`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.
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`225 South Sixth Street, Suite 4200
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`Minneapolis, MN 55402
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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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`
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`TEVA PHARMACEUTICALS USA, INC.
`Petitioner,
`
`v.
`
`ALLERGAN, INC.,
`Patent Owner.
`
`
`
`Case No. IPR2017-00586
`Patent No. 9,248,191
`
`
`
`PETITION FOR INTER PARTES REVIEW OF
`U.S. PATENT NO. 9,248,191
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`TABLE OF CONTENTS
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`INTRODUCTION ................................................................................................. 1
`
`OVERVIEW ........................................................................................................ 3
`
`A. Brief Overview of the ’191 Patent ........................................................ 3
`
`B. Brief Overview of the Prosecution History ........................................... 4
`
`C. Brief Overview of the Scope and Content of the Prior Art ................... 7
`
`i.
`
`ii.
`
`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) .............................................. 9
`
`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) ........................................................ 10
`
`iv. U.S. Patent No. 5,578,586 to Glonek et al.
`(“Glonek,” EX1009) ................................................................. 10
`
`
`
`I.
`
`II.
`
`D. Brief Overview of the Level of Skill in the Art .................................. 11
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`III. GROUNDS FOR STANDING ............................................................................... 12
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`IV. MANDATORY NOTICES UNDER 37 C.F.R. § 42.8 ............................................. 12
`
`V.
`
`STATEMENT OF THE PRECISE RELIEF REQUESTED ........................................... 14
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`VI. STATEMENT OF NON-REDUNDANCY ............................................................... 15
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`VII. CLAIM CONSTRUCTION ................................................................................... 16
`
`A.
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`“buffer” ................................................................................................ 16
`i
`
`
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`
`
`B.
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`C.
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`D.
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`E.
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`“substantially no detectable concentration” ........................................ 17
`
`“effective,” “lacrimal gland tearing,” “overall efficacy
`substantially equal to,” “as much therapeutic efficacy as” ................. 17
`
`“demonstrates a reduction in adverse events” ..................................... 19
`
`“breaks down” ..................................................................................... 19
`
`VIII. BACKGROUND KNOWLEDGE IN THE ART PRIOR TO SEPTEMBER 15, 2003 ...... 20
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`IX. DETAILED EXPLANATION OF GROUNDS FOR UNPATENTABILITY .................... 26
`
`A.
`
`[Ground 1] Claims 1-16 and 21-27 are Obvious under
`35 U.S.C. § 103 over Ding ’979 and Sall ............................................ 26
`
`i.
`
`Claims 1-16 ............................................................................... 29
`
`ii. Claims 21-27 ............................................................................. 38
`
`[Ground 2] Claims 1-16 and 21-27 are Obvious under
`35 U.S.C. § 103 over Ding ’979, Sall, and Acheampong ................... 48
`
`[Ground 3] Claims 17-20 are Obvious under 35 U.S.C.
`§ 103 over Ding ’979, Sall, and Glonek .............................................. 49
`
`[Ground 4] Claim 20 is Obvious under 35 U.S.C. § 103
`over Ding ’979, Sall, Glonek, and Acheampong ................................ 53
`
`B.
`
`C.
`
`D.
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`X. NO OBJECTIVE INDICIA OF NON-OBVIOUSNESS: NO UNEXPECTED
`RESULTS ......................................................................................................... 54
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`XI. CONCLUSION ................................................................................................... 65
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`XII. CERTIFICATE OF COMPLIANCE ........................................................................ 67
`
`XIII. PAYMENT OF FEES UNDER 37 C.F.R. §§ 42.15(A) AND 42.103 ....................... 68
`
`XIV. APPENDIX – LIST OF EXHIBITS ........................................................................ 69
`
`
`
`ii
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`
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`I.
`
`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.
`
`9,248,191 to Acheampong et al. (“the ’191 patent,” EX1001) that issued on
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`February 2, 2016. PTO records indicate the ’191 patent is assigned to Allergan,
`
`Inc. (“Patent Owner”). This Petition demonstrates that there is a reasonable
`
`likelihood that claims 1-27 of the ’191 patent are unpatentable for failing to
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`distinguish over prior art. Additional petitions are being filed to address related
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`patents that are assigned to Patent Owner. All challenged patents are continuations
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`from the same family and are terminally disclaimed over one another. The patents
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`claim an ophthalmic emulsion for the treatment of overlapping ocular disorders, or
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`conventional methods of administering the emulsion.
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`In particular, the ’191 patent claims concern conventional methods of
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`treating dry eye disease, such as keratoconjunctivitis sicca (“KCS”) by the “twice a
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`day” topical ophthalmic administration of an emulsion containing cyclosporin A
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`(“CsA”), castor oil, and other standard ingredients, as generally claimed in related
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`U.S. Patent No. 8,685,930. Each element of the emulsion, including the claimed
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`CsA and castor oil percentages and methods for administering them to treat dry eye
`
`disease/KCS, were disclosed in a single prior art reference (Ding ’979) for use in
`
`
`
`1
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`
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`topical ophthalmic emulsions to enhance and restore lacrimal gland tear production
`
`and treat dry eye disease. During prosecution of a parent application, applicants
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`admitted the claimed emulsion containing 0.05% CsA / 1.25% castor oil “is
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`squarely within the teaching of the Ding [’979] reference” and “would have been
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`obvious” to a person of skill in the art at the time of the invention. EX1005, 0435;
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`EX1026, ¶20. A second 102(b) prior art reference, Sall, discloses twice-daily
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`administration of a 0.05% CsA-in-castor oil emulsion for the same purpose.
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`In prosecuting a continuation application, applicants changed course and
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`attempted to withdraw the admissions regarding Ding ’979, arguing that data
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`collected after their earlier admissions established patentability. EX1004, 0803. In
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`a parent application of the ’191 patent before the same examiner, Patent Owner
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`alleged that patentability was established by an unexpected result that the emulsion
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`was “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.” EX1023, 0195; EX1026, ¶¶22-24.
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`But the supposed “unexpected results” are weak, at best, and fail to rebut the
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`strong evidence of obviousness. The data relied upon by applicants lack scientific
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`parameters necessary to demonstrate statistical significance and materiality and, in
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`many cases, appear to be copies of previously published graphs from the 102(b)
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`prior art reference, Sall. Thus, Patent Owner’s cited evidence does not support non-
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`
`
`2
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`
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`obviousness of the claims, and merely confirms that the results were expected in
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`view of and were already disclosed in the prior art.
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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 ’191 patent on the same grounds
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`raised herein.
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`Ground 1: Claims 1–16 and 21–27 as obvious over Ding ’979 and Sall;
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`Ground 2: Claims 1–16 and 21–27 as obvious over Ding ’979, Sall, and
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`Acheampong;
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`Ground 3: Claims 17–20 as obvious over Ding ’979, Sall, and Glonek; and
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`Ground 4: Claim 20 as obvious over Ding ’979, Sall, Glonek, and
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`Acheampong.
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`Mylan Pharmaceuticals Inc. v. Allergan Inc., IPR2016-01132 (Paper No. 8).
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`Petitioner Teva hereby files its own petition on the same grounds and concurrently
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`seeks to join the instituted IPR proceedings on these challenged claims.
`
`A. Brief Overview of the ’191 Patent
`
`The ’191 patent has an earliest claimed priority date of September 15, 2003.
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`Claims 1, 13, 17, and 21 are independent claims that each recite administering a
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`first topical opthalmic emulsion comprising 0.05% CsA, 1.25% castor oil,
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`polysorbate 80, acrylate/C10-30 alkyl acrylate cross-polymer (“cross-polymer”),
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`3
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`and water, twice-daily. They state that the method is either for treating dry eye
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`disease or “enhancing” or “restoring” tearing. Some claims state that the method
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`“is therapeutically effective in treating dry eye disease” or is effective in
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`“enhancing” or “restoring” tearing, or “provides overall efficacy substantially
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`equal to” or “achieves at least as much therapeutic efficacy as” administering a
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`0.10% CsA / 1.25% castor oil emulsion. Certain claims also recite the CsA blood
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`concentration resulting from the method. Some dependent claims recite known
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`emulsion excipients, known percentages of those excipients, or known pH values
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`for the emulsions.
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`Claim 21 recites that administration of the emulsion demonstrates a
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`reduction in adverse events compared to administering a 0.10% CsA / 1.25%
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`castor oil emulsion. Some of its dependent claims recite that the adverse events are
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`visual distortion or eye irritation. Claim 17 recites that the first topical ophthalmic
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`emulsion breaks down more quickly in the eye than a second emulsion with 50%
`
`as much castor oil.
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`B.
`
`Brief Overview of the Prosecution History
`
`U.S. Patent Application No. 14/222,478 (“the ’478 application”) was filed
`
`on March 21, 2014, and issued on February 2, 2016, as the ’191 patent. The ’478
`
`application is a continuation, via U.S. applications 13/961,828, and 11/897,177, of
`
`
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`4
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`
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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
`
`that Composition II, which is identical to the emulsion claimed in the ’191 patent
`
`(EX1026, ¶¶20-21), was “squarely within the teachings of Ding [’979]”:
`
`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....
`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[.]
`
`
`EX1005, 0435 (emphases added).
`
`During prosecution of the ’478 application, the applicants acknowledged
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`their prior admissions, but claimed they had collected evidence to support the
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`patentability of the claims “[s]ince these comments have been filed.” EX1004,
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`0803. The examiner then rejected the claims on the ground of non-statutory double
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`patenting over U.S. Patent Nos. 8,685,930, 8,629,111, 8,633,162, 8,642,556, and
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`8,648,048. Id. at 0349-52. The Patent Owner subsequently filed a terminal
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`disclaimer for all five patents. Id. at 0153-54.
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`In remarks accompanying a Notice of Allowance, (id. at 0012), the examiner
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`relied on declarations submitted by Drs. Schiffman and Attar during the
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`prosecution of the parent U.S. application 13,961,828, which issued as the ’930
`5
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`
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`patent. Id. at 0018, 0116. The examiner stated that “the claimed formulations,
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`including 0.05% by weight cyclosporin A with 1.25% by weight castor oil,
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`demonstrate surprising and unexpected results, including improved Schirmer Tear
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`Test scores and corneal staining scores (key objective measures of efficacy for dry
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`eye or [KCS.]” EX1004, 0022.
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`The alleged “unexpected results” are addressed in the declaration of Dr.
`
`Walter Chambliss that accompanies this Petition. EX1026, ¶¶131-55. 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 unexpected results. Id.
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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 discussed in this
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`Petition that made them unreliable. As such, and because of the new information
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`presented herein and supported by Dr. Chambliss’s testimony, the Board should
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`not defer to the examiner’s conclusions based on one-sided information.
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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 new insight about how a person
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`of ordinary skill in the art would interpret the disclosure of Ding ’979. Among
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`
`
`6
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`
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`other things, Dr. Chambliss’s testimony establishes that the emulsion of the
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`claimed method would have been immediately apparent to one of ordinary skill in
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`the art based on Ding ’979. EX1026, ¶¶97-98, 114.
`
`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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`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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`On February 16, 2016, Patent Owner requested a Certificate of Correction
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`for nearly fifty errors, including: changing “005%” to “0.05%” in claim 1 and
`
`making claim 11 depend on claim 6 instead of claim 2. EX1004, 0006. None of the
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`requested corrections bar the relief requested in this Petition.
`
`C. Brief Overview of the Scope and Content of the Prior Art
`
`In obviousness cases, Graham v. John Deere Co. of Kansas City, requires an
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`evaluation of any differences between the claimed subject matter and the asserted
`
`prior art. 383 U.S. 1, 17-18 (1966). As noted in KSR Int’l Co. v. Teleflex Inc., the
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`
`
`7
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`
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`obviousness inquiry may account for inferences that would be employed by a
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`person of ordinary skill in the art. 550 U.S. 398, 418 (2007).
`
`i.
`
`U.S. Patent No. 5,474,979 to Ding et al. (“Ding ’979,”
`EX1006)
`
`Ding ’979 issued on December 12, 1995, and is prior art under 35 U.S.C.
`
`
`
`§ 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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`0.625-5.00% castor oil, 1.00% polysorbate 80, 0.05% Pemulen® (an acrylate/C10-
`
`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, ¶63.
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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,
`8
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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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`0435; EX1026, ¶¶67, 98. Ding ’979 does not expressly discuss twice-daily
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`administration of the emulsions.
`
`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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`
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`randomized, double-masked Phase 3 clinical trial that assesses the safety and
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`efficacy of enhancing and restoring lacrimal tear production and treating dry eye
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`disease/KCS by twice-daily ophthalmic administration of 0.05% or 0.10% CsA in
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`a castor oil emulsion, compared to the emulsion vehicle without CsA in the same
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`regimen. EX1007, 631-32 & n.1; id. at figs. 1-4; EX1026, ¶¶73-74. Sall teaches
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`that the 0.05% CsA emulsion was safe and effective, was at least as effective as the
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`0.10% CsA emulsion, and resulted in fewer adverse side effects and in CsA blood
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`concentrations below 0.1 ng/mL. EX1007, 631, 634-37; EX1026, ¶¶73-77, 80. Sall
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`
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`9
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`
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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;
`
`EX1026, ¶73.
`
`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
`
`
`
`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.
`
`iv. U.S. Patent No. 5,578,586 to Glonek et al. (“Glonek,” EX1009)
`
`Glonek issued Nov. 6, 1996 and is prior art under 35 U.S.C. § 102(b).
`
`EX1009. Glonek teaches that “an emulsion over the surface of the eye is expected
`
`to cause blurring. The duration of the blurring is dependent upon the time required
`
`for the emulsion to differentiate and form separate layers.” EX1009, 6:37-40;
`
`EX1026, ¶¶87-88. Glonek discloses topical emulsions for the treatment of dry eye
`
`disease, “whereby blurred vision is reduced.” EX1009, 3:5-6; EX1026, ¶87. In
`
`
`
`10
`
`
`
`comparing the relative amounts of surfactant and oil and their effects on visual
`
`blurring, Glonek teaches that higher concentrations of oil lead to faster
`
`differentiation and decreased blurring. EX1009, 20:24-30; EX1026, ¶88.
`
`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
`
`would likely have some combination of: (a) experience formulating pharmaceutical
`
`products; (b) experience designing and preparing drug emulsions intended for
`
`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.
`
`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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`
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`11
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`
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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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`III. GROUNDS FOR STANDING
`
`Petitioner certifies that, under 37 C.F.R. § 42.104(a), the ’191 patent is
`
`available for inter partes review, and Petitioner is not barred or estopped from
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`requesting Inter Partes Review of the ’191 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 (37 C.F.R. § 42.8(b) (1)): The following real parties
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`in-interest are identified: Mylan Pharmaceuticals Inc., the Petitioner in this matter
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`and a wholly owned subsidiary of Mylan Inc.; Mylan Inc., which is an indirectly
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`wholly owned subsidiary of Mylan N.V.; and Mylan N.V.
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`
`
`12
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`
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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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`IPR petitions were previously filed by Apotex Corp. and Apotex, Inc. for the
`
`related patents U.S. Patent Nos. 8,648,048 (IPR2015-01284), 8,633,162 (IPR2015-
`
`01278), 8,629,111 (IPR2015- 01282), 8,685,930 (IPR2015-01283), and 8,642,556
`
`(IPR2015-01286), but all were terminated prior to an institution decision.
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`An IPR petition for the ’191 patent was previously filed by Mylan as
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`IPR2016-01132 and has been instituted.
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`IPR petitions for the related patents 8,685,930 (IPR2016-01127), 8,629,111
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`(IPR2016-01128), 8,642,556 (IPR2016-01129), 8,633,162 (IPR2016-01130), and
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`8,648,048 (IPR2016-01131) have been filed by Mylan and have been instituted.
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`U.S. Application No. 15/011,159, filed January 29, 2016, claims the benefit of the
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`’478 application.
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`Teva filed IPR petitions for the related patents 8,685,930 (IPR2017-00576),
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`8,629,111 (IPR2017-00578), 8,642,556 (IPR2017-00579), 8,633,162 (IPR2017-
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`00583), and 8,648,048 (IPR2017-00585) on the same grounds and concurrently
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`seeks to join these instituted IPR proceedings on the same challenged claims.
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`Petitioner and other entities are involved in litigation over the ’191 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. in the Eastern District
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`of Texas. Petitioner also identifies the following pending action: Allergan, Inc., v.
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`Innopharma, Inc. and Pfizer, Inc., No. 2:15cv1504, in the Eastern District of
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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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`Email: gspeier@carlsoncaspers.com, mschuman@carlsoncaspers.com and
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`IPRCyclosporine@carlsoncaspers.com.
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`Post: CARLSON, CASPERS, VANDENBURGH, LINDQUIST &
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`SCHUMAN, P.A.
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`225 South Sixth Street, Suite 4200, Minneapolis, MN 55402
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`Tel.: (612) 436-9600 Fax: (612) 436-9605
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`V.
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`STATEMENT OF THE PRECISE RELIEF REQUESTED
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`Petitioners request review of claims 1-27 of the ’191 patent under 35 U.S.C.
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`§ 311 and AIA § 6 and that each of the claims be canceled as unpatentable:
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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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`1 asserts obviousnness of claiims 1-16 annd 21-27 bbased on DDing ’979 aand Sall. DDing
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`’979 teaaches the cclaimed emmulsion for enhancingg and restooring tear pproduction
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`treatingg dry eye diisease. Sall teaches twwice-dailyy administrration of a 00.05% CsAAin-
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`castor ooil emulsion, and exppressly teacches certainn propertiees intrinsic
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`emulsioon, includinng efficacyy, relative eefficacy, reelative advverse eventts, and CsAA
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`blood cooncentratioon at trouggh levels, aand providees additionnal reasons
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`use the emulsion. Ground 2 challengess claims 1--16 and 21--27 based DDing ’979
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`Sall, and Acheamppong. Achheampong eexpressly tteaches thee emulsionn results in
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`substanttially no deetectable CCsA blood concentrattion at trouugh and peeak levels.
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`d oil conceentration. GGround 4
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`challengges claim 220 based on Ding ’9779, Sall, Gllonek, andd Acheamppong to inc
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`lude
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`Acheammpong’s teaaching of nno detectabble blood cconcentratiion.
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`15
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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, 14, 18, and 24 of the ’191
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`patent. Claims 5 and 10 state “the buffer is sodium hydroxide.” The patent states,
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`“[t]he pH of the emulsions can be adjusted in a conventional manner using sodium
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`hydroxide ... to a physiological pH level.” EX1001, 12:25-27. In light of the
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`specification, the broadest reasonable interpretation of the term “buffer” includes
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`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 1 and
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`12 of the ’191 patent. Claims 12, 13, 20, 22, and 27 each recite the CsA blood
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`concentration is “less than about 0.1 ng/mL.” According to the specification,
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`“[c]yclosporin component concentration in blood preferably is determined using a
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`liquid chromatography-mass spectroscopy-mass spectroscopy (LC-MS/MS), which
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`test has a cyclosporin component detection limit of 0.1 ng/ml. Cyclosporin
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`component concentrations below or less than 0.1 ng/ml are therefore considered
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`substantially undetectable.” EX1001, 5:57-63. A skilled artisan could measure
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`blood concentration at either peak or trough levels. EX1026, ¶39. In light of the
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`specification, the broadest reasonable interpretation of the phrase “substantially no
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`detectable concentration” includes a blood concentration below 0.1 ng/mL
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`measured at either peak or trough levels.
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`C.
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`“effective,” “lacrimal gland tearing,” “overall efficacy
`substantially equal to,” “as much therapeutic efficacy as”
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`Independent claims 1 and 13 state that the emulsion is “therapeutically
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`effective in treating dry eye disease.” Independent claims 13 and 21 respectively
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`recite that the purpose of the method is “enhancing” or “restoring” tearing.
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`Dependent claims 16 and 26 respectively recite that the method is “effective” in
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`the enhancement or restoration of lacrimal gland tearing. The lacrimal glands are
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`the tear glands, and “tears” are “the fluid secreted by the lacrimal glands.”
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`EX1022, 0008 (lacrimal), 0009 (tear); EX1026, ¶40. Thus, “lacrimal gland tearing”
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`refers to tearing.
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`The ’191 patent teaches that it is believed that CsA “acts to enhance or
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`restore lacrimal gland tearing in providing the desired therapeutic effect.” EX1001,
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`9:15-16. KCS, an “inflammation of the conjunctiva and of the cornea” that is
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`“associated with decreased tears,” is a species of, and is often used interchangeably
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`with, or as a partial synonym of, dry eye disease. EX1022, 0003
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`(keratoconjunctivitis sicca); EX1026, ¶¶40-42. During prosecution, Patent Owner
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`relied on an increase in tearing to assert unexpected therapeutic efficacy of the
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`emulsion for treating dry eye disease/KCS. EX1004, 0020-22; EX1023, 0195;
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`EX1026, ¶¶142-53. Because a patient with dry eye disease/KCS has decreased
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`tears, methods of increasing tearing in a patient suffering from dry eye
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`disease/KCS are also methods of enhancing and restoring tearing. EX1026, ¶¶40-
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`42. Thus, in light of the specification, an emulsion effective in increasing tear
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`production is an example of an emulsion therapeutically effective in enhancing and
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`restoring lacrimal gland tearing and in treating dry eye disease.
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`Claim 1 further describes the method of claim 1 as providing “overall
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`efficacy substantially equal to” a second emulsion with 0.10% CsA and 1.25%
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`castor oil. Claims 13 and 21 recite that the method “achieves at least as much
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`therapeutic efficacy as” the method of administering this second emulsion. The
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`plain meaning of the word “therapeutic” includes palliative (remediating)
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`treatments as well as curative treatments. EX1026, ¶¶42-43; EX1022, 0007
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`(therapeutic), 0004 (palliative), 0005 (remedy). Accordingly, the broadest
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`reasonable interpretation of these terms includes palliative treatments as well as
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`curative treatments.
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`D.
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`“demonstrates a reduction in adverse events”
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`Claim 21 and its dependent claim 23 respectively recite that the claimed
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`emulsion demonstrates a reduction in “adverse events” relative to a second
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`emulsion containing 0.10% CsA and 1.25% castor oil, and that the “adverse
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`events” are “selected from the group consisting of visual distortion and eye
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`irritation.” Accordingly, the broadest reasonable interpretation of adverse events in
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`the context of the specification includes either visual distortion or eye irritation.
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`E.
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`“breaks down”
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`Independent claim 17 recites that the first emulsion "breaks down" more
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`quickly in the eye of a human as compared to a second emulsion containing only
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`50% as much castor oil. The ’191 patent states that “a relatively high concentration
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`of hydrophobic componen