aniline, whereas ketorolac is not.
`
`59. A person of ordinary skill in the art would expect these differences to
`
`lead to significantly different functional and chemical properties, as discussed
`
`below.
`
`PAGE25 OF 56
`
`24
`
`

`
`II
`60. For example, the electron density disbibution will vary significantly
`
`between bromfenac and ketorolac based on their different chemical structures,
`
`leading to different hydrogen bonding abilities. Specifically, a person of ordinary
`
`skill in the art would expect the amino groups in bromfena