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. 8,629,111 B2 to Acheampong et al.
`Issue Date: January 14, 2014
`Title: Methods of Providing Therapeutic Effects Using Cyclosporin Components
`________________________________
`
`Inter Partes Review Trial No. 2017-00567
`________________________________
`
`Petition for Inter Partes Review of U.S. Patent No. 8,629,111
`
`
`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. 8,629,111 B2
`
`TABLE OF CONTENTS
`
`
`EXHIBIT LIST PURSUANT TO 37 C.F.R. § 42.63(e) AND TABLE
`OF ABBREVIATIONS ......................................................................... iv
`
`I.
`
`INTRODUCTION. .................................................................................. 1
`
`II. MANDATORY NOTICES (37 C.F.R. § 42.8(a)(1)). ............................. 3
`
`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 ’111 PATENT. ................................................... 7
`
`A.
`
`B.
`
`’111 Patent Claims. ....................................................................... 7
`
`’111 Patent Prosecution History. ................................................... 8
`
`VI. PERSON OF ORDINARY SKILL IN THE ART. ...............................10
`
`VII. STATE OF THE ART AS OF SEPTEMBER 15, 2003. ......................11
`
`VIII. PRIOR ART. ..........................................................................................13
`
`A. Ding ’979 (EX1006). ...................................................................13
`
`B.
`
`C.
`
`Sall (EX1007). .............................................................................15
`
`Acheampong (EX1008). ..............................................................15
`
`IX. CLAIM CONSTRUCTION. .................................................................16
`
`
`
`i
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`

`

`Petition for Inter Partes Review of U.S. Patent No. 8,629,111 B2
`
`A.
`
`B.
`
`C.
`
`“therapeutically effective” and “effective” .................................16
`
`“buffer” ........................................................................................18
`
`“substantially no detectable concentration” ................................18
`
`X.
`
`EXPLANATION OF GROUNDS FOR UNPATENTABILITY. ........19
`
`A. Ding ’979 Claim Chart. ...............................................................19
`
`B.
`
`Ground 1: Claims 1-27 Are Unpatentable Under 35 U.S.C.
`§ 102 by Ding ’979. .....................................................................26
`
`1.
`
`Claims 1-10, 12-15 and 18-19. .........................................26
`
`a.
`b.
`c.
`d.
`
`Preamble Elements .................................................26
`CsA and Castor Oil Elements .................................27
`Additional Composition Elements .........................29
`Ding
`’979
`taught
`the entire claimed
`Composition II formulation. ...................................31
`“No detectable concentration” Claims 11 and 16. ............35
`
`“Effective in treating” (Claims 17, 20-27). ......................36
`
`2.
`
`3.
`
`C.
`
`Ground 2: Claims 1-27 Are Unpatentable Under 35 U.S.C.
`§ 103 in View of Ding ’979 and Sall. .........................................38
`
`1.
`
`Claims 1-10, 12-15 and 18-19. .........................................39
`
`Preamble Elements .................................................39
`a.
`CsA Elements .........................................................41
`b.
`Castor Oil Elements ................................................42
`c.
`Additional Composition Elements .........................46
`d.
`“No Detectable Concentration” (Claims 11 and 16) ........46
`
`“Effective” (Claims 17 and 20-27) ...................................48
`
`2.
`
`3.
`
`D. Ground 3: Claims 11 and 16 Are Unpatentable Under 35
`U.S.C. 103 in View of Ding ’979, Sall, and Acheampong. ........50
`ii
`
`
`
`

`

`Petition for Inter Partes Review of U.S. Patent No. 8,629,111 B2
`
`XI. ALLERGAN’S ALLEGED SECONDARY
`CONSIDERATIONS DO NOT OVERCOME PETITIONER’S
`STRONG SHOWING OF OBVIOUSNESS ........................................52
`
`A. No Unexpected Results. ..............................................................56
`
`1.
`
`2.
`
`3.
`
`4.
`
`Schiffman Exhibit B .........................................................57
`
`Schiffman Exhibit C/Attar Exhibit B ................................61
`
`Schiffman Exhibit D .........................................................64
`
`Schiffman Exhibits E and F/Attar Exhibits D and E. .......69
`
`B.
`
`Near-Simultaneous Invention. .....................................................73
`
`XII. CONCLUSION......................................................................................74
`
`XIII. CERTIFICATE OF COMPLIANCE ....................................................75
`
`
`
`
`
`
`
`
`iii
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`

`

`Petition for Inter Partes Review of U.S. Patent No. 8,629,111 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. 8,629,111 B2 to Acheampong et al., filed August 14,
`2013 (“the ’111 patent”)
`Declaration of Dr. Peter Kador
`Declaration of Dr. Michael A. Lemp
`File history of U.S. Patent No. 8,629,111 to Acheampong et al., filed
`August 14, 2013 (“’111 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. 8,629,111 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)
`Intentionally Blank
`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., IPR2016-01128, 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. 8,629,111 B2
`
`
`Famy Care Limited (“Famy Care” or “Petitioner”) petitions for Inter Partes
`
`Review, seeking cancellation of claims 1-27 of U.S. Patent No. 8,629,111 B2,
`
`which issued on January 14, 2014, to Acheampong et al. (“the ’111 patent”)
`
`(Exhibit (“Ex.”) 1001). PTO records identify Allergan, Inc. as the ’111 patent’s
`
`assignee (“Patent Owner”). This Petition demonstrates the reasonable likelihood
`
`that claims 1-27 of the ’111 patent are unpatentable over the asserted prior art.
`
`Petitioner has filed additional petitions to address related patents assigned to 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 administration.
`
`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 $29,200 fee
`
`required under 37 C.F.R. § 42.15(a) has been paid from Deposit Acct. No. 503626.
`
`The Office is authorized to charge any underpayments and credit overpayments to
`
`Deposit Acct. No. 503626.
`
`I.
`
`INTRODUCTION.
`
`The ’111 patent (EX1001) claims a 0.05% by weight cyclosporine A
`
`(“CsA”) topical ophthalmic emulsion used to increase tear production and treat
`
`keratoconjuntivitis sicca or dry eye syndrome (“KCS”)—which the specification
`
`labels “Composition II.” EX1001, 14:20-30. The specification asserts that
`
`
`
`1
`
`

`

`Petition for Inter Partes Review of U.S. Patent No. 8,629,111 B2
`
`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., 14:20-30, 35-40.
`
`The ’111 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, ¶¶144-45. 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
`
`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. EX1006, 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, ¶56.
`
` 2
`
`
`
`
`
`

`

`Petition for Inter Partes Review of U.S. Patent No. 8,629,111 B2
`
`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. EX1004-0240. 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, ¶¶148-190.
`
`As this Petition explains, the claims of the ’111 patent are anticipated and/or
`
`obvious on multiple grounds.
`
`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).
`
`
`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. 8,629,111 B2
`
`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 ’111 patent
`
`(IPR2016-1128), as well as petitions for related Patent Nos. 8,685,930 (IPR2016-
`
`1127), 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 (e.g., Mylan Pharm., Inc. v. Allergan, Inc., IPR2016-
`
`01128, Paper No. 8 (P.T.A.B. Dec. 8, 2016) (EX1031).
`
`Argentum Pharmaceuticals LLC (“Argentum”) filed an IPR petition for the
`
`’111 patent (IPR2016-1232). Apotex Corp. and Apotex Inc. filed an IPR petition
`
`for the ’111 patent (IPR2015-01282), as well as petitions for related Patent Nos.
`
`8,648,048 (IPR2015-01284), 8,633,162 (IPR2015-01278), 8,642,556 (IPR2015-
`
`01286), and 8,685,930 (IPR2015-01283). These petitions were all terminated
`
` 4
`
`
`
`before institution decisions.
`
`
`
`

`

`Petition for Inter Partes Review of U.S. Patent No. 8,629,111 B2
`
`Allergan asserted the ’111 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 ’111 patent against Petitioner was
`
`served no earlier than April 15, 2016. Petitioner identifies the following pending
`
`actions involving the ’111 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)).
`
`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
`
`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
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`
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`

`

`Petition for Inter Partes Review of U.S. Patent No. 8,629,111 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, and jpolivick@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 ’111 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 1-27 of the ’111 patent based on the meaningfully distinct grounds set forth
`
`in the table below (and instituted in IPR2016-01128, Paper No. 8 (EX1031) at
`
`0017, 0021, 0022):
`
`Statutory Basis Reference(s)
`Ground Claims
`§ 102
`Ding ’979
`1
`1-27
`§ 103
`Ding ’979 and Sall
`2
`1-27
`3
`11 and 16 § 103
`Ding ’979, Sall, and Acheampong
`
`
`Petitioner sets forth its proposed claim constructions and unpatentability
`
`grounds for the ’111 patent below. Declarations from technical experts Peter
`
`Kador, Ph.D. (EX1002; EX1032) and Michael Lemp, M.D. (EX1003; EX1033)
`
` 6
`
`
`
`
`
`

`

`Petition for Inter Partes Review of U.S. Patent No. 8,629,111 B2
`
`accompany this Petition. Petitioner also relies on other exhibits set forth on the
`
`concurrently-filed Exhibit List.
`
`V. OVERVIEW OF THE ’111 PATENT.
`
`A.
`
`’111 Patent Claims.
`
`Independent claim 1 is representative, requiring a topical ophthalmic
`
`emulsion for treating an eye of a human comprising by weight: 0.05% CsA;
`
`1.25% castor oil; polysorbate 80; acrylate/C10-30 alkyl acrylate cross-polymer
`
`(“cross-polymer”); and water, wherein CsA is the only peptide present in the
`
`emulsion. Claims 2-12 and 20-22 depend from claim 1. Independent claim 13
`
`recites an emulsion incorporating the limitations of claims 1, 7-9 and 12. Claims
`
`14-17 and 23-24 depend from claim 13. Independent claim 18 recites an emulsion
`
`incorporating the limitations of claims 1 and 6-10. Claims 19 and 25-27 depend
`
`from claim 18.
`
`Claims 2-6, 9-10, and 14-15 require the emulsion to comprise a tonicity or
`
`demulcent agent, specifically glycerine, and/or a buffer, specifically sodium
`
`hydroxide.
`
`Claims 7-8 specify known weight percentages of polysorbate 80 and cross-
`
`polymer, respectively.
`
` Claims 11 and 16 require that when the emulsion is administered there be
`
`substantially no detectable concentration of CsA in the blood.
`
` 7
`
`
`
`
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`

`

`Petition for Inter Partes Review of U.S. Patent No. 8,629,111 B2
`
`Claims 12 and 19 specify a range of pH values for the emulsions of claim 6
`
`and 18, respectively, which each comprise glycerine and a buffer.
`
`Claims 17 requires that the emulsion be effective in treating KCS.
`
`Claims 20, 23, and 25 require that the emulsion be therapeutically effective
`
`in treating dry eye disease.
`
`Claims 21 and 26 require that the emulsion be therapeutically effective in
`
`treating KCS.
`
`Claims 22, 24, and 27 require that the emulsion be therapeutically effective
`
`in increasing tear production.
`
`Applying the most detailed claim requirements for the “topical ophthalmic
`
`emulsion” yields the ’111 patent’s specification’s “Composition II.” EX1001,
`
`14:20-30, 15:13-16:59; EX1002, ¶143.
`
`B.
`
`’111 Patent Prosecution History.
`
`U.S. Patent Application No. 13/967,163 (“the ’163 application”) was filed
`
`on August 14, 2013, and issued on January 14, 2014 as the ’111 patent. The ’163
`
`application is a continuation, via U.S. applications 13/961,828, 11/897,177, and
`
`10/927,857 (“the ’857 application,” EX1005), which claims the benefit of U.S.
`
`provisional application 60/503,137, filed September 15, 2003.
`
`The Examiner issued obviousness, rather than anticipation, rejections. But
`
`during prosecution of the related ’857 application, Allergan admitted that the
`
` 8
`
`
`
`
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`

`

`Petition for Inter Partes Review of U.S. Patent No. 8,629,111 B2
`
`specification’s Composition II—fully claimed by the ’111 patent (EX1002, ¶¶48-
`
`50)— 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,
`Example 1B (wherein the ratio of cyclosporin to castor oil is 0.04)
`teaches that the concentration of castor oil should be 1.250% (0.05% /
`1.250% = 0.04). The applicants concede that in making this selection
`(0.05% cyclosporin and 1.250% castor oil) there would have been a
`reasonable expectation of success; the differences between Examples
`1A-1E and Composition II are too small to believe otherwise.
`
`The formulation of Composition II is squarely within the teachings
`of the Ding reference, and the Office should disregard any
`statements by the applicants suggesting otherwise [.]
`
`EX1005-0435 (emphases added).
`
`When prosecuting the ’163 application, Allergan acknowledged its prior
`
`admission, but alleged new unexpected results evidence justified patentability over
`
`Ding ’979. EX1004-0007. As Section XI below discusses, it does not.
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`Petition for Inter Partes Review of U.S. Patent No. 8,629,111 B2
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`VI. PERSON OF ORDINARY SKILL IN THE ART.
`
`For the ’111 patent, a person of ordinary skill in the relevant field as of
`
`September 15, 20032 would likely have some combination of: (a) knowledge
`
`regarding designing and preparing products intended for ocular administration;
`
`and/or (b) the ability to understand results and findings presented or published by
`
`others in the field. Typically this person would have an advanced degree, such as
`
`an M.D., 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. EX1002, ¶56; EX1003,
`
`¶¶71-72.
`
`The ordinarily-skilled artisan typically would work as part of a multi-
`
`disciplinary team and draw upon not only his or her own skills, but also take
`
`advantage of certain specialized skills of others in the team to solve a given
`
`problem. By September 15, 2003, the state of the art included the teachings
`
`provided by the references discussed in each of the unpatentability grounds set
`
`forth below. Additionally, a person of ordinary skill in the art would have been
`
`
`2 The earliest provisional date; Petitioner reserves its priority challenge rights in
`
`this or other proceedings.
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`Petition for Inter Partes Review of U.S. Patent No. 8,629,111 B2
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`aware of other important information and references relating to dry eye, its causes,
`
`and useful treatments. EX1002, ¶57; EX1003, ¶74.
`
`VII. STATE OF THE ART AS OF SEPTEMBER 15, 2003.
`
`Prior to September 15, 2003, the art recognized inflammation contributed to
`
`certain dry eye diseases. E.g., EX1012-0001-02; EX1003, ¶¶51-61. Dry eye
`
`disease was defined as “a deficiency in either the aqueous or mucin components of
`
`the precorneal tear film. The most commonly encountered aqueous-deficient dry
`
`eye in the United States is keratoconjunctivitis sicca [KCS]….” EX1013-0004;
`
`EX1002, ¶86; EX1003, ¶51.
`
`Topical ophthalmic administration of CsA, a known anti-inflammatory
`
`agent, had been shown to significantly reduce inflammation markers associated
`
`with dry eye. EX1012-0001; EX1002, ¶¶87-88; EX1003, ¶52. Allergan’s experts
`
`conceded during prosecution that “[i]t was known in the art at the time this
`
`application was filed that cyclosporin could be administered topically locally to the
`
`eye to target and treat dry eye by using cyclosporin A’s immunomodulatory
`
`properties[.]” EX1004-0248, 0272-73.
`
`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, 5:55-63; EX1002, ¶¶93-104. Methods to
`
`determine optimal oil-to-drug ratios were well established in the art before
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`Petition for Inter Partes Review of U.S. Patent No. 8,629,111 B2
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`September 2003. See generally EX1009. The art recognized that higher
`
`concentrations of castor oil in a vehicle increased ocular residence time. EX1010,
`
`2:61-65 (“relief is limited by the retention time of the administered 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).
`
`Clinical trials established the safety and efficacy of CsA/castor oil emulsions
`
`for treatment of dry eye disease/KCS. EX1003, ¶54-55. Kunert reported that
`
`topical 0.05% CsA emulsions in castor oil significantly decreased lymphocyte
`
`activation markers, concluding that this treatment “may help to reduce the
`
`pathophysiological factors contributing to the development of KCS.” EX1012-
`
`0007. Turner reported that topical 0.05% CsA emulsions in castor oil decreased
`
`inflammation markers in dry eye patients. EX1014-0001. Stevenson concluded
`
`from a Phase 2 dose-ranging trial (0.05%-0.4% CsA emulsions) that 0.05% and
`
`0.10% CsA emulsions were “the most appropriate…” because “no additional
`
`benefits were observed with the higher concentrations.” EX1015-0001; EX1002,
`
`¶87; EX1003, ¶¶54-55.
`
`Clinical trials conducted before September 2003 showed castor oil provided
`
`a “large therapeutic effect” to patients suffering from KCS. E.g., EX1014-0005;
`
`EX1015-0007; EX1002, ¶¶98-102; EX1003, ¶¶54-57. This “therapeutic effect of
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`Petition for Inter Partes Review of U.S. Patent No. 8,629,111 B2
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`the [castor] oil-in-water vehicle” was “expected, as topical application of certain
`
`lipid mixtures can accelerate epidermal barrier recovery after defined barrier
`
`insults in mice.” EX1014-0005.
`
`Thus, the art well knew 0.05% CsA/castor oil formulations were effective to
`
`increase tear production and relieve dry eye disease/KCS. EX1002, ¶¶93-104;
`
`EX1003, ¶51-62.
`
`VIII. PRIOR ART.
`
`A. Ding ’979 (EX1006).
`
`Ding ’979, assigned to Allergan, issued December 12, 1995, and is 35
`
`U.S.C. § 102(b) prior art. EX1002, ¶¶105-116; EX1003, ¶¶63-66, 100. It explains
`
`CsA behaves “as an immunosuppressant” and is useful for “the enhancement or
`
`restoring of lacrimal gland tearing.” EX1006, 1:10-16, 37-39. Ding ’979 also
`
`teaches topical CsA ophthalmic emulsions to treat KCS. Id., 5:9-12. Claims 7-8
`
`specifically recite emulsions containing 0.05-0.40% CsA, 0.625-5.00% castor oil,
`
`1.00% polysorbate 80, 0.05% Premulen®
`
`, 2.20% glycerine, sodium hydroxide, and
`
`water, and having a pH range of 7.2-7.6. EX1006, 6:27-42; EX1002, ¶¶105-109..
`
`Ding ’979 discloses four specific castor oil-based vehicles (Examples 2A-D)
`
`for delivery of CsA. EX1006, 4:44-54. Ding ’979’s CsA-containing emulsions in
`
`
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`Petition for Inter Partes Review of U.S. Patent No. 8,629,111 B2
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`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;
`
`6:27-42; EX1002, ¶¶110-11.
`
`Ding ’979 explicitly teaches a “more preferred” range for the CsA to castor
`
`oil ratio: 0.02-0.12. Example 1’s specific formulations each had a 0.04 or 0.08
`
`ratio. Id., 3:17-20; 4:31-43; EX1002, ¶116.
`
`Ding ’979 taught the Example 1 formulations “were made for treatment of
`
`keratoconjunctivitis sicca (dry eye) syndrome” and that Examples 2-4 were
`
`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
`
`tested, there were “no differences in toxicity” and they had comparable ocular
`
`bioavailability. Id., 5:15-28; 3:7-9 (compositions of the invention are “non-
`
`irritating” and “with high comfort level”).
`
`
`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. 8,629,111 B2
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`B.
`
`Sall (EX1007).
`
`Sall is prior art under 35 U.S.C. § 102(b). EX1002, ¶¶117-32; EX1003,
`
`¶¶56-57. 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. EX1007-0001-0002,
`
`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, 0004-
`
`07; EX1002, ¶¶118-128; EX1003, ¶113. Sall compared the 0.05% and 0.10% CsA
`
`emulsions to the same control vehicle, and reported trough CsA blood
`
`concentrations were undetectable in all 0.05% CsA samples; but quantifiable in six
`
`0.10% CsA samples. EX1007-0002, 0006-07; EX1002, ¶129; EX1003, ¶132.
`
`Sall noted existing palliative dry eye
`
`treatments, and deemed
`
`its
`
`formulations “the first therapeutic treatment specifically for dry eye disease and a
`
`significant breakthrough in the management of this common and frustrating
`
`condition.” EX1007-0007-08.
`
`C. Acheampong (EX1008).
`
`Acheampong is prior art under 35 U.S.C. § 102(b). EX1002, ¶¶133-136;
`
`EX1003, ¶141. Acheampong describes a Patent Owner study in which CsA
`
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`Petition for Inter Partes Review of U.S. Patent No. 8,629,111 B2
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`percentages ranging from 0.05%-0.4% were administered to human patients with
`
`KCS twice a day for three months. EX1008-0004. Acheampong measured CsA
`
`blood concentration at peak and trough levels following topical ophthalmic
`
`administration. Id. CsA was not detected in patients receiving the 0.05% CsA
`
`emulsion. Id., 0004-06.
`
`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.
`
`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.
`
`A.
`
`“therapeutically effective” and “effective”
`
`Claims 20, 23, and 25 (dry eye disease), and claims 21 and 26 (KCS) all
`
`recite the emulsion is “therapeutically effective” in treating the recited medical
`
`condition, while claims 22, 24 and 27 recite the emulsion is “therapeutically
`
`effective” in increasing tear production. Claim 17 recites the emulsion is
`
`“effective” in treating KCS. In