IN THE UNITED 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.
`
`U.S. Patent No. 8,129,431 to Sawa et al.
`Issue Date: March 6, 2012
`Title: Aqueous Liquid Preparation Containing
`2-Amino-3-(4-bromobenzoyl) phenylacetic Acid
`
`
`
`Inter Partes Review No.: IPR2015-00903
`
`
`
`DECLARATION OF PAUL A. LASKAR, PH.D.
`
`
`
`Innopharma EX1003, Page 1
`
`SENJU EXHIBIT 2249
`LUPIN v SENJU
`IPR2015-01105
`
`PAGE 1 OF 85
`
`

`

`TABLE OF CONTENTS
`
`Introduction ...................................................................................................... 1
`
`
`I.
`
`II.
`
`List of Documents Considered ........................................................................ 7
`
`III. My background and qualifications ................................................................12
`
`IV. Person of ordinary skill in the art (POSA) ....................................................16
`
`V.
`
`The ’431 patent ..............................................................................................16
`
`VI. State of the art as of January, 2003 ................................................................18
`
`A. Non-steroidal anti-inflammatory compounds were known and
`approved for ophthalmic use ...............................................................18
`
`B.
`
`C.
`
`D.
`
`E.
`
`BAC was the preservative of choice in ophthalmic formulations ......22
`
`It was known that non-ionic surfactants stabilized aqueous
`preparations containing an NSAID and BAC .....................................24
`
`Tyloxapol is a non-ionic surfactant that was known and widely
`used in ophthalmic formulations by January 2003 .............................25
`
`There is nothing inventive in the ’431 patent in view of the
`prior art ................................................................................................30
`
`VII. Obviousness of Claims 1-22 of the ’431 patent ............................................31
`
`A.
`
`B.
`
`The basis of my analysis with respect to obviousness ........................31
`
`Obviousness Ground 1 - Ogawa and Sallmann...................................33
`
`1.
`
`2.
`
`3.
`
`4.
`
`5.
`
`6.
`
`Independent Claims 1 and 18 ....................................................35
`
`Claims 2, 5, 11 and 19 ..............................................................47
`
`Claims 3 and 4 ...........................................................................51
`
`Claims 6 and 15.........................................................................55
`
`Claims 7, 8, 13, 14, 16 and 17 ..................................................58
`
`Claims 9 and 10.........................................................................62
`ii
`
`
`
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`PAGE 2 OF 85
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`
`
`Declaration of Dr. Paul A. Laskar (EX1003)
`
`7.
`
`8.
`
`9.
`
`Claim 12 ....................................................................................65
`
`Claims 21, and 22......................................................................67
`
`Claim 20 ....................................................................................68
`
`VIII. The claimed invention of the ’431 patent does not possess
`unexpectedly superior properties ...................................................................68
`
`A.
`
`B.
`
`Tyloxapol’s stabilization of an aqueous ophthalmic bromfenac
`preparation is not unexpected in view of the prior art ........................69
`
`The stabilization of bromfenac preparations by tyloxapol is not
`observed across the entire range of the claimed preparations .............72
`
`1.
`
`2.
`
`The supposed unexpected stability of aqueous bromfenac
`preparations is not observed across the entire range of
`claimed pH ................................................................................73
`
`The supposedly unexpected increase in stability of
`aqueous bromfenac preparations is not observed across
`the entire range of claimed benzalkonium chloride
`homologues ...............................................................................75
`
`C.
`
`Tyloxapol’s stabilization of the preservative effect of BAC is
`not unexpected in view of prior art .....................................................75
`
`D. No long-felt, unmet need existed for an ophthalmic NSAID
`preparation formulated with BAC .......................................................78
`
`E.
`
`F.
`
`The claimed bromfenac preparations were not met with
`skepticism ............................................................................................79
`
`The claimed bromfenac ophthalmic formulations have not
`received any praise ..............................................................................80
`
`G. Additional evidence of secondary considerations ...............................80
`
`IX. Conclusion .....................................................................................................81
`
`
`
`iii
`
`
`
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`PAGE 3 OF 85
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`

`

`Declaration of Dr. Paul A. Laskar (EX1003)
`
`I.
`
`Introduction
`
`1.
`
`I am over the age of eighteen (18) and otherwise competent to make
`
`this Declaration.
`
`2.
`
`I have been retained as an expert witness on behalf of Petitioner for
`
`the above captioned inter partes review (“IPR”). I am being compensated for my
`
`time in connection with this IPR at my standard consulting rate, which is $250 per
`
`hour. My compensation is in no way dependent on the outcome of this IPR.
`
`3.
`
`I understand that the petition for IPR involves U.S. Patent No.
`
`8,129,431 (“the ’431 patent”), (EX1001), which issued on March 6, 2012, from
`
`U.S. Application No. 10/525,006 (“the ‘006 application”), naming Shirou Sawa
`
`and Shuhei Fujita as the inventors. The ‘006 application is the U.S. National Stage
`
`of PCT Application No. PCT/JP2004/000350 (“the ‘350 application), filed on
`
`January 16, 2004. The ‘350 application claims priority to Japanese Application
`
`No. 2003-12427, filed on January 21, 2003. It is my understanding that the earliest
`
`possible priority date of the ’431 patent is January 21, 2003, the filing date of the
`
`Japanese priority application. I further understand that, according to the USPTO
`
`records, the ’431 patent is currently assigned to Senju Pharmaceutical Co., Ltd.
`
`(“Senju,” “the patentee,” or “the patent owner”). I understand that the ’431 patent
`
`is currently subject to IPR. Metrics, Inc. v. Senju Pharmaceuticals Co., Ltd.,
`
`IPR2014-01041. I understand that Petitioner seeks to become a party to
`
`1
`
`Innopharma EX1003, Page 4
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`
`
`Declaration of Dr. Paul A. Laskar (EX1003)
`
`proceedings in IPR2014-01041. Because IPR of the ’431 patent has already been
`
`instituted, I have reviewed the materials submitted with the petition filed in that
`
`proceeding, including the petition itself (Second Corrected Petition, IPR2014-
`
`01041, Paper 9), the Second Corrected Declaration of Dr. Uday B. Kompella
`
`(IPR2014-01041, EX1003), the Board’s Decision Instituting Inter Partes Review
`
`(IPR2014-01041, Paper 19), and the prior art and materials cited in each. I note
`
`that I agree with the analysis and opinions set forth by the petitioner’s expert, Dr.
`
`Kompella, in the declaration that was submitted in the Metrics IPR proceeding and
`
`share many of those same opinions below. Because my independent analysis of
`
`the claims and prior art led to the same conclusions as the expert in the Metrics
`
`IPR, I have incorporated many of his opinions and characterizations below as my
`
`own. I understand that in its Decision Instituting Inter Partes Review the Board
`
`concluded that Petitioner Metrics, Inc. demonstrated a reasonable likelihood of
`
`prevailing on its assertion that claims 1-22 of the ’431 patent are unpatentable.
`
`Specifically, the Board instituted review on two grounds: (1) claims 1-5, 7-14, and
`
`18-19 are unpatentable over the Owaga and Sallmann references; and (2) claims 6,
`
`15-17, and 20-22 are unpatentable over the Ogawa, Sallmann and Fu references.
`
`(IPR2014-01041, Paper 19, pg. 20). Therefore, because Petitioner is seeking to
`
`join the instituted review of the ’431 patent, the opinions expressed herein are
`
`2
`
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`
`
`Declaration of Dr. Paul A. Laskar (EX1003)
`
`limited to the references discussed in the petition and supporting materials filed in
`
`that proceeding.
`
`4.
`
`Claim 1 of the ’431 patent is reproduced below.
`
`1.
`
`An aqueous liquid preparation consisting essentially of the
`
`following two components, wherein the first component is 2-amino-3-
`
`(4-bromobenzoyl)-phenylacetic
`
`acid
`
`or
`
`a
`
`pharmacologically
`
`acceptable salt thereof or a hydrate thereof, wherein the hydrate is at
`
`least one selected from a 1/2 hydrate, 1 hydrate, and 3/2 hydrate and
`
`the second component is tyloxapol, wherein said liquid preparation is
`
`formulated for ophthalmic administration, and wherein when a
`
`quaternary ammonium compound
`
`is
`
`included
`
`in said
`
`liquid
`
`preparation, the quaternary ammonium compound is benzalkonium
`
`chloride.
`
`(EX1001, 11:66-12:9) (emphasis added).
`
`5.
`
`Claims 2-17 depend, either directly or indirectly, from claim 1 and
`
`further recite certain salts of 2-amino-3-(4-bromobenzoyl) phenyl acetic acid
`
`sodium salt (bromfenac), concentrations of tyloxapol and/or bromfenac or its
`
`sodium salt, the pH of the preparations, and additional additives. (EX1001, 12:10-
`
`13:15).
`
`6.
`
`Claim 18 of the ’431 patent is reproduced below.
`
`18. An aqueous liquid preparation consisting essentially of:
`(a)
`
`2-amino-3-(4-bromobenzoyl)phenylacetic acid or a
`
`pharmacologically acceptable salt thereof or a hydrate thereof,
`
`3
`
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`
`
`Declaration of Dr. Paul A. Laskar (EX1003)
`
`wherein the hydrate is at least one selected from a 1/2 hydrate,
`
`tyloxapol,
`
`boric acid,
`
`benzalkonium chloride,
`
`polyvinylpyrrolidone,
`
`1 hydrate, and 3/2 hydrate,
`(b)
`(c)
`(d)
`sodium tetraborate,
`(e) EDTA sodium salt,
`(f)
`(g)
`(h)
`
`sodium sulfite,
`
`wherein said liquid preparation is formulated for ophthalmic
`
`administration, and
`
`wherein benzalkonium chloride
`
`is
`
`the only quaternary
`
`ammonium compound which is included in said liquid
`
`preparation.
`
`(EX1001, 13:16-14:9.)
`
`7.
`
`Claims 19-22 depend from claim 18 and further recite
`
`the
`
`concentrations of tyloxapol and bromfenac or its sodium salt. (EX1001, 14:10-22).
`
`8.
`
`In preparing this Declaration, in addition to those materials listed
`
`above, I have reviewed the ’431 patent and considered the file history of the ’431
`
`patent, and each of the documents cited herein, in light of the general knowledge in
`
`the art as of January 2003. In formulating my opinions, I have relied upon my
`
`experience in the relevant art. I have also considered the viewpoint of a person of
`
`ordinary skill in the art (“POSA”) (i.e., a person of ordinary skill in the field of
`
`ophthalmic formulations and drug delivery including formulation of aqueous liquid
`
`4
`
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`Declaration of Dr. Paul A. Laskar (EX1003)
`
`anti-inflammatory preparations) as of January 2003. I agree with the conclusions,
`
`opinions and bases expressed by Dr. Kompella in his declaration submitted in the
`
`Metrics IPR proceedings, as well as the Board in its Decision Instituting Inter
`
`Partes Review, that the challenged claims are invalid in light of Ogawa, Sallmann,
`
`and Fu. As described in detail below, I offer the following opinions in this
`
`declaration:
`
`a.
`
`A POSA would have had reason to combine the disclosures of U.S.
`
`Patent. No. 4,910,225 (“Ogawa”) (EX1004) and U.S. Patent No. 6,107,343
`
`(“Sallmann”) (EX1009) to arrive at the claimed invention as recited in
`
`independent claims 1 and 18 of the ’431 patent, and such a POSA would
`
`have had a reasonable expectation of success in making the claimed
`
`preparations.
`
`b.
`
`The additional features recited in dependent claims 2-5, 7-14, 16-19,
`
`21 and 22 would have been obvious to a POSA in view of Ogawa (EX1004)
`
`and Sallmann (EX1009) when considered in light of other prior art
`
`references discussed in this declaration, which make up the general
`
`knowledge in the art related to aqueous formulations of anti-inflammatory
`
`drugs for ophthalmic administration. For the reasons discussed in this
`
`declaration a POSA would have had reason to combine the teachings of
`
`Ogawa (EX1004) and Sallmann (EX1009), when considered in light of the
`
`5
`
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`
`Declaration of Dr. Paul A. Laskar (EX1003)
`
`other prior art references discussed in this declaration to arrive at the
`
`claimed inventions of claims 2-5, 7-14, 16-19, 21 and 22, and such a POSA
`
`would have had a reasonable expectation of success in making the claimed
`
`inventions.
`
`c.
`
`A POSA would have also had a reason to combine the disclosures of
`
`Ogawa (EX1004), Sallmann (EX1009), and Australian Patent No. AU-
`
`B22042/88 (“Fu”) (EX1011)1 when considered in light of other prior art
`
`references discussed in this declaration to arrive at the claimed invention as
`
`recited in claims 6, 15, and 20 of the ’431 patent, and would have had a
`
`reasonable expectation of success in making the claimed inventions.
`
`d.
`
`I have also considered arguments that may be asserted by Senju
`
`regarding objective indicia of nonobviousness. Even in view of these
`
`potential arguments, the prior art references discussed in this declaration
`
`would have rendered obvious the claimed invention to a person of ordinary
`
`skill in the art.
`
`
`1 I understand that the Fu reference has a related US patent (U.S. Patent No.
`
`5,110,493) which contains a similar disclosure.
`
`6
`
`Innopharma EX1003, Page 9
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`
`II.
`
`List of Documents Considered
`
`Declaration of Dr. Paul A. Laskar (EX1003)
`
`9.
`
`In formulating my opinion, I have considered all documents cited in
`
`this Declaration and all documents cited in the Petition for Inter Partes Review of
`
`U.S. Patent No. 8,129,431, as well as the following documents:
`
`Exhibit
`#
`
`Description
`
`1001
`
`1002
`
`1003
`
`1004
`
`1005
`
`1006
`
`1007
`
`1008
`
`1009
`
`Sawa et al., U.S. Patent No. 8,129,431 B2, "Aqueous Liquid
`Preparation Containing 2-Amino-3-(4-Bromobenzoyl) Phenylacetic
`Acid"
`
`Certified Translation of: Hara, Yoshiyuki , "Bromfenac sodium
`hydrate," Clinics & Drug Therapy 19:1014-1015 (2002)
`
`Declaration of Dr. Paul A. Laskar, PH.D.
`
`Ogawa et al., U.S. Patent No. 4,910,225 "Locally Administrable
`Therapeutic Composition for Inflammatory Disease"
`
`Desai et al., U.S. Patent No. 5,603,929, "Preserved Ophthalmic
`Drug Compositions Containing Polymeric Quaternary
`Ammonium Compounds"
`
`Desai, et al., U.S. Patent No. 5,558,876, "Topical Ophthalmic
`Acidic Drug Formulations"
`
`Certified English translation of "Bromfenac sodium hydrate" in
`the Japanese Pharmacopoeia 2001 Edition: 27-29, Yakuji Nippo
`Limited (2001)
`
`FDA approved "BROMDAYTM (bromfenac ophthalmic
`solution, .09%) Product Label," U.S. Approval: March 24, 2005,
`ISTA Pharmaceuticals, Inc.
`
`Sallmann et al., U.S. Patent No. 6,107,343, "Ophthalmic And
`Aural Compositions Containing Diclofenac Potassium"
`
`7
`
`Innopharma EX1003, Page 10
`
`PAGE 10 OF 85
`
`

`

`
`
`Exhibit
`#
`
`1010
`
`1011
`
`1012
`
`1013
`
`1014
`
`Declaration of Dr. Paul A. Laskar (EX1003)
`
`Description
`
`Guttman et al., "Solubilization of Anti-inflammatory steroids
`by Aqueous Solutions of Triton-WR-1339," Journal of
`Pharmaceutical Sciences 50: 305-307 (1961)
`
`Fu et al., Australian Patent No. AU-B-22042/88,
`"Preservative System For Ophthalmic Formulations"
`
`Yasueda et al., U.S. Patent No. 6,274,609, "Aqueous Liquid
`Pharmaceutical Composition Containing as Main Component
`Benzopyran Derivative"
`
`"Orange Book: Approved Drug Products with Therapeutic
`Equivalence Evaluations," Appl. No. N203168, U.S. FDA, accessed
`at
`http://www.accessdata.fda.gov/scripts/cder/ob/docs/patexclnew.cfm
`?Appl_No=203168&Product_No=001&table1=OB_Rx
`
`"Orange Book: Approved Drug Products with Therapeutic
`Equivalence Evaluations," Appl. No. N203168, Active Ingredient
`Bromfenac Sodium, accessed at
`http://www.accessdata.fda.gov/scripts/cder/ob/docs/obdetail.cfm?A
`ppl_No=203168&TABLE1=OB_Rx, last accessed on February 14,
`2014
`
`1015
`
`Reserved
`
`1016
`
`1017
`
`1018
`
`Kapin, et al., International Patent No. WO 2002/13804,
`"Method For Treating Angiogenesis-Related Disorders Using
`Benzoyl Phenylacetic Acid"
`
`Flach, Allan., "Topical Nonsteroidal Antiinflammatory Drugs
`for Ophthalmic Uses," Ophthalmic NSAIDS: 77-83 (1996)
`
`Prince, S., et al., "Analysis of benzalkonium chloride and its
`homologs: HPLC versus HPCE," Journal of Pharmaceutical
`and Biomedical Analysis 19: 877-882, Elsevier Science B.V.,
`Netherlands (1999)
`
`8
`
`Innopharma EX1003, Page 11
`
`PAGE 11 OF 85
`
`

`

`
`
`Exhibit
`#
`
`Declaration of Dr. Paul A. Laskar (EX1003)
`
`Description
`
`1019
`
`1020
`
`1021
`
`1022
`
`1023
`
`1024
`
`1025
`
`1026
`
`1027
`
`1028
`
`Bergamini et al., U.S. Patent No. 5,597,560, "Diclofenac And
`Tobramycin Formulations For Ophthalmic And Otis Topical use"
`
`Wong, Michelle, International Patent No. WO 94/15597,
`“Ophthalmic Compositions Comprising
`Benzyllauryldimethylammonium Chloride” (filed January
`11, 1993); issued July 21, 1994)
`
`Reddy, Indra K., Ocular Therapeutics and Drug Delivery: A Multi-
`Disciplinary Approach: 42-43, 390 (1996)
`
`Story, M., et al., European Patent No. 0274870, "Micelles
`containing a non-steroidal antiinflammatory compound" (filed
`December 12, 1987; issued July 7, 1988)
`
`"Borax (Sodium tetraborate)," Biochemicals and Reagents:
`175, Sigma-Aldrich (2000-2001)
`
`Schott, H., "Comparing the Surface Chemical Properties and
`the Effect of Salts on the Cloud Point of a Conventional
`Nonionic Surfactant, Octoxynol 9 (Triton X-100), and of Its
`Oligomer, Tyloxapol (Triton WR-1339)," Journal of Colloid
`and Interface Science 205: 496-502 (1998)
`
`Regev, O., et al., "Aggregation Behavior of Tyloxapol, a Nonionic
`Surfactant Oligomer, in Aqueous Solution," Journal of Colloid and
`Interface Science 210: 8-17 (1999)
`
`Aviv, H., International Patent No. WO 94/05298,
`"Submicron Emulsions as Ocular Drug Delivery Vehicles"
`
`Gennaro, A., “Boric Acid,” Remington: The Science and Practice of
`Pharmacy 20: 1041, University of Sciences, United States (2000)
`
`Wade, A., and Weller, P., "Edetic Acid," and "Sodium
`Metabisulfite," Handbook of Pharmaceutical Excipients 2: 176-
`179, 451-453, American Pharmaceutical Association, United States
`(1994)
`
`9
`
`Innopharma EX1003, Page 12
`
`PAGE 12 OF 85
`
`

`

`
`
`Exhibit
`#
`
`Declaration of Dr. Paul A. Laskar (EX1003)
`
`Description
`
`1029
`
`1030
`
`1031
`
`1032
`
`1033
`
`1034
`
`1035
`
`1036
`
`1037
`
`1038
`
`Selected pages from the file history of U.S. Patent No.
`8,129,431, March 28, 2005 Amendment.
`
`"DuractTM," Physician’s Desk Reference 52:3035-3037 (1998).
`
`"monohydrate," Webster’s New World Dictionary of the
`American Language: 920, New World Dictionaries / Simon and
`Schuster (1980).
`
`"Voltaren," Orange Book: Approved Drug Products with
`Therapeutic Equivalence Evaluations, Appl. No. N020037, U.S.
`FDA, accessed at
`http://www.accessdata.fda.gov/scripts/cder/ob/docs/obdetail.cfm?A
`ppl_No=020037&TABLE1=OB_Rx
`
`Yanni et al., U.S. Patent No. 5,475,034, "Topically Administrable
`Compositions Containing 3-Benzoylphenylacetic Acid Derivatives
`for Treatment of Ophthalmic Inflammatory Disorders".
`
`"ISTA Pharmaceuticals Submits New Drug Application for
`XibromTM QD (once-daily), News Release, ISTA
`Pharmaceuticals (December 20, 2007)
`
`"Acular®" and "AzoptTM," Physician’s Desk Reference 54:
`486- 487, 491-492 (2000).
`
`Doughty, M., "Medicines Update for optical practitioners- Part
`11.," Optician 5853 (223), (2002).
`
`Fan, T., "Determination of Benzalkonium Chloride in Ophthalmic
`Solutions Containing Tyloxapol by Solid-Phase Extraction and
`Reversed-Phase High-Performance Liquid Chromatography,"
`Journal of Pharmaceutical Sciences 82 (11): 1172-1174,
`American Pharmaceutical Association, United States (1993).
`
`Guy et al., U.S. Patent No. 5,540,930, "Suspension of Loteprednol
`Etabonate for Ear, Eye, or Nose Treatment" (filed October 25,
`1993; issued July 30, 1996).
`
`10
`
`Innopharma EX1003, Page 13
`
`PAGE 13 OF 85
`
`

`

`
`
`Exhibit
`#
`
`1039
`
`1040
`
`1041
`
`1042
`
`1043
`
`1044
`
`1045
`
`1046
`
`1047
`
`1048
`
`1049
`
`Declaration of Dr. Paul A. Laskar (EX1003)
`
`Description
`
`FDA approved "ALREXTM (loteprednol etabonate ophthalmic
`suspension) 0.2% Product Label," U.S. Approval: 1998, Bausch
`& Lomb Pharmaceuticals.
`
`etabonate
`(loteprednol
`"LOTEMAXTM
`approved
`FDA
`ophthalmic suspension) 0.5% Product Label," U.S. Approval:
`1998, Bausch & Lomb Pharmaceuticals.
`
`"TOBRADEX®" Physician’s Desk Reference 54: 490 (2000
`
`"Alomide® 0.1%" Physician’s Desk Reference 50: 469 (1996).
`
`Kawabata et al., Canadian Patent No. CA 2 383 971 A1,
`"Prophylactic and Therapeutic Medicaments for Ophthalmic Uses".
`
`Johnson, R., et al., U.S. Patent No. 2,880,130, "Anti-
`Inflammatory Steroid Solutions".
`
`Johnson, R., et al., U.S. Patent No. 2,880,138, "Anti-
`Inflammatory Steroid Solutions".
`
`Patani, G., et al., "Bioisoterism: A Rational Approach in
`Drug Design," Chem. Rev. 96: 3147-3176 (1996).
`
`Ostrovskii, V.A., et al., "Acid-base properties of 5-substituted
`tetrazoles," Chemistry of Heterocyclic Compounds 17: 412-
`416 (1981)
`
`FDA approved "XIBROMTM (bromfenac ophthalmic
`solution, .09%) Product Label," ISTA Pharmaceuticals, Inc.
`
`Senju Pharmaceutical Co., Ltd. Press Releases, "The approval of
`BRONUCK® (bromfenac sodium hydrate ophthalmic solution) as
`an import drug in China," http://www.senju.co.jp/, accessed at
`http://www.senju.co.jp/english/news/__icsFiles/afieldfile/2009/11/1
`8/2009111814br.pdf, published November 17, 2009, 1 page.
`
`11
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`Innopharma EX1003, Page 14
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`Declaration of Dr. Paul A. Laskar (EX1003)
`
`Description
`
`FDA approved "PROLENSATM (bromfenac ophthalmic
`solution, 0.07%) Product Label," U.S. Approval: April 5, 2013,
`Bausch & Lomb Incorporated
`
`The United States Pharmacopeia 24: The National Formulary
`19: 1809-1813, 1864-1866, The United States Pharmacopeial
`Convention, Inc. (1999).
`
`Ali, et al., U.S. Patent No. 6,071,904, "Process for
`Manufacturing Ophthalmic Suspensions".
`
`Exhibit
`#
`
`1050
`
`1051
`
`1052
`
`1053
`
`Curriculum Vitae of Dr. Paul A. Laskar, Ph.D.
`
`
`
`
`
`III. My background and qualifications
`
`10.
`
`I am an expert in the field of formulations and drug delivery,
`
`specifically pharmaceutical formulations for ophthalmic administration, including
`
`aqueous liquid topical preparations, and I have been an expert in this field since
`
`prior to 2003. Throughout the remainder of this declaration, I will refer to the field
`
`of ophthalmic formulations, and specifically pharmaceutical formulations for
`
`topical ophthalmic administration, including those comprising anti-inflammatory
`
`drugs such as NSAIDs, as the relevant field or the relevant art. In formulating my
`
`opinions, I have relied upon my training, knowledge, and experience in the
`
`relevant art. A copy of my current curriculum vitae is provided as EX1053, and it
`
`provides a comprehensive description of my academic and employment history.
`
`12
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`Declaration of Dr. Paul A. Laskar (EX1003)
`
`11. As an expert in the relevant field since prior to 2003, I am qualified to
`
`provide an opinion as to what a POSA would have understood, known, or
`
`concluded as of 2003. Since 1965, I have accumulated significant training and
`
`experience in the relevant field and related fields.
`
`12.
`
`I have a Ph.D. in Pharmaceutical Sciences from Oregon State
`
`University with a Minor in Biostatistics; a M.B.A. in General Management,
`
`International Management and Marketing from the University of California at
`
`Irvine; a M.S. in Pharmacy and a B.S. in Pharmacy from the University of Illinois;
`
`and a B.A. in General Science (Chemistry, Biology) from the University of
`
`Rochester.
`
`13.
`
`I am currently, and have been since October 2006, the President of
`
`Paul Laskar Associates, Inc., a pharmaceutical development consulting firm which
`
`I founded. My client base consists of start-up and established pharmaceutical
`
`companies with whom I consult in the areas of pharmaceutical development
`
`including formulation development and evaluation. A significant fraction of my
`
`clients focus on ophthalmic products. From 2003 to 2006, I was Senior Director,
`
`Pharmaceutical Development at Dey LP, at that time owned by Merck KGaA. In
`
`that capacity I supervised the formulation development, clinical supply, technology
`
`transfer, pilot operations, and preclinical functions. While most of Dey’s projects
`
`were for inhalation, I worked on two generic ophthalmic projects.
`
`13
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`
`
`Declaration of Dr. Paul A. Laskar (EX1003)
`
`14. From 1994 to 2003, I was initially Director, then Vice President,
`
`Pharmaceutical Development, and subsequently Principal Director, Pharmaceutics
`
`and Technology, at Santen Inc., the U.S. subsidiary of the Japanese ophthalmic
`
`pharmaceutical company, Santen Ltd. My responsibilities included directing
`
`ophthalmic formulation development, stability assessment, preparation of internal
`
`reports and regulatory documents, and review of in-license candidates. The areas I
`
`supervised included formulation development, analytical chemistry and stability
`
`assessment, clinical supplies, and non-clinical development. During my tenure
`
`with Santen Inc., three ophthalmic projects, Quixin, Betimol, and Alamast, resulted
`
`in successful New Drug Applications (“NDAs”) by the Food and Drug
`
`Administration (“FDA”) and commercial launch. A fourth NDA, Iquix, and a
`
`prostaglandin compound, tafluprost (now marketed in the U.S. as Zioptan®), to
`
`which I contributed to its formulation as well as chemistry, manufacturing and
`
`control (“CMC”) development strategy, were approved subsequent to my leaving
`
`Santen. Alamast whose active ingredient is pemirolast potassium is an acidic drug
`
`though not a NSAID (see paragraph 27 for further discussion of acidic drugs). We
`
`faced an analogous dilemma regarding turbidity and precipitate formation of
`
`pemirolast with BAC. In this case we were able to solve the issue by choosing the
`
`C12-BAC homologue as the quaternary ammonium preservative.
`
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`Declaration of Dr. Paul A. Laskar (EX1003)
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`15. From 1993 to 1994, I was Director, Pharmaceutical Development, at
`
`CoCensys, a start-up pharmaceutical company. During this time, I directed CMC
`
`development of two new chemical entities (“NCE”), one for oral use as a
`
`suspension and solid drug product, and the second as a parenteral. The oral NCE
`
`was successfully formulated as a suspension and submitted as an investigational
`
`new drug (“IND”) application to the FDA.
`
`16. From 1982 to 1993, I was employed by Allergan, Inc., an ophthalmic
`
`specialty company. Initially, I was a Scientist, Product Development, then I
`
`became a Section Manager and eventually Manager in the same area, and, finally,
`
`Director, Product Development. While at Allergan, I was involved in the
`
`formulation and subsequent development of a number of ophthalmic and
`
`dermatological drug products, many of which were approved as NDAs by the FDA
`
`and their equivalents in other countries/jurisdictions. From 1973 to 1982, I was
`
`Assistant Professor of Pharmacy at the College of Pharmacy, University of Illinois-
`
`Medical Center (now University of Illinois-Chicago Campuses) and then Associate
`
`Professor of Pharmacy at the School of Pharmacy at Creighton University. During
`
`this time, among the courses I taught were those in dosage form development
`
`including oral solids, ophthalmics, and dermatologicals.
`
`17. At present, I provide consulting services to start-up and established
`
`pharmaceutical companies for pharmaceutical projects. The nature of the projects
`
`15
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`Declaration of Dr. Paul A. Laskar (EX1003)
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`includes ophthalmics, sterile parenterals, dermatologicals, and liquid and solid oral
`
`drug products. The areas in which I consult include active pharmaceutical
`
`ingredient (API) synthesis and qualification, formulation development, stability
`
`assessment, analytical development, manufacturing process development and
`
`transfer, contract laboratory and manufacturer identification and their management,
`
`and preparation of regulatory documents.2
`
`IV. Person of ordinary skill in the art (POSA)
`
`18.
`
`I understand that a POSA is a hypothetical person who is presumed to
`
`be aware of all pertinent art, thinks along conventional wisdom in the art, and is a
`
`person of ordinary creativity. With respect to the ’431 patent, a POSA would
`
`have had education and/or experience in ophthalmic formulations and drug
`
`delivery, and knowledge of the scientific literature concerning the same,
`
`specifically
`
`pharmaceutical
`
`formulations
`
`comprising
`
`anti-inflammatory
`
`compounds such as NSAIDs, for ophthalmic administration as of 2003. The
`
`education and experience levels may vary between persons of ordinary skill, with
`
`some persons holding a basic Bachelor’s degree, but with 5-10 years of relevant
`
`work experience, or others holding more advanced degrees—e.g., Pharm.D.,
`
`Ph.D., or M.D.—but having fewer years of experience. A POSA may also work
`
`
`2 I reserve the right to further explain my background and qualifications in
`
`deposition where needed.
`
`16
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`Declaration of Dr. Paul A. Laskar (EX1003)
`
`as part of a multi-disciplinary team and draw upon not only his or her own skills,
`
`but also take advantage of certain specialized skills of others in the team, to solve
`
`a given problem.
`
`V.
`
`The ’431 patent
`
`19.
`
`I have considered the disclosure of the ’431 patent in light of general
`
`knowledge in the relevant field as of the earliest possible priority date of the ’431
`
`patent, which I understand to be January 21, 2003.
`
`20. The ’431 patent specification is directed to an aqueous liquid
`
`preparation containing 2-amino-3-(4-bromobenzoyl)phenylacetic acid (otherwise
`
`known as its generic name, bromfenac (see EX1030, 2-3) or its pharmacologically
`
`acceptable salt thereof or a hydrate thereof. Bromfenac as the free acid has the
`
`following chemical structure:
`
`
`(EX1001, 1:24-34). The bromfenac aqueous liquid preparations described in the
`
`
`
`’431 patent also include a surfactant of the alkyl aryl polyether alcohol type or a
`
`polyethylene glycol fatty acid ester type. (EX1001, Abstract).
`
`21. The ’431 patent further specifies
`
`that
`
`the pharmacologically
`
`acceptable salt of bromfenac can be the sodium salt, and that the bromfenac
`
`17
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`Declaration of Dr. Paul A. Laskar (EX1003)
`
`sodium salt hydrates can be 1/2 hydrate (also known as “hemihydrate”), 1 hydrate
`
`(also known as “monohydrate”) or 3/2 hydrate (also known as “sesquihydrate”).3
`
`(EX1001, 3:22-25; 4:20-27). In addition, the ’431 patent specifies that among
`
`alkyl aryl polyether alcohol type surfactants, tyloxapol, is especially preferred.
`
`(EX1001, 4:65-67).
`
`22. The ’431 patent is more specifically directed to an aqueous liquid
`
`ophthalmic preparation containing bromfenac and tyloxapol, with or without the
`
`preservative benzalkonium chloride (“BAC”, “BAK,” or “BKC”), that is stable
`
`within a pH range that gives no irritation to the eye, and in which a decrease in the
`
`preservative effect of BAC (when present) is inhibited. (EX1001, 2:14-22; 6:5-
`
`10).
`
`VI. State of the art as of January, 2003
`
`A. Non-steroidal anti-inflammatory compounds were known and
`approved for ophthalmic use
`
`23. Prior to 2003, non-steroidal anti-inflammatory drugs (NSAIDs) were
`
`widely used for managing postoperative ocular inflammation, preventing and
`
`
`3 1/2 hydrate corresponds to a ratio of 1 molecule of water per 2 molecules
`
`of a drug; 1 hydrate corresponds to a ratio of 1 molecule of water per 1 molecule of
`
`a drug; and 3/2 hydrate corresponds to a ratio of 3 molecules of water per 2