`
`
`
`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. 8,669,290 to Sawa et al.
`Issue Date: March 11, 2014
`Title: Aqueous Liquid Preparation Containing
`2-Amino-3-(4-
`bromobenzoyl) Phenylacetic Acid
`
`
`
`Inter Partes Review No.: IPR2015-00902
`
`
`
`
`
`
`Petition for Inter Partes Review of U.S. Patent No. 8,669,290 Under
`35 U.S.C. §§ 311-319 and 37 C.F.R. §§ 42.1-.80, 42.100-.123
`
`
`
`
`
`
`
`
`
`
`
`
`Mail Stop “PATENT BOARD”
`Patent Trial and Appeal Board
`U.S. Patent and Trademark Office
`P.O. Box 1450
`Alexandria, VA 22313-1450
`
`
`
`
`
`

`

`
`
`
`
`
`
`TABLE OF CONTENTS
`
`Page
`
`I.
`
`INTRODUCTION ........................................................................................... 1
`
`II.
`
`OVERVIEW .................................................................................................... 1
`
`A.
`
`The ’290 patent ...................................................................................... 2
`
`B.
`
`The Scope and Content of the Prior Art ................................................ 4
`
`1.
`
`2.
`
`Aqueous Opthalmic Preparation of Bromfenac .......................... 4
`
`Tyloxapol and Related Surfactants in NSAID Aqueous
`Ophthalmic Preparations ......................................................... 5
`
`C.
`
`The Differences Between the Challenged Claims and the Prior
`Art .......................................................................................................... 6
`
`III.
`
`STANDING (37 C.F.R. § 42.104(a); PROCEDURAL
`STATEMENTS) ............................................................................................10
`
`IV. MANDATORY NOTICES (37 C.F.R. § 42.8(a)(1)) ....................................11
`
`A.
`
`Each Real Party-In-Interest (37 C.F.R. § 42.8(b)(1)) .........................11
`
`B.
`
`Notice of Related Matters (37 C.F.R. § 42.8(b)(2)) ............................11
`
`1.
`
`2.
`
`Judicial Matters: ........................................................................11
`
`Administrative Matters: ............................................................13
`
`C.
`
`Designation of Lead and Back-Up Counsel (37 C.F.R. §
`42.8(b)(3)): ..........................................................................................15
`
`D. Notice of Service Information (37 C.F.R. § 42.8(b)(4)): ....................15
`
`i
`
`

`

`
`
`V.
`
`STATEMENT OF THE PRECISE RELIEF REQUESTED AND THE
`REASONS THEREFOR (37 C.F.R. § 42.22(a)) ..........................................15
`
`VI. THE ’290 PATENT AND CLAIM CONSTRUCTION ...............................16
`
`VII. PERSON OF SKILL IN THE ART (“POSA”) & STATE OF THE
`ART ...............................................................................................................17
`
`VIII. IDENTIFICATION OF CHALLENGE (37 C.F.R. § 42.104(b)) .................18
`
`A.
`
`Independent Claims 1, 8, and 14 .........................................................19
`
`1.
`
`Ogawa in View of Sallmann .....................................................19
`
`B.
`
`Dependent Claims ...............................................................................32
`
`1.
`
`2.
`
`3.
`
`4.
`
`5.
`
`6.
`
`Claims 2, 9, 15, and 21—Quaternary Ammonium Salt ............32
`
`Claims 3 and 16—Sodium Salt of Bromfenac .........................35
`
`Claims 4-5, 7, 11, 13, 17, 19, 23, and 25—Bromfenac
`Sodium and Tyloxapol Concentrations.................................37
`
`Claims 6, 12, 18, and 24—pH Ranges ......................................42
`
`Claims 10, 20 and 22—Storage Stability..................................43
`
`Claims 26-30—Preservative Efficacy Test ...............................44
`
`C.
`
`Objective Indicia of Nonobviousness .................................................48
`
`1.
`
`2.
`
`No Unexpected Results Over the Closest Prior Art ..................48
`
`Other Objective Indicia .............................................................50
`
`IX. CONCLUSION ..............................................................................................53
`
`CERTIFICATE OF SERVICE
`
`
`ii
`
`

`

`
`
`
`
`
`CASES
`
`TABLE OF AUTHORITIES
`
`Page(s)
`
`Amneal Pharmaceuticals, LLC v. Supernus Pharmaceuticals, Inc., IPR2013-
`00368 ......................................................................................................................................48
`
`Chapman v. Casner,
`315 Fed. App’x 294 (Fed. Cir. 2009) .......................................................................38, 43
`
`Friskit, Inc. v. Real Networks, Inc.,
`306 F. App’x 610 (Fed. Cir. 2009) .................................................................................50
`
`Galderma Labs., L.P., v. Tolmar, Inc.,
`737 F.3d 731 (Fed. Cir. 2013) ...................................................................................39, 40
`
`In re Aller,
`220 F.2d 456 ...................................................................................................................41, 47
`
`In re Baxter Travenol Labs.,
`952 F.2d 388 (Fed. Cir. 1991)..............................................................................31, 44, 47
`
`In re De Blauwe,
`736 F.2d 699 (Fed. Cir. 1984)..........................................................................................48
`
`In re Malagari,
`499 F.2d 1297 (C.C.P.A. 1974) .......................................................................................43
`
`In re Merchant,
`575 F.2d 865 (C.C.P.A. 1978) .........................................................................................48
`
`In re Peterson,
`315 F.3d 1325 (Fed. Cir. 2003) ...........................................................................41, 43, 50
`
`In re Woodruff,
`919 F.2d 1575 (Fed. Cir. 1990) .......................................................................................43
`
`Iron Grip Barbell Co., Inc., v. USA Sports, Inc.,
`392 F.3d 1317 (Fed. Cir. 2004) ......................................................................................38
`
`
`
`iii
`
`

`

`
`
`KSR International Co. v. Teleflex Inc.,
`550 U.S. 398 (2007) ...........................................................................................2, 17, 25, 32
`
`Metrics, Inc. v. Senju Pharmaceutical Co., Ltd., IPR2014-01043 .........1, 11, 12, 13, 16
`
`Newell Cos., Inc. v. Kenney Mfg. Co.,
`864 F.2d 757 (Fed. Cir. 1988)..........................................................................................48
`
`Ormco Corp. v. Align Tech., Inc.,
`463 F.3d 1299 (Fed. Cir. 2006) .......................................................................................51
`
`Purdue Pharma Prods. L.P. v. Par Pharm., Inc.,
`377 Fed App’x 978 (Fed. Cir. 2010) ..............................................................................52
`
`Sakraida v. AG Pro, Inc.,
`425 U.S. 273 (1976) ..........................................................................................................25
`
`Santarus v. Par Pharm,
`694 F.3d 1344 (Fed. Cir. 2012) ...........................................................................31, 44, 47
`
`Sinclair & Carroll Co., v. Interchemical Corp.,
`325 U.S. 327 (1945) ...........................................................................................................24
`
`Stratoflex, Inc. v. Aeroquip Corp.,
`713 F.2d 1530 (Fed. Cir. 1983) .................................................................................51, 52
`
`Sundance, Inc. v. DeMonte Fabricating Ltd.,
`550 F.3d 1356 (Fed Cir. 2008) ....................................................................................7, 28
`
`Titanium Metals Corp. of Amer. v. Banner,
`778 F.2d 775, 227 USPQ 773 (Fed. Cir. 1985) ...........................................................40
`
`Tokai Corp. v. Eason Enters., Inc.,
`632 F.3d 1358 (Fed. Cir. 2011) .......................................................................................52
`
`Wm. Wrigley Jr. Co. v. Cadbury Adams USA LLC,
`683 F.3d 1356 (Fed Cir. 2012) ..................................................................................25, 29
`
`STATUTES
`
`35 U.S.C. § 102(b) ..............................................................................................................19, 20
`
`35 U.S.C. § 103 .....................................................................................................................1, 18
`
`iv
`
`

`

`
`
`35 U.S.C. § 315(a)(1) .........................................................................................................10, 11
`35 U.S.C. § 315(a)(1) ......................................................................................................... 10,11
`
`35 U.S.C. § 315(c) ....................................................................................................................13
`35 U.S.C. § 315(c) .................................................................................................................... 13
`
`OTHER AUTHORITIES
`OTHER AUTHORITIES
`
`37 C.F.R. § 42.6(d) .................................................................................................. 18
`37 CPR. § 42.6(d) .................................................................................................. 18
`
`37 C.F.R. § 42.8(b)(1) .............................................................................................. 11
`37 CPR. § 42.8(b)(1) .............................................................................................. 11
`
`37 C.F.R. § 42.8(b)(2) .............................................................................................. 11
`37 CPR. § 42.8(b)(2) .............................................................................................. 11
`
`37 C.F.R. § 42.8(b)(3) .............................................................................................. 15
`37 CPR. § 42.8(b)(3) .............................................................................................. 15
`
`37 C.F.R. § 42.8(b)(4) .............................................................................................. 15
`37 CPR. § 42.8(b)(4) .............................................................................................. 15
`
`37 C.F.R. § 42.10(b) ................................................................................................ 10
`37 CPR. § 42.10(b) ................................................................................................ 10
`
`37 C.F.R. § 42.22 ..................................................................................................... 13
`37 CPR. § 42.22 ..................................................................................................... 13
`
`37 C.F.R. § 42.22(a) ................................................................................................. 15
`37 CPR. § 42.22(a) ................................................................................................. 15
`
`37 C.F.R. § 42.63(e) ................................................................................................. 10
`37 CPR. § 42.63(e) ................................................................................................. 10
`
`37 C.F.R. § 42.100(b) .............................................................................................. 16
`37 CPR. § 42.100(b) .............................................................................................. 16
`
`37 C.F.R. § 42.104(a) ............................................................................................... 10
`37 CPR. § 42.104(a) ............................................................................................... 10
`
`37 C.F.R. § 42.104(b) .............................................................................................. 18
`37 CPR. § 42.104(b) .............................................................................................. 18
`
`37 C.F.R. § 42.106(a) ............................................................................................... 10
`37 CPR. § 42.106(a) ............................................................................................... 10
`
`37 C.F.R. § 42.122(b) .............................................................................................. 13
`37 CPR. § 42.122(b) .............................................................................................. 13
`
`v
`
`

`

`
`
`InnoPharma
`Exhibit #
`
`Petitioner’s Exhibit List
`
`
`Description
`
`1001
`
`1002
`
`1003
`
`1004
`
`1005
`
`1006
`
`1007
`
`1008
`
`1009
`
`1010
`
`1011
`
`1012
`
`Sawa et al., U.S. Patent No. 8,669,290, “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)
`
`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”
`
`vi
`
`

`

`
`
`InnoPharma
`Exhibit #
`
`Description
`
`1013
`
`1014
`
`“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=0B_Rx
`
`“Orange Book: Approved Drug Products with Therapeutic
`Equivalence Evaluations,” Appl. No. N203168, Active Ingredient
`Bromfenac Sodium, accessed at
`http://wvvw.accessdata.fda.gov/scripts/cder/ob/docs/obdetail.cfm?Ap
`p 1 No=203168&TABLE1=0B Rx, last accessed on January 24, 2014
`
`1015
`
` Reserved
`
`1016
`
` Reserved
`
`1017
`
`1018
`
`1019
`
`1020
`
`1021
`
`1022
`
`1023
`
`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)
`
`Regev, 0., 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
`
`vii
`
`

`

`
`
`InnoPharma
`Exhibit #
`
`1024
`
` Reserved
`
`Description
`
`1025
`
`U.S. Patent Application No. 13/687,242, Applicant
`Arguments/Remarks Made in an Amendment, 10/22/2013, pp. 9-15
`
`1026
`
`1027
`
`1028
`
`1029
`
`1030
`
`1031
`
`1032
`
`1033
`
`"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)
`
`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)
`
`"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).
`
`viii
`
`

`

`
`
`InnoPharma
`Exhibit #
`
`1034
`
`1035
`
`1036
`
`1037
`
`1038
`
`Description
`
`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
`(loteprednol
`"LOTEMAXTM
`approved
`FDA
`ophthalmic suspension) 0.5% Product Label," U.S. Approval:
`1998, Bausch & Lomb Pharmaceuticals.
`
`1039
`
`"TOBRADEX®" Physician’s Desk Reference 54: 490 (2000).
`
`1040
`
`"Alomide® 0.1%" Physician’s Desk Reference 50: 469 (1996).
`
`1041
`
`1042
`
`1043
`
`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".
`
`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.
`
`ix
`
`

`

`
`
`
`
`
`
`
`InnoPharma
`Exhibit #
`
`1046
`
`1047
`
`1048
`
`1049
`
`1050
`
`1051
`
`1052
`
`Description
`
`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.
`
`x
`
`

`

`Petition for Inter Partes Review
` of U.S. Patent No. 8,669,290
`
`
`I.
`
`INTRODUCTION
`
`InnoPharma Licensing, Inc., InnoPharma Licensing LLC, InnoPharma Inc.,
`
`InnoPharma LLC, Mylan Pharmaceuticals Inc., and Mylan Inc. (collectively,
`
`“Petitioner”) petition for Inter Partes Review, seeking cancellation of claims 1-30
`
`(“challenged claims”) of U.S. Patent No. 8,669,290 (“the ’290 patent”) (EX1001),
`
`owned by Senju Pharmaceutical Co., Ltd. (“Patent Owner”).
`
`II. OVERVIEW
`
`The Board has already issued its Decision Instituting Inter Partes Review
`
`(“Decision”) on all challenged claims of the ’290 patent on the Ogawa/Sallmann
`
`ground raised herein. Metrics, Inc. v. Senju Pharmaceutical Co., Ltd., IPR2014-
`
`01043 (Paper 19). In its Decision, the Board found that Petitioner Metrics, Inc.
`
`had demonstrated a reasonable likelihood that claims 1-30 of the ’290 patent are
`
`unpatentable for failing to satisfy the nonobviousness requirement of 35 U.S.C.
`
`§ 103. Id. The Board instituted IPR of the challenged claims on the ground that
`
`claims 1-30 are reasonably likely to be obvious over Ogawa and Sallmann under
`
`35 U.S.C. § 103. Id. at Paper 19, pg. 16. Petitioner hereby files its own petition on
`
`the same ground and concurrently seeks to join the instituted IPR proceedings on
`
`these challenged claims.
`
`The challenged claims all are directed to a stable aqueous formulation of
`
`bromfenac (a non-steroidal anti-inflammatory drug (“NSAID”)) with tyloxapol (a
`
`1
`
`

`

`Petition for Inter Partes Review
` of U.S. Patent No. 8,669,290
`
`
`non-ionic surfactant). At the relevant time, tyloxapol was a known non-ionic
`
`surfactant in aqueous formulations of NSAIDs while bromfenac was a known
`
`NSAID previously formulated with another non-ionic surfactant, polysorbate 80.
`
`Thus, the purported inventors of the aqueous preparations of the challenged claims
`
`simply switched polysorbate 80 for tyloxapol (both well-known non-ionic
`
`surfactants). Or, viewed another way, the purported inventors of the challenged
`
`claims of the ’290 patent merely switched diclofenac for bromfenac (both well-
`
`known structurally similar NSAIDs). Swapping known alternatives from the
`
`prior art, according to their known functions to achieve predictable results, is
`
`not innovation. See, e.g., KSR International Co. v. Teleflex Inc., 550 U.S. 398, 416
`
`(2007) (“[W]hen a patent claims a structure already known in the prior art that is
`
`altered by the mere substitution of one element for another known in the field, the
`
`combination must do more than yield a predictable result.”).
`
`A. The ’290 patent
`
`The challenged claims of the ’290 patent are directed to stable
`
`aqueous liquid preparations for ophthalmic administration. Independent claims 1,
`
`8, and 14 are reproduced below:
`
`1. 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
`
`2
`
`

`

`
`
`Petition for Inter Partes Review
` of U.S. Patent No. 8,669,290
`
`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; 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.
`
`8. A stable aqueous liquid preparation comprising: (a) a first
`
`component; and (b) a second component; wherein the first
`
`component is 2-amino-3-(4-bromobenzoy)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; the second component is tyloxapol; wherein
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`said stable liquid preparation is formulated for ophthalmic
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`administration; and wherein the stable aqueous liquid
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`preparation is characterized in that greater than about 90% of
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`the original amount of the first component remains in the
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`preparation after storage at about 60° C. for 4 weeks.
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`14. A stable aqueous liquid preparation comprising: (a) a
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`first component; and (b) a second component; wherein the
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`first component is 2-amino-3-(4- bromobenzoy)phenylacetic
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`acid or a pharmacologically acceptable salt thereof or a
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`hydrate thereof, wherein the hydrate is at least one selected
`
`from a 1/2 hydrate, 1 hydrate, and 3/2 hydrate; the first
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`Petition for Inter Partes Review
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`component is the sole pharmaceutical active ingredient
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`contained in the preparation; the second component is
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`tyloxapol; wherein said stable
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`liquid preparation
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`is
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`formulated for ophthalmic administration; provided that the
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`liquid preparation does not include mannitol.
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`(EX1001, 12:1-13; 12:41-53; 13:14-25)1 (emphasis added).
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`In pertinent part, each of the three independent claims of the ’290 patent is
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`directed to a stable, aqueous liquid preparation comprising two components:
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`(1) bromfenac (or its salts and hydrates); and (2) tyloxapol.
`
`In the context of the ’290 patent, the word “comprising’ means that, at a
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`minimum, the claimed ophthalmic formulation must contain both bromfenac (as
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`the sole active ingredient) and tyloxapol. However, the formulation may further
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`include any other unlisted ingredient, including “conventional various additives
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`such as isotonics, buffers, thickeners, stabilizers, chelating agents, pH controlling
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`agents, perfumes and the like.” (EX1001, 6:9-12; claims 7, 13, 19, 25).
`
`B.
`
`The Scope and Content of the Prior Art
`
`1.
`
`Aqueous Ophthalmic Preparation of Bromfenac
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`Bromfenac, diclofenac, and ketorolac were well-known NSAIDs useful for
`
`treating inflammation in the eye. (EX1002, 2:1:2; EX1003,2 ¶¶ 25-31).
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`1 Citations are as
`
`(col:lines; patent); X:Y:Z
`
`follows: X:YY-ZZ
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`(page:col:para; journal article); X:Y (page:para; journal article).
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`Petition for Inter Partes Review
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`Bromfenac, diclofenac, and ketorolac are NSAIDs possessing a carboxylic acid
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`group (—COOH). By January 21, 2003, bromfenac had been formulated with
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`non-ionic surfactants, including but not limited to tyloxapol and polysorbate 80, in
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`aqueous preparations for ophthalmic delivery.
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`The Ogawa patent (EX1004) described (and exemplified) an aqueous
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`ophthalmic formulation containing: (1) bromfenac and (2) polysorbate 80.
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`(EX1004, 9:5-10:19). Similarly, U.S. Patent No. 5,603,929 to Desai et al. (“the
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`Desai ’929 patent”) described a storage-stable ophthalmic formulation containing
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`bromfenac, and optionally any one of a number of conventional surfactants,
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`including tyloxapol. (EX1005, 3:38-41; see also, Hara (EX1002), U.S. Patent No.
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`5,558,876 to Desai et al. (“the ’876 Desai patent”) (EX1006), BRONUCK,
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`Japanese Pharmacopeia (EX1007), and BROMDAY Prescribing Information
`
`(EX1008)).
`
`2.
`
`Tyloxapol and Related Surfactants in NSAID Aqueous
`Ophthalmic Preparations
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`By January 21, 2003, tyloxapol and related alkylaryl polyether surfactants
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`were well-known non-ionic surfactants formulated in the prior art with NSAIDs.
`
`For example, the Sallmann patent (EX1009) described liquid ophthalmic
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`
`2 This Petition is accompanied by the Declaration of Paul A. Laskar, Ph.D.
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`(EX1003).
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`formulations containing (1) diclofenac sodium (an NSAID) and (2) tyloxapol
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`Petition for Inter Partes Review
` of U.S. Patent No. 8,669,290
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`surfactant. (EX1009, 2:6-8, 4:52-62).
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`Tyloxapol, like polysorbate 80, was successfully used to stabilize aqueous
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`ophthalmic formulations as early as the 1960s. (EX1009, 4:62; EX1010, 4:2:2-
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`4:2:4; EX1003, ¶¶ 36-41). Notably, the prior art taught that tyloxapol was
`
`effective in stabilizing NSAIDs, like bromfenac. (EX1003, ¶ 36; EX1011). The
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`prior art further disclosed examples where tyloxapol was a preferred non-ionic
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`surfactant for use in ophthalmic formulations containing acidic NSAIDs, like
`
`bromfenac (EX1009, 4:62; EX1003, ¶¶ 36, 41, 62), and where tyloxapol was
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`superior to polysorbate 80 as a surfactant in aqueous liquid formulations of an
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`acidic compound. (EX1012, 7:20-43). In fact, in the prior art, only a finite
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`number of non-ionic surfactants, including tyloxapol and polysorbate 80, had been
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`used in approved ophthalmic formulations. (EX1012, 4:51-64; EX1009, 4:52-62).
`
`C. The Differences Between the Challenged Claims and the Prior Art
`
`Petitioner relies on its primary prior art references, Ogawa (EX1004) and
`
`Sallmann (EX1009) in combination with each other. Each discloses a prior art
`
`ophthalmic formulation of an NSAID and a non-ionic surfactant, similar to what is
`
`claimed in the ’290 patent. The challenged claims of the ’290 patent differ from
`
`prior art aqueous liquid ophthalmic formulations of an NSAID only in the
`
`substitution of one well-known NSAID (bromfenac) for another well-known
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`Petition for Inter Partes Review
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`NSAID (diclofenac), or alternately, in the replacement of one well-known non-
`
`ionic surfactant (tyloxapol) for another well-known non-ionic surfactant
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`(polysorbate 80), as illustrated in the following.
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`
`
`’290 Patent
`Claim 1
`
`Ogawa
`Example 6
`(EX1004)
`
`Sallmann
`Example 2
`(EX1009)
`
`NSAID
`
`Bromfenac Bromfenac Diclofenac
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`Surfactant Tyloxapol Polysorbate 80 Tyloxapol
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`
`
`When viewed against the prior art, it is clear that the alleged inventors of the
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`’290 patent did nothing more than swap one well-known component from a prior
`
`art formulation with another known to be used for the same purpose. Thus, the
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`alleged inventors simply substituted tyloxapol (from Sallmann) for polysorbate 80
`
`(both well-known non-ionic surfactants) in the formulation described in Ogawa.
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`Alternately, the alleged inventors merely switched bromfenac (from Ogawa) for
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`diclofenac—both well-known structurally similar NSAIDS—in the formulation
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`described in Sallmann. Swapping known alternatives from the prior art is not
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`innovation. Sundance, Inc. v. DeMonte Fabricating Ltd., 550 F.3d 1356, 1366-
`
`1367 (Fed Cir. 2008) (“a combination is more likely to be obvious where it ‘simply
`
`arranges old elements with each performing the same function it had been known
`
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`to perform’ and yields no more than one would expect from such an
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`Petition for Inter Partes Review
` of U.S. Patent No. 8,669,290
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`arrangement”).
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`All that the challenged claims accomplished was the mere obvious
`
`replacement of known components, according to their known functions, to achieve
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`predictable results. (EX1003, ¶¶ 61-64). A person of ordinary skill in the art at the
`
`time (“POSA”) could have readily performed
`
`these simple component
`
`substitutions—tyloxapol for polysorbate 80 or bromfenac for diclofenac—because
`
`the functions of these components were well known in the art and the results of the
`
`substitutions were predictable. (EX1003, ¶¶ 61-64).
`
`Finally, the prior art disclosed only a finite number of non-ionic surfactants
`
`for ophthalmic formulations. As such, it would have been obvious to try
`
`substituting any of these known non-ionic surfactants (including tyloxapol) for
`
`polysorbate 80 in order to modify the teachings of Ogawa and arrive predictably at
`
`the claimed inventions, with a reasonable expectation of success.
`
`Further, Sallmann disclosed ophthalmic formulations containing NSAIDs,
`
`including diclofenac and ketorolac,
`
`together with non-ionic ethoxylated
`
`octylphenol surfactants, including tyloxapol. (EX1003, ¶ 57). A POSA would
`
`have been motivated to substitute bromfenac for diclofenac in Sallmann’s
`
`ophthalmic formulations because of the structural and functional similarities
`
`between bromfenac and diclofenac (EX1002, 2:1:4-2:2:1; EX1003, ¶ 68), and the
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`Petition for Inter Partes Review
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`known preference for bromfenac over diclofenac (EX1002; EX1003, ¶ 68). The
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`prior art also disclosed a finite number of NSAIDs for ophthalmic application,
`
`such that it would have been obvious to try substituting any of these known anti-
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`inflammatory com