IN THE UNITED STATES PATENT AND TRADEMARK OFFICE
`________________________________
`
`BEFORE THE PATENT TRIAL AND APPEAL BOARD
`________________________________
`
`FAMY CARE LIMITED
`Petitioner
`v.
`ALLERGAN, INC.
`Patent Owner
`U.S. Patent No. 8,685,930 B2 to Acheampong et al.
`Issue Date: April 1, 2014
`Title: Methods of Providing Therapeutic Effects Using Cyclosporin Components
`________________________________
`
`Inter Partes Review Trial No. 2017-00571
`________________________________
`
`Petition for Inter Partes Review of U.S. Patent No. 8,685,930
`
`
`Mail Stop "PATENT BOARD"
`Patent Trial and Appeal Board
`U.S. Patent and Trademark Office
`P.O. Box 1450
`Alexandria, VA 22313-1450
`
`
`
`
`
`

`

`Petition for Inter Partes Review of U.S. Patent No. 8,685,930 B2
`
`TABLE OF CONTENTS
`
`
`EXHIBIT LIST PURSUANT TO 37 C.F.R. § 42.63(e) AND TABLE
`OF ABBREVIATIONS ................................................................................... iv
`
`I.
`
`INTRODUCTION. ................................................................................. 2
`
`II. MANDATORY NOTICES (37 C.F.R. § 42.8(a)(1)). ............................ 4
`
`A.
`
`B.
`
`C.
`
`D.
`
`Real Party-In-Interest (37 C.F.R. § 42.8(b)(1)). ........................... 4
`
`Related Matters (37 C.F.R. § 42.8(b)(2)). ..................................... 4
`
`Lead and Back-Up Counsel (37 C.F.R. § 42.8(b)(3)). .................. 5
`
`Service Information (37 C.F.R. § 42.8(b)(4)). .............................. 6
`
`III. GROUNDS FOR STANDING (37 C.F.R. § 42.104(a)). ....................... 6
`
`IV. SPECIFIC IDENTIFICATION OF CHALLENGE (37 C.F.R.
`§ 42.104(b)). ........................................................................................... 6
`
`V. OVERVIEW OF THE ’930 PATENT. .................................................. 7
`
`A.
`
`B.
`
`’930 Patent Claims. ....................................................................... 7
`
`’930 Patent Prosecution History. ................................................... 8
`
`VI. PERSON OF ORDINARY SKILL IN THE ART. ................................ 9
`
`VII. STATE OF THE ART AS OF SEPTEMBER 15, 2003. ..................... 10
`
`VIII. PRIOR ART. ......................................................................................... 12
`
`A. Ding ’979 (EX1006). ...................................................................12
`
`B.
`
`C.
`
`Sall (EX1007). .............................................................................14
`
`Acheampong (EX1008). ..............................................................15
`
`IX. CLAIM CONSTRUCTION. ................................................................ 15
`
`
`
`i
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`Petition for Inter Partes Review of U.S. Patent No. 8,685,930 B2
`
`A.
`
`B.
`
`C.
`
`“therapeutically effective” and “effective amount” ....................16
`
`“buffer” ........................................................................................17
`
`“substantially no detectable concentration” ................................18
`
`X.
`
`EXPLANATION OF UNPATENTABILITY GROUNDS. ................ 18
`
`A. Ding ’979 Claim Chart. ...............................................................18
`
`B.
`
`Ground 1: Claims 1-36 Are Unpatentable Under 35 U.S.C.
`§ 102 by Ding ‘979. .....................................................................24
`
`1.
`
`Claims 1-10, 12-22, 24-34 and 36. ...................................25
`
`a.
`b.
`c.
`d.
`
`Preamble and Efficacy Elements ............................25
`CsA and Castor Oil Elements .................................26
`Additional Composition Elements .........................27
`Ding
`’979
`taught
`the entire claimed
`Composition II formulation. ...................................29
`Therapeutic effectiveness .......................................30
`e.
`Claims 11, 23 and 35. .......................................................33
`
`2.
`
`C.
`
`Ground 2: Claims 1-36 Are Unpatentable Under 35 U.S.C.
`§ 103 in View of Ding ’979 and Sall. .........................................34
`
`1.
`
`Claims 1-10, 12-22, 24-34 and 36. ...................................35
`
`Preamble and Efficacy Elements: ...........................35
`a.
`CsA Elements .........................................................37
`b.
`Castor Oil Elements ................................................38
`c.
`Additional Composition Elements .........................42
`d.
`Efficacy. ..................................................................42
`e.
`Claims 11, 23 and 35. .......................................................43
`
`2.
`
`D. Ground 3: Claims 11, 23, and 35 Are Unpatentable Under
`35 U.S.C. § 103 in View of Ding ‘979, Sall and
`Acheampong. ...............................................................................44
`ii
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`Petition for Inter Partes Review of U.S. Patent No. 8,685,930 B2
`
`XI. ALLERGAN’S ALLEGED SECONDARY
`CONSIDERATIONS DO NOT OVERCOME PETITIONER’S
`STRONG SHOWING OF OBVIOUSNESS ....................................... 46
`
`A. No Unexpected Results. ..............................................................50
`
`1.
`
`2.
`
`3.
`
`4.
`
`Schiffman Exhibit B .........................................................51
`
`Schiffman Exhibit C/Attar Exhibit B ................................55
`
`Schiffman Exhibit D .........................................................58
`
`Schiffman Exhibits E and F/Attar Exhibits D and E. .......63
`
`B.
`
`Near-Simultaneous Invention. .....................................................67
`
`XII. CONCLUSION..................................................................................... 67
`
`XIII. CERTIFICATE OF COMPLIANCE ................................................... 69
`
`
`
`
`
`
`
`iii
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`Petition for Inter Partes Review of U.S. Patent No. 8,685,930 B2
`
`Exhibit
`1001
`
`1002
`1003
`1004
`
`1005
`
`1006
`
`1007
`
`1008
`
`EXHIBIT LIST PURSUANT TO 37 C.F.R. § 42.63(e) AND
`TABLE OF ABBREVIATIONS
`
`Description of Exhibit
`U.S. Patent No. 8,685,930 B2 to Acheampong et al., filed August 7,
`2013 (“the ’930 patent”)
`Declaration of Dr. Peter Kador
`Declaration of Dr. Michael A. Lemp
`File history of U.S. Patent No. 8,685,930 to Acheampong et al., filed
`August 7, 2013 (“’930 patent FH”)
`File history of U.S. Patent Application No. 10/927,857 to
`Acheampong et al., filed August 27, 2004 (“’857 application FH”)
`U.S. Patent No. 5,474,979 to Ding et al., filed May 17, 1994 (“Ding
`’979”)
`K. Sall et al., Two Multicenter, Randomized Studies of the Efficacy
`and Safety of Cyclosporine Ophthalmic Emulsion in Moderate to
`Severe Dry Eye Disease, 107 OPHTHALMOLOGY 631 (2000) (“Sall”)
`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, in
`2 LACRIMAL GLAND, TEAR FILM, & DRY EYE SYNDROMES 1001
`(David A. Sullivan et al. eds., 1998) (“Acheampong”)
`U.S. Patent No. 5,578,586 to Glonek et al., filed February 4, 1994
`(“Glonek”)
`U.S. Patent No. 5,981,607 to Ding et al., filed January 20, 1998
`(“Ding ’607”)
`R. Kaswan, Intraocular Penetration of Topically Applied
`Cyclosporine, 20 TRANSPL. PROC. 650 (1988) (“Kaswan”)
`K. Kunert et al., Analysis of Topical Cyclosporine Treatment of
`Patients with Dry Eye Syndrome, 118 ARCH OPHTHALMOL 1489
`(2000) (“Kunert”)
`PHYSICIANS’ DESK REFERENCE FOR OPHTHALMOLOGY 13-18 (Medical
`Economics Co., 27th ed. 1999) (“Ophthalmic PDR”)
`K. Turner et al., Interleukin-6 Levels in the Conjunctival Epithelium
`of Patients with Dry Eye Disease Treated with Cyclosporine
`Ophthalmic Emulsion, 19 CORNEA 492 (2000) (“Turner”)
`D. Stevenson et al., Efficacy and Safety of Cyclosporin A Ophthalmic
`Emulsion in the Treatment of Moderate-to-Severe Dry Eye Disease,
`107 OPHTHALMOLOGY 967 (2000) (“Stevenson”)
`
`1009
`
`1010
`
`1011
`
`1012
`
`1013
`
`1014
`
`1015
`
`
`
`iv
`
`

`

`Petition for Inter Partes Review of U.S. Patent No. 8,685,930 B2
`
`1016
`
`1017
`
`1018
`
`1019
`
`1020
`
`1021
`
`1022
`
`1023
`
`1024
`
`1025
`
`1026
`1027
`1028
`
`1029
`
`1030
`
`REMINGTON’S 20TH EDITION: THE SCIENCE AND PRACTICE OF
`PHARMACY (A. Gennaro ed. 2003) (“Remington”)
`E. Goto et al., Low-Concentration Homogenized Castor Oil Eye
`Drops for Noninflamed Obstructive Meibomian Gland Dysfunction,
`109 OPHTHALMOLOGY 2030 (2002) (“Goto”)
`A. Kanpolat et al., Penetration of Cyclosporin A into the Rabbit
`Cornea and Aqueous Humor after Topical Drop and Collagen Shield
`Administration, 20 CLAO J. 119 (1994) (“Kanpolat”)
`C. Vieira et al., Effect of Ricinoleic Acid in Acute and Subchronic
`Experimental Models of Inflammation, 9 MEDIATORS INFLAMMATION
`223 (2000) (“Vieira”)
`R. Murphy, The Once and Future Treatment of Dry Eye, REVIEW OF
`OPTOMETRY ONLINE (Feb. 15, 2000) (“Murphy”)
`D. Small et al., Blood Concentrations of Cyclosporin A During Long-
`Term Treatment with Cyclosporin A Ophthalmic Emulsions in
`Patients with Moderate to Severe Dry Eye Disease, 18 J. OCULAR
`PHARMACOLOGY & THERAPEUTICS 411 (2002) (“Small”)
`STEDMAN’S MEDICAL DICTIONARY 944, 1300, 1548, 1634, 1821 (27th
`ed. 2000) (“Stedman’s”)
`Allergan, Inc.’s Complaint for Patent Infringement, Allergan, Inc. v.
`Famy Care Ltd., No. 2:16-cv-401 (E.D. Tex. Apr. 12, 2016)
`APPROVED DRUG PRODUCTS WITH THERAPEUTIC EQUIVALENCE
`EVALUATIONS (34th ed. 2014) (Excerpts)
`File history of U.S. Patent No. 8,629,111 B2 to Acheampong et al.,
`filed August 14, 2013 (“’111 patent FH”)
`7/30/2003 Allergan Correspondence to FDA regarding RESTASIS™
`RESTASIS Orange Book Listing (dated Jan. 12, 2015)
`U.S. Patent No. 6,635,654 B1 to Chang et al., filed January 9, 2003
`(“the ’654 patent”)
`U.S. Patent No. 6,984,628 B2 to Bakhit et al., filed July 15, 2003
`(“the ’628 patent”)
`S. Pflugfelder et al., The Diagnosis and Management of Dry Eye, 19
`CORNEA 644 (2000) (“Pflugfelder”)
`1031 Mylan Pharm., Inc. v. Allergan, Inc., IPR2016-01127, Paper No. 8
`(P.T.A.B. Dec. 8, 2016)
`Curriculum Vitae of Dr. Peter Kador
`Curriculum Vitae of Dr. Michael A. Lemp
`
`
`1032
`1033
`
`
`
`v
`
`

`

`Petition for Inter Partes Review of U.S. Patent No. 8,685,930 B2
`
`
`Famy Care Limited (“Famy Care” or “Petitioner”) petitions for Inter Partes
`
`Review, seeking cancellation of claims 1-36 of U.S. Patent No. 8,685,930 B2,
`
`which issued on April 1, 2014, to Acheampong et al. (“the ’930 patent”) (Exhibit
`
`(“Ex.”) 1001). PTO records identify Allergan, Inc. as the ’930 patent’s assignee
`
`(“Patent Owner”). This Petition demonstrates the reasonable likelihood that claims
`
`1-36 of the ’930 patent are unpatentable over the asserted prior art. Petitioner has
`
`filed companion petitions addressing related patents assigned to the Patent Owner.
`
`All challenged patents are continuations from the same family and terminally
`
`disclaimed over one another. The patents claim an ophthalmic emulsion for
`
`treating various ocular disorders, or conventional methods of administeration.
`
`Petitioner has concurrently filed a Power of Attorney and Exhibit List
`
`pursuant to 37 C.F.R. §§ 42.10(b) and 42.63(e), respectively. The $34,600 fee
`
`required under 37 C.F.R. § 42.15(a) was paid from Deposit Acct. No. 503626. The
`
`Office is authorized to charge underpayments and credit overpayments to Deposit
`
`Acct. No. 503626.
`
`
`
`
`
`
`
`1
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`

`

`Petition for Inter Partes Review of U.S. Patent No. 8,685,930 B2
`
`I.
`
`INTRODUCTION.
`
`The ’930 patent (EX1001) claims a 0.05% by weight cyclosporine A
`
`(“CsA”) topical ophthalmic emulsion used to treat keratoconjuntivitis sicca or dry
`
`eye syndrome (“KCS”)—which the specification labels “Composition II.”
`
`EX1001, 13:48-58. The claims also include using Composition II to increase tear
`
`production in humans with KCS (claim 25). The specification states that
`
`Composition II “provides overall efficacy in treating dry eye disease substantially
`
`equal to that of Composition I,” which is identical to Composition II except that it
`
`contains 0.1% by weight CsA. Id., 13:48-58, 13:63-67.
`
`The ’930 patent’s 0.1% CsA Composition I comparator matches Example
`
`1D of Allergan’s Ding ’979 prior art patent. EX1006, 4:31-43. But Ding ’979
`
`Example 1E was a 0.05% by weight CsA formulation with 50% less castor oil
`
`(0.0625%) than Composition II (1.25%). Id. Ding ’979 taught “pharmaceutical
`
`emulsion[s]” encompassing them all. Id., 6:35-42 (claim 8—ingredients of
`
`between “about 0.05% and about 0.40%” CsA; and “about 0.625% and about
`
`5.0%” castor oil). The Example 1 formulations used only 0.04 or 0.08 CsA/castor
`
`oil ratios—the claimed Composition II uses 0.04. EX1002 ¶¶31, 57. Ding ’979
`
`taught: preferences narrowing the scope of preferred formulations (id., 3:15-20);
`
`uses “for treatment of keratoconjunctivitis sicca (dry eye) syndrome” (id., 5:10-
`
`12); and that the Example 1A-D formulations shared in vivo similarities in “ocular
`
` 2
`
`
`
`
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`

`Petition for Inter Partes Review of U.S. Patent No. 8,685,930 B2
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`bioavailability” while showing “no difference in toxicity” as CsA and castor oil
`
`amounts varied. Id., 5:15:28. Thus, the specific CsA or castor oil amounts are not
`
`critical to operability. Id., 4:31-43, 5:10-28, 6:35-42. Allergan’s published clinical
`
`trial data (e.g., EX1007) confirmed comparable human clinical outcomes for
`
`0.05% and 0.1% CsA formulations. EX1003, ¶¶65-66.
`
`On obviousness, while prosecuting a parent application, Allergan1 admitted
`
`the claimed Composition II emulsion “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.
`
`Allergan disavowed its admission after creating purported “unexpected
`
`results” that Composition II was “equally or more therapeutically effective” than
`
`Composition I. EX1004-0195. But Allergan’s unpublished and later-generated pK
`
`and/or population data cannot alter the expectations of ordinarily-skilled artisans;
`
`and the comparative-performance attributes were known, inherent or otherwise
`
`reasonably expected by the prior art. Long felt need or commercial success lack
`
`nexus. Allergan’s “secondary considerations” evidence thus cannot show
`
`nonobviousness. EX1003, ¶¶157-99.
`
`Consequently, as this Petition explains, the claims of the ’930 patent are
`
`anticipated and/or obvious on multiple grounds.
`
`1 Petitioner uses “Allergan” to include the individual patent applicants.
`
` 3
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`Petition for Inter Partes Review of U.S. Patent No. 8,685,930 B2
`
`II. MANDATORY NOTICES (37 C.F.R. § 42.8(a)(1)).
`
`The following mandatory notices as part of this Petition are provided below
`
`pursuant to 37 C.F.R. §§ 42.8(a)(1) and 42.8(b).
`
`A. Real Party-In-Interest (37 C.F.R. § 42.8(b)(1)).
`
`Petitioner Famy Care Limited is a real party in interest, as are its partners for
`
`its cyclosporine product: Lupin Atlantis Holdings S.A. and Axar Pharmaceuticals,
`
`Inc. Out of an abundance of caution, Famy Care Limited also identifies certain
`
`other entities as potential additional real parties in interest: Lupin Pharmaceuticals,
`
`Inc., Lupin Limited, and Lupin Inc.
`
`B. Related Matters (37 C.F.R. § 42.8(b)(2)).
`
`Mylan Pharmaceuticals Inc. filed an IPR petition for the ’930 patent
`
`(IPR2016-1127), as well as petitions for related Patent Nos. 8,629,111 (IPR2016-
`
`1128), 8,642,556 (IPR2016-01129), 8,633,162 (IPR2016-01130), 8,648,048
`
`(IPR2016-01131), and 9,248,191
`
`(IPR2016-01132).
`
` Allergan submitted
`
`preliminary responses, and on December 8, 2016 the Office instituted inter partes
`
`review on these patents. Mylan Pharm., Inc. v. Allergan, Inc., IPR2016-01127,
`
`Paper No. 8 (P.T.A.B. Dec. 8, 2016) (EX1031).
`
`Argentum Pharmaceuticals LLC (“Argentum”) filed an IPR petition for U.S.
`
`Patent No. 8,629,111 (IPR2016-01232). Apotex Corp. and Apotex Inc. filed an
`
`IPR petition for the ’930 patent (IPR2015-01283), as well as petitions for related
`
` 4
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`

`Petition for Inter Partes Review of U.S. Patent No. 8,685,930 B2
`
`Patent Nos. 8,648,048 (IPR2015-01284), 8,633,162 (IPR2015-01278), 8,642,556
`
`(IPR2015-01286), and 8,629,111 (IPR2015-01282). These petitions were all
`
`terminated before institution decisions.
`
`Allergan asserted the ’930 patent and related patents against Petitioner Famy
`
`Care in Allergan, Inc. v. Famy Care Ltd., No. 2:16-cv-0401, in the Eastern District
`
`of Texas (EX1023). A complaint asserting the ’930 patent against Petitioner was
`
`served no earlier than April 15, 2016. Petitioner identifies the following pending
`
`actions involving the ’930 patent: Allergan, Inc. v. Teva Pharmaceuticals USA,
`
`Inc., et al., No. 2:15-cv-1455; and Allergan, Inc., v. DEVA Holding AS, No. 2:16-
`
`cv-1447, both in the Eastern District of Texas.
`
`C. Lead and Back-Up Counsel (37 C.F.R. § 42.8(b)(3)).
`
`Back-Up Counsel
`William A. Rakoczy
`Pro hac vice to be filed
`wrakoczy@rmmslegal.com
`Rakoczy Molino Mazzochi Siwik LLP
`6 West Hubbard Street, Suite 500,
`Chicago, Illinois 60654
`Tel.: 312-527-2157
`
`John D. Polivick
`Reg. No. 57,926
`jpolivick@rmmslegal.com
`Rakoczy Molino Mazzochi Siwik LLP
`6 West Hubbard Street, Suite 500
`Chicago, Illinois 60654
`Tel.: 312-527-2157
`
` 5
`
`
`
`Lead Counsel
`Deanne M. Mazzochi
`Reg. No. 50,158
`dmazzochi@rmmslegal.com
`Rakoczy Molino Mazzochi Siwik LLP
`6 West Hubbard Street, Suite 500,
`Chicago, Illinois 60654
`Tel.: 312-527-2157
`
`
`
`
`
`

`

`Petition for Inter Partes Review of U.S. Patent No. 8,685,930 B2
`
`D.
`
`Service Information (37 C.F.R. § 42.8(b)(4)).
`
`Petitioner consents to service by email at: dmazzochi@rmmslegal.com,
`
`wrakoczy@rmmslegal.com,
`
`jpolivick@rmmslegal.com,
`
`and
`
`FamyCareIPR@rmmslegal.com. Please direct all correspondence regarding this
`
`Petition to counsel at the above addresses.
`
`III. GROUNDS FOR STANDING (37 C.F.R. § 42.104(a)).
`
`Petitioner certifies that the ’930 patent is available for inter partes review.
`
`Petitioner is not barred or estopped from requesting an inter partes review
`
`challenging the patent claims on the grounds identified herein.
`
`IV. SPECIFIC
`§ 42.104(b)).
`
`IDENTIFICATION OF CHALLENGE
`
`(37 C.F.R.
`
`Petitioner respectfully requests inter partes review and cancellation of
`
`claims 1-36 of the ’930 patent based on the meaningfully distinct grounds set forth
`
`in the table below (and instituted in IPR2016-01127, Paper No. 8 (EX1031) at
`
`0019, 0023-24):
`
`Statutory Basis Reference(s)
`Ground Claims
`§ 102
`Ding ’979
`1
`1-36
`§ 103
`Ding ’979 and Sall
`2
`1-36
`3
`11, 23, 35 § 103
`Ding ’979, Sall, and Acheampong
`
`
`Petitioner’s proposed claim constructions and unpatentability grounds for
`
`the ’930 patent are set forth below. This Petition is accompanied by declarations
`
`from technical experts Peter Kador, Ph.D. (EX1002; EX1032) and Michael Lemp,
`
` 6
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`

`Petition for Inter Partes Review of U.S. Patent No. 8,685,930 B2
`
`M.D. (EX1003; EX1033). The petitioner further relies on other Exhibits set forth
`
`on the Exhibit List filed concurrently herewith.
`
`V. OVERVIEW OF THE ’930 PATENT.
`
`A.
`
`’930 Patent Claims.
`
`Independent claim 1 is representative, requiring a topical ophthalmic
`
`emulsion for treating an eye of a human having KCS, comprising by weight:
`
`0.05% CsA; 1.25% castor oil; polysorbate 80; acrylate/C10-30 alkyl acrylate
`
`cross-polymer (“cross-polymer”); and water. Claim 1 requires the composition to
`
`be “therapeutically effective in treating” KCS. Independent claims 13 and 25
`
`recite an identical emulsion, but require respectively that it be “therapeutically
`
`effective in treating dry eye” and “therapeutically effective in increasing tear
`
`production” in eyes of humans having KCS. Claims 2-12, 14-24, and 26-36
`
`ultimately depend respectively from claims 1, 13, and 25.
`
`Claims 2-6, 9-10, 14-18, 21-22, 26-30, and 33-34 require the emulsion to
`
`comprise a tonicity or demulcent agent, specifically glycerine, and/or a buffer,
`
`specifically sodium hydroxide.
`
`Claims 12, 24, and 36 specify a range of pH values for the emulsions of
`
`claims 6, 18, or 30, respectively, which each comprise glycerine and a buffer.
`
`Claims 7-8, 19-20, and 31-32 specify known weight percentages of
`
`polysorbate 80 and a cross-polymer, respectively.
`
` 7
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`

`Petition for Inter Partes Review of U.S. Patent No. 8,685,930 B2
`
`Claims 11, 23, and 35 each require that when the emulsion is administered
`
`there be substantially no detectable CsA concentration in the blood.
`
`Applying the most detailed claim requirements above for the “topical
`
`ophthalmic emulsion” yields the ‘930 patent specification’s “Composition II.”
`
`EX1001, 13:45-59, 14:41-16:50; EX1002, ¶152.
`
`B.
`
`’930 Patent Prosecution History.
`
`U.S. Patent Application No. 13/961,828 (“the ’828 application”) was filed
`
`on August 7, 2013, and issued on April 1, 2014 as the ’930 patent. The ’828
`
`application was a continuation, via U.S. applications 11/897,177 and 10/927,857
`
`(“the ’857 application,” EX1005), which claimed benefit to U.S. provisional
`
`application 60/503,137, filed September 15, 2003.
`
`The Examiner issued obviousness, rather than anticipation, rejections. But
`
`during prosecution of
`
`the ’857 application, Allergan admitted
`
`that
`
`the
`
`specification’s Composition II—fully claimed by the ’930 patent (EX1002, ¶¶57-
`
`58)— falls “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,
`
` 8
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`

`Petition for Inter Partes Review of U.S. Patent No. 8,685,930 B2
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`Example 1B (wherein the ratio of cyclosporin to castor oil is 0.04)
`teaches that the concentration of castor oil should be 1.250% (0.05% /
`1.250% = 0.04). The applicants concede that in making this selection
`(0.05% cyclosporin and 1.250% castor oil) there would have been a
`reasonable expectation of success; the differences between Examples
`1A-1E and Composition II are too small to believe otherwise.
`
`The formulation of Composition II is squarely within the teachings
`of the Ding reference, and the Office should disregard any
`statements by the applicants suggesting otherwise [.]
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`EX1005-0435 (emphases added).
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`When prosecuting the ’828 application, Allergan acknowledged its prior
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`admission, but alleged new unexpected results evidence justified patentability over
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`Ding ’979. EX1004-0007. As Section XI below discusses, it does not.
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`VI. PERSON OF ORDINARY SKILL IN THE ART.
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`For the ’930 patent, the ordinarily-skilled artisan in the relevant field as of
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`September 15, 20032 would have some combination of: (a) knowledge regarding
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`designing and preparing products intended for ocular administration; and/or (b) the
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`ability to understand results and findings presented or published by others in the
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`field. EX1002, ¶65. Typically this person would have an advanced degree, such as
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`2 The earliest provisional date; Petitioner reserves its priority challenge rights in
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`Petition for Inter Partes Review of U.S. Patent No. 8,685,930 B2
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`an M.D., or a Ph.D. in organic chemistry, pharmaceutical chemistry, medicinal
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`chemistry, pharmaceutics, physical pharmacy, or a related field, or less education
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`but considerable professional experience in these fields. Id.
`
`The ordinarily-skilled artisan typically would work as part of a multi-
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`disciplinary team and draw upon not only his or her own skills, but also take
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`advantage of certain specialized skills of others in the team to solve a given
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`problem. EX1002, ¶66. As of September 15, 2003, the state of the art included the
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`teachings provided by the references discussed in each of the unpatentability
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`grounds set forth below. Additionally, a person of ordinary skill in the art would
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`have been aware of other important information and references relating to dry eye,
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`its causes, and useful treatments. Id.
`
`VII. STATE OF THE ART AS OF SEPTEMBER 15, 2003.
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`Prior to September 15, 2003, the art recognized inflammation contributed to
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`certain dry eye diseases. E.g., EX1012-0001-02; EX1002, ¶¶94-113; EX1003,
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`¶¶60-72. Dry eye disease was defined as “a deficiency in either the aqueous or
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`mucin components of the precorneal tear film. The most commonly encountered
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`aqueous-deficient dry eye in the United States is keratoconjunctivitis sicca
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`[KCS]….” EX1013-0004; EX1003, ¶60.
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`Topical ophthalmic administration of CsA, a known anti-inflammatory
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`agent, significantly reduced inflammation markers associated with dry eye.
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`Petition for Inter Partes Review of U.S. Patent No. 8,685,930 B2
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`EX1012-0001; EX1002, ¶¶96-97; EX1003, ¶¶61, 63-67. Allergan’s experts
`
`conceded during prosecution that “[i]t was known in the art … that cyclosporin
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`could be administered topically locally to the eye to target and treat dry eye by
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`using cyclosporin A’s immunomodulatory properties[.]” EX1004-0201.
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`Castor oil vehicles were used for topical ophthalmic administration of highly
`
`lipophilic drugs, like CsA, that must be formulated in a water-solubilized form.
`
`EX1006, 1:40-44, 3:7-14; EX1010, 5:57-63; EX1002, ¶¶102-13. Methods to
`
`determine optimal oil-to-drug ratios were well established in the art before
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`September 2003. See generally EX1009; EX1002, ¶104. The art recognized that
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`higher castor oil concentrations in a vehicle increased ocular residence time.
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`EX1010, 2:61-65 (“relief is limited by the retention time of the administered
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`artificial tear solution in the eye.”), 6:1-8:25, Figs. 2-6 (reporting that castor oil
`
`vehicles without CsA were effective in treating KCS), Fig. 7 (showing ocular
`
`residence times for 2.5%, 1.25%, 0.625% and 0.125% castor oil).
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`Clinical trials established the safety and efficacy of CsA/castor oil emulsions
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`for treatment of dry eye disease/KCS. EX1002, ¶¶96-97, 107; EX1003, ¶¶63-67.
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`Kunert reported that topical 0.05% CsA emulsions in castor oil significantly
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`decreased lymphocyte activation markers, concluding that this treatment “may help
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`to reduce the pathophysiological factors contributing to the development of KCS.”
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`EX1012-0007; EX1003, ¶63. Turner reported that topical 0.05% CsA emulsions
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`Petition for Inter Partes Review of U.S. Patent No. 8,685,930 B2
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`in castor oil decreased inflammation markers in dry eye patients. EX1014-0001;
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`EX1003, ¶63. Stevenson concluded from a Phase 2 dose-ranging trial (0.05%-
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`0.4% CsA emulsions) that 0.05% and 0.10% CsA emulsions were “the most
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`appropriate” because “no additional benefits were observed with the higher
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`concentrations.” EX1015-0001; EX1003, ¶64.
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`Clinical trials conducted before September 2003 showed castor oil provided
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`a “large therapeutic effect” to patients suffering from KCS. E.g., EX1014-0005;
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`EX1015-0007; EX1002, ¶¶102-07; EX1003, ¶¶63-64. This “therapeutic effect of
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`the [castor] oil-in-water vehicle” was “expected, as topical application of certain
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`lipid mixtures can accelerate epidermal barrier recovery after defined barrier
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`insults in mice.” EX1014-0005.
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`Thus, the art well knew 0.05% CsA/castor oil formulations were effective to
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`increase tear production and relieve dry eye disease/KCS. EX1002, ¶¶102-13;
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`EX1003, ¶¶71-79.
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`VIII. PRIOR ART.
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`A. Ding ’979 (EX1006).
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`Ding ’979, assigned to Allergan, issued December 12, 1995, and is 35
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`U.S.C. § 102(b) prior art. EX1006-0001. It explains CsA behaves “as an
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`immunosuppressant” and is useful for “the enhancement or restoring of lacrimal
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`gland tearing.” Id., 1:10-16, 37-39. It teaches topical CsA ophthalmic emulsions
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`Petition for Inter Partes Review of U.S. Patent No. 8,685,930 B2
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`to treat KCS. Id., 5:9-12. Claims 7-8 specifically recite emulsions containing
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`0.05-0.40% CsA, 0.625-5.00% castor oil, 1.00% polysorbate 80, 0.05% Premulen®
`,
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`2.20% glycerine, sodium hydroxide, and water, and having a pH range of 7.2-7.6.
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`Id., 6:27-41; EX1002, ¶¶115-17; EX1003, ¶¶72-75.
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`Ding ’979 discloses four specific castor oil-based vehicles (Examples 2A-
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`D). EX1006, 4:44-54. Ding ’979’s CsA-containing emulsions in Example 1 used
`
`the Example 2 vehicles.3 Id., 4:32-54. Example 1’s emulsions use specific CsA
`
`and castor oil percentages across the ranges recited in Ding ‘979 claims 7 and 8
`
`(0.05% - 0.40% CsA and 0.625% - 5.00% castor oil). Id., 4:32-43.
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`Ding ’979 explicitly teaches a “more preferred” range for the CsA to castor
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`oil ratio: 0.02-0.12. Example 1’s specific formulations each had a 0.04 or 0.08
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`ratio. Id., 3:17-20; 4:31-43; EX1002, ¶¶119-20.
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`Ding ’979 taught the Example 1 formulations “were made for treatment of
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`keratoconjunctivitis sicca (dry eye) syndrome” and that Examples 2-4 were
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`prepared without CsA to “determine the toxicity of the emulsified components.”
`
`EX1006, 5:9-14. Ding ’979 reports that the Examples 1A-D formulations, even
`
`when applied eight times a day for seven days, produced at most “slight to mild
`
`discomfort” or “slight hyperemia”; and as between the formulation/vehicle ranges
`
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`3 Example 2C’s vehicle is identical to the challenged claims’ castor oil vehicle.
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`Petition for Inter Partes Review of U.S. Patent No. 8,685,930 B2
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`tested, there were “no differences in toxicity” and they had comparable ocular
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`bioavailability. Id., 5:15-28; 3:7-9 (compositions of the invention are “non-
`
`irritating” and “with high comfort level”).
`
`B.
`
`Sall (EX1007).
`
`Sall is prior art under 35 U.S.C. § 102(b). EX1002, ¶¶126-41; EX1003,
`
`¶121. Sall describes Patent Owner’s multi-center, randomized, double-masked
`
`Phase 3 clinical trial assessing the safety and efficacy in KCS treatment of twice-
`
`daily topical ophthalmic administration of 0.05% or 0.10% CsA in a castor oil
`
`emulsion, compared to the emulsion vehicle without CsA. EX1007-0001-02,
`
`0005-06 (figs. 1-4). Sall taught the 0.05% CsA emulsion was safe and effective—
`
`at least as effective as the 0.10% CsA emulsion—resulting in fewer adverse side
`
`effects and CsA blood concentrations below detectible levels. EX1007-0001,
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`0004-07; EX1002, ¶¶128-39; EX1003, ¶¶65-66, 122. Sall compared the 0.05%
`
`and 0.10% CsA emulsions to the same control vehicle, and reported trough CsA
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`blood concentrations were undetectable in all 0.05% CsA samples; but quantifiable
`
`in six 0.10% CsA samples. EX1007-0002, 0006-07; EX1002, ¶138; EX1003,
`
`¶115.
`
`Sall noted existing palliative dry eye
`
`treatments, and deemed
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`its
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`formulations “the first therapeutic treatment specifically for dry eye disease and a
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`significant breakthrough in the management of this common and frustrating
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`condition.” EX1007-0007-08.
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`C. Acheampong (EX1008).
`
`Acheampong is prior art under 35 U.S.C. § 102(b). EX1002, ¶¶142-45;
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`EX1003, ¶¶70, 150. Acheampong describes a Patent Owner study in which CsA
`
`percentages ranging from 0.05%-0.4% were administered to human patients with
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`KCS twice a day for three months. EX1008-0004. Acheampong measured CsA
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`blood concentration at peak and trough levels following topical ophthalmic
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`administration. Id. CsA was not detected in patients receiving the 0.05% CsA
`
`emulsion. Id., 0004-06.
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`Even after 12 weeks, the 0.05% CsA formulations’ blood concentrations fell
`
`below the trough concentrations used to monitor patient safety with systemic CsA
`
`therapy. EX1008-0006.
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`IX. CLAIM CONSTRUCTION.
`
`Under 37 C.F.R. § 42.100(b), claim terms of a challenged patent are
`
`presumed to take on their ordinary and customary meaning based on the broadest
`
`reasonable interpretation (“BRI”) of the claim language in light of the
`
`specification.
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`Petition for Inter Partes Review of U.S. Patent No. 8,685,930 B2
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`A.
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`“therapeutically effective” and “effective amount”
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`Independent claims 1, 13, and 25 recite “wherein” clauses directed to the
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`intended result of the claimed emulsion, reciting respectively that the emulsion is
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`“therapeutically effective” in treating KCS, treating dry eye disease, or increasing
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`tear production. Claims 11, 23, and 35 respectively recite administering “an
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`effective amount” in treating KCS, treating dry eye, and increasing tear pro