Filed on behalf of: Mylan Pharmaceuticals Inc.
`By: Steven W. Parmelee
`
`Michael T. Rosato
`
`Jad A. Mills
`
`WILSON SONSINI GOODRICH & ROSATI
`701 Fifth Avenue, Suite 5100
`Seattle, WA 98104-7036
`
`
`
`
`Paper No. ____
`Filed: June 3, 2016
`
`UNITED STATES PATENT AND TRADEMARK OFFICE
`_____________________________
`
`BEFORE THE PATENT TRIAL AND APPEAL BOARD
`
`_____________________________
`
`
`MYLAN PHARMACEUTICALS INC.,
`Petitioner,
`
`v.
`
`ALLERGAN, INC.,
`Patent Owner.
`
`_____________________________
`
`Case No. IPR2016-01128
`Patent No. 8,629,111
`
`_____________________________
`
`PETITION FOR INTER PARTES REVIEW OF
`U.S. PATENT NO. 8,629,111
`
`

`

`
`
`TABLE OF CONTENTS
`
`I. 
`
`INTRODUCTION ................................................................................................. 1 
`
`Page
`
`A. 
`
`B. 
`
`C. 
`
`Brief Overview of the ’111 Patent ........................................................ 2 
`
`Brief Overview of the Prosecution History ........................................... 3 
`
`Brief Overview of the Scope and Content of the Prior Art ................... 6 
`
`i. 
`
`ii. 
`
`U.S. Patent No. 5,474,979 to Ding et al. (“Ding ’979,”
`EX1006) ...................................................................................... 7 
`
`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) ..................................................... 8 
`
`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) .......................................................... 9 
`
`D. 
`
`Brief Overview of the Level of Skill in the Art .................................... 9 
`
`II. 
`
`GROUNDS FOR STANDING ............................................................................... 10 
`
`III.  MANDATORY NOTICES UNDER 37 C.F.R. § 42.8 ............................................. 11 
`
`IV.  STATEMENT OF THE PRECISE RELIEF REQUESTED FOR EACH CLAIM
`CHALLENGED .................................................................................................. 12 
`
`V. 
`
`STATEMENT OF NON-REDUNDANCY ............................................................... 12 
`
`VI.  CLAIM CONSTRUCTION ................................................................................... 13 
`
`A. 
`
`B. 
`
`“buffer” ................................................................................................ 13 
`
`“substantially no detectable concentration” ........................................ 14 
`
`-i-
`
`

`

`
`“effective,” and “therapeutically effective” ........................................ 14 
`
`C. 
`
`VII.  BACKGROUND KNOWLEDGE IN THE ART PRIOR TO SEPTEMBER 15, 2003 ...... 15 
`
`VIII.  DETAILED EXPLANATION OF GROUNDS FOR UNPATENTABILITY ................... 20 
`
`A. 
`
`[Ground 1] Claims 1-27 are Anticipated under 35 U.S.C.
`§ 102(b) by Ding ’979 ......................................................................... 20 
`
`i. 
`
`ii. 
`
`Claims 1-10, 12-15, and 18-19 ................................................. 20 
`
`Claims 17, 20-27 ....................................................................... 27 
`
`iii.  Claims 11 and 16....................................................................... 28 
`
`B. 
`
`[Ground 2] Claims 1-27 are Obvious under 35 U.S.C. § 103
`over Ding ’979 and Sall ...................................................................... 35 
`
`i. 
`
`ii. 
`
`Claims 1-16, and 18-19 ............................................................. 35 
`
`Claims 17, 20-27 ....................................................................... 37 
`
`iii.  Claims 11 and 16....................................................................... 38 
`
`C. 
`
`[Ground 3] Claims 11 and 16 are Obvious under 35 U.S.C.
`§ 103 over Ding ’979, Sall, and Acheampong .................................... 43 
`
`IX.  NO OBJECTIVE INDICIA OF NON-OBVIOUSNESS .............................................. 44 
`
`A.  No Unexpected Results ....................................................................... 45 
`
`B. 
`
`C. 
`
`No Evidence of Commercial Success ................................................. 55 
`
`No Industry Praise. .............................................................................. 56 
`
`D.  No Long-Felt, Unmet Need ................................................................. 57 
`
`E. 
`
`No Failure of Others ............................................................................ 57 
`
`X. 
`
`CONCLUSION ................................................................................................... 58 
`
`XI.  CERTIFICATE OF COMPLIANCE ........................................................................ 59 
`
`XII.  PAYMENT OF FEES UNDER 37 C.F.R. §§ 42.15(A) AND 42.103 ....................... 60 
`
`-ii-
`
`

`

`
`XIII.  APPENDIX – LIST OF EXHIBITS ........................................................................ 61 
`
`XIII. APPENDIX — LIST OF EXHIBITS ...................................................................... ..61
`
`-iii-
`
`-iii-
`
`

`

`
`
`I.
`
`INTRODUCTION
`
`Mylan Pharmaceuticals Inc. (“Petitioner”) requests review of U.S. Patent
`
`No. 8,629,111 to Acheampong et al. (“the ’111 patent,” EX1001) that issued on
`
`January 14, 2014. PTO records indicate the ’111 patent is assigned to Allergan,
`
`Inc. (“Patent Owner”). This Petition demonstrates that there is a reasonable
`
`likelihood that claims 1-27 of the ’111 patent are unpatentable for failure to
`
`distinguish over the asserted prior art. Additional petitions are being filed to
`
`address related patents that are assigned to Patent Owner. All challenged patents
`
`are continuations from the same family and are terminally disclaimed over one
`
`another. The patents claim an ophthalmic emulsion for the treatment of
`
`overlapping ocular disorders, or conventional methods of administering the
`
`emulsion.
`
`In particular, the ’111 patent claims a topical ophthalmic emulsion as in
`
`related U.S. Patent No. 8,685,930, but further recites that cyclosporin A (“CsA”)
`
`is the only peptide present in the emulsion. Each element of the emulsion,
`
`however, including the claimed CsA and castor oil percentages, preferred ratios for
`
`combining them, and CsA as the only peptide present in the emulsion, was
`
`disclosed in a single prior art reference (Ding ’979) for use in topical ophthalmic
`
`emulsions to treat the same dry eye disease, such as keratoconjunctivitis sicca
`
`(“KCS”). In fact, during prosecution of a parent application, applicants admitted
`
`that the claimed emulsion containing 0.05% CsA and 1.25% castor oil “is squarely
`
`within the teaching of the Ding [’979] reference” and “would have been obvious”
`
`to a person of skill in the art at the time of the invention. EX1005, 0435; EX1002,
`
`1
`
`

`

`
`
`¶18.
`
`Four years later, in prosecuting the ’111 patent as a continuation application,
`
`applicants changed course and attempted to withdraw these admissions. EX1004,
`0007. They argued that data collected after their earlier admissions established
`
`patentability because of an alleged unexpected result that the emulsion was
`
`“equally or more therapeutically effective for the treatment of dry
`
`eye/keratoconjunctivitis sicca than the formulation containing 0.10% by weight
`
`cyclosporin A and 1.25% by weight castor oil.” EX1004, 0007, 0205; EX1002,
`
`¶¶20-22. The supposed “unexpected results” are weak, at best, and fail to rebut the
`
`strong evidence of obviousness. The data relied upon by applicants lack scientific
`
`parameters necessary to demonstrate statistical significance and materiality and, in
`
`many cases, appear to be copies of graphs from a 102(b) prior art reference, Sall.
`
`Thus, Patent Owner’s cited evidence does not support non-obviousness of the
`
`claims, and merely confirms that the results were expected in view of and were
`
`already disclosed in the prior art.
`A. Brief Overview of the ’111 Patent
`The ’111 patent has an earliest claimed priority date of September 15, 2003.
`
`Independent claim 1 recites an emulsion of 0.05% CsA in 1.25% castor oil,
`
`polysorbate 80, acrylate/C10-30 alkyl acrylate cross-polymer (“cross-polymer”)
`
`and water, wherein CsA is the only peptide present in the emulsion. Claims 2-6
`
`and 9-10 recite that the emulsion comprises a tonicity or demulcent agent,
`
`specifically glycerine, and/or a buffer, specifically sodium hydroxide. Claim 12
`
`specifies a range of pH values for the emulsion of claim 6, which comprises
`
`-2-
`
`

`

`
`
`glycerine and a buffer. Claims 7-8 are dependent claims that specify known
`
`weight percentages of polysorbate 80 and cross-polymer, respectively. Claim 11
`
`recites that when the emulsion is adminstered to the eye there is substantially no
`
`detectable concentration of CsA in the blood.
`
`Independent claim 13 recites an emulsion incorporating the ingredients
`
`and/or weight percentage limitations of claims 1 and 7-9, and the pH value recited
`
`in claim 12. Dependent claims 14-17 further specify that the buffer is sodium
`
`hydroxide, the tonicity component is glycerine, the blood has substantially no
`
`detectable concentration of CsA, and that the emulsion is effective in treating KCS.
`
`Independent claim 18 recites the same emulsion as claim 13 but specifies
`
`glycerine as the tonicity/demulcent agent and sodium hydroxide as the buffer.
`
`Dependent claim 19 recites the same pH range as claims 1 and 13.
`
`Claims 20-22 depend from claim 1, claims 23-24 depend from claim 13, and
`
`claims 25-27 depend from claim 18. Claims 20, 23, and 25, claims 21 and 26, and
`
`claims 22, 24, and 27, respectively recite that the emulsion is therapeutically
`
`effective in treating dry eye disease or KCS, or in increasing tear production.
`B.
`U.S. Patent Application No. 13/967,163 (“the ’163 application”) was filed
`
`Brief Overview of the Prosecution History
`
`
`
`on August 14, 2013, and issued five months later on January 14, 2014, as the ’111
`
`patent. The ’163 application is a continuation, via U.S. applications 13/961,828
`
`and 11/897,177, of U.S. application 10/927,857 (“the ’857 application,” EX1005),
`
`which further claims the benefit of U.S. provisional application 60/503,137, filed
`
`September 15, 2003.
`
`-3-
`
`

`

`
`
`During prosecution of the related ’857 application, Patent Owner admitted
`
`that Composition II, which is identical to the emulsion claimed in the ’111 patent
`
`(EX1002, ¶¶18-19), 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, 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 [.]
`EX1005, 0435 (emphases added).
`
`During prosecution of the ’163 application, the applicants acknowledged
`
`their prior admissions, but claimed that they had collected evidence to support the
`
`patentability of the claims “[s]ince these comments have been filed.” EX1004,
`
`0007. The examiner then rejected the claims as obvious over Ding ’979. Id. at
`
`0170-89. Patent Owner responded to the rejection, nakedly asserting that “the
`
`prima facie case of obviousness has not been properly established against the
`
`pending claims,” but arguing that the claims were patentable based on objective
`
`-4-
`
`

`

`
`
`indicia. Id. at 0235. It also filed a terminal disclaimer for the applications or parent
`
`applications that resulted in the ’930, ’556, ’162, ’048, and ’191 patents. Id. at
`
`0159-60.
`
`In remarks accompanying a Notice of Allowance (id. at 0428; EX1002, ¶23)
`
`the examiner concluded that applicants had failed to demonstrate commercial
`
`success or long-felt need. EX1004, 0439-41. However, relying on declarations
`
`submitted by Drs. Schiffman and Attar, the examiner stated that, “the specific
`
`combination of 0.05% by weight cyclosporin A with 1.25% by weight castor oil is
`
`surprisingly critical for therapeutic effectiveness in the treatment of dry eye or
`
`keratoconjunctivitis sicca,” and therefore, “demonstrate[s] surprising and
`
`unexpected results.” Id. at 0443.
`
`The alleged “unexpected results” are addressed in the declaration of Dr.
`
`Mansoor Amiji that accompanies this Petition. EX1002, ¶¶122-46. As noted by Dr.
`
`Amiji, the data presented by applicants lacked scientific parameters necessary to
`
`demonstrate statistical significance and materiality. In many cases, the data appear
`
`to be repackaged from graphs published in the prior art Sall reference that is
`
`presently asserted against the claims. Thus, the declarations do not support a
`
`finding of surprising or unexpected results. Id.
`
`During prosecution, the Patent Owner did not identify, and the examiner did
`
`not address, deficiencies in the Schiffman and Attar Declarations that made them
`
`unreliable, which are discussed in this Petition. As such, and because of the new
`
`information presented herein and supported by Dr. Amiji’s testimony, the
`
`-5-
`
`

`

`
`
`examiner’s conclusions based on one-sided information should not receive any
`
`deference by the Board.
`
`In addition to demonstrating the flaws in Patent Owner’s alleged unexpected
`
`results, Dr. Amiji’s declaration also provides insight not previously presented to
`
`the Patent Office about how a person of ordinary skill in the art would interpret the
`
`disclosure of Ding ’979. Among other things, Dr. Amiji’s testimony establishes
`
`that the presently claimed emulsion would have been immediately apparent to one
`
`of ordinary skill in the art based on Ding ’979. EX1002, ¶¶97-98, 114. The Patent
`
`Owner’s alleged evidence of unexpected results cannot render patentable an
`
`anticipated claim. In re Wiggins, 488 F.2d 538, 543, (C.C.P.A. 1973).
`
`Further, this Petition presents new arguments based on expert testimony as
`
`to why the claims are obvious over Ding ’979 and other references that were not
`
`substantively analyzed during prosecution. Among other things, Dr. Amiji
`
`explains that the 1.25% castor oil emulsion vehicle of Example 2C in Ding ’979
`
`was the only vehicle that was most preferred for both the 0.05% and 0.10% CsA
`
`emulsions, and that Sall’s 0.05% and 0.10% CsA emulsions used the same castor
`
`oil vehicle. Petitioner provides an even stronger prima facie obviousness case than
`
`the examiner considered during prosecution. Accordingly, the Board should
`
`institute review without deference to the limited analysis during prosecution.
`C. Brief Overview of the Scope and Content of the Prior Art
`A prior art reference anticipates a claim if it discloses all of the elements of
`
`the claim in the claimed combination, or if the claimed combination would be
`
`“immediately apparent to one of ordinary skill in the art,” or “at once envisaged”
`
`-6-
`
`

`

`
`
`from the prior art reference. Wm. Wrigley Jr. Co. v. Cadbury Adams USA LLC,
`
`683 F.3d 1356, 1361 (Fed. Cir. 2012). In obviousness cases, Graham v. John
`
`Deere Co. of Kansas City, requires an 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 obviousness inquiry may account for
`
`inferences that would be employed by a 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
`
`treatment of keratoconjunctivitis sicca (“KCS” or “dry eye disease/KCS”). Id. at
`
`5:9-12; EX1002, ¶61. Claims 7-8 recite emulsions containing 0.05-0.40% CsA in
`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,
`
`and having a pH range of 7.2-7.6. EX1006, 4:4-5; id. at 6:27-42; EX1002, ¶64.
`
`Ding ’979 teaches that CsA is effective in treating dry eye disease/KCS “as an
`
`immunosuppressant and in the enhancement or restoring of lacrimal gland tearing.”
`
`EX1006, 1:10-16, 37-39.
`
`Ding ’979 discloses four examples of castor oil-based vehicles (Examples
`
`2A-D) for delivery of CsA. EX1006, 4:44-54; EX1002, ¶65. Example 2C is the
`
`exact same castor oil vehicle used in the challenged claims. Ding ’979 discloses
`
`CsA-containing emulsions in Example 1 using the vehicles from Example 2.
`
`EX1006, 4:32-54. The emulsions in Example 1 have CsA and castor oil
`
`-7-
`
`

`

`
`
`percentages covering the ranges disclosed in claims 7 and 8 (0.05% - 0.40% CsA
`
`and 0.625% - 5.00% castor oil) of Ding ’979. Id. at 4:32-43; EX1002, ¶¶66, 70.
`
`One emulsion (Example 1D) specifically used the 1.25% castor oil vehicle
`
`(Example 2C) to deliver 0.10% CsA. EX1006, 4:32-43.
`
`Ding ’979 explicitly sets forth a “more preferred” range for the ratio of CsA
`
`to castor oil of 0.02-0.12. Id. at 3:17-20; EX1002, ¶67. Each of the exemplified
`
`CsA-containing emulsions in Ding ’979 fall within an even narrower ratio range of
`
`0.04-0.08, which, for the 1.25% castor oil vehicle (Example 2C) disclosed in Ding
`
`’979, equates to a CsA range of 0.05% to 0.10% CsA. EX1006, 4:32-43; EX1005,
`
`0435; EX1002, ¶¶67, 94. Ding ’979 does not expressly discuss twice-daily
`
`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,
`
`randomized, double-masked Phase 3 clinical trial that assesses the safety and
`
`efficacy of increasing tear production and treating dry eye disease/KCS by twice-
`
`daily ophthalmic administration of 0.05% or 0.10% CsA in a castor oil emulsion,
`
`compared to the emulsion vehicle without CsA in the same regimen. EX1007, 631-
`
`32 & n.1; id. at figs. 1-4; EX1002, ¶¶73-74. Sall teaches the 0.05% CsA emulsion
`
`was safe and effective, was at least as effective as the 0.10% CsA emulsion, and
`
`resulted in fewer adverse side effects and in trough CsA blood concentrations
`
`below 0.1 ng/mL. EX1007, 631, 634-37; EX1002, ¶¶73-77, 80. Sall does not
`
`-8-
`
`

`

`
`
`expressly disclose the exact composition of the vehicle, but compares the 0.05%
`
`and 0.10% CsA emulsions to the same vehicle. EX1007, 632; EX1002, ¶¶111-12.
`
`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
`
`human patients with KCS twice a day for a period of three months. EX1008 at
`
`1002; EX1002, ¶¶85-86. Acheampong measured CsA blood concentration at both
`
`peak and trough levels following topical ophthalmic administration. EX1008 at
`
`1002. No detectable amount of CsA was measured in patients receiving the 0.05%
`
`CsA emulsion. EX1008 at 1002, 1004; EX1002, ¶¶85-86.
`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
`
`presented or published by others in the field. EX1002, ¶36. Typically this person
`
`would have an advanced degree, such as a medical degree, or a Ph.D. in organic
`
`chemistry, pharmaceutical chemistry, medicinal chemistry, pharmaceutics,
`
`physical pharmacy, or a related field, or less education but considerable
`
`professional experience in these fields. Id. at ¶35.
`
`-9-
`
`

`

`
`
`Petitioner’s expert, Dr. Mansoor Amiji, is the Bouvé College Distinguished
`
`Professor in the Department of Pharmaceutical Sciences at Northeastern University
`
`in Boston, Massachusetts. EX1002, ¶1; EX1003 (CV). Dr. Amiji is also an affiliate
`
`faculty member in the Departments of Chemical Engineering and Biomedical
`
`Engineering at Northeastern, as well as a Distinguished Adjunct Professor of
`
`Pharmacy at King Abdulaziz University. EX1002, ¶1; EX1003. Dr. Amiji has
`
`authored or co-authored more than 200 peer-reviewed journal articles and 43 book
`
`chapters. EX1002, ¶¶6-7; EX1003. He has served on the editorial board of 13 peer-
`
`reviewed journals, including Drug Design: Development and Therapy, Expert
`
`Opinion on Drug Delivery, Pharmaceutical Formulations and Quality, and Tissue
`
`Barriers. EX1002, ¶5; EX1003.
`
`Dr. Amiji received a Ph.D. in Pharmaceutical Science/Biomaterials Science
`
`from Purdue University in 1992, and he has extensive experience with ophthalmic
`
`pharmaceutical emulsions, including castor oil emulsions. EX1002, ¶¶3-4;
`
`EX1003. Dr. Amiji is well qualified as an expert, possessing the necessary
`
`scientific, technical, and other specialized knowledge and training to assist in an
`
`understanding of the evidence presented herein, as well as possessing the expertise
`
`necessary to determine and explain the level of ordinary skill in the art as of
`
`September 2003. EX1003.
`II. GROUNDS FOR STANDING
`Petitioner certifies that, under 37 C.F.R. § 42.104(a), the ’111 patent is
`
`available for inter partes review, and Petitioner is not barred or estopped from
`
`requesting inter partes review of the ’111 patent on the grounds identified.
`
`-10-
`
`

`

`
`
`III. MANDATORY NOTICES UNDER 37 C.F.R. § 42.8
`Real Parties-in-Interest (37 C.F.R. § 42.8(b) (1)): The following real parties-
`
`in-interest are identified: Mylan Pharmaceuticals Inc., the Petitioner in this matter
`
`and a wholly owned subsidiary of Mylan Inc.; Mylan Inc., which is an indirectly
`
`wholly owned subsidiary of Mylan N.V.; and Mylan N.V.
`
`Related Matters (37 C.F.R. § 42.8(b) (2)): An IPR petition for the ’111
`
`patent was previously filed by Apotex Corp. and Apotex Inc. as IPR2015-01282,
`
`as were petitions for related U.S. Patent Nos. 8,648,048 (IPR2015-01284),
`
`8,633,162 (IPR2015-01278), 8,642,556 (IPR2015-01286 ), and 8,685,930
`
`(IPR2015-01283), but all were terminated prior to institution decisions. IPR
`
`petitions for the related patents 8,685,930, 8,642,556, 8,633,162, 8,648,048, and
`
`9,248,191 are being filed by the present Petitioner as IPR2016-1127, IPR2016-
`
`01129, IPR2016-01130, IPR2016-01131, and IPR2016-01132, respectively. U.S.
`
`Application No. 15/011,159, filed January 29, 2016, claims the benefit of U.S.
`
`Application No. 14/222,478 (the ’191 patent), which is a continuation, via U.S.
`
`Application Nos. 13/961,828 and 11/897,177, of the ’857 application.
`
`
`
`Petitioner and other entities are involved in litigation over the ’111 patent
`
`and related patents in the action styled Allergan, Inc. v. Teva Pharmaceuticals
`
`USA, Inc., et al., No. 2:15-cv-01455, filed by Allergan, Inc. in the Eastern District
`
`of Texas (EX1023). A complaint asserting the ’111 patent against Petitioner was
`
`served no earlier than August 24, 2015. Petitioner also identifies the following
`
`pending actions involving the ’111 patent: Allergan, Inc., v. Innopharma, Inc. and
`
`Pfizer, Inc., No. 2:15cv1504, in the Eastern District of Texas.
`
`-11-
`
`

`

`
`
`Lead and Back-Up Counsel (37 C.F.R. § 42.8(b) (3)):
`
`Lead Counsel: Steven W. Parmelee (Reg. No. 31,990)
`
`Back-Up Counsel: Michael T. Rosato (Reg. No. 52,182)
`
`Back-Up Counsel: Jad A. Mills (Reg. No. 63,344)
`
`Service Information (37 C.F.R. § 42.8(b) (4)):
`
`Petitioner hereby consents to electronic service.
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`Email: sparmelee@wsgr.com; mrosato@wsgr.com; jmills@wsgr.com
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`Post: WILSON SONSINI GOODRICH & ROSATI
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`701 Fifth Avenue, Suite 5100, Seattle, WA 98104-7036
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`Tel.: 206-883-2542 Fax: 206-883-2699
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`IV. STATEMENT OF THE PRECISE RELIEF REQUESTED FOR EACH CLAIM
`CHALLENGED
`Petitioners request review of claims 1-27 of the ’111 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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`Description
`Ground Claims
`Anticipated under §102 by Ding ’979
`1
`1-27
`Obvious under §103 over Ding ’979 and Sall
`2
`1-27
`3
`11 and 16 Obvious under §103 over Ding ’979, Sall, and Acheampong
`STATEMENT OF NON-REDUNDANCY
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`V.
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`Each of the Grounds raised in this Petition is meaningfully distinct. Ground
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`1 asserts anticipation of claims 1-27 based on Ding ’979. Ground 2 asserts
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`obviousness of claims 1-27 based on Ding ’979 and Sall. Sall expressly teaches
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`certain intrinsic properties of the claimed emulsion, including efficacy, relative
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`efficacy, and substantially no detectable blood concentration at trough levels, and
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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 and 16 based Ding
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`’979, Sall, and Acheampong. Acheampong expressly teaches the claimed emulsion
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`results in substantially no detectable blood concentration at trough and peak levels.
`VI. CLAIM CONSTRUCTION
`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.
`A.
`The term “buffer” appears in claims 4-6, 9-10, and 13-14 of the ’111 patent.
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`“buffer”
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`Claims 5, 10, and 14 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, 12:17-18. In light of the
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`specification, the broadest reasonable interpretation of the term “buffer” includes
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`sodium hydroxide. EX1002, ¶38.
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`“substantially no detectable concentration”
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`B.
`The term “substantially no detectable concentration” appears in claims 11
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`and 16 of the ’111 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, 5:65–6:4. A
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`skilled artisan could measure blood concentration at either peak or trough levels.
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`EX1002, ¶39. In light of the specification, the broadest reasonable interpretation
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`of the phrase “substantially no detectable concentration” includes a blood
`concentration below 0.1 ng/mL measured at either peak or trough levels.
`C.
`Dependent claims 17 and 20-27 state the emulsion is “effective” or
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`“effective,” and “therapeutically effective”
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`“therapeutically effective” in increasing tear production, treating dry eye disease or
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`treating KCS. The ’111 patent characterizes KCS as “an absolute or partial
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`deficiency in aqueous tear production.” EX1001, 3:3-6. This is consistent with its
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`plain meaning. EX1022, 0003 (keratoconjunctivitis sicca is an “inflammation of
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`the conjunctiva and of the cornea” that is “associated with decreased tears” and is a
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`species of, and is often used interchangeably with, or as a partial synonym of, dry
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`eye disease); EX1002, ¶¶40-41. During prosecution, Patent Owner relied on an
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`increase in tearing to assert unexpected therapeutic efficacy of the claimed
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`emulsion for treating dry eye disease/KCS. EX1004, 0253; EX1002, ¶42. The
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`plain meaning of the word “therapeutic” includes palliative (remediating)
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`treatments as well as curative treatments. EX1002, ¶¶43-44; EX1022, 0007
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`(therapeutic), 0004 (palliative), 0005 (remedy). Thus, in the context of the ’111
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`patent, an emulsion that is effective in increasing tear production is an example of
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`an emulsion therapeutically effective in treating dry eye disease/KCS.
`VII. BACKGROUND KNOWLEDGE IN THE ART PRIOR TO SEPTEMBER 15, 2003
`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); EX1002, ¶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; EX1002, ¶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
`CsA therapy, Sandimmune®, was readily available, and was prescribed for ocular
`disorders including conjunctivitis and keratitis. Id. at 18; EX1002, ¶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. EX1002, ¶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 administration of a 0.05% CsA in a castor oil
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`emulsion, teaching that treatment with 0.05% CsA in castor oil “may help to
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`reduce the pathophysiological factors contributing to the development of KCS.”
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`EX1012, 1495. Turner established that the 0.05% CsA-in-castor oil emulsion was
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`at least as effective in decreasing inflammation markers as the 0.10% CsA-in-
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`castor oil emulsion. K. Turner et al., Interleukin-6 Levels in the Conjunctival
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`Epithelium of Patients with Dry Eye Disease Treated with Cyclosporine
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`Ophthalmic Emulsion 19 CORNEA 492 (2000) (EX1014) at 492; EX1002, ¶¶48, 51.
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`Stevenson conducted a Phase 2 clinical trial, and states that 0.05% and 0.10%
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`CsA-in-castor oil emulsions were “the most appropriate formulations ... because no
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`additional benefits were observed with the higher concentra