UNITED STATES PATENT AND TRADEMARK OFFICE
`
`_______________________________
`
`BEFORE THE PATENT TRIAL AND APPEAL BOARD
`
`_______________________________
`
`LUPIN LTD. and LUPIN PHARMACEUTICALS INC.
`Petitioners
`
`v.
`
`SENJU PHARMACEUTICAL CO., LTD.
`Patent Owner
`
`____________________
`
`Inter Partes Review No.: Unassigned
`____________________
`
`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
`
`

`

`Petition for Inter Partes Review of
`U.S. Patent No. 8,669,290
`
`TABLE OF CONTENTS
`
`I.
`II.
`III.
`
`INTRODUCTION ..........................................................................................1
`OVERVIEW...................................................................................................1
`STANDING (37 C.F.R. § 42.104(a)); PROCEDURAL
`STATEMENTS ..............................................................................................1
`IV. MANDATORY NOTICES (37 C.F.R. § 42.8(a)(1)).....................................2
`V.
`STATEMENT OF THE PRECISE RELIEF REQUESTED AND THE
`REASONS THEREFORE (37 C.F.R. § 42.22(a)).........................................4
`VI. CLAIM CONSTRUCTION ...........................................................................5
`VII. PERSON OF ORDINARY SKILL IN THE ART AND STATE OF
`THE ART........................................................................................................6
`A.
`Person of Ordinary Skill in the Art ......................................................6
`B.
`State of the Art .....................................................................................6
`VIII. IDENTIFICATION OF CHALLENGE AND RELIEF REQUESTED ......11
`A.
`Ground 1: Claims 1-30 Are Unpatentable Under 35 U.S.C. §
`103(a) over the ’225 patent in view of EP ’984.................................12
`1.
`Independent claims 1, 8, and 14...............................................16
`2.
`Stability (claims 10, 20, and 22)..............................................23
`3.
`Pharmacologically acceptable salts (claims 2, 3, 9, 15,
`16, and 21)................................................................................24
`a.
`Quaternary Ammonium Salt (claims 2, 9, 15 and
`21)..................................................................................24
`Sodium Salt (claims 3 and 16).......................................25
`b.
`pH (claims 6, 12, 18, and 24)...................................................26
`Concentration of Components (dependent claims 4, 5, 7,
`11, 13, 17, 19, 23, and 25) .......................................................27
`a.
`Bromfenac Concentration (claims 4, 5, 7, 11, 13,
`17, 19, 23 and 25) ..........................................................27
`Tyloxapol Concentration (claims 4, 11, 17 and 23)......29
`Additional Components (claims 7, 13, 19, and 25).......30
`i
`
`4.
`5.
`
`b.
`c.
`
`

`

`Petition for Inter Partes Review of
`U.S. Patent No. 8,669,290
`
`6.
`
`B.
`
`Preservative Efficacy Standard of EP-criteria B (claims
`26 – 30) ....................................................................................32
`Ground 2: Claims 1-30 Are Unpatentable Under 35 U.S.C. §
`103(a) over the ’913 patent in view of the ’225 patent......................34
`1.
`Independent claims 1, 8, and 14...............................................36
`2.
`Stability (claims 10, 20, and 22)..............................................40
`3.
`Pharmacologically acceptable salts (claims 2, 3, 9, 15,
`16, and 21)................................................................................41
`a.
`Quaternary Ammonium Salt (claims 2, 9, 15, and
`21)..................................................................................41
`Sodium Salt (claims 3 and 16).......................................42
`b.
`pH (claims 6, 12, 18, and 24)...................................................43
`Concentration of Components (dependent claims 4, 5, 7,
`11, 13, 17, 19, 23, and 25) .......................................................44
`a.
`Bromfenac Concentration (claims 4, 5, 7, 11, 13,
`17, 19, 23 and 25) ..........................................................44
`Tyloxapol Concentration (claims 4, 11, 17, and 23).....47
`b.
`Additional Components (claims 7, 13, 19, and 25).......49
`c.
`Preservative Efficacy Standard of EP-criteria B (claims
`26 – 30) ....................................................................................50
`Objective indicia of nonobviousness .................................................52
`1.
`Any assertions of unexpected stability in the claimed
`formulations do not support patentability................................53
`Other Objective Indicia............................................................57
`2.
`IX. CONCLUSION.............................................................................................60
`
`4.
`5.
`
`6.
`
`C.
`
`ii
`
`

`

`Petition for Inter Partes Review of
`U.S. Patent No. 8,669,290
`
`Exhibit
`#
`
`1001
`
`1002
`
`1003
`
`Petitioners’ Exhibit List
`
`Description
`
`Sawa et al., U.S. Patent No. 8,669,290, "Aqueous Liquid Preparation
`Containing 2-Amino-3-(4-Bromobenzoyl) Phenylacetic Acid," issued
`March 11, 2014.
`
`Sawa et al., U.S. Patent No. 8,754,131, "Aqueous Liquid Preparation
`Containing 2-Amino-3-(4-Bromobenzoyl) Phenylacetic Acid," issued
`June 17, 2014.
`
`Sawa et al., U.S. Patent No. 8,871,813, "Aqueous Liquid Preparation
`Containing 2-Amino-3-(4-Bromobenzoyl) Phenylacetic Acid," issued
`October 28, 2014.
`
`1004
`
`Sawa et al., U.S. Patent No. 8,927,606, "Aqueous Liquid Preparation
`Containing 2-Amino-3-(4-Bromobenzoyl) Phenylacetic Acid," issued
`January 6, 2015.
`1005 Declaration of Dr. Jayne Lawrence
`1006 Hara, Y., "Bromfenac sodium hydrate," Clinics & Drug Therapy
`19:1014-1015 (2002).
`
`1007
`
`Yanni et al., U.S. Patent No. 5,475,034, "Topically Administrable
`Compositions Containing 3-Benzoylphenylacetic Acid Derivatives for
`Treatment of Ophthalmic Inflammatory Disorders,” issued December 12,
`1995.
`1008 FDA Approved “Xibrom™ (bromfenac ophthalmic solution, 0.09%)
`Product Label,” ISTA Pharmaceuticals, Inc.
`FDA Approved “BROMDAY™ (bromfenac ophthalmic solution, 0.09%)
`Product Label,” U.S. Approval March 24, 2005, ISTA Pharmaceuticals,
`Inc.
`
`1009
`
`iii
`
`

`

`Petition for Inter Partes Review of
`U.S. Patent No. 8,669,290
`
`1010
`
`1011
`
`Ogawa et al., U.S. Patent No. 4,910,225, "Locally Administrable
`Therapeutic Composition for Inflammatory Disease," issued March 20,
`1990.
`
`Sallmann et al., U.S. Patent No. 6,107,343, "Ophthalmic And Aural
`Compositions Containing Diclofenac Potassium," issued August 22,
`2000.
`
`1012
`
`Desai et al., U.S. Patent No. 5,603,929, "Preserved Ophthalmic Drug
`Compositions Containing Polymeric Quaternary Ammonium
`Compounds," issued February 18, 1997.
`1013 Desai et al., U.S. Patent No. 5,558,876, "Topical Ophthalmic Acidic
`Drug Formulations,” issued September 24, 1996.
`
`1014
`
`1015
`
`Fu et al., European Patent Application No. 88114804.3, “Preservative
`System for Ophthalmic Formulations,” published as EP 0 306 984 A1 on
`March 15, 1989.
`
`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).
`
`1016
`
`"Acular®" and "Azopt™," Physician’s Desk Reference, 54:486-487, and
`491-492 (2000).
`1017 Doughty, M., "Medicines Update for optical practitioners - Part 11,"
`Optician, 5853:223 (2002).
`
`1018
`
`1019
`
`1020
`
`FDA approved "ALREX™ (loteprednol etabonate ophthalmic
`suspension) 0.2% Product Label," U.S. Approval: 1998, Bausch &
`Lomb Pharmaceuticals.
`
`FDA approved "LOTEMAX™ (loteprednol etabonate ophthalmic
`suspension) 0.5% Product Label," U.S. Approval: 1998, Bausch & Lomb
`Pharmaceuticals.
`“Alomide®”, Physician’s Desk Reference, 50:469 (1996).
`
`iv
`
`

`

`Petition for Inter Partes Review of
`U.S. Patent No. 8,669,290
`
`1021 Sallmann et al., U.S. Patent No. 5,891,913, “Ophthalmic and Aural
`Compositions Containing Diclofenac Potassium,” issued April 6, 1999.
`
`1022
`
`Yasueda et al., U.S. Patent No. 6,274,609, "Aqueous Liquid
`Pharmaceutical Composition Containing as Main Component
`Benzopyran Derivative," issued August 14, 2001.
`1023 Claim Chart, U.S. Patent No. 8,669,290.
`1024 Claim Chart, U.S. Patent No. 8,754,131.
`1025 Claim Chart, U.S. Patent No. 8,871,813.
`1026 Claim Chart, U.S. Patent No. 8,927,606.
`Wong, M., International Patent Application No. PCT/US94/00188,
`“Ophthalmic Compositions Comprising
`Benzyllauryldimethylammonium Chloride,” published July 21, 1994 as
`WO 94/15597.
`
`1027
`
`1028
`
`1029
`
`Regev et al., "Aggregation Behavior of Tyloxapol, a Nonionic
`Surfactant Oligomer, in Aqueous Solution," Journal of Colloid and
`Interface Science, 210: 8-17 (1999).
`
`"TOBRADEX®" Physician’s Desk Reference 54: 490-491 (2000).
`
`1030
`
`Orange Book Listing, Nevanac:
`http://www.accessdata.fda.gov/scripts/cder/ob/docs/obdetail.cfm?Appl_
`No= 021862&TABLE1=OB_Rx
`1031 Nevanac Label: http://ecatalog.alcon.com/ PI/Nevanac_us_en.pdf
`1032 Wong, W., U.S. Patent No. 7,834,059, “Topical Nepafenac
`Formulations,” issued November 16, 2010.
`
`1033
`
`Gamache et al., International Patent No. PCT/US01/25319, “Method of
`Treating Neurodegenerative Disorders of the Retina and Optic Nerve
`Head,” published February 21, 2002 as WO 02/13805.
`
`v
`
`

`

`Petition for Inter Partes Review of
`U.S. Patent No. 8,669,290
`
`1034
`
`1035
`
`Gamache et al., U.S. Patent Application Publication No. 2002/0049255,
`“Method of Treating Neurodegenerative Disorders of the Retina and
`Optic Nerve Head,” published April 25, 2002
`
`Gamache et al., U.S. Patent No. 6,638,976, “Method of Treating
`Neurodegenerative Disorders of the Retina and Optic Nerve Head,”
`issued October 28, 2003.
`
`1036
`
`Kapin et al., International Patent No. PCT/US01/25318, “Method for
`Treating Angiogenesis-Related Disorders Using Benzoyl Phenylacetic
`Acid,” published February 21, 2002 as WO 2002/13804.
`1037 Patani, G. and LaVoie, E., “Bioisosterism: A Rational Approach in Drug
`Design,” Chem. Rev. 96: 3147-3176 (1996).
`1038 Ostrovskii et al., “Acid-Base Properties of 5-Substituted Tetrazoles,”
`Chemistry of Heterocyclic Compounds, 17:412-416 (1981).
`
`1039
`
`Bergamini et al., U.S. Patent No. 5,597,560, "Diclofenac And
`Tobramycin Formulations For Ophthalmic And Otis Topical Use," issued
`January 28, 1997.
`1040 Ali et al., U.S. Patent No. 6,071,904, "Process for Manufacturing
`Ophthalmic Suspensions,” issued June 6, 2000.
`1041 Shupe, I., U.S. Patent No. 3,272,700, “Stabilized Aqueous Solution of
`Tetracine Salt,” issued September 13, 1966.
`
`1042
`
`Guttman et al., "Solubilization of Anti-inflammatory Steroids by
`Aqueous Solutions of Triton-WR-1339," Journal of Pharmaceutical
`Sciences, 50: 305-307 (1961).
`1043 U.S. Patent No. 8,129,431 (App. No. 10/525,006) - PAIR File History
`1044 U.S. Patent No. 8,497,304 (App. No. 13/353,653) - PAIR File History
`1045 U.S. Patent No. 8,669,290 (App. No. 13/687,242) - PAIR File History
`1046 U.S. Patent No. 8,754,131 (App. No. 14/165,976) - PAIR File History
`
`vi
`
`

`

`Petition for Inter Partes Review of
`U.S. Patent No. 8,669,290
`
`1047 U.S. Patent No. 8,871,813 (App. No. 14/261,720) - PAIR File History
`1048
`8,927,606 (App. No. 14493903) - PAIR File History
`1049 FDA approved “PROLENSA® Product Label,” approved April 5, 2013,
`Bausch & Lomb Inc.
`
`1050
`
`1051
`
`“Benzalkonium chloride,” Remington: The Science and Practice of
`Pharmacy, A.R. Gennaro (Ed.), Mack, PA, 1995, p. 1264.
`
`“Tyloxapol,” Remington: The Science and Practice of Pharmacy, A.R.
`Gennaro (Ed.), Mack, PA, 1995, pp. 1415-1416
`
`1052
`
`Senju Pharmaceutical Co., Ltd. Press Release, “The approval of
`BRONUCK® (bromfenac sodium hydrate ophthalmic solution) as an
`import drug in China.”
`1053 Certified English translation of “Bromfenac sodium hydrate,” Japanese
`Pharmacopoeia 2001, 27-29, Yukuji Nippo Ltd.
`1054 Curriculum Vitae of Dr. Jayne Lawrence
`Fan et al., “Determination of Benzalkonium Chloride in Ophthalmic
`Solutions Containing Tyloxapol by Solid-Phase Extraction and
`Reversed-Phase High-Performance Liquid Chromatography,” J. of
`Pharmaceutical Sciences, 82:11 (November 1993).
`1056 Moser et al., “Comparison of Compendial Antimicrobial Effectiveness
`Tests: A Review,” AAPS PharmaSciTech, 12:222-26 (March 2011).
`
`1055
`
`1057
`
`Prince et al., “Analysis of Benzalkonium Chloride and its Homologs:
`HPlC versus HPCE,” J. of Pharmaceutical and Biomedical Analysis,
`19:877 (1999).
`1058 Hecht, G., “Ophthalmic Preparations,” Remington: The Science and
`Practice of Pharmacy, 3:1563–1576 (Genaro, A.R. ed., 19th ed. 1995).
`1059 FDA Approved Drug Products web page for Voltaren® by Novartis
`1060 FDA Approved Drug Products web page for Ocufen®, Allergan
`
`vii
`
`

`

`Petition for Inter Partes Review of
`U.S. Patent No. 8,669,290
`
`1061 FDA Approved Drug Products web page for Profenal® Alcon
`“Indocin® (Indomethacin)”, Physicians’ Desk Reference, 55:1946-1950
`1062
`(2001).
`1063 Walsh et al., “Antiinflamatory Agents,” J. Medicinal Chemistry,
`27:1379-88(1984).
`
`1064
`
`Lucero, J., U.S. Patent No. 5,504,113, “Enhancement Of Benzalkonium
`Chloride Preservative Activity In Formulations Containing An
`Incompatible Drug,” issued April 2, 1996.
`1065 Amselem et al., U.S. Patent No. 5,747,061, “Suspension of Loteprednol
`Etabonate for Ear, Eye, or Nose Treatment,” issued May 5, 1998.
`
`1066
`
`1067
`
`1068
`
`1069
`
`Lang et al., Design and Evaluation of Ophthalmic Pharmaceutical
`Products, Modern Pharmaceutics, 415-472 (Banker et al. eds. 4h ed.
`2002).
`
`Dennis et al., International Patent Application No. PCT/US01/24167,
`“Novel Microemulsion and Micelle Systems for Solubilizing Drugs,”
`published February 7, 2002 as WO 02/09671.
`
`Aviv et al., International Patent Application No. PCT/US93/00044,
`“Submicron Emulsions as Ocular Drug Delivery Vehicles,” published
`March 17, 1994 as WO 94/05298.
`
`Inada et al., U. S. Patent No. 5,916,550, “Aqueous Suspension of
`Loteprednol Etabonate,” issued June 29, 1999.
`
`1070
`
`Naka et al., U. S. Patent No. 6,624,193, “Preventive and Therapeutic
`Agents for Eye Diseases,” issued September 23, 2003 (PCT published
`March 15, 2001).
`1071 Guy et al., U. S. Patent No. 5,540,930, “Suspension of Loteprednol
`Etabonate for Ear, Eye or Nose Treatment,” issued July 30, 1996.
`1072 Elworthy et al., “Physiological Activity of Nonionic Surfactants,”
`Nonionic Surfactants, 923-970 (Schick, M. ed., Marcel Dekker 1967)
`
`viii
`
`

`

`Petition for Inter Partes Review of
`U.S. Patent No. 8,669,290
`
`1073 Cagle et al., U.S. Patent No. 6,440,964, “Compositions and Methods for
`Treating Ophthalmic and Otic Infections,” issued August 27, 2002.
`
`1074
`
`“<51> Antimicrobial Effectiveness Testing,” The United States
`Pharmacopeia, USP 37, Vol. 1 (May 1, 2014).
`
`ix
`
`

`

`Petition for Inter Partes Review of
`U.S. Patent No. 8,669,290
`
`I.
`
`INTRODUCTION
`
`Petitioners Lupin Ltd. and Lupin Pharmaceuticals, Inc. (“Lupin”;
`
`“Petitioners”) respectfully request inter partes review under 35 U.S.C. § 311 and
`
`37 C.F.R. § 42.101 of claims 1-30 of U.S. Patent No. 8,669,290 (“the ’290
`
`Patent”), titled “Aqueous Liquid Preparation Containing 2-amino-3-(4-
`
`bromobenzoyl) phenylacetic acid” (EX 1001).
`
`II. OVERVIEW
`
`The challenged claims of the '290 patent recite stable aqueous formulations
`
`of bromfenac with tyloxapol. Bromfenac was a known non-steroidal anti-
`
`inflammatory drug (NSAID) for use in treating ophthalmic pain and inflammation.
`
`Aqueous formulations containing bromfenac and polysorbate 80 were
`
`known in the art and indeed, were on the market at the time of the claimed
`
`invention. Tyloxapol was a known non-ionic surfactant for use in aqueous
`
`formulations, including those containing NSAIDs structurally similar to
`
`bromfenac, such as diclofenac. The benefits of tyloxapol over polysorbate 80 in
`
`aqueous NSAID formulations were also known. Thus, the claims of the ‘290
`
`patent are at least obvious.
`
`III.
`
`STANDING (37 C.F.R. § 42.104(a)); PROCEDURAL STATEMENTS
`
`Petitioners certify that (1) the ’290 Patent is available for IPR and (2)
`
`Petitioners are not barred or estopped from requesting IPR of any claim of the ’290
`
`1
`
`

`

`Petition for Inter Partes Review of
`U.S. Patent No. 8,669,290
`
`Patent. This Petition is filed in accordance with 37 CFR § 42.106(a). This Petition
`
`is being filed less than one year from the date on which the Petitioners were served
`
`with a complaint by the Patent Owner regarding the ’290 Patent. A Power of
`
`Attorney and an Exhibit List are filed concurrently herewith. The required fee is
`
`paid online via credit card. The Office is authorized to charge fee deficiencies and
`
`credit overpayments to Deposit Acct. No. 05-1323 (Customer ID No. 23911).
`
`IV. MANDATORY NOTICES (37 C.F.R. § 42.8(a)(1))
`Real Party-In-Interest (37 C.F.R. § 42.8(b)(1)) is:
`
`Petitioners Lupin Ltd. and Lupin Pharmaceuticals, Inc. are the real parties-
`
`in-interest.
`
`Related Matters (37 C.F.R. § 42.8(b)(2)):
`
`The ‘290 patent is currently the subject of the following litigations: Senju
`
`Pharmaceutical Co., Ltd., et al. v. Lupin, Ltd.et al., C.A. No. 1:14-CV-4149-JBS-
`
`KMW (D.N.J.); Senju Pharmaceutical Co., Ltd., et al. v Metrics, Inc.,et al., C.A.
`
`No. 1:14-cv-04964-JBS-KMW (D.N.J.); Senju Pharmaceutical Co., Ltd., et al. v
`
`Metrics, Inc.,et al., C.A. No. 1:14-cv-03962-JBS-KMW (D.N.J.); Senju
`
`Pharmaceutical Co., Ltd., et al. v Metrics, Inc.,et al., C.A. No. 4:14-cv-00141-BO
`
`(E.D.N.C.); Senju Pharmaceutical Co., Ltd., et al. v Apotex, Inc.,et al., C.A. No.
`
`1:15-cv-00336-JBS-KMW (D.N.J.); Senju Pharmaceutical Co., Ltd., et al v.
`
`2
`
`

`

`Petition for Inter Partes Review of
`U.S. Patent No. 8,669,290
`
`InnoPharma Licensing, Inc. et al., C.A. No. 1:14-cv-06893-JBS-KMW (D.N.J.);
`
`Senju Pharmaceutical Co., Ltd., et al v. Paddock Laboratories, LLC et al., C.A.
`
`No. 1:15-cv-00087-SLR (D. Del.); and Senju Pharmaceutical Co., Ltd., et al v.
`
`Paddock Laboratories, LLC et al., C.A. No. 1:15-cv-00337-JBS-KMW (D.N.J.).
`
`The ‘290 patent is currently the subject of inter partes review IPR2014-
`
`01043, which was instituted on February 19, 2015, as to claims 1-30.
`
`Additionally, on March 19, 2015, IPR2015-00902 was filed together with a motion
`
`to join IPR2014-01043. Lupin is not a party to IPR2014-01043. In the current
`
`petition, Lupin raises additional arguments and additional prior art than what was
`
`raised in IPR2014-01043.
`
`US Patent No. 8,129,431 (“the ’431 patent”), grandparent to the ‘290 patent,
`
`is the subject of inter partes review IPR2014-01041, which was instituted on
`
`February 19, 2015, as to claims 1-22. Additionally, on March 19, 2015, IPR2015-
`
`00903 was filed together with a motion to join IPR2014-01041. Lupin is not a
`
`party to IPR2014-01041.
`
`Petitioners have filed concurrently with this Petition, Petitions for inter
`
`partes review of the following U.S. Patents which each claim priority to the
`
`application that issued as the ‘290 patent: (1) U.S. 8,754,131 (“the ‘131 patent”),
`
`which issued on June 17, 2014; (2) U.S. 8,871,813 (“the ‘813 patent), which issued
`
`3
`
`

`

`Petition for Inter Partes Review of
`U.S. Patent No. 8,669,290
`
`on October 28, 2014; and (3) U.S. 8,927,606 (“the ‘606 patent”), which issued on
`
`January 6, 2015.
`
`U.S. Application Serial Nos. 14/269,692, and 14/502,014 are pending and
`
`claim common priority to the ‘290 patent.
`
`Designation of Lead and Back-Up Counsel (37 C.F.R. § 42.8(b)(3)):
`
`Lead Counsel
`Deborah H. Yellin (Reg. No. 45,904)
`CROWELL & MORING LLP
`Intellectual Property Group
`1001 Pennsylvania Avenue, N.W.
`Washington, DC 20004-2595
`Telephone No.: (202) 624-2947
`Facsimile No.: (202) 628-5116
`DYellin@Crowell.com
`
`Back-Up Counsel
`Jonathan Lindsay (Reg. No. 45,810)
`CROWELL & MORING LLP
`Intellectual Property Group
`1001 Pennsylvania Avenue, N.W.
`Washington, DC 20004-2595
`Telephone No.: (949) 798-1325
`Facsimile No.: (949) 263-8414
`JLindsay@Crowell.com
`
`Notice of Service Information (37 C.F.R. § 42.8(b)(4)): Please direct all
`
`correspondence regarding this Petition to lead counsel at the above address.
`
`Petitioners consent to service by email at: DYellin@Crowell.com and
`
`JLindsay@Crowell.com.
`
`V.
`
`STATEMENT OF THE PRECISE RELIEF REQUESTED AND THE
`REASONS THEREFORE (37 C.F.R. § 42.22(a))
`
`Petitioners request IPR and cancellation of claims 1-30. Petitioners’ full
`
`statement of the reasons for the relief requested is set forth in detail in § VIII.
`
`4
`
`

`

`Petition for Inter Partes Review of
`U.S. Patent No. 8,669,290
`
`VI. CLAIM CONSTRUCTION
`In an inter partes review, claim terms in an unexpired patent are interpreted
`
`according to their broadest reasonable construction in light of the specification of
`
`the patent in which they appear. 37 C.F.R. § 42.100(b); Office Patent Trial Practice
`
`Guide, 77 Fed. Reg. 48,756, 48,766 (Aug. 14, 2012). Claim terms are given their
`
`ordinary and customary meaning, as understood by one of ordinary skill in the art
`
`in the context of the entire disclosure. In re Translogic Tech., Inc., 504 F.3d 1249,
`
`1257 (Fed. Cir. 2007). If an inventor acts as his or her own lexicographer, the
`
`definition must be set forth in the specification with reasonable clarity,
`
`deliberateness, and precision. Renishaw PLC v. Marposs Societa’ per Azioni, 158
`
`F.3d 1243, 1249 (Fed. Cir. 1998). The construction that stays true to the claim
`
`language, and most naturally aligns with the inventor’s description, is likely the
`
`correct interpretation. (Id. at 1250). In accordance with 37 C.F.R. § 42.100(b), the
`
`challenged claims must be given their broadest reasonable interpretations in light
`
`of the specification of the '290 patent. The Board recently determined that “[n]o
`
`claim term [in the challenged claims] requires express construction” for the
`
`5
`
`

`

`Petition for Inter Partes Review of
`U.S. Patent No. 8,669,290
`
`purposes of rendering a decision to institute review. Metrics, Inc. v. Senju
`
`Pharmaceutical Co., Ltd., IPR2014-01043 [Paper No. 19, pg. 10].1
`
`VII. PERSON OF ORDINARY SKILL IN THE ART AND STATE OF THE
`ART
`
`A.
`
`Person of Ordinary Skill in the Art
`
`The person of ordinary skill in the art (“POSA”) to which the ’290 patent is
`
`directed would generally be a pharmaceutical scientist involved in the research and
`
`development of pharmaceuticals, and would have a Ph.D. and several years of
`
`experience in the field. The amount of post-graduate level experience would
`
`depend upon the level of formal education and particular experience in the field. A
`
`person of ordinary skill in the art relevant to the ’290 patent would easily have
`
`understood the prior art references referred to herein and would have had the
`
`capacity to draw inferences from them. (See also EX 1005, ¶40).
`
`B.
`
`State of the Art
`
`Prior to 2003, non-steroidal anti-inflammatory drugs (NSAIDs), including
`
`diclofenac and bromfenac, were well known for the treatment and management of
`
`1 To the extent Patent Owner asserts any differing claim constructions,
`
`Petitioners reserve the right to respond thereto in later briefing.
`
`6
`
`

`

`Petition for Inter Partes Review of
`U.S. Patent No. 8,669,290
`
`ocular inflammation and pain, including symptoms seen following eye surgery.
`
`(EX 1005, ¶¶69-74, and EX 1006 (“Hara”); EX 1007 (“Yanni”); EX 1016; EX
`
`1059; EX 1060; EX 1061; and EX 1062).
`
`Bromfenac, as well as salt and hydrate forms were known prior to January
`
`2003. Moreover, prior to 2003, bromfenac was known to have a beneficial anti-
`
`inflammatory effect when compared with other NSAIDs. (EX 1005, ¶76; EX 1006;
`
`EX 1007). Bromfenac was known to be a preferred and effective NSAID. (EX
`
`1005, ¶ 77; EX 1006; EX 1007). In preparing an aqueous formulation of
`
`bromfenac, including a formulation for ocular use, one would look to the physico-
`
`chemical characteristics of bromfenac and structurally related molecules, including
`
`the presence of any acidic/basic groups and, if present, their associated pKa’s. (EX
`
`1005, ¶93). In addition, one would look to salt forms of the drug, the molecules’
`
`solubility in oil and water, how it varies as a function of pH and temperature, and
`
`the molecules’ stability as a function of pH and temperature. (Id.).
`
`In addition, one of ordinary skill in the art would also seek out existing
`
`formulations of bromfenac to determine what excipients and other factors, such as
`
`pH, were successfully used to prepare an aqueous formulation of bromfenac. (EX
`
`1005, ¶94).
`
`7
`
`

`

`Petition for Inter Partes Review of
`U.S. Patent No. 8,669,290
`
`In 1990, Ogawa disclosed an ophthalmic formulation of bromfenac with
`
`polysorbate 80. (EX 1010, 10:5-18). Bromfenac was available as an eye drop in
`
`Japan since 2000, sold in Japan as Bronuck. (EX 1005, ¶79; EX 1001, 1:26-55;
`
`EX 1053, 27, Table 1; EX 1010, 3:16-5:4; 14:65-16:44) In 1995, Yanni described
`
`an ophthalmic formulation of bromfenac derivatives and esters. (EX 1007). In
`
`1998, Desai described ophthalmic formulations of bromfenac, which could contain
`
`tyloxapol. (EX 1005, ¶97; EX 1012, abstract, 2:18-23; 3:30-45; 6:13-16 and 6:25-
`
`28).
`
`Many aqueous formulations include a preservative to prevent
`
`microbiological growth. It would have been common practice prior to 2003 to
`
`include such a preservative. (EX 1005, ¶68). Prior to 2003, a common preservative
`
`was benzylalkonium chloride (BAC). (Id.). However, it was also known prior to
`
`2003 that NSAIDs may form insoluble complexes in the presence of a quaternary
`
`ammonium preservative such as BAC, including in aqueous preparations. (EX
`
`1005, ¶83; EX 1013, 1:10-17; EX 1014, 2:13-16, 2:32-36, 2:40-44).
`
`It was known prior to 2003 that non-ionic surfactants could stabilize aqueous
`
`preparations containing both NSAIDs and BAC. (EX 1005, ¶84). In the late
`
`1980’s, EP ‘984 indicated that other non-ionic surfactants in the ethoxylated
`
`octylphenol class, such as Octoxynol 9 and Octoxynol 40, can stabilize aqueous
`
`8
`
`

`

`Petition for Inter Partes Review of
`U.S. Patent No. 8,669,290
`
`liquid ophthalmic NSAID preparations that contained BAC, even in the absence of
`
`PVP or a sulfite. (EX 1005, ¶85; EX 1014, 5:23-28, and Example 5). Importantly,
`
`preservative efficacy in the preparations of EP ‘984 was maintained throughout the
`
`2 year shelf-life. (EX 1005, ¶85-86; EX 1014, Example 5). Therefore, it was
`
`known, prior to 2003, that ethoxylated octylphenol surfactants could eliminate
`
`instability caused by the interaction of an acidic NSAID with BAC.
`
`Tyloxapol was well-known as a non-ionic surfactant from the ethoxylated
`
`octylphenols class prior to 2003. (EX 1005, ¶87; EX 1015, 496). Tyloxapol was
`
`used to stabilize aqueous ophthalmic preparations of NSAIDs and other acidic
`
`drugs. (EX 1005, ¶87).
`
`Non-ionic ethoxylated octylphenol surfactants such as Octoxynol 9 of EP
`
`‘984’s disclosure were described as more effective than polysorbate 80 in
`
`stabilizing aqueous liquid ophthalmic preparations of NSAIDs. (EX 1005, ¶86; EX
`
`1014, 5:23-28, Example 5).
`
`Tyloxapol was also commonly used in commercial ophthalmic formulations
`
`by January 2003. (EX 1005, ¶89; EX 1016, 54:486-487; EX 1029, 490; EX 1017,
`
`18, Table 1; EX 1018; EX 1019; EX 1020, 469). A number of ophthalmic
`
`formulations containing tyloxapol were also described in the prior art by January
`
`2003. For example, the ‘913 patent disclosed an ophthalmic formulation containing
`
`9
`
`

`

`Petition for Inter Partes Review of
`U.S. Patent No. 8,669,290
`
`tyloxapol, BAC, and the NSAID diclofenac. (EX 1005, ¶89; EX 1021, 8:1-15).
`
`Desai described “storage-stable preserved ophthalmic compositions” of NSAIDs,
`
`including bromfenac, which could contain tyloxapol as a surfactant. (EX 1005,
`
`¶97; EX 1012, abstract; 2:18-23; 3:30-45; 6:13-16 and 6:25-28). Prior to 2003, it
`
`also was known that tyloxapol was known to be preferred over polysorbate 80 in
`
`some respects. (EX 1005, ¶92). Tyloxapol, as a surfactant and solubilizing agent,
`
`was known to stabilize negatively charged drugs in aqueous preparations better
`
`than polysorbate 80. (Id.). For example, Yasueda compared tyloxapol and
`
`polysorbate 80 in their ability to solubilize aqueous ophthalmic solutions
`
`containing the acidic drug pranlukast. (EX 1022, “Yasueda”). Yasueda
`
`demonstrated that tyloxapol was better than polysorbate 80 at solubilizing
`
`pranlukast in an ophthalmic solution. (EX 1005, ¶92; EX 1022, 6:55-7:43, Tables 4
`
`and 5). Thus, prior to January 21, 2003, aqueous liquid preparations comprising
`
`acidic drugs such as NSAIDs, and in particular bromfenac, were known. Non-ionic
`
`surfactants were also used to stabilize these formulations because of the known
`
`problems associated with formulating bromfenac and BAC. And in particular,
`
`tyloxapol was a preferred non-ionic surfactant known to be useful in a number of
`
`ophthalmic formulations including those of bromfenac and other NSAIDs and
`
`acidic drugs. (EX 1005, ¶99).
`
`10
`
`

`

`Petition for Inter Partes Review of
`U.S. Patent No. 8,669,290
`
`VIII. IDENTIFICATION OF CHALLENGE AND RELIEF REQUESTED
`
`Petitioners request cancellation of claims 1-30 of the ’290 Patent in view of
`
`the following prior art references:
`
`Patent No.
`
`Filing Date
`
`January 24, 1989
`
`Date of Issuance/
`Publication
`March 20, 1990
`
`US 4,910,225
`“the ’225 patent”
`EP 0 306 984
`“EP ’984”
`US 5,891,913
`“the ’913 patent”
`
`September 9, 1988
`
`March 15, 1989
`
`August 27, 1997
`
`April 6, 19992
`
`Exhibit No.
`
`1010
`
`1014
`
`1021
`
`Petitioners assert the following specific grounds of rejection:
`
`Ground
`No.
`1
`
`2
`
`Claim No(s).
`
`1-30
`
`1-30
`
`Proposed Statutory Rejections
`for the ’290 Patent
`Is obvious under 35 U.S.C. § 103(a) over
`’225 patent in view of EP ’984
`Is obvious under 35 U.S.C. § 103(a)
`over the ’913 patent in view of the ’225 patent
`
`2 The ‘913 patent also published as PCT Publication No. WO 96/11003 on
`
`April 18, 1996.
`
`11
`
`

`

`Petition for Inter Partes Review of
`U.S. Patent No. 8,669,290
`
`A.
`
`Ground 1: Claims 1-30 Are Unpatentable Under 35 U.S.C. §
`103(a) over the ’225 patent in view of EP ’984
`
`U.S. Patent No. 4,910,225 (“the ’225 patent”) issued on March 20, 1990 and
`
`thus is prior art to the ’290 patent under 35 U.S.C. § 102(b).
`
`The ’225 patent describes formulations for ophthalmic solutions containing
`
`bromfenac sodium monohydrate (referred to in the ’225 patent as “sodium 3-(4-
`
`bromobenzoyl)-2-aminophenylacetate monohydrate”) as the active ingredient.
`
`One such formulation is Example 6, which reads as follows:
`
`(EX 1010, Example 6; EX 1005, ¶101).
`
`The formulation described in Example 6 of the ’225 patent is very similar to
`
`the formulation that was marketed in Japan beginning in 2000 under the brand
`
`name Bronuck® and marketed in the United States beginning in 2005 under the
`
`brand name Xibrom®. (Id.).
`
`12
`
`

`

`Petition for Inter Partes Review of
`U.S. Patent No. 8,669,290
`
`European patent application 88114804.3 was published as EP 0 306 984 A1
`
`(“EP ’984”) on March 15, 1989, and thus is prior art to the ’290 patent under 35
`
`U.S.C. § 102(b).
`
`EP ’984 is directed to an improved preservative system for ophthalmic
`
`formulations containing non-steroidal anti-inflammatory drugs (“NSAIDs”) that
`
`have a carboxyl (–COOH) group (i.e., that are acidic). The inventors of EP ’984
`
`explain that at the time of their invention, benzalkonium chloride (“BAC”) was
`
`“widely used in ophthalmic solutions, and [was] considered to be the preservative
`
`of choice.” (EX 1005, ¶102; EX 1014, 2:31-33). However, EP ’984 further reports
`
`that BAC had proven to be incompatible with NSAIDs that contain a carboxyl
`
`group because of the formation of a complex between BAC and the carboxyl
`
`group, which reduces the activity of both BAC and the NSAID. (EX 1005, ¶102;
`
`EX 1014, 2:40-44). For example, when an ophthalmic solution was made with
`
`ketorolac (an NSAID with a carboxyl group), BAC and polysorbate 80 as a
`
`surfactant, the solution became cloudy or turbid after a short period of time,
`
`indicating that a complex had formed between BAC and the NSAID. (EX 1005,
`
`¶102; EX 1014, 2:46-49).
`
`One of the goals of EP ’984 was to solve this problem. (EX 1005, ¶103).
`
`One of the ways in which the inventors solved this problem was by including “a
`
`13
`
`

`

`Petition for Inter Partes Review of
`U.S. Patent No. 8,669,290
`
`stabilizing amount of an ethoxylated octylphenol as a nonionic surfactant.” (EX
`
`1005, ¶103; EX 1014, 3:1-3). The specific examples of ethoxylated octylphenols
`
`given by EP ’984 are Octoxynol 9, Octoxynol 12, Octoxynol 13 and Octoxynol 40.
`
`(EX 1005, ¶103; EX 1014, 5:23-28).
`
`EP ’984 describes an experiment (Example 5) in which six formulations
`
`were tested for their stability under a variety of conditions. (EX 1005, ¶104; EX
`
`1014, Example 5). Each of these formulations contained ketorolac (an NSAID
`
`having a carboxyl group), BAC, and a surfactant. The various conditions included
`
`1 month at 60ºC, 40ºC, room temperature, and 4-40ºC, and 5 months at 60ºC, 40ºC
`
`and room temperature. (EX 1005,