`
`Paper No.
`Filed: January 6, 2017
`
`Filed on behalf of Teva Pharmaceuticals USA, Inc.
`By: Gary J. Speier
`
`Mark D. Schuman
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`CARLSON, CASPERS, VANDENBURGH,
`
`LINDQUIST & SCHUMAN, P.A.
`
`225 South Sixth Street, Suite 4200
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`Minneapolis, MN 55402
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`
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`UNITED STATES PATENT AND TRADEMARK OFFICE
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`
`
`BEFORE THE PATENT TRIAL AND APPEAL BOARD
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`
`
`TEVA PHARMACEUTICALS USA, INC.
`Petitioner,
`
`v.
`
`ALLERGAN, INC.,
`Patent Owner.
`
`
`
`Inter Partes Review No.: IPR2017-00576
`Patent No. 8,685,930
`
`
`
`PETITION FOR INTER PARTES REVIEW OF
`U.S. PATENT NO. 8,685,930
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`I.
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`II.
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`TABLE OF CONTENTS
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`INTRODUCTION ................................................................................................. 1
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`OVERVIEW ........................................................................................................ 3
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`A. Brief Overview of the ’930 Patent ........................................................ 4
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`B. Brief Overview of the Prosecution History ........................................... 5
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`C. Brief Overview of the Scope and Content of the Prior Art ................... 8
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`i.
`
`ii.
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`U.S. Patent No. 5,474,979 to Ding et al.
`(“Ding ’979,” EX1006) ............................................................... 8
`
`Sall et al., Two Multicenter, Randomized Studies
`of the Efficacy and Safety of Cyclosporine Ophthalmic
`Emulsion in Moderate to Severe Dry Eye Disease,
`107 OPHTH. 631 (2000) (EX1007) ............................................ 10
`
`iii. A. Acheampong et al., Cyclosporine Distribution
`into the Conjunctiva, Cornea, Lacrimal Gland, and
`Systemic Blood following Topical Dosing of
`Cyclosporine to Rabbit, Dog, and Human Eyes,
`2 LACRIMAL GLAND, TEAR FILM, AND DRY EYE
`SYNDROMES 1001 (1998) (“Acheampong,” EX1008) .............. 11
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`D. Brief Overview of the Level of Skill in the Art .................................. 11
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`III. GROUNDS FOR STANDING ............................................................................... 13
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`IV. Mandatory Notices Under 37 C.F.R. § 42.8 .................................................. 13
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`V.
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`Statement of the Precise Relief Requested for Each Claim Challenged ....... 15
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`VI. STATEMENT OF NON-REDUNDANCY ............................................................... 15
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`VII. CLAIM CONSTRUCTION ................................................................................... 16
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`A.
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`B.
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`C.
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`“buffer” ................................................................................................ 16
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`“substantially no detectable concentration” ........................................ 17
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`“therapeutically effective” ................................................................... 17
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`
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`i
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`VIII. Background Knowledge in the Art Prior to September 15, 2003 ................. 18
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`IX. Detailed Explanation of Grounds for Unpatentability .................................. 24
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`A.
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`[Ground 1] Claims 1-36 are Anticipated under 35 U.S.C.
`§ 102(b) by Ding ’979 ......................................................................... 24
`
`i.
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`Claims 1-10, 12-22, 24-34, and 36 ........................................... 25
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`ii. Claims 11, 23, and 35 ............................................................... 32
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`B.
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`[Ground 2] Claims 1-36, are Obvious under 35 U.S.C.
`§ 103 over Ding ’979 and Sall ............................................................ 44
`
`i.
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`Claims 1-10, 12-22, 24-34, and 36 ........................................... 45
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`iii. Claims 11, 23, and 35 ............................................................... 48
`
`C.
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`[Ground 3] Claims 11, 23, and 35 are Obvious under 35 U.S.C. § 103
`over Ding ’979, Sall, and Acheampong. ............................................. 52
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`X. Objective Indicia of Non-Obviousness: No Unexpected Results ................. 54
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`A. No Unexpected Results ....................................................................... 54
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`B. No Evidence of Commercial Success ................................................. 66
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`C. No Industry Praise ............................................................................... 68
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`D. No Long-Felt, Unmet Need ................................................................. 68
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`E. No Failure of Others ............................................................................ 69
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`XI. CONCLUSION ................................................................................................... 69
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`XI. CERTIFICATE OF COMPLIANCE ........................................................................ 71
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`XII. PAYMENT OF FEES UNDER 37 C.F.R. §§ 42.15(A) AND 42.103 ...................... 72
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`XIII. APPENDIX – LIST OF EXHIBITS ........................................................................ 75
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`
`
`
`
`ii
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`I.
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`INTRODUCTION
`
`Pursuant to the provisions of 35 U.S.C. § 311 and § 6 of the Leahy-Smith
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`America Invents Act (“AIA”), and to 37 C.F.R. Part 42, Teva Pharmaceuticals
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`USA, Inc. (“Petitioner” or “Teva”) hereby requests review of U.S. Patent No.
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`8,685,930 to Acheampong et al. (“the ’930 patent,” EX1001) that issued on April
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`1, 2014. PTO records indicate the ’930 patent is assigned to Allergan, Inc. (“Patent
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`Owner”). This Petition demonstrates, by a preponderance of the evidence, that
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`there is a reasonable likelihood that claims 1-36 of the ’930 patent are unpatentable
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`for failure to distinguish over asserted prior art. Additional petitions are being filed
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`to address related patents that are assigned to Patent Owner. All challenged patents
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`are continuations from the same family and are terminally disclaimed over one
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`another. The patents claim an ophthalmic emulsion for the treatment of
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`overlapping ocular disorders, or conventional methods of administering the
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`emulsion.
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`In particular, the ’930 patent claims a topical ophthalmic emulsion for
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`treating dry eye disease, such as keratoconjunctivitis sicca (“KCS”), which
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`contains 0.05 percent by weight (“%”) cyclosporin A (“CsA”), 1.25% castor oil,
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`and other standard emulsion ingredients in a combination well known in the art.
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`EX1001, 14:41-16:49. In fact, each element of the emulsion, including the claimed
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`CsA and castor oil percentages and preferred ratios for combining them, was
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`1
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`
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`disclosed in a single prior art reference (Ding ’979) for use in topical ophthalmic
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`emulsions to treat dry eye disease/KCS. Indeed, during prosecution of a parent
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`application, applicants admitted that the claimed emulsion containing 0.05% CsA
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`and 1.25% castor oil “is squarely within the teaching of the Ding [’979] reference”
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`and “would have been obvious” to a person of skill in the art at the time of the
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`invention. EX1005, 0435; EX1026, ¶18.
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`Four years later, in prosecuting the ’930 patent as a continuation application,
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`applicants changed course and attempted to withdraw these admissions. EX1004,
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`0007. They argued that data collected after their earlier admissions established
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`patentability because of an alleged unexpected result that the emulsion was
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`“equally or more therapeutically effective for the treatment of dry
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`eye/keratoconjunctivitis sicca than the formulation containing 0.10% by weight
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`cyclosporin A and 1.25% by weight castor oil.” EX1004, 0007, 0195; EX1026,
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`¶¶20-22. But the supposed “unexpected results” are weak, at best, and fail to rebut
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`the strong evidence of obviousness. The data relied upon by applicants lack
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`scientific parameters necessary to demonstrate statistical significance and
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`materiality and, in many cases, appear to be copies of previously published graphs
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`from a 102(b) prior art reference, Sall. Thus, Patent Owner’s cited evidence does
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`not support non-obviousness of the claims, and merely confirms that the results
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`were expected in view of and were already disclosed in the prior art.
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`2
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`II. OVERVIEW
`
`
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`The Board has already issued its Decision Instituting Inter Partes Review
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`(“Decision”) on all challenged claims of the ’930 patent on the same grounds
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`raised herein. Mylan Pharmaceuticals Inc. v. Allergan Inc., Case IPR2016-01127
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`(Paper No. 8). In its Decision, the Board found that Petitioner Mylan
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`Pharmaceuticals Inc. (“Mylan”) had demonstrated a reasonable likelihood that
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`claims 1-36 of the ’930 patent are unpatentable for failing to satisfy the novelty
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`requirement of 35 U.S.C. 102 and the nonobviousness requirement of 35 U.S.C.
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`103. Id. The Board instituted IPR of the challenged claims on three separate
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`grounds:
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`Ground 1: Claims 1−36 of the ’930 patent under 35 U.S.C. § 102 as
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`anticipated by Ding ’979;
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`Ground 2: Claims 1−36 of the ’930 patent under 35 U.S.C. § 103(a) as
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`obvious over the combination of Ding ’979 and Sall; and
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`Ground 3: Claims 11, 23, and 35 of the ’930 patent under 35 U.S.C. § 103(a)
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`as obvious over the combination of Ding ’979, Sall, and Acheampong.
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`IPR2016-01127 (Paper No. 8). Petitioner Teva hereby files its own petition on the
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`same grounds and concurrently seeks to join the instituted IPR proceedings on
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`these challenged claims.
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`3
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`
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`A. Brief Overview of the ’930 Patent
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`The ’930 patent has an earliest claimed priority date of September 15, 2003.
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`Independent claim 1 recites an emulsion of 0.05% CsA in 1.25% castor oil,
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`polysorbate 80, acrylate/C10-30 alkyl acrylate cross-polymer (“cross-polymer”)
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`and water, wherein the topical ophthalmic emulsion is therapeutically effective in
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`treating keratoconjunctivitis sicca. Independent claims 13 and 25 recite an identical
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`emulsion but state respectively that it is “therapeutically effective in treating dry
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`eye” or “therapeutically effective in increasing tear production” in the eye of the
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`human having KCS. Claims 2-12, 14-24, and 26-36 depend respectively from
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`claims 1, 13, and 25.
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`Claims 2-6, 9-10, 14-18, 21-22, 26-30, and 33-34 recite that the emulsion
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`comprises a tonicity or demulcent agent, specifically glycerine, and/or a buffer,
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`specifically sodium hydroxide. Claims 12, 24, and 36 specify a range of pH values
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`for the emulsion of claims 6, 18, or 30, respectively, which each comprises
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`glycerine and a buffer. Claims 7-8, 19-20, and 31-32 specify known weight
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`percentages of polysorbate 80 and cross-polymer, respectively. Claims 11, 23, and
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`35 each recite that when the emulsion is administerd to the eye there is
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`substantially no detectable concentration of CsA in the blood.
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`4
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`B.
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`Brief Overview of the Prosecution History
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`U.S. Patent Application No. 13/961,828 (“the ’828 application”) was filed
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`on August 7, 2013, and issued eight months later on April 1, 2014, as the ’930
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`patent. The ’828 application is a continuation, via U.S. application 11/897,177, of
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`U.S. application 10/927,857 (“the ’857 application,” EX1005), which claims the
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`benefit of U.S. provisional application 60/503,137, filed September 15, 2003.
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`During prosecution of the related ’857 application, Patent Owner admitted
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`that Composition II, which is identical to the emulsion claimed in the ’930 patent
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`(EX1026, ¶¶18-19), was “squarely within the teachings of Ding [’979]”:
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`The applicants concede that it would have been obvious to modify
`examples 1A-1E of the Ding reference to arrive at Composition II of
`the present application. The differences are insignificant.... As the
`examiner correctly observes, one of ordinary skill in the art “would
`readily envisage” such a composition, especially in view of Example
`1B: having selected 0.05% as the concentration of cyclosporin,
`Example 1B (wherein the ratio of cyclosporin to castor oil is 0.04)
`teaches that the concentration of castor oil should be 1.250% (0.05% /
`1.250% = 0.04). The applicants concede that in making this selection
`(0.05% cyclosporin and 1.250% castor oil) there would have been a
`reasonable expectation of success; the differences between Examples
`1A-1E and Composition II are too small to believe otherwise.
`The formulation of Composition II is squarely within the teachings
`of the Ding reference, and the Office should disregard any
`statements by the applicants suggesting otherwise[.]
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`EX1005, 0435 (emphases added).
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`During prosecution of the ’828 application, the applicants acknowledged
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`their prior admissions, but claimed that they had collected evidence to support the
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`5
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`patentability of the claims “[s]ince these comments have been filed.” EX1004,
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`0007. Patent Owner submitted an amendment, nakedly asserting that “a prima
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`facie case of obviousness cannot be properly established,” but arguing that the
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`claims were patentable based on unexpected results. Id. at 0196. The Patent Owner
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`also filed a terminal disclaimer for the applications or parent applications that
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`resulted in the ’111, ’162, ’048, ’556, and ’191 patents. Id. at 0261-62 (e.g.,
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`11/897,177).
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`In remarks accompanying a Notice of Allowance (id. at 0268; EX1026, ¶23)
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`the examiner stated that, “the specific combination of 0.05% by weight
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`cyclosporine A with 1.25% by weight castor oil is surprisingly critical for
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`therapeutic effectiveness in the treatment of dry eye or keratoconjunctivitis sicca,”
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`and therefore, “demonstrate[s] surprising and unexpected results.” Id. at 0276.
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`The alleged “unexpected results” are addressed in the declaration of Dr.
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`Walter Chambliss that accompanies this Petition. EX1026, ¶¶122-46. As noted by
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`Dr. Chambliss, the data presented by applicants lacked scientific parameters
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`necessary to demonstrate statistical significance and materiality. In many cases, the
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`data appear to be repackaged from graphs published in the prior art Sall reference
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`that is presently asserted against the claims. Thus, the declarations do not support a
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`finding of surprising or unexpected results. Id.
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`6
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`During prosecution, the Patent Owner did not identify, and the examiner did
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`not address, deficiencies in the Schiffman and Attar Declarations that made them
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`unreliable, which are discussed in this Petition. As such, and because of the new
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`information presented herein and supported by Dr. Chambliss’s testimony, the
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`examiner’s conclusions based on one-sided information should not receive any
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`deference by the Board.
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`In addition to demonstrating the flaws in Patent Owner’s alleged unexpected
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`results, Dr. Chambliss’s declaration also provides insight not previously presented
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`to the Patent Office about how a person of ordinary skill in the art would interpret
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`the disclosure of Ding ’979. Among other things, Dr. Chambliss’s testimony
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`establishes that the presently claimed emulsion would have been immediately
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`apparent to one of ordinary skill in the art based on Ding ’979. EX1026, ¶¶97-98,
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`114. The Patent Owner’s alleged evidence of unexpected results cannot render
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`patentable an anticipated claim. In re Wiggins, 488 F.2d 538, 543, (C.C.P.A.
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`1973).
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`Further, this Petition presents new arguments based on expert testimony as
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`to why the claims are obvious over Ding ’979 and other references that were not
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`substantively analyzed during prosecution. Among other things, Dr. Chambliss
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`explains that the 1.25% castor oil emulsion vehicle of Example 2C in Ding ’979
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`was the only vehicle that was most preferred for both the 0.05% and 0.10% CsA
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`7
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`
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`emulsions, and that Sall’s 0.05% and 0.10% CsA emulsions used the same castor
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`oil vehicle. Petitioner provides an even stronger prima facie obviousness case than
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`the examiner considered during prosecution. Accordingly, the Board should
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`institute review without deference to the limited analysis during prosecution.
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`C. Brief Overview of the Scope and Content of the Prior Art
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`A prior art reference anticipates a claim if it discloses all of the elements of
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`the claim in the claimed combination, or if the claimed combination would be
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`“immediately apparent to one of ordinary skill in the art,” or “at once envisaged”
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`from the prior art reference. Wm. Wrigley Jr. Co. v. Cadbury Adams USA LLC, 683
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`F.3d 1356, 1361 (Fed. Cir. 2012). In obviousness cases, Graham v. John Deere Co.
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`of Kansas City, requires an evaluation of any differences between the claimed
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`subject matter and the asserted prior art. 383 U.S. 1, 17-18 (1966). As noted in
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`KSR Int’l Co. v. Teleflex Inc., the obviousness inquiry may account for inferences
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`that would be employed by a person of ordinary skill in the art. 550 U.S. 398, 418
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`(2007).
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`i.
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`U.S. Patent No. 5,474,979 to Ding et al. (“Ding ’979,”
`EX1006)
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`Ding ’979 issued on December 12, 1995, and is prior art under 35 U.S.C.
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`§ 102(b). EX1006. Ding ’979 teaches topical ophthalmic emulsions for the
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`treatment of keratoconjunctivitis sicca (“KCS” or “dry eye disease/KCS”). Id. at
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`5:9-12; EX1026, ¶61. Claims 7-8 recite emulsions containing 0.05-0.40% CsA in
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`8
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`
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`0.625-5.00% castor oil, 1.00% polysorbate 80, 0.05% Pemulen® (an acrylate/C10-
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`30 alkyl acrylate cross-polymer), 2.20% glycerine, sodium hydroxide, and water,
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`and having a pH range of 7.2-7.6. EX1006, 4:4-5; id. at 6:27-42; EX1026, ¶64.
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`Ding ’979 teaches that CsA is effective in treating dry eye disease/KCS “as an
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`immunosuppressant and in the enhancement or restoring of lacrimal gland tearing.”
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`EX1006, 1:10-16, 37-39.
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`Ding ’979 discloses four examples of castor oil-based vehicles (Examples
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`2A-D) for delivery of CsA. EX1006, 4:44-54; EX1026, ¶65. Example 2C is the
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`exact same castor oil vehicle used in the challenged claims. Ding ’979 also
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`discloses CsA-containing emulsions in Example 1 using the vehicles from
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`Example 2. EX1006, 4:32-54. The emulsions in Example 1 have CsA percentages
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`and castor oil percentages covering the ranges disclosed in claims 7 and 8 (0.05% -
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`0.40% CsA and 0.625% - 5.00% castor oil) of Ding ’979. Id. at 4:32-43; EX1026,
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`¶¶66-67. One emulsion (Example 1D) specifically used the 1.25% castor oil
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`vehicle (Example 2C) to deliver 0.10% CsA. EX1006, 4:32-43.
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`Ding ’979 explicitly sets forth a “more preferred” range for the ratio of CsA
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`to castor oil of 0.02-0.12. Id. at 3:17-20; EX1026, ¶67. Each of the exemplified
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`CsA-containing emulsions in Ding ’979 fall within an even narrower ratio range of
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`0.04-0.08, which, for the 1.25% castor oil vehicle (Example 2C) disclosed in Ding
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`’979, equates to a CsA range of 0.05% to 0.10% CsA. EX1006, 4:32-43; EX1005,
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`
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`9
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`
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`0435; EX1026, ¶67, 94. Ding ’979 does not expressly discuss twice-daily
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`administration of the emulsions.
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`ii.
`
`Sall et al., Two Multicenter, Randomized Studies of the Efficacy
`and Safety of Cyclosporine Ophthalmic Emulsion in Moderate
`to Severe Dry Eye Disease, 107 OPHTH. 631 (2000) (EX1007)
`
`
`
`Sall is prior art under 35 U.S.C. § 102(b). Sall describes a multi-center,
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`randomized, double-masked Phase 3 clinical trial that assesses the safety and
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`efficacy of increasing tear production and treating dry eye disease/KCS by twice-
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`daily ophthalmic administration of 0.05% or 0.10% CsA in a castor oil emulsion,
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`compared to the emulsion vehicle without CsA in the same regimen. EX1007, 631-
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`32 & n.1; id. at figs. 1-4; EX1026, ¶¶73-74. Sall teaches that the 0.05% CsA
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`emulsion was safe and effective, was at least as effective as the 0.10% CsA
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`emulsion, and resulted in fewer adverse side effects and in trough CsA blood
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`concentration below 0.1 ng/mL. EX1007, 631, 634-37; EX1026, ¶¶73-77, 80. Sall
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`does not expressly disclose the exact composition of the castor oil vehicle, but
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`compares the 0.05% and 0.10% CsA emulsions to the same vehicle. EX1007, 632;
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`EX1026, ¶73.
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`
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`10
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`
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`iii. A. Acheampong et al., Cyclosporine Distribution into the
`Conjunctiva, Cornea, Lacrimal Gland, and Systemic Blood
`following Topical Dosing of Cyclosporine to Rabbit, Dog, and
`Human Eyes, 2 LACRIMAL GLAND, TEAR FILM, AND DRY EYE
`SYNDROMES 1001 (1998) (“Acheampong,” EX1008)
`
`Acheampong is prior art under 35 U.S.C. § 102(b). Acheampong describes a
`
`
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`study in which CsA percentages ranging from 0.05%-0.4% were administered to
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`human patients with KCS twice a day for a period of three months. EX1008 at
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`1002; EX1026, ¶¶84-85. Acheampong measured CsA blood concentration at both
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`peak and trough levels following topical ophthalmic administration. EX1008 at
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`1002. No detectable amount of CsA was measured in patients receiving the 0.05%
`
`CsA emulsion. EX1008 at 1002, 1004; EX1026, ¶¶84-85.
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`D. Brief Overview of the Level of Skill in the Art
`
`A person of ordinary skill in the relevant field as of September 15, 2003
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`would likely have some combination of: (a) experience formulating pharmaceutical
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`products; (b) experience designing and preparing drug emulsions intended for
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`topical ocular administration; and (c) the ability to understand results and findings
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`presented or published by others in the field. EX1026, ¶36. Typically this person
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`would have an advanced degree, such as a medical degree, or a Ph.D. in organic
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`chemistry, pharmaceutical chemistry, medicinal chemistry, pharmaceutics,
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`physical pharmacy, or a related field, or less education but considerable
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`professional experience in these fields. Id. at ¶35.
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`
`
`11
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`
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`Teva’s expert, Dr. Walter Chambliss, is a Professor of Pharmaceutics at the
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`University of Mississippi. EX1026, ¶3; EX1027 (CV). Dr. Chambliss is also a
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`Research Professor in the Research Institute of Pharmaceutical Sciences at the
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`University of Mississippi. EX1026, ¶3; EX1027. Dr. Chambliss has authored over
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`twenty publications in the field of pharmaceutical development, including a book
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`chapter concerning delivery of pharmaceutical products to the eye. EX1026, ¶¶5;
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`EX1027. He worked for seventeen years in research and development in the
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`pharmaceutical industry at G.D. Searle, Bristol-Myers and Schering-Plough, where
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`he was involved in formulation development and/or process development of over
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`300 products. EX1026, ¶2; EX1027.
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`Dr. Chambliss received a B.S. in Pharmacy in 1977 and a Ph.D. in
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`Pharmaceutics in 1982 from the University of Mississippi, and he has experience
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`with ophthalmic pharmaceutical emulsions, including numerous oil-based and
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`water-based formulations. EX1026, ¶¶ 1,7; EX1027. Dr. Chambliss is well
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`qualified as an expert, possessing the necessary scientific, technical, and other
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`specialized knowledge and training to assist in an understanding of the evidence
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`presented herein, as well as possessing the expertise necessary to determine and
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`explain the level of ordinary skill in the art as of September 2003. EX1027.
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`
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`12
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`
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`III. GROUNDS FOR STANDING
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`
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`Petitioner certifies that, under 37 C.F.R. § 42.104(a), the ’930 patent is
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`available for inter partes review, and Petitioner is not barred or estopped from
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`requesting inter partes review of the ’930 patent on the grounds identified.
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`IV. MANDATORY NOTICES UNDER 37 C.F.R. § 42.8
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`Real parties-in-interest (§42.8(b)(1)): Teva Pharmaceuticals USA, Inc. is a
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`real party-in-interest. Teva Pharmaceuticals USA, Inc. is a subsidiary of Teva
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`Pharmaceuticals Industries, Inc.
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`Related Matters (37 C.F.R. § 42.8(b) (2)): Petitioner indicates that the
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`following judicial matters may affect or be affected by a decision in this
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`proceeding:
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`An IPR petition for the ’930 patent was previously filed by Apotex Corp.
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`and Apotex Inc. as IPR2015-01283, as were petitions for the related patents U.S.
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`Patent Nos. 8,648,048 (IPR2015-01284), 8,633,162 (IPR2015-01278), 8,642,556
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`(IPR2015-01286), and 8,629,111 (IPR2015-01282), but all were terminated prior
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`to an institution decision.
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`An IPR petition for the ’930 patent was previously filed by Mylan as
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`IPR2016-01127 and has been instituted.
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`Mylan filed IPR petitions for the related patents 8,629,111 (IPR2016-
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`01128), 8,642,556 (IPR2016-01129), 8,633,162 (IPR2016-01130), 8,648,048
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`(IPR2016-01131), and 9,248,191 (IPR2016-01132) and have been instituted. Teva
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`filed IPR petitions for the related patents 8,629,111 (IPR2017-00578), 8,642,556
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`(IPR2017-00579), 8,633,162 (IPR2017-00583), 8,648,048 (IPR2017-00585), and
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`9,248,191 (IPR2017-00586) on the same grounds and concurrently seeks to join
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`these instituted IPR proceedings on the same challenged claims.
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`U.S. Application No. 15/011,159, filed January 29, 2016, claims the benefit
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`of U.S. Application No. 14/222,478 (the ’191 patent), which is a continuation, via
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`U.S. Application Nos. 13/961,828 and 11/897,177, of the ’857 application.
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`Petitioner and other entities are involved in litigation over the ’930 patent
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`and related patents in the action styled Allergan, Inc. v. Teva Pharmaceuticals
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`USA, Inc., et al., No. 2:15-cv-01455, filed by Allergan, Inc. (E.D. Texas)
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`(EX1023). Petitioner also identifies the following pending actions involving the
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`’930 patent: Allergan, Inc., v. Innopharma, Inc. and Pfizer, Inc., No. 2:15cv1504
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`(E.D. Texas); and and Allergan, Inc. v. Famy Care, Ltd., No. 2:16-cv-0401 (E.D.
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`Texas).
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`Lead and Back-Up Counsel (37 C.F.R. § 42.8(b) (3)):
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`Lead Counsel: Gary J. Speier (Reg. No. 45,458)
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`Back-Up Counsel: Mark D. Schuman (Reg. No. 31,197)
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`Service Information (37 C.F.R. § 42.8(b) (4)):
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`Petitioner hereby consents to electronic service.
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`PPost: CARLLSON, CAASPERS, VVANDENBBURGH, LLINDQUISST &
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`V. SSTATEMENT OF THE PPRECISE RRELIEF REQ
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`PPetitioners rrequest revview of claaims 1-36 oof the ’9300 patent unnder 35 U.SS.C.
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`§ 311 annd AIA § 66 and that each of thee claims bee canceled
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`VI. SSTATEMENT OF NON--REDUNDAANCY
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`EEach of the Grounds rraised in thhis Petitionn is meaninngfully disttinct. Grouund
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`ion of claimms 1-36 baased on Diing ’979. GGround 2 aasserts
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`obvioussness of claaims 1-36 bbased on DDing ’979 aand Sall. SSall expresssly teachess
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`certain pproperties intrinsic too the claimmed emulsioon, includiing efficaccy, relative
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`efficacyy, and subsstantially nno detectable blood cooncentratioon at trouggh levels, aand
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`provides additional reasons to make and use the claimed emulsion to treat dry eye
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`disease. Ground 3 asserts obviousness of dependent claims 11, 23, and 35 based
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`Ding ’979, Sall, and Acheampong. Acheampong expressly teaches the claimed
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`emulsion results in substantially no detectable blood concentration at trough and
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`VII. CLAIM CONSTRUCTION
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`In an inter partes review, a claim in an unexpired patent is given its broadest
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`reasonable construction in light of the specification. 37 C.F.R. § 42.100(b); In re
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`Cuozzo Speed Techs., LLC, 793 F.3d 1268, 1275-1280 (Fed. Cir. 2015), cert.
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`granted sub nom. Cuozzo Speed Techs., LLC v. Lee, 2016 U.S. LEXIS 632 (U.S.
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`Jan. 15, 2016) (No. 15-446). Claims terms are also “generally given their ordinary
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`and customary meaning,” which is the meaning that the term would have to a
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`person of ordinary skill in the art at the time of the invention in view of the
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`specification. In re Translogic Tech., Inc., 504 F.3d 1249, 1257 (Fed. Cir. 2007).
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`Under either standard, there is a reasonable likelihood that Petitioner will prevail
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`with respect to the challenged claims. A few terms are discussed below.
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`A.
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`“buffer”
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`The term “buffer” appears in claims 4-6, 9-10, 16-18, 21-22, 28-30, and 33-
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`34 of the ’930 patent. Claims 5, 10, 17, 22, 29, and 34 state “the buffer is sodium
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`hydroxide.” The patent states, “[t]he pH of the emulsions can be adjusted in a
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`conventional manner using sodium hydroxide ... to a physiological pH level.”
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`EX1001, 11:44-46. In light of the specification, the broadest reasonable
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`interpretation of the term “buffer” includes sodium hydroxide. EX1026, ¶38.
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`B.
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`“substantially no detectable concentration”
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`The term “substantially no detectable concentration” appears in claims 11,
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`23, and 35 of the ’930 patent with regard to measuring CsA in human blood.
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`According to the specification, “[c]yclosporin component concentration in blood
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`preferably is determined using a liquid chromatography-mass spectroscopy-mass
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`spectroscopy (LC-MS/MS), which test has a cyclosporin component detection
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`limit of 0.1 ng/ml. Cyclosporin component concentrations below or less than 0.1
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`ng/ml are therefore considered substantially undetectable.” EX1001, 5:27-33. A
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`skilled artisan could measure blood concentration at either peak or trough levels.
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`EX1026, ¶¶39-40. In light of the specification, the broadest reasonable
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`interpretation of the phrase “substantially no detectable concentration” includes a
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`blood concentration below 0.1 ng/mL measured at either peak or trough levels.
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`C.
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`“therapeutically effective”
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`Dependent claims 1, 13, and 25 state that the emulsion is “therapeutically
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`effective” in increasing tear production, treating dry eye disease or treating KCS.
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`The ’930 patent characterizes KCS as “an absolute or partial deficiency in aqueous
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`tear production.” EX1001, 3:2-5. This is consistent with its plain meaning. EX1022
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`at 0003 (keratoconjunctivitis sicca is an “inflammation of the conjunctiva and of
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`the cornea” that is “associated with decreased tears” and is a species of, and is
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`often used interchangeably with, or as a partial synonym of, dry eye disease);
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`EX1026, ¶41. During prosecution, Patent Owner relied on an increase in tearing to
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`assert unexpected therapeutic efficacy of the claimed emulsion for treating dry eye
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`disease/KCS. EX1004, 0195; EX1026, ¶42. The broadest reasonable interpretation
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`of the word “therapeutic” includes palliative (remediating) treatments as well as
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`curative treatments. EX1026, ¶¶43-44; EX1022, 0007 (therapeutic), 0004
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`(palliative), 0005 (remedy). Thus, in the context of the ’930 patent, an emulsion
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`that is effective in increasing tear production is an example of an emulsion
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`therapeutically effective in treating dry eye disease/KCS.
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`VIII. BACKGROUND KNOWLEDGE IN THE ART PRIOR TO SEPTEMBER 15, 2003
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`The background publications below reflect knowledge skilled artisans would
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`bring to bear in reading the prior art at the time of the invention, i.e., September 15,
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`2003, and thereby assist in understanding why one would have been motivated to
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`combine or modify the references as asserted in this Petition. Ariosa Diagnostics v.
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`Verinata Health, Inc., No. 15-1215, slip op. 1, 11-12 (Fed. Cir. Nov. 16, 2015). As
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`established in KSR, 550 U.S. at 406, the knowledge of a skilled artisan is part of
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`the store of public knowledge that must be consulted when considering whether a
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`claimed invention would have been obvious. Randall Mfg. v. Rea, 733 F.3d 1355,
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`1362-63 (Fed. Cir. 2013).
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`Prior to September 15, 2003, it was known that inflammation contributed to
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`dry eye diseases such as KCS. E.g., K. Kunert et al., Analysis of Topical
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`Cyclosporine Treatment of Patients with Dry Eye Syndrome 118 ARCH.
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`OPHTHALMOL. 1489 (2000) (“Kunert,” EX1012); EX1026, ¶47. CsA, a known
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`anti-inflammatory agent, had been shown to significantly reduce inflammation
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`markers associated with dry eye upon topical ophthalmic administration. EX1012,
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`1489; EX1026, ¶48. Dry eye disease was defined in the art as, “a deficiency in
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`either the aqueous or mucin components of the precorneal tear film. The most
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`commonly encountered aqueous-deficient dry eye in the United States is
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`keratoconjunctivitis sicca [KCS].” Medications for Dry Eye (1999) In PHYSICIANS’
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`DESK REFERENCE FOR OPHTHALMOLOGY (27th ed.) Montvale, NJ: PDR Network
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`(“Ophthalmic PDR,” EX1013) at 13. The Ophthalmic PDR also notes that a topical
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`CsA therapy, Sandimmune®, was readily available, and was prescribed for ocular
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`disorders including conjunctivitis and keratitis. Id. at 18; EX1026, ¶49.
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`Clinical trials establishing the efficacy and safety of CsA-in-castor oil
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`emulsions for treatment of dry eye disease/KCS were known prior to September
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`2003. EX1026, ¶48. Several clinical studies were performed in the late 1990’s and
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`early 2000’s. For example, Kunert established a decrease in lymphocyte activation
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`markers after topical ophthalmic administrat