Paper No. ______
`
`Filed on behalf of Akorn Inc.
`By: Michael R. Dzwonczyk
`
`Azy S. Kokabi
`
`Travis B. Ribar
`
`Sughrue Mion, PLLC
`
`2100 Pennsylvania Ave., NW
`
`Washington, DC 20037
`
`Telephone: 202-293-7060
`
`Facsimile: 202-293-7860
`mdzwonczyk@sughrue.com
`
`email:
`
`
`
`akokabi@sughrue.com
`
`
`
`tribar@sughrue.com
`
`
`IN THE UNITED STATES PATENT AND TRADEMARK OFFICE
`__________________
`
`BEFORE THE PATENT TRIAL AND APPEAL BOARD
`__________________
`
`AKORN INC.
`Petitioner
`
`v.
`
`ALLERGAN, INC.
`Patent Owner
`__________________
`
`Case No. IPR2017-00600
`Patent No. 8,648,048
`__________________
`
`PETITION FOR INTER PARTES REVIEW OF
`U.S. PATENT NO. 8,648,048
`
`
`
`

`
`TABLE OF CONTENTS
`
`
`
`I.
`
`
`Page
`
`INTRODUCTION ................................................................................................. 1
`
`A.
`
`Brief Overview of the '048 Patent ......................................................... 3
`
`B.
`
`Brief Overview of the Prosecution History ........................................... 5
`
`C.
`
`Brief Overview of the Scope and Content of the Prior Art ................... 8
`
`i.
`
`ii.
`
`U.S. Patent No. 5,474,979 to Ding et al. (“Ding ’979,” EX1006)9
`
`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)
`(“Sall,” 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
`
`iv. U.S. Patent No. 5,578,586 to Glonek et al. (“Glonek,” EX1009)11
`
`D.
`
`Brief Overview of the Level of Skill in the Art .................................. 12
`
`
`
` GROUNDS FOR STANDING ............................................................................... 13 II.
`
`
`
` MANDATORY NOTICES UNDER 37 C.F.R. §42.8 ............................................. 13 III.
`
`
`
` STATEMENT OF THE PRECISE RELIEF REQUESTED ........................................... 16 IV.
`
`
`
` V.
`
`STATEMENT OF NON-REDUNDANCY .......................................................... 16
`
`
`
` CLAIM CONSTRUCTION ............................................................................... 16 VI.
`
`A.
`
`“buffer” ................................................................................................ 17
`
`B.
`
`“substantially no detectable concentration” ........................................ 17
`
`-i-
`
`

`
`C.
`
`“effective,” “substantially therapeutically effective as,” and “as much
`therapeutic effectiveness as” ............................................................... 18
`
`D.
`
`“adverse events” and “side effects” .................................................... 19
`
`E.
`
`“breaks down” ..................................................................................... 20
`
`
`
` BACKGROUND KNOWLEDGE IN THE ART PRIOR TO SEPTEMBER 15, 2003 ...... 20 VII.
`
`
`
` DETAILED EXPLANATION OF GROUNDS FOR UNPATENTABILITY .................... 26 VIII.
`
`A.
`
`[Ground 1] Claims 1-10, 12-14, 16-20, and 22-23 are Obvious under
`35 U.S.C. § 103 over Ding ’979 and Sall............................................ 26
`
`i.
`
`Claims 1-10, 12, 18-20, and 22-23 ........................................... 27
`
`ii.
`
`Claims 13 and 14....................................................................... 43
`
`iii. Claims 16 and 17....................................................................... 45
`
`[Ground 2] Claims 11 and 21 are Obvious under 35 U.S.C. § 103
`over Ding ’979, Sall, and Acheampong .............................................. 47
`
`[Ground 3] Claim 15 is Obvious under 35 U.S.C. § 103 over Ding
`’979, Sall, and Glonek ......................................................................... 49
`
`B.
`
`C.
`
`
`
` NO OBJECTIVE INDICIA OF NON-OBVIOUSNESS .............................................. 51 IX.
`
`A. No Unexpected Results ....................................................................... 51
`
`B. No Evidence of Commercial Success ................................................. 63
`
`C. No Industry Praise. .............................................................................. 65
`
`D. No Long-Felt, Unmet Need ................................................................. 65
`
`E.
`
`No Failure of Others ............................................................................ 66
`
`
`X.
`
`CONCLUSION ................................................................................................... 67
`
`
`
` Certificate Of Compliance ............................................................................. 68 XI.
`
`
`
` Payment Of Fees Under 37 C.F.R. §§ 42.15(A) and 42.103......................... 69 XII.
`
`-ii-
`
`

`
`
`
` APPENDIX- LIST OF EXHIBITS ......................................................................... 70 XIII.
`
`CERTIFICATE OF SERVICE ................................................................................ 73
`
`
`
`-iii-
`
`

`
`
`I.
`
`INTRODUCTION
`
`On December 8, 2016, the Board instituted IPR2016-01131, stating that
`
`there was a reasonable likelihood that claims 1-23 of U.S. Patent No. 8,648,048 to
`
`Acheampong et al. (“the ’048 patent,” EX1001) are unpatentable based as obvious.
`
`Mylan Pharm., Inc. v. Allergan, Inc., IPR2016-01131, slip op. at 22 (PTAB
`
`December 8, 2016) (Paper 8). The present Petition presents the same grounds of
`
`unpatentability and the same arguments and evidence as the Petition in IPR2016-
`
`01131. The present Petitioner has received permission from Mylan
`
`Pharmaceuticals, Inc., the petitioner in IPR2016-01131, to rely upon the same
`
`expert. The present Petition is substantially identical to the Petition filed in
`
`IPR2016-01131. Accordingly, it is believed that the present Petition should be
`
`granted for the same reasons that the Board instituted IPR2016-01131.
`
`In particular, Akorn Inc. (“Petitioner”) requests review of the ’048 patent
`
`that issued on February 11, 2014. PTO records indicate the '048 patent is assigned
`
`to Allergan, Inc. (“Patent Owner”). This Petition demonstrates that there is a
`
`reasonable likelihood that claims 1-23 of the ’048 patent are unpatentable for
`
`failure to distinguish over prior art. Additional petitions are being filed to address
`
`related patents that are assigned to Patent Owner. All challenged patents are
`
`continuations from the patent family and are terminally disclaimed over one
`
`-1-
`
`

`
`another. The patents claim an ophthalmic emulsion for the treatment of
`
`overlapping ocular disorders, or conventional methods of administering the
`
`emulsion.
`
`The ’048 patent claims concern conventional methods of treating the dry eye
`
`disease keratoconjunctivitis sicca (hereinafter “dry eye disease/KCS”) by the
`
`“twice a day” topical ophthalmic administration of an emulsion containing
`
`cyclosporin A (“CsA”), castor oil, and other standard ingredients, as generally
`
`claimed in related U.S. Patent No. 8,685,930. Each element of the emulsion,
`
`including the claimed 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). 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, ¶18. A second 102(b) prior art reference, Sall, discloses twice-daily
`
`administration of a 0.05% CsA-in-castor oil emulsion for the same purpose.
`
`In prosecuting the ’048 patent as a continuation application, applicants
`
`changed course and attempted to withdraw the admissions regarding Ding ’979.
`
`EX1004, 0007. They argued that data collected after their earlier admissions
`
`established patentability because of an alleged unexpected result that the emulsion
`
`-2-
`
`

`
`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, 0253; EX1002,
`
`¶¶20-22. But 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 previously published graphs
`
`from the 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 '048 Patent
`
`The ’048 patent has an earliest claimed priority date of September 15, 2003.
`
`Independent claim 1 recites a method of increasing tear production in the eye,
`
`comprising administering twice-daily an emulsion of 0.05% CsA in 1.25% castor
`
`oil, polysorbate 80, acrylate/C10-30 alkyl acrylate cross-polymer (“cross-
`
`polymer”), and water. 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 glycerine and a buffer. Claims 7-8 are dependent claims
`
`that specify known weight percentages of polysorbate 80 and cross-polymer,
`
`-3-
`
`

`
`respectively. Claim 11 recites that when the emulsion is administered to the eye
`
`there is substantially no detectable concentration of CsA in the blood.
`
`Claims 13-16 compare the therapeutic effect of the claimed emulsion with
`
`emulsions with different percentages of CsA or castor oil. Claims 13-14 and 16-17
`
`respectively compare the therapeutic efficacy or adverse events of the claimed
`
`emulsion verses one with 0.10% CsA. Claim 15 compares the breakdown rate of
`
`the claimed with a second emulsion containing half as much castor oil.
`
`Claim 18 recites a method of treating keratoconjunctivitis sicca (KCS) using
`
`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 19-21
`
`further specify sodium hydroxide as the buffer and glycerine as the
`
`tonicity/demulcent agent, and that the blood of the human has substantially no
`
`detectable concentration of CsA.
`
`Independent claim 22 recites the same method as claim 18 but specifies
`
`glycerine as the tonicity/demulcent agent and sodium hydroxide as the buffer and
`
`that the method increases tear production in a person having KCS. Dependent
`
`claim 23 simply recites a pH range for the emulsion of claim 22.
`
`-4-
`
`

`
`B. Brief Overview of the Prosecution History
`
`U.S. Patent Application No. 13/967,168 (“the ’168 application”) was filed
`
`on August 14, 2013, and issued six months later on February 11, 2014, as the ’048
`
`patent. The ’168 application is a continuation, via U.S. applications 13/961,835
`
`and 11/897,177, of U.S. application 10/927,857 (“the ’857 application,” EX1005),
`
`which claims the benefit of U.S. provisional application 60/503,137, filed
`
`September 15, 2003.
`
`During prosecution of the related ’857 application, Patent Owner admitted
`
`that Composition II, which is identical to the emulsion claimed in the ’048 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
`
`-5-
`
`

`
`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 ’168 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 rej ected the claims as obvious over Ding ’979. Id. at
`
`0178-92. Patent Owner responded to the rejection, nakedly asserting that “the
`
`prima facie case of obviousness has not been properly established,” but arguing
`
`that the claims were patentable based on objective indicia. Id. at 0247. It also filed
`
`a terminal disclaimer for the applications or parent applications that resulted in the
`
`’930, ’111, ’162, ’556, and ’191 patents. Id. at 0164-65.
`
`In remarks accompanying a Notice of Allowance (id. at 0461; EX1002, ¶23)
`
`the examiner concluded that applicants had failed to demonstrate commercial
`
`success or long-felt need. EX1004, 0469-71. 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
`
`-6-
`
`

`
`surprisingly critical for therapeutic effectiveness in the treatment of dry eye or
`
`keratoconjunctivitis sicca,” and therefore, “demonstrate[s] surprising and
`
`unexpected results.” Id. at 0473.
`
`The alleged “unexpected results” are addressed in the declaration of Dr.
`
`Mansoor Amiji that accompanies this Petition. EX1002, ¶¶128-52. 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
`
`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
`
`-7-
`
`

`
`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.
`
`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
`
`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).
`
`-8-
`
`

`
`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, ¶62. 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, ¶65.
`
`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, ¶66. Example 2C is the
`
`exact same castor oil vehicle used in the challenged claims. Ding ’979 also
`
`discloses CsA-containing emulsions in Example 1 using the vehicles from
`
`Example 2. EX1006, 4:32-54. The emulsions in Example 1 have CsA percentages
`
`and castor oil 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,
`
`¶¶67-68. One emulsion (Example 1D) specifically used the 1.25% castor oil
`
`vehicle (Example 2C) to deliver 0.10% CsA. EX1006, 4:32-43.
`
`-9-
`
`

`
`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, ¶68. 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, ¶¶68, 99. 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) (“Sall,” 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, ¶¶74-75. Sall states that 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, ¶¶74-78, 81. Sall
`
`does not expressly disclose the exact composition of the castor oil vehicle, but
`
`-10-
`
`

`
`compares the 0.05% and 0.10% CsA emulsions to the same vehicle. EX1007, 632;
`
`EX1002, ¶74.
`
`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.
`
`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;
`
`EX1002, ¶¶88-89. Glonek discloses topical emulsions for the treatment of dry eye
`
`disease, “whereby blurred vision is reduced.” EX1009, 3:5-6; EX1002, ¶88. In
`
`comparing the relative amounts of surfactant and oil and their effects on visual
`
`-11-
`
`

`
`blurring, Glonek teaches that higher concentrations of oil lead to faster
`
`differentiation and decreased blurring. EX1009, 20:24-30; EX1002, ¶89.
`
`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.
`
`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; EX1003. He has served on the editorial board of 13 peer-
`
`-12-
`
`

`
`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.
`
`
`
` GROUNDS FOR STANDING II.
`
`Petitioner certifies that, under 37 C.F.R. § 42.104(a), the ’048 patent is
`
`available for inter partes review, and Petitioner is not barred or estopped from
`
`requesting inter partes review of the ’048 patent on the grounds identified in
`
`view of the Motion for Joinder submitted herewith.
`
`
`
` MANDATORY NOTICES UNDER 37 C.F.R. §42.8 III.
`
`Real Parties-in-Interest (37 C.F.R. § 42.8(b) (1)): The following real party-
`
`in-interest is identified: Akorn Inc.
`
`-13-
`
`

`
`Related Matters (37 C.F.R. § 42.8(b) (2)): IPR2016-01131, discussed above,
`
`involves the ‘048 patent, and that IPR was instituted on December 8, 2016. In
`
`addition, an IPR petition for the ’048 patent was previously filed by Apotex Corp.
`
`and Apotex Inc. as IPR2015-01284, as were petitions for related U.S. Patent Nos.
`
`8,629,111 (IPR2015-01282), 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 related 8,685,930, 8,629,111, 8,642,556,
`
`8,633,162 and 9,248,191 were also filed by the petitioner in IPR2016-01131 as
`
`IPR2016-01127, IPR2016-01128, IPR2016-01129, IPR2016-01130 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 (now 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 ’ 048 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 ’048 patent against Petitioner was
`
`served no earlier than August 24, 2015. Petitioner also identifies the following
`
`pending actions involving the ’048 patent: Allergan, Inc., v. Innopharma, Inc. and
`
`Pfizer, Inc., No. 2:15-cv-1504; Allergan, Inc., v. DEVA Holding A.S., No. 2:16-cv-
`
`-14-
`
`

`
`01447; Allergan, Inc., v. Twi Pharmaceuticals, Inc. et al., No. 2:16-cv-00820;
`
`Allergan, Inc. v. Famy Care Ltd., No. 2:16-cv-00401, all in the Eastern District of
`
`Texas. Petitioner also identifies the following terminated action involving the ‘048
`
`patent: Allergan, Inc. v. Actavis et al., No. 2: 14-cv-00638, in the Eastern District
`
`of Texas.
`
`Lead and Back-Up Counsel (37 C.F.R. § 42.8(b) (3)):
`
`Lead Counsel: Michael R. Dzwonczyk (Reg. No. 36,787)
`
`Back-Up Counsel: Azy S. Kokabi (Reg. No. 58,902)
`
`Back-Up Counsel: Travis B. Ribar (Reg. No. 61,446)
`
`Service Information (37 C.F.R. § 42.8(b) (4)):
`
`Petitioner hereby consents to electronic service.
`
`Email: mdzwonczyk@sughrue.com; akokabi@sughrue.com;
`
`tribar@sughrue.com; sughrue@sughrue.com
`
`Post: Sughrue Mion, PLLC
`
`
`
`
`
`
`
`
`
`2100 Pennsylvania Ave, NW
`
`Suite 800
`
`Washington, DC 20037
`
`Tel.: (202) 293-7060
`
`Fax: (202) 293-7860
`
`-15-
`
`

`
`
`
` STATEMENT OF THE PRECISE RELIEF REQUESTED IV.
`
`Petitioners request review of claims 1-23 of the ’048 patent under 35 U.S.C.
`
`§ 311 and AIA § 6 and that each of the claims be canceled as unpatentable:
`
`Ground
`
`Claims
`
`Obvious under §103 over
`
`1
`
`2
`
`3
`
`1-10, 12-14, 16-20, and 22-23 Ding ’ 979 and Sall
`
`11 and 21
`
`Ding ’979, Sall, and Acheampong
`
`15
`
`Ding ’979, Sall, and Glonek
`
`
`V.
`
`STATEMENT OF NON-REDUNDANCY
`
`Each of the Grounds raised in this Petition is meaningfully distinct. Ground
`
`1 asserts obviousness of claims 1-10, 12-14, 16-20, and 22-23 based on Ding ’979
`
`and Sall. Ground 2 challenges dependent claims 11 and 21, based Ding ’979,
`
`Sall, and Acheampong. Acheampong expressly teaches the claimed emulsion
`
`results in substantially no detectable blood concentration at trough and peak
`
`levels. Ground 3 challenges dependent claim 15 based on Ding ’979, Sall, and
`
`Glonek. Glonek expressly teaches the reduction in blurring from more rapid
`
`emulsion break down, and the relationship between break down rate and oil
`
`concentration.
`
`
`
` CLAIM CONSTRUCTION VI.
`
`In an inter partes review, a claim in an unexpired patent is given its broadest
`
`reasonable construction in light of the specification. 37 C.F.R. § 42.100(b); In re
`
`Cuozzo Speed Techs., LLC, 793 F.3d 1268, 1275-1280 (Fed. Cir. 2015), cert.
`
`-16-
`
`

`
`granted sub nom. Cuozzo Speed Techs., LLC v. Lee, 2016 U.S. LEXIS 632 (U.S.
`
`Jan. 15, 2016) (No. 15-446). Claims terms are also “generally given their ordinary
`
`and customary meaning,” which is the meaning that the term would have to a
`
`person of ordinary skill in the art at the time of the invention in view of the
`
`specification. In re Translogic Tech., Inc., 504 F.3d 1249, 1257 (Fed. Cir. 2007).
`
`Under either standard, there is a reasonable likelihood that Petitioner will prevail
`
`with respect to the challenged claims. A few terms are discussed below.
`
`A.
`
`“buffer”
`
`The term “buffer” appears in claims 4-6, 9-10, and 18-19 of the ’048 patent.
`
`Claims 5, 10, and 19 state “the buffer is sodium hydroxide.” The patent states,
`
`“[t]he pH of the emulsions can be adjusted in a conventional manner using sodium
`
`hydroxide ... to a physiological pH level.” EX1001, 12:15-17. In light of the
`
`specification, the broadest reasonable interpretation of the term “buffer” includes
`
`sodium hydroxide. EX1002, ¶38.
`
`B.
`
`“substantially no detectable concentration”
`
`The term “substantially no detectable concentration” appears in claims 11
`
`and 21 of the ’048 patent with regard to measuring CsA in human blood.
`
`According to the specification, “[c]yclosporin component concentration in blood
`
`preferably is determined using a liquid chromatography-mass spectroscopy-mass
`
`spectroscopy (LC-MS/MS), which test has a cyclosporin component detection
`
`-17-
`
`

`
`limit of 0.1 ng/ml. Cyclosporin component concentrations below or less than 0.1
`
`ng/ml are therefore considered substantially undetectable.” EX1001, 5:64—6:3. A
`
`skilled artisan could measure blood concentration at either peak or trough levels.
`
`EX1002, ¶39. In light of the specification, broadest reasonable interpretation of the
`
`phrase “substantially no detectable concentration” includes a blood concentration
`
`below 0.1 ng/mL measured at either peak or trough levels.
`
`C.
`
`“effective,” “substantially therapeutically effective as,” and
`“as much therapeutic effectiveness as”
`
`Independent claims 1 and 22 state the emulsion is “effective in increasing
`
`tear production,” and independent claim 18 states the emulsion is “effective in
`
`treating [KCS].” The ’048 patent characterizes KCS as “an absolute or partial
`
`deficiency in aqueous tear production.” EX1001, 3:2-5. This is consistent with its
`
`plain meaning. EX1022, 0003 (keratoconjunctivitis sicca is an “inflammation of
`
`the conjunctiva and of the cornea” that is “associated with decreased tears” and is a
`
`species of, and is often used interchangeably with, or as a partial synonym of, dry
`
`eye disease); EX1002, ¶40. During prosecution, Patent Owner relied on an
`
`increase in tearing to assert unexpected therapeutic efficacy of the claimed
`
`emulsion for treating dry eye disease/KCS. EX1004, 0253; EX1002, ¶40. Thus, in
`
`the context of the ’048 patent, an emulsion that is effective in increasing tear
`
`-18-
`
`

`
`production is an example of an emulsion therapeutically effective in treating dry
`
`eye disease/KCS.
`
`Claims 13 and 14 respectively describe the emulsion of claim 1 as being “as
`
`substantially therapeutically effective as” and having “at least as much therapeutic
`
`effectiveness as” a second emulsion with 0.10% CsA and 1.25% castor oil. The
`
`plain meaning of the word “therapeutic” includes palliative (remediating)
`
`treatments as well as curative treatments. EX1002, ¶¶41-42; EX1022, 0007
`
`(therapeutic), 0004 (palliative), 0005 (remedy). Accordingly, the broadest
`
`reasonable interpretation of these terms include palliative treatment as well as
`
`curative treatments.
`
`D.
`
`“adverse events” and “side effects”
`
`Claims 16 recites that the emulsion of the claimed method has fewer
`
`“adverse events” relative to a second emulsion, and claim 17 further recites that the
`
`“adverse events” are “side effects.” The specification also defines adverse events to
`
`include undesirable side effects. EX1001, 15:1-8. The plain meaning of “side
`
`effects” is “A result of a drug or other therapy in addition to or in extension of the
`
`desired therapeutic effect; usually but not necessarily, denoting an undesired
`
`effect.” EX1022, 0006 (side effect). The broadest reasonable interpretation of the
`
`term “adverse events” thus includes undesirable side effects, including burning
`
`eye, stinging eye, and general eye pain. EX1002, ¶43.
`
`-19-
`
`

`
`E.
`
`“breaks down”
`
`Claim 15 recites that the first emulsion “breaks down” more quickly in the
`
`eye of a human as compared to a second emulsion containing only 50% as much
`
`castor oil. The ’048 patent states that “a relatively high concentration of
`
`hydrophobic component is believed to provid