Paper No. ______
`
`Filed on behalf of Akorn Inc.
`By: Michael R. Dzwonczyk
`
`Azy S. Kokabi
`
`Travis 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. IPR2017-00601
`Patent No. 9,248,191
`__________________
`
`PETITION FOR INTER PARTES REVIEW OF
`U.S. PATENT NO. 9,248,191
`
`
`
`Filed on behalf of Akorn Inc.
`By: Michael R. Dzwonczyk
`
`Azy S. Kokabi
`
`Travis 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. IPR2017-00601
`Patent No. 9,248,191
`__________________
`
`PETITION FOR INTER PARTES REVIEW OF
`U.S. PATENT NO. 9,248,191
`
`
`
`
`
`I.
`
`TABLE OF CONTENTS
`
`Page
`
`Introduction ...................................................................................................... 1
`
`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 ................... 8
`
`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) (“Sall”
`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)11
`
`D.
`
`Brief Overview of the Level of Skill in the Art .................................. 11
`
`II. Grounds For Standing .................................................................................... 13
`
`III. Mandatory Notices Under 37 C.F.R. § 42.8 .................................................. 13
`
`IV. Statement Of The Precise Relief Requested .................................................. 15
`
`V.
`
`Statement Of Non-Redundancy ..................................................................... 15
`
`VI. Claim Construction ........................................................................................ 16
`
`A.
`
`“buffer” ................................................................................................ 17
`
`-i-
`
`
`
`B.
`
`“substantially no detectable concentration” ........................................ 17
`
`C.
`
`“effective,” “lacrimal gland tearing,” “overall efficacy substantially
`equal to,” “as much therapeutic efficacy as” ...................................... 18
`
`D.
`
`“demonstrates a reduction in adverse events” ..................................... 20
`
`E.
`
`“breaks down” ..................................................................................... 20
`
`VII. Background Knowledge in the Art Prior to September 15, 2003 ................. 21
`
`VIII. Detailed Explanation of Grounds for Unpatentability .................................. 27
`
`A.
`
`[Ground 1] Claims 1-16 and 21-27 are Obvious under 35 U.S.C. § 103
`over Ding ’979 and Sall ...................................................................... 27
`
`i.
`
`Claims 1-16 ............................................................................... 31
`
`ii.
`
`Claims 21-27 ............................................................................. 41
`
`[Ground 2] Claims 1-16 and 21-27 are Obvious under 35 U.S.C. § 103
`over Ding ’979, Sall, and Acheampong .............................................. 50
`
`[Ground 3] Claims 17-20 are Obvious under 35 U.S.C. § 103 over
`Ding ’979, Sall, and Glonek ................................................................ 52
`
`[Ground 4] Claim 20 is Obvious under 35 U.S.C. § 103 over Ding
`’979, Sall, Glonek, and Acheampong. ................................................ 56
`
`B.
`
`C.
`
`D.
`
`IX. No Objective Indicia of Non-Obviousness: No Unexpected Results ........... 57
`
`X.
`
`Conclusion ..................................................................................................... 69
`
`XI. Certificate Of Compliance ............................................................................. 71
`
`XII. Payment Of Fees Under 37 C.F.R. §§ 42.15(A) AND 42.103 ...................... 72
`
`XIII. Appendix – List Of Exhibits .......................................................................... 73
`
`
`
`-ii-
`
`
`
`
`
`I.
`
`INTRODUCTION
`
`On December 8, 2016, the Board instituted IPR2016-01132, stating that
`
`there was a reasonable likelihood that claims 1-27 of U.S. Patent No. 9,248,191 to
`
`Acheampong et al. (“the ’191 patent,” EX1001) are unpatentable as obvious.
`
`Mylan Pharm., Inc. v. Allergan, Inc., IPR2016-01132, slip op. at 24 (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-
`
`01132. The present Petitioner has received permission from Mylan
`
`Pharmaceuticals, Inc., the petitioner in IPR2016-01132, to rely upon the same
`
`expert. The present Petition is substantially identical to the Petition filed in
`
`IPR2016-01132. Accordingly, it is believed that the present Petition should be
`
`granted for the same reasons that the Board instituted IPR2016-01132.
`
`In particular, Akorn Inc. (“Petitioner”) requests review of the ’191 patent
`
`that issued on 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 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 same family and are terminally disclaimed over one
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`-1-
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`
`
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`another. The patents claim an ophthalmic emulsion for the treatment of
`
`overlapping ocular disorders, or conventional methods of administering the
`
`emulsion.
`
`The ’191 patent claims concern conventional methods of treating dry eye
`
`disease, such as keratoconjunctivitis sicca (“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) for use in
`
`topical ophthalmic emulsions to enhance and restore lacrimal gland tear production
`
`and treat dry eye disease. During prosecution of a parent application, applicants
`
`admitted the claimed emulsion containing 0.05% CsA / 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, ¶20. 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 a continuation application, applicants changed course and
`
`attempted to withdraw the admissions regarding Ding ’979, arguing that data
`
`-2-
`
`
`
`
`collected after their earlier admissions established patentability. EX1004, 0803. In
`
`a parent application of the ’191 patent before the same examiner, Patent Owner
`
`alleged that patentability was established by an 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.” EX1023, 0195; EX1002, ¶¶22-24.
`
`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 ’191 Patent
`
`The ’191 patent has an earliest claimed priority date of September 15, 2003.
`
`Claims 1, 13, 17, and 21 are independent claims that each recite administering a
`
`first topical opthalmic emulsion comprising 0.05% CsA, 1.25% castor oil,
`
`polysorbate 80, acrylate/C10-30 alkyl acrylate cross-polymer (“cross-polymer”),
`
`and water, twice-daily. They state that the method is either for treating dry eye
`
`-3-
`
`
`
`
`disease or “enhancing” or “restoring” tearing. Some claims state that the method
`
`“is therapeutically effective in treating dry eye disease” or is effective in
`
`“enhancing” or “restoring” tearing, or “provides overall efficacy substantially
`
`equal to” or “achieves at least as much therapeutic efficacy as” administering a
`
`0.10% CsA / 1.25% castor oil emulsion. Certain claims also recite the CsA blood
`
`concentration resulting from the method. Some dependent claims recite known
`
`emulsion excipients, known percentages of those excipients, or known pH values
`
`for the emulsions.
`
`Claim 21 recites that administration of the emulsion demonstrates a
`
`reduction in adverse events compared to administering a 0.10% CsA / 1.25%
`
`castor oil emulsion. Some of its dependent claims recite that the adverse events are
`
`visual distortion or eye irritation. Claim 17 recites that the first topical ophthalmic
`
`emulsion breaks down more quickly in the eye than a second emulsion with 50%
`
`as much castor oil.
`
`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
`
`-4-
`
`
`
`
`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 ’191 patent
`
`(EX1002, ¶¶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
`
`their prior admissions, but claimed they had collected evidence to support the
`
`patentability of the claims “[s]ince these comments have been filed.” EX1004,
`
`0803. The examiner then rejected the claims on the ground of non-statutory
`
`double patenting over U.S. Patent Nos. 8,685,930, 8,629,111, 8,633,162,
`
`-5-
`
`
`
`
`8,642,556, and 8,648,048. Id. at 0349-52. The Patent Owner subsequently filed a
`
`terminal disclaimer for all five patents. Id. at 0153-54.
`
`In remarks accompanying a Notice of Allowance, (id. at 0012), The
`
`Examiner relied on declarations submitted by Drs. Schiffman and Attar during the
`
`prosecution of the parent U.S. application 13,961,828, which issued as the ’930
`
`patent. Id. at 0018, 0116. The examiner stated that “the claimed formulations,
`
`including 0.05% by weight cyclosporin A with 1.25% by weight castor oil,
`
`demonstrate surprising and unexpected results, including improved Schirmer Tear
`
`Test scores and corneal staining scores (key objective measures of efficacy for dry
`
`eye or [KCS.]” EX1004, 0022.
`
`The alleged “unexpected results” are addressed in the declaration of Dr.
`
`Mansoor Amiji that accompanies this Petition. EX1002, ¶¶131-55. 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 unexpected results. Id.
`
`During prosecution, the Patent Owner did not identify, and the examiner did
`
`not address, deficiencies in the Schiffman and Attar Declarations discussed in this
`
`-6-
`
`
`
`
`Petition that made them unreliable. As such, and because of the new information
`
`presented herein and supported by Dr. Amiji’s testimony, the Board should not
`
`defer to the examiner’s conclusions based on one-sided information.
`
`In addition to demonstrating the flaws in Patent Owner’s alleged unexpected
`
`results, Dr. Amiji’s declaration also provides new insight 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 emulsion of the claimed method
`
`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.
`
`-7-
`
`
`
`
`
`On February 16, 2016, Patent Owner requested a Certificate of Correction
`
`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
`
`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
`
`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, ¶63.
`
`Ding ’979 teaches that CsA is effective in treating dry eye disease/KCS “as an
`
`-8-
`
`
`
`
`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 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,
`
`¶¶66-67. 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, 98. 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
`
`-9-
`
`
`
`
`
`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 enhancing and restoring lacrimal 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
`
`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 CsA blood
`
`concentrations below 0.1 ng/mL. EX1007, 631, 634-37; EX1002, ¶¶73-77, 80.
`
`Sall does not expressly disclose the exact composition of the castor oil vehicle, but
`
`compares the 0.05% and 0.10% CsA emulsions to the same vehicle. EX1007, 632;
`
`EX1002, ¶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
`
`human patients with KCS twice a day for a period of three months. EX1008 at
`
`-10-
`
`
`
`
`1002; EX1002, ¶¶84-85. 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, ¶¶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;
`
`EX1002, ¶¶87-88. Glonek discloses topical emulsions for the treatment of dry eye
`
`disease, “whereby blurred vision is reduced.” EX1009, 3:5-6; EX1002, ¶87. In
`
`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; EX1002, ¶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
`
`-11-
`
`
`
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`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-
`
`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;
`
`-12-
`
`
`
`
`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 ’191 patent is
`
`available for inter partes review, and Petitioner is not barred or estopped from
`
`requesting Inter Partes Review of the ’191 patent on the grounds identified in view
`
`of the Motion for Joinder submitted herewith.
`
`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 party-
`
`in-interest is identified: Akorn Inc.
`
`Related Matters (37 C.F.R. § 42.8(b) (2)): IPR2016-01132, discussed above,
`
`involves the ’191 patent, and that IPR was instituted on December 8, 2016. In
`
`addition, 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
`
`-13-
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`decision. IPR petitions for the related patents 8,685,930, 8,629,111, 8,642,556,
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`8,633,162, and 8,648,048 were also filed by the petitioner in IPR2016-01132 as
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`IPR2016-01127, IPR2016-01128, and IPR2016-01129, IPR2016-01130 and
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`IPR2016-01131, respectively. U.S. Application No. 15/011,159, filed January 29,
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`2016, claims the benefit of the ’478 application.
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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. An amended complaint asserting the ’191 patent against Petitioner was
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`served no earlier than February 18, 2016 (EX1025). Petitioner also identifies the
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`following pending actions: Allergan, Inc., v. Innopharma, Inc. and Pfizer, Inc., No.
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`2:15-cv-1504; Allergan, Inc., v. DEVA Holding A.S., No. 2:16-cv-01447; Allergan,
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`Inc., v. Twi Pharmaceuticals, Inc. et al., No. 2:16-cv-00820; Allergan, Inc. v. Famy
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`Care Ltd., No. 2:16-cv-00401, all in the Eastern District of Texas.
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`Lead and Back-Up Counsel (37 C.F.R. § 42.8(b) (3)):
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`Lead Counsel: Michael R. Dzwonczyk (Reg. No. 36,787)
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`Back-Up Counsel: Azy S. Kokabi (Reg. No. 58,902)
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`Back-Up Counsel: Travis B. Ribar (Reg. No. 61,446)
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`Service Information (37 C.F.R. § 42.8(b) (4)):
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`-14-
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`Petitioner hereby consents to electronic service.
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`Email: mdzwonczyk@sughrue.com; akokabi@sughrue.com;
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`tribar@sughrue.com; sughrue@sughrue.com
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`Post: Sughrue Mion, PLLC
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`2100 Pennsylvania Ave., NW
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`Suite 800
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`Washington, DC 20037
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`Tel.: (202) 293-7060 Fax: (202) 293-7860
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`IV. 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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`Ground
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`Claims
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`Obvious Under § 103 over
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`1
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`2
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`3
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`4
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`1-16 and 21-27 Ding ’979 and Sall
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`1-16 and 21-27 Ding ’979, Sall, and Acheampong
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`17-20
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`Ding ’979, Sall, and Glonek
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`20
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`Ding ’979, Sall, Acheampong, and Glonek
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`V.
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`STATEMENT OF NON-REDUNDANCY
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`Each of the Grounds raised in this Petition is meaningfully distinct. Ground
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`1 asserts obviousness of claims 1-16 and 21-27 based on Ding ’979 and Sall. Ding
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`’979 teaches the claimed emulsion for enhancing and restoring tear production and
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`
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`treating dry eye disease. Sall teaches twice-daily administration of a 0.05% CsA-
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`in-castor oil emulsion, and expressly teaches certain properties intrinsic to the
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`emulsion, including efficacy, relative efficacy, relative adverse events, and CsA
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`blood concentration at trough levels, and provides additional reasons to make and
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`use the emulsion. Ground 2 challenges claims 1-16 and 21-27 based Ding ’979,
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`Sall, and Acheampong. Acheampong expressly teaches the emulsion results in
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`substantially no detectable CsA blood concentration at trough and peak levels.
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`Ground 3 challenges claims 17-20 based on Ding ’979, Sall, and Glonek. Glonek
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`expressly teaches the reduction in blurring from more rapid emulsion break down,
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`and the relationship between break down rate and oil concentration. Ground 4
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`challenges claim 20 based on Ding ’979, Sall, Glonek, and Acheampong to include
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`Acheampong’s teaching of no detectable blood concentration.
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`VI. 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. EX1002, ¶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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`-17-
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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. EX1002, ¶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); EX1002, ¶40. Thus, “lacrimal gland
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`tearing” 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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`-18-
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`(keratoconjunctivitis sicca); EX1002, ¶¶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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`EX1002, ¶¶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. EX1002, ¶¶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. EX1002, ¶¶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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`-19-
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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
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`in 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 component is believed to provide for a more quick or rapid
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`breaking down or resolving of the emulsion in the eye, which reduces vision
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`distortion which may be caused by the presence of the emulsion in the eye and/or
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`facilitates the therapeutic effectiveness of the composition.” EX1001, 2:45-51. As
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`explained by Dr. Amiji, a person of ordinary skil
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