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. 8,754,131 to Sawa et al
`Issue Date: June 17, 2014
`
`Title: Aqueous Liquid Preparation Containing 2-Amino-3-(4-
`Bromobenzoyl)Phenylacetic Acid
`
`Inter Partes Review No: IPR2016-00089
`
`DECLARATION OF PAUL A. LASKAR, PH.D.
`
`Innopharma EX1003, Page 1
`
`

`
`TABLE OF CONTENTS
`
`Page
`
`B.
`C.
`
`D.
`
`Introduction......................................................................................................1
`I.
`List of documents I considered in formulating my opinion............................7
`II.
`III. My background and qualifications ................................................................12
`IV.
`Person of ordinary skill in the art (POSA) ....................................................16
`V.
`The ’131 patent..............................................................................................17
`VI.
`State of the art as of January 2003.................................................................18
`A.
`Non-steroidal anti-inflammatory compounds were known and
`approved for ophthalmic use...............................................................18
`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 ’131 patent in view of the
`prior art................................................................................................30
`VII. Obviousness of Claims 1-30 of the ’131 patent ............................................32
`A.
`The basis of my analysis with respect to obviousness........................32
`B.
`Obviousness Ground 1 – Ogawa and Sallmann..................................34
`1.
`Claim 1......................................................................................35
`2.
`Claim 7......................................................................................39
`3.
`Claim 13....................................................................................41
`4.
`Further Discussion Regarding Claims 1, 7, and 13 ..................42
`5.
`Claims 2, 8, 14 and 20—Quaternary Ammonium Salt.............52
`6.
`Claims 3 and 15—Bromfenac Sodium Salt..............................53
`7.
`Claims 4, 6, 10, 12, 16, 18, 22, and 24—Concentrations.......54
`8.
`Claims 6, 12, 18, and 24—Additional Additives......................58
`9.
`Claims 5, 11, 17, and 23—pH Ranges......................................64
`10. Claims 9, 19, and 21—Stability................................................65
`11. Claims 25-29—Preservative Efficacy Test...............................67
`Obviousness Ground 2 – Ogawa and Sallmann and Fu......................71
`1.
`Claims 1, 7, and 13....................................................................72
`
`E.
`
`C.
`
`ii
`
`Innopharma EX1003, Page 2
`
`

`
`2.
`
`D.
`
`Claims 4, 6, 10, 12, 16, 18, and 22—Tyloxapol
`Concentrations ........................................................................74
`Obviousness Ground 3 – Ogawa and Sallmann and Yasueda ............76
`1.
`Claims 1, 7, and 13....................................................................78
`2.
`Claims 4, 6, 10, 12, 16, 18, and 22—Tyloxapol
`Concentrations ........................................................................79
`VIII. No Unexpected Results Over the Closest Prior Art ......................................81
`A.
`Tyloxapol’s stabilization of an aqueous ophthalmic bromfenac
`preparation is not unexpected in view of the prior art ........................82
`Scope of Stabilizing Effects ................................................................86
`B.
`IX. No long-felt, unmet need existed for an ophthalmic NSAID
`preparation formulated with BAC ................................................................88
`The claimed bromfenac preparations were not met with skepticism............89
`The claimed bromfenac ophthalmic formulations have not received
`any praises .....................................................................................................90
`XII. Additional evidence of secondary considerations.........................................90
`XIII. Conclusion .....................................................................................................91
`
`X.
`XI.
`
`iii
`
`Innopharma EX1003, Page 3
`
`

`
`Declaration of Dr. Paul A. Laskar (EX1003); IPR2016-00089
`
`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 inter partes review involves U.S.
`
`Patent No. 8,754,131 (“the ’131 patent”) (EX1001), which was issued on June 17,
`
`2014, from U.S. Application No. 14/165,976 (“the ’976 application”), naming
`
`Shirou Sawa and Shuhei Fujita as the inventors. The ’976 application is a division
`
`of application No. 13/687,242 application (“the ’242 application”), now U.S.
`
`Patent No. 8,669,290, which is a division of application No. 13/353,653 (“the ’653
`
`application”), now U.S. Pat. No. 8,497,304, which is a division of application No.
`
`10/525,006 (“the ’006 application”), which was 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 ’131 patent is January 21, 2003, the filing date of the Japanese
`
`priority application. I further understand that, according to the USPTO records, the
`
`1
`
`Innopharma EX1003, Page 4
`
`

`
`Declaration of Dr. Paul A. Laskar (EX1003); IPR2016-00089
`
`’131 patent is currently assigned to Senju Pharmaceutical Co., Ltd. (“Senju,” “the
`
`patentee,” or “the patent owner”).
`
`4.
`
`Claim 1 of the ’131 patent is reproduced below:
`
`(a) a first
`1. A stable aqueous liquid preparation comprising:
`component; and (b) a second component; 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;
`the
`first
`component
`is
`the
`sole
`pharmaceutical active ingredient contained in the preparation and is
`present in the preparation at a concentration from about 0.05 w/v % to
`about 0.2 w/v %; the second component is tyloxapol and is present in
`said liquid preparation in an amount sufficient to stabilize said first
`component; and wherein said stable liquid preparation is formulated
`for ophthalmic administration.
`
`(EX1001, 12:2-15).
`5.
`Claims 2-6, 25-26, and 30 either depend directly or indirectly from
`
`Claim 1. Claims 3-6 and 30 recite the addition of a quaternary ammonium salt,
`
`concentrations of tyloxapol and/or bromfenac or its sodium salt, the pH of the
`
`preparations, and additional additives. Claim 2 recites that the bromfenac is a
`
`sodium salt. Claims 25 and 26 recites a preservative efficacy standard.
`
`2
`
`Innopharma EX1003, Page 5
`
`

`
`Declaration of Dr. Paul A. Laskar (EX1003); IPR2016-00089
`
`6.
`
`Claim 7 is reproduced below:
`
`(a) a first
`7. A stable aqueous liquid preparation comprising:
`component; and (b) a second component; 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;
`the
`first
`component
`is
`the
`sole
`pharmaceutical active ingredient contained in the preparation and is
`present in the preparation at a concentration from about 0.05 w/v % to
`about 0.2 w/v %; the second component is tyloxapol; wherein said
`stable liquid preparation is formulated for ophthalmic administration;
`and 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.
`(EX1001, 12:37-51).
`7.
`Claims 8-12, 27, and 28 depend directly or indirectly from claim 7.
`
`Claims 8 and 10-12 recite the addition of a quaternary ammonium salt,
`
`concentrations of tyloxapol and/or bromfenac or its sodium salt, the pH of the
`
`preparations, and additional additives. Claim 9 recites an aqueous formulation of
`
`claim 7 in which greater than about 92% of the original amount of bromfenac
`
`remains in the preparation after storage at about 60° C for 4 weeks. Claims 27 and
`
`28 recites a preservative efficacy standard.
`
`3
`
`Innopharma EX1003, Page 6
`
`

`
`Declaration of Dr. Paul A. Laskar (EX1003); IPR2016-00089
`
`8.
`
`Claim 13 is reproduced below:
`
`13. A stable aqueous liquid preparation comprising: (a) a first
`
`component; and (b) a second component; 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;
`
`the
`
`first
`
`component
`
`is
`
`the
`
`sole
`
`pharmaceutical active ingredient contained in the preparation and is
`
`present in the preparation at a concentration from about 0.05 w/v % to
`
`about 0.2 w/v %; the second component is tyloxapol; wherein said
`
`stable liquid preparation is formulated for ophthalmic administration;
`
`provided that the liquid preparation does not include mannitol.
`
`(EX1001, 13:13-24).
`9.
`Claims 14-24 and 29 depend directly or indirectly from claim 13.
`
`Claims 14, 16-18, 20, and 22-24 recite the addition of a quaternary ammonium salt,
`
`concentrations of tyloxapol and/or bromfenac or its sodium salt, the pH of the
`
`preparations, and additional additives. Claim 15 recites that the bromfenac is a
`
`sodium salt. Claims 19 and 21 recite a preparation wherein greater than about 90%
`
`and 92%, respectively, of bromfenac remains in the preparation after storage at
`
`about 60° C for 4 weeks. Claim 29 recites a preservative efficacy standard.
`
`4
`
`Innopharma EX1003, Page 7
`
`

`
`Declaration of Dr. Paul A. Laskar (EX1003); IPR2016-00089
`
`10.
`
`In preparing this Declaration, in addition to those materials listed
`
`above, I have reviewed the ’131 patent and considered the file history of the ’131
`
`patent, and each of the documents cited herein, in light of general knowledge in the
`
`art as of before January, 21 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
`
`anti-inflammatory preparations) as of before January 21, 2003. 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, 7, and 13 of the ’131 patent and such a POSA would
`
`have had a reasonable expectation of success in making the claimed
`
`preparations.
`
`b.
`
`A POSA would have been further motivated to combine Ogawa and
`
`Sallmann in view of Australian Patent No. AU-B-22042/88 (“Fu”)
`
`(EX1011) to arrive at the claimed invention as recited in independent claims
`
`1, 7, and 13 of the ’131 patent and such a POSA would have had a
`
`reasonable expectation of success in making the claimed preparations.
`
`5
`
`Innopharma EX1003, Page 8
`
`

`
`Declaration of Dr. Paul A. Laskar (EX1003); IPR2016-00089
`
`c.
`
`A POSA would have been further motivated to combine Ogawa and
`
`Sallmann in view of U.S. Patent No. 6,274,609 (“Yasueda”) (EX1012) to
`
`arrive at the claimed invention as recited in independent claims 1, 7, and 13
`
`of the ’131 patent and such a POSA would have had a reasonable
`
`expectation of success in making the claimed preparations.
`
`d.
`
`The additional features recited in dependent claims 2-6, 8-12, and 14-
`
`30 would have been obvious to a POSA in view of Ogawa (EX1004) and
`
`Sallmann (EX1009), or in the alternative in further view of Fu (EX1011), or
`
`in further view of Yasueda (EX1012), and when considered in light of the
`
`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), or in the alternative
`
`in further view in Fu (EX1011) or Yasueda (EX1012), and when considered
`
`in light of the other prior art references discussed in this declaration, to
`
`arrive at the claimed inventions of claims 2-6, 8-12, and 14-30 and such a
`
`POSA would have had a reasonable expectation of success in making the
`
`claimed inventions.
`
`6
`
`Innopharma EX1003, Page 9
`
`

`
`Declaration of Dr. Paul A. Laskar (EX1003); IPR2016-00089
`
`e.
`
`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.
`
`II.
`
`List of documents I considered in formulating my opinion
`11.
`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. 8,754,131, as well as the following documents:
`
`InnoPharma
`Exhibit #
`1001
`
`1002
`
`1003
`1004
`
`1005
`
`1006
`
`1007
`
`Description
`
`Sawa et al., U.S. Patent No. 8,754,131, “Aqueous Liquid Preparation
`Containing 2-Amino-3-(4-Bromobenzoyl) Phenylacetic Acid”
`Certified English translation of: Hara, Yoshiyuki , “Bromfenac
`sodium hydrate,” Clinics & Drug Therapy 19:1014-1015 (2002)
`
`Declaration of 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)
`
`7
`
`Innopharma EX1003, Page 10
`
`

`
`InnoPharma
`Exhibit #
`1008
`
`1009
`
`1010
`
`1011
`
`1012
`
`1013
`
`1014
`
`1015
`
`1016
`
`1017
`
`1018
`
`1019
`
`Declaration of Dr. Paul A. Laskar (EX1003); IPR2016-00089
`
`Description
`
`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”
`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”
`U.S. Patent Application No. 13/687,242, Office Action of August
`1, 2013
`U.S. Patent Application No. 10/525,006, Applicant Remarks in
`support of amendment March 26, 2008
`U.S. Patent Application No. 10/525,006, Applicant Remarks in
`support of amendment, September 6, 2011
`The Pharmacopeia of the United States of America, Twenty-Sixth
`Revision and the National Formulary, Twenty-First Edition
`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)
`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)
`
`8
`
`Innopharma EX1003, Page 11
`
`

`
`InnoPharma
`Exhibit #
`1020
`
`1021
`
`1022
`
`1023
`
`1024
`
`1025
`
`1026
`
`1027
`
`1028
`
`1029
`
`1030
`
`Declaration of Dr. Paul A. Laskar (EX1003); IPR2016-00089
`
`Description
`
`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”
`Bergamini et al., U.S. Patent No. 5,597,560, “Diclofenac And
`Tobramycin Formulations For Ophthalmic And Otis Topical Use”
`U.S. Patent Application No. 13/687,242, Applicant Remarks in
`support of amendment, November 28, 2012
`Excerpt of Plaintiffs’ Opening Markman Brief filed in Senju
`Pharma. Co., Ltd. et al. v. InnoPharma Licensing, Inc. et al., C.A.
`No. 1:15-cv-03240-JBA-KMW (D.N.J.) D.I. 16 (Aug. 10, 2015).
`
`U.S. Patent Application No. 13/687,242, Applicant Remarks in
`support of amendment, October 22, 2013
`"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?
`Appl_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)
`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)
`
`9
`
`Innopharma EX1003, Page 12
`
`

`
`InnoPharma
`Exhibit #
`1031
`
`1032
`
`1033
`
`1034
`
`1035
`
`1036
`
`1037
`
`1038
`
`1039
`
`1040
`1041
`
`1042
`
`Declaration of Dr. Paul A. Laskar (EX1003); IPR2016-00089
`
`Description
`
`“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).
`Reddy, Indra K., Ocular Therapeutics and Drug Delivery: A
`Multi-Disciplinary Approach: 42-43, 390 (1996).
`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).
`Wong, Michelle, International Patent No. WO 94/15597,
`“Ophthalmic Compositions Comprising
`Benzyllauryldimethylammonium Chloride” (filed January 11,
`1993; issued July 21, 1994).
`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).
`FDA approved “ALREXTM (loteprednol etabonate ophthalmic
`suspension) 0.2% Product Label,” U.S. Approval: 1998, Bausch
`& Lomb Pharmaceuticals.
`etabonate
`FDA approved
`“LOTEMAXTM (loteprednol
`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).
`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”.
`
`10
`
`Innopharma EX1003, Page 13
`
`

`
`Declaration of Dr. Paul A. Laskar (EX1003); IPR2016-00089
`
`Description
`
`Kawabata et al., Canadian Patent No. CA 2 383 971 A1,
`“Prophylactic and Therapeutic Medicaments for Ophthalmic
`Uses”.
`Patani, G., et al., “Bioisoterism: A Rational Approach in
`Drug Design,” Chem. Rev. 96: 3147-3176 (1996).
`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.
`
`FDA approved “PROLENSATM (bromfenac ophthalmic
`solution, 0.07%) Product Label,” U.S. Approval: April 5,
`2013, Bausch & Lomb Incorporated
`
`“Borax (Sodium tetraborate),” Biochemicals and Reagents:
`175, Sigma-Aldrich (2000-2001).
`Ali, et al., U.S. Patent No. 6,071,904, “Process for
`Manufacturing Ophthalmic Suspensions”.
`Story, M., et al., European Patent No. 0274870, “Micelles
`containing a non-steroidal antiinflammatory compound”
`(filed December 12, 1987; issued July 7, 1988)
`
`“DuractTM,” Physician’s Desk Reference 52:3035-3037 (1998).
`Curriculum Vitae of Paul A. Laskar, Ph.D.
`U.S. Patent Application No. 10/525,006, Applicant Remarks in
`support of amendment Oct. 25, 2010
`
`InnoPharma
`Exhibit #
`1043
`
`1044
`
`1045
`
`1046
`
`1047
`
`1048
`
`1049
`
`1050
`
`1051
`1052
`
`1053
`
`11
`
`Innopharma EX1003, Page 14
`
`

`
`Declaration of Dr. Paul A. Laskar (EX1003); IPR2016-00089
`
`III. My background and qualifications
`12.
`I am an expert
`in the field of formulations and drug delivery,
`
`specifically pharmaceutical formulations for ophthalmic administration, including
`
`topical aqueous liquid 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 Exhibit 1052, and it provides a comprehensive description of my academic
`
`and employment history.
`
`13. 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.
`
`14.
`
`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
`
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`Declaration of Dr. Paul A. Laskar (EX1003); IPR2016-00089
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`Illinois; and a B.A. in General Science (Chemistry, Biology) from the University
`
`of Rochester.
`
`15.
`
`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.
`
`16.
`
`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
`
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`Declaration of Dr. Paul A. Laskar (EX1003); IPR2016-00089
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`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 29 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.
`
`17.
`
`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.
`
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`Declaration of Dr. Paul A. Laskar (EX1003); IPR2016-00089
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`18.
`
`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.
`
`19. At present, I provide consulting services to start-up and established
`
`pharmaceutical companies for pharmaceutical projects. The nature of the projects
`
`include 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
`
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`Declaration of Dr. Paul A. Laskar (EX1003); IPR2016-00089
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`transfer,
`
`contract
`
`laboratory and manufacturer
`
`identification and their
`
`management, and preparation of regulatory documents.1
`
`IV.
`
`Person of ordinary skill in the art (POSA)
`20.
`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 ’131 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
`
`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.
`
`1 I reserve the right to further explain my background and qualifications in
`
`deposition where needed.
`
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`Declaration of Dr. Paul A. Laskar (EX1003); IPR2016-00089
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`V.
`
`The ’131 patent
`21.
`I have considered the disclosure of the ’131 patent
`
`in light of
`
`general knowledge in the relevant field as of the earliest possible priority date of
`
`the ’131 patent, which I understand to be January 21, 2003.
`
`22.
`
`The ’131 patent specification is directed to an aqueous liquid
`
`preparation containing 2-amino-3-(4-bromobenzoyl) phenylacetic acid (otherwise
`
`known as its generic name, bromfenac), (EX1051, 2-3) or its pharmacologically
`
`acceptable salt thereof or a hydrate thereof.
`
`(EX1001, 1:18-44). The bromfenac
`
`aqueous liquid preparations described in the ’131 patent also include an alkyl aryl
`
`polyether alcohol
`
`type surfactant or a polyethylene glycol
`
`fatty acid ester
`
`surfactant. (EX1001, 1:15-17).
`
`23.
`
`The ’131 patent
`
`further
`
`specifies
`
`that
`
`the pharmacologically
`
`acceptable salt of bromfenac can be the sodium salt, and that the bromfenac
`
`sodium salt can be one of several hydrates: 1/2 hydrate, 1 hydrate or 3/2 hydrate.2
`
`2 1/2 hydrate or hemihydrate corresponds to a ratio of 1 molecule of water
`
`per 2 molecules of a drug; 1 hydrate or monohydrate corresponds to a ratio of 1
`
`molecule of water per 1 molecule of a drug; and 3/2 hydrate or sesquihydrate
`
`corresponds to a ratio of 3 molecules of water per 2 molecules of a drug.
`
`(EX1026, 3).
`
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`Declaration of Dr. Paul A. Laskar (EX1003); IPR2016-00089
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`(EX1001, 4:23-26).
`
`In addition, the ’131 patent specifies that among alkyl aryl
`
`polyether alcohol type surfactants, tyloxapol is especially preferred.
`
`(EX1001,
`
`4:65-67).
`
`24.
`
`The ’131 patent is more specifically directed to an aqueous liquid
`
`ophthalmic preparation containing bromfenac and tyloxapol, with or without a
`
`preservative, such as benzalkonium chloride (“BAK,” “BAC,” 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, 2:11-18,
`
`23-29, 57-59).
`
`VI.
`
`State of the art as of January 2003
`A.
`Non-steroidal anti-inflammatory compounds were known and
`approved for ophthalmic use
`Prior to 2003, non-steroidal anti-inflammatory drugs (NSAIDs) were
`
`25.
`
`widely used for managing postoperative ocular inflammation, preventing and
`
`treating cystoid macular edema after cataract surgery, preventing intraoperative
`
`miosis during cataract
`
`surgery,
`
`relieving symptoms of
`
`seasonal allergic
`
`conjunctivitis, and reducing ocular discomfort
`
`following refractive surgery.
`
`(EX1018, 1:1).
`
`26. As of January 21, 2003, a number of NSAIDs, formulated for
`
`ophthalmic use, were FDA-approved and sold in the United States. For example,
`
`diclofenac 0.1% (Voltaren® Ophthalmic Solution, Novartis) was approved in 1991
`
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`Declaration of Dr. Paul A. Laskar (EX1003); IPR2016-00089
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`for minimizing postoperative inflammation after cataract surgery.
`
`(EX1027).
`
`Diclofenac free acid has the following chemical structure:
`
`27. An ophthalmic formulation of ketorolac tromethamine 0.5% (Acular®
`
`Ophthalmic Solution, Allergan) was approved in 1992 for treating seasonal allergic
`
`conjunctivitis.
`
`(EX1018, 2:1). Ketorolac free acid has the following chemical
`
`structure:
`
`28.
`
`Flurbiprofen
`
`sodium 0.03% (Ocufen® Ophthalmic Solution,
`