UNITED STATES PATENT AND TRADEMARK OFFICE
`
`_______________________________
`
`BEFORE THE PATENT TRIAL AND APPEAL BOARD
`
`_______________________________
`
`LUPIN LTD. and LUPIN PHARMACEUTICALS INC.
`Petitioner
`
`v.
`
`SENJU PHARMACEUTICAL CO., LTD.
`Patent Owner
`____________________
`
`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.: Unassigned
`____________________
`
`DECLARATION OF M. JAYNE LAWRENCE, PH.D
`
`LUPIN EX1054, Page 1
`
`

`
`Contents
`Introduction ....................................................................................................... 1
`I.
`II.
`List of Documents Considered .......................................................................... 7
`III. Qualifications .................................................................................................. 11
`IV. Person of ordinary skill in the art (POSA) ...................................................... 15
`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. BAC was the preservative of choice in ophthalmic formulations ............. 21
`C. It was known that non-ionic surfactants stabilized aqueous
`preparations containing an NSAID and BAC....................................... 22
`D. Tyloxapol is a non-ionic surfactant that was known and widely used
`in ophthalmic formulations by January 2003 ....................................... 24
`E. There is nothing inventive in the ’431 patent in view of the prior art ....... 28
`VII. Obviousness of Claims 1-22 of the ’431 patent .............................................. 29
`A. The basis of my analysis with respect to obviousness ............................... 29
`B. Obviousness Ground 1 - Ogawa and Sallmann ......................................... 31
`1. Independent Claims 1 and 18 .......................................................... 33
`2. Claims 2, 5, 11 and 19 ..................................................................... 43
`3. Claims 3 and 4 ................................................................................. 47
`4. Claims 6 and 15 ............................................................................... 50
`5. Claims 7, 8, 13, 14, 16 and 17 ......................................................... 52
`6. Claims 9 and 10 ............................................................................... 56
`7. Claim 12 ........................................................................................... 58
`8. Claims 21, and 22 ............................................................................ 60
`9. Claim 20 ........................................................................................... 61
`VIII. The claimed invention of the ’431 patent does not possess unexpectedly
`superior properties ..................................................................................................... 61
`
`i
`
`
`LUPIN EX1054, Page 2
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`

`
`A. Tyloxapol’s stabilization of an aqueous ophthalmic bromfenac
`preparation is not unexpected in view of the prior art .......................... 62
`B. The stabilization of bromfenac preparations by tyloxapol is not
`observed across the entire range of the claimed preparations .............. 65
`1. The supposedly unexpected stability of aqueous bromfenac
`preparations is not observed across the entire range of
`claimed pH ....................................................................................... 66
`2. The supposedly unexpected increase in stability of aqueous
`bromfenac preparations is not observed across the entire
`range of claimed benzalkonium chloride homologues .................... 67
`C. Tyloxapol’s stabilization of the preservative effect of BAC is not
`unexpected in view of prior art ............................................................. 68
`D. No long-felt, unmet need existed for an ophthalmic NSAID
`preparation formulated with BAC ........................................................ 70
`E. The claimed bromfenac preparations were not met with skepticism ........ 71
`F. The claimed bromfenac ophthalmic formulations have not received
`any praise .............................................................................................. 72
`G. Additional evidence of secondary considerations ..................................... 72
`IX. Conclusion ....................................................................................................... 73
`
`
`ii
`
`
`LUPIN EX1054, Page 3
`
`

`
`
`
`
`
`I, Jayne Lawrence, Ph.D., declare and state as follows:
`
`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 Lupin Ltd. and Lupin
`
`Pharmaceuticals Inc. (“Petitioner”) for the above captioned inter partes review (“Lupin
`
`IPR”). I am being compensated for my time in connection with this IPR at my standard
`
`consulting rate, which is GBP300 per hour. My compensation is not contingent on the
`
`conclusions I reach herein or on the specifics of my testimony. I have no financial stake
`
`in the outcome of this proceeding.
`
`3.
`
`I understand that the Lupin 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
`
`1
`
`
`LUPIN EX1054, Page 4
`
`

`
`
`
`understand that the ’431 patent is currently subject to a previous IPR, InnoPharma
`
`Licensing, Inc. v. Senju Pharmaceuticals Co., Ltd., IPR2015-00903 (the “InnoPharma
`
`IPR”), as well as a now-settled IPR, Metrics, Inc. v. Senju Pharmaceutical Co., Ltd.,
`
`IPR2014-01041 (the “Metrics IPR”). I understand that Petitioner seeks to become a
`
`party to the InnoPharma IPR. I have reviewed the materials submitted with the
`
`petition filed in the InnoPharma IPR, including the petition itself (IPR2015-00903,
`
`Paper 2), the Declaration of Dr. Paul A. Laskar (IPR2015-00903, Exhibit 1003), the
`
`Board’s Decision Instituting Inter Partes Review (IPR2015-00903, Paper 15), and the
`
`prior art and materials cited in each. I have also reviewed the materials submitted in
`
`connection with the Metrics IPR, including the petition itself (Second Corrected
`
`Petition, IPR2014-01041, Paper 9), the Second Corrected Declaration of Dr. Uday B.
`
`Kompella (IPR2014-01041, Exhibit 1003), the Patent Owner’s Preliminary Response
`
`(IPR2014-01041, Paper 13), and Board’s Decision Instituting Inter Partes Review
`
`(IPR2014-01041, Paper 19). I note that I agree in all material respects with the
`
`analysis and opinions set forth by the petitioner InnoPharma’s expert, Dr. Laskar, in
`
`the declaration that was submitted in the InnoPharma IPR and share the same opinions
`
`below.1 I also note that I agree in all material respects with the analysis and opinions
`
`1 I do not independently address claim construction in this Declaration, because I
`
`understand that, in instituting IPR20115-00903, the Board has credited the testimony of
`
`Dr. Laskar “on the views of a hypothetical person of ordinary skill in the art at the time
`
`of the invention,” and has already determined that the claim terms are to be given their
`
`2
`
`
`LUPIN EX1054, Page 5
`
`

`
`
`
`set forth by petitioner Metrics’ expert, Dr. Kompella. Because my independent
`
`analysis of the claims and prior art led to the same conclusions as Dr. Laskar, coupled
`
`with the fact that the Petitioner is seeking to become a party to the InnoPharma IPR, I
`
`have incorporated Dr. Laskar’s opinions and characterizations below as my own. I
`
`understand that in its Decision Instituting Inter Partes Review in connection with the
`
`InnoPharma IPR, the Board concluded that Petitioner InnoPharma 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. (IPR2015-00903, Paper 15, pg. 19). Therefore, because Petitioner is
`
`seeking to join the instituted review of the ’431 patent, the opinions expressed herein
`
`are 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
`
`
`ordinary and customary meaning, as understood by one of ordinary skill in the art.
`
`IPR2015-00903, Paper 15, page 4-5. Accordingly, for purposes of this Declaration
`
`only, I will adopt the constructions set forth by Dr. Laskar in his Declaration.
`
`3
`
`
`LUPIN EX1054, Page 6
`
`

`
`
`
`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,
`
`wherein the hydrate is at least one selected from a 1/2 hydrate, 1
`
`hydrate, and 3/2 hydrate,
`
`(b)
`tyloxapol,
`(c) boric acid,
`(d)
`sodium tetraborate,
`(e) EDTA sodium salt,
`(f)
`benzalkonium chloride,
`(g) polyvinylpyrrolidone,
`(h)
`sodium sulfite,
`wherein said liquid preparation is formulated for ophthalmic
`
`administration, and
`
`4
`
`
`LUPIN EX1054, Page 7
`
`

`
`
`
`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 anti-inflammatory preparations)
`
`as of January 2003. I agree with the conclusions, opinions and bases expressed by Dr.
`
`Laskar in his declaration submitted in the InnoPharma 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
`
`5
`
`
`LUPIN EX1054, Page 8
`
`

`
`
`
`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 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)2 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.
`
`2 I understand that the Fu reference has a related US patent (U.S. Patent No. 5,110,493)
`
`which contains a similar disclosure.
`
`6
`
`
`LUPIN EX1054, Page 9
`
`

`
`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.
`
`
`
`II. List of Documents Considered
`
`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 #
`
`1001
`
`1002
`
`Description
`
`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)
`
`1003 Declaration of Dr. Paul A. Laskar, Ph.D.
`
`1004 Ogawa et al., U.S. Patent No. 4,910,225 "Locally Administrable Therapeutic
`Composition for Inflammatory Disease"
`
`1005 Desai et al., U.S. Patent No. 5,603,929, "Preserved Ophthalmic Drug
`Compositions Containing Polymeric Quaternary Ammonium Compounds"
`
`1006 Desai, et al., U.S. Patent No. 5,558,876, "Topical Ophthalmic Acidic Drug
`Formulations"
`
`1007
`
`1008
`
`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.
`
`7
`
`
`LUPIN EX1054, Page 10
`
`

`
`
`
`1009
`
`Sallmann et al., U.S. Patent No. 6,107,343, "Ophthalmic And Aural
`Compositions Containing Diclofenac Potassium"
`
`1010
`
`Guttman et al., "Solubilization of Anti-inflammatory steroids by Aqueous
`Solutions of Triton-WR-1339," Journal of Pharmaceutical Sciences 50:
`305-307 (1961)
`
`1011
`
`Fu et al., Australian Patent No. AU-B-22042/88, "Preservative System For
`Ophthalmic Formulations"
`
`1012
`
`1013
`
`1014
`
`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
`
`Kapin, et al., International Patent No. WO 2002/13804, "Method For
`Treating Angiogenesis-Related Disorders Using Benzoyl Phenylacetic
`Acid"
`
`1017
`
`Flach, Allan., "Topical Nonsteroidal Antiinflammatory Drugs for
`Ophthalmic Uses," Ophthalmic NSAIDS: 77-83 (1996)
`
`1018
`
`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)
`
`1019
`
`Bergamini et al., U.S. Patent No. 5,597,560, "Diclofenac And Tobramycin
`Formulations For Ophthalmic And Otis Topical use"
`
`1020 Wong, Michelle, International Patent No. WO 94/15597, “Ophthalmic
`Compositions Comprising Benzyllauryldimethylammonium Chloride”
`
`8
`
`
`LUPIN EX1054, Page 11
`
`

`
`
`
`(filed January 11, 1993); issued July 21, 1994)
`
`1021
`
`Reddy, Indra K., Ocular Therapeutics and Drug Delivery: A Multi-
`Disciplinary Approach: 42-43, 390 (1996)
`
`1022
`
`Story, M., et al., European Patent No. 0274870, "Micelles containing a
`non-steroidal antiinflammatory compound" (filed December 12, 1987;
`issued July 7, 1988)
`
`1023
`
`"Borax (Sodium tetraborate)," Biochemicals and Reagents: 175, Sigma-
`Aldrich (2000-2001)
`
`1024
`
`1025
`
`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)
`
`1026
`
`Aviv, H., International Patent No. WO 94/05298, "Submicron Emulsions as
`Ocular Drug Delivery Vehicles"
`
`1027 Gennaro, A., “Boric Acid,” Remington: The Science and Practice of
`Pharmacy 20: 1041, University of Sciences, United States (2000)
`
`1028
`
`Wade, A., and Weller, P., "Edetic Acid," and "Sodium Metabisulfite,"
`Handbook of Pharmaceutical Excipients 2: 176179, 451-453, American
`Pharmaceutical Association, United States (1994)
`
`1029
`
`Selected pages from the file history of U.S. Patent No. 8,129,431, March
`28, 2005 Amendment.
`
`1030
`
`"DuractTM," Physician’s Desk Reference 52:3035-3037 (1998).
`
`1031
`
`"monohydrate," Webster’s New World Dictionary of the American
`Language: 920, New World Dictionaries / Simon and Schuster (1980).
`
`1032
`
`"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
`
`9
`
`
`LUPIN EX1054, Page 12
`
`

`
`
`
`1033
`
`1034
`
`1035
`
`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).
`
`1036 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).
`
`FDA approved "ALREXTM (loteprednol etabonate ophthalmic suspension)
`0.2% Product Label," U.S. Approval: 1998, Bausch & Lomb
`Pharmaceuticals.
`
`"LOTEMAXTM
`(loteprednol etabonate ophthalmic
`FDA approved
`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).
`
`1037
`
`1038
`
`1039
`
`1040
`
`1041
`
`1042
`
`1043 Kawabata et al., Canadian Patent No. CA 2 383 971 A1, "Prophylactic and
`Therapeutic Medicaments for Ophthalmic Uses".
`
`1044
`
`1045
`
`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
`
`
`LUPIN EX1054, Page 13
`
`

`
`
`
`1046
`
`Patani, G., et al., "Bioisoterism: A Rational Approach in Drug Design,"
`Chem. Rev. 96: 3147-3176 (1996).
`
`1047 Ostrovskii, V.A., et al., "Acid-base properties of 5-substituted tetrazoles,"
`Chemistry of Heterocyclic Compounds 17: 412416 (1981)
`
`1048
`
`FDA approved "XIBROMTM (bromfenac ophthalmic solution, .09%)
`Product Label," ISTA Pharmaceuticals, Inc.
`
`1049
`
`1050
`
`1051
`
`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
`
`The United States Pharmacopeia 24: The National Formulary 19: 1809-
`1813, 1864-1866, The United States Pharmacopeial Convention, Inc.
`(1999).
`
`1052 Ali, et al., U.S. Patent No. 6,071,904, "Process for Manufacturing
`Ophthalmic Suspensions".
`
`1053
`
`Curriculum Vitae of Dr. Paul A. Laskar, Ph.D.
`
`
`III. Qualifications
`
`10.
`
`I am an expert in the field of formulation and drug delivery, specifically
`
`pharmaceutical formulation for oral and parenteral use (i.e., non-oral, including
`
`intravenous intramuscular, nasal, respiratory and ophthalmic), including aqueous liquid
`
`preparations. I have been an expert in this field since prior to 2003. In formulating my
`
`opinions, I have relied upon my training, knowledge, and experience in the relevant art.
`
`11
`
`
`LUPIN EX1054, Page 14
`
`

`
`
`
`A copy of my current curriculum vitae is provided as Exhibit 1055, and it provides a
`
`comprehensive description of my academic and employment history.
`
`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 1984, I have accumulated significant training and experience in the
`
`relevant field and related fields.
`
`12.
`
`I received a BSc with first class (top) honors from Liverpool Polytechnic in
`
`1981, and a Ph.D. in Pharmacy from Manchester University in 1985. The subject of my
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`PhD studies was the design, synthesis and physic-chemical characterization of novel
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`non-ionic surfactants for use in aqueous pharmaceutical formulations. I performed my
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`PhD studies under the supervision of Professors P.H. Elworthy and D. Attwood. From
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`1984 to the present time I have held full-time, tenured academic positions of increasing
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`seniority in Pharmacy (Lecturer 1984-1997, Senior Lecturer 1997-1999), Drug Delivery
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`(Reader 2000-2003) and, most recently Biophysical Pharmaceutics (Professor 2003-to
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`date) at King’s College London. I note that my professorship at King’s College London
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`is the United Kingdom equivalent of a full, tenured Professorship in a university in the
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`United States. In 1993 I spent a 6 month sabbatical working in Respiratory Product
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`Development in Glaxo Group Research (now GSK) concerned with the potential use of
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`surfactants in the new propellant formulations. I am currently Head of the
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`Pharmaceutical Biophysics Group of The Institute of Pharmaceutical Science, King’s
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`College London and I have held this position since 2002. The Pharmaceutical
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`Biophysics Group of The Institute of Pharmaceutical Science, King’s College London
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`currently consists of 6 academics and associated post-doctoral fellows and PhD
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`students. The work of the group is concerned with securing an understanding at the
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`molecular level of the physicochemical and biological properties of drug and gene
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`delivery systems, through the combined application of advanced analytical techniques.
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`13. Since 2007, I have also held the role of Chief Scientist at the Royal
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`Pharmaceutical Society on a part-time secondment from King’s College London. At the
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`present time, I equally divide my time between these two roles. My role at the Royal
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`Pharmaceutical Society involves me representing it at the highest levels to outside
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`organisations and key stakeholders (including government and public bodies), acting as
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`its spokesperson on pharmaceutical sciences in the media and ensuring high quality
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`pharmaceutical science input to policy development and implementation.
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`14. My past and current research has been in relation to pharmaceutical
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`formulation and drug/gene delivery. I have been a principal or co-investigator on many
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`formulation and drug/gene delivery studies, recent examples of which include the
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`development of novel microemulsions for parenteral delivery, including for ocular
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`administration; synthesis and characterisation of novel, non-ionic and zwitterionic
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`surfactants with enhanced drug solubilisation capacity; the development of novel
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`polymeric surfactants for pulmonary delivery; nanoparticles for the targeted delivery of
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`therapeutic agents to the brain; and development of new injectable composites for gene
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`delivery. I have co-authored over 120 full scientific publications, with numerous
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`
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`conference papers and other scientific outputs such as articles for the scientific
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`magazines. I have given over 150 invited (national and international) presentations. I
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`have also been involved in the organisation of many pharmaceutical science meetings
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`and conferences including the annual Academy of Pharmaceutical Sciences conference.
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`15. As listed in my curriculum vitae, I have also received numerous awards
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`pertaining to my research and teaching. For example, in 2013 I became a Faculty Fellow
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`of the Royal Pharmaceutical Society (“FFRPS”), while in 2012 I was awarded an
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`Eminent Fellowship of the Royal Pharmaceutical Society (“EFAPS”), one of only 20
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`such Fellowships. I currently hold senior positions in a number of national and
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`international scientific committees, including the Academy of Pharmaceutical Sciences
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`of Great Britain where I am currently vice-chair and
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`the Formulation and
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`Pharmaceutical Technology Special Interest Group of the International Pharmaceutical
`
`Federation where I am vice-chair but will become chair next year.
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`16.
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`In addition to gaining expertise through educational training, professional
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`experiences, and research experiences described above, I have kept abreast of the field
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`of drug/gene delivery and formulation, particularly of aqueous liquid preparations, by
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`reading scientific literature, attending or presenting at scientific conferences, and
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`attending or presenting at academic symposia. I have also been invited to participate in
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`the peer review process for various scientific journals, and have reviewed many
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`manuscripts submitted by other scientists relating to drug delivery, including ocular
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`delivery. Some of the scientific journals for which I have reviewed scientific
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`LUPIN EX1054, Page 17
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`manuscripts include: International Journal of Pharmaceutics, Journal of Pharmaceutical
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`Science, Langmuir, and Biochim. Biophys. Acta. Furthermore, I have collaborated with,
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`or have communicated with, many researchers in the field of formulation and drug/gene
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`delivery. Accordingly, I am an expert in the field of formulation and drug/gene delivery.
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`17. As set forth in more detail below, the patents at issue here, U.S. Patent Nos.
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`8,669,290; 8,754,131; 8,871,813; and 8,927,606 (collectively referred to herein as “the
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`subject patents”), relate generally to an aqueous formulation for ophthalmic use
`
`containing bromfenac and tyloxapol, and the method of treating an inflammatory
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`disease of an eye using the same aqueous formulation. Similar to the patents at issue,
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`my previous research and industry experience focused on the design and formulation of
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`aqueous formulations including, for example, novel surfactant and polymer containing
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`formulations for parenteral (including ocular) delivery. The opinions and conclusions I
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`express in this declaration are based on my education, my extensive experience in this
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`field, and my review of the materials related to this matter.3
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`IV. Person of ordinary skill in the art (POSA)
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`18.
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`I understand that a POSA is a hypothetical person who is presumed to be
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`aware of all pertinent art, thinks along conventional wisdom in the art, and is a person of
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`ordinary creativity. With respect to the ’431 patent, a POSA would have had education
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`and/or experience in ophthalmic formulations and drug delivery, and knowledge of the
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`3 I reserve the right to further explain my background and qualifications in deposition
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`where needed.
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`scientific literature concerning the same, specifically pharmaceutical formulations
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`comprising anti-inflammatory compounds such as NSAIDs,
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`for ophthalmic
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`administration as of 2003. The education and experience levels may vary between
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`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.,
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`Pharm.D., Ph.D., or M.D.—but having fewer years of experience. A POSA may also
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`work as part of a multi-disciplinary team and draw upon not only his or her own skills,
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`but also take advantage of certain specialized skills of others in the team, to solve a
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`given problem.
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`V. The ’431 patent
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`19.
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`I have considered the disclosure of the ’431 patent in light of general
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`knowledge in the relevant field as of the earliest possible priority date of the ’431
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`patent, which I understand to be January 21, 2003.
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`20. The ’431 patent specification is directed to an aqueous liquid preparation
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`containing 2-amino-3-(4-bromobenzoyl)phenylacetic acid (otherwise known as its
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`generic name, bromfenac (see EX1030, 2-3) or its pharmacologically acceptable salt
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`thereof or a hydrate thereof. Bromfenac as the free acid has the following chemical
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`structure:
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`
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`LUPIN EX1054, Page 19
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`(EX1001, 1:24-34). The bromfenac aqueous liquid preparations described in the ’431
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`patent also include a surfactant of the alkyl aryl polyether alcohol type or a polyethylene
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`
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`glycol fatty acid ester type. (EX1001, Abstract).
`
`21. The ’431 patent further specifies that the pharmacologically acceptable salt
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`of bromfenac can be the sodium salt, and that the bromfenac sodium salt hydrates can
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`be 1/2 hydrate (also known as “hemihydrate”), 1 hydrate (also known as
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`“monohydrate”) or 3/2 hydrate (also known as “sesquihydrate”).4
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` (EX1001, 3:22-25;
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`4:2