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. 9,248,191 B2 to Acheampong et al.
`Issue Date: February 2, 2016
`Title: Methods of Providing Therapeutic Effects Using Cyclosporin Components
`________________________________
`
`Inter Partes Review Trial No. 2017-00569
`________________________________
`
`Petition for Inter Partes Review of U.S. Patent No. 9,248,191
`
`
`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. 9,248,191 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 ’191 PATENT. .................................................. 7
`
`A.
`
`B.
`
`’191 Patent Claims. ....................................................................... 7
`
`’191 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). .............................................................................14
`
`Acheampong (EX1008). ..............................................................15
`
`D. Glonek (EX1009). .......................................................................16
`
`
`
`i
`
`

`

`Petition for Inter Partes Review of U.S. Patent No. 9,248,191 B2
`
`IX. CLAIM CONSTRUCTION. ................................................................ 16
`
`A.
`
`B.
`
`C.
`
`D.
`
`E.
`
`“therapeutically effective,” “effective,” “lacrimal gland
`tearing,” “overall efficacy substantially equal to,” “as
`much therapeutic efficacy as” .....................................................17
`
`“buffer” ........................................................................................18
`
`“substantially no detectable concentration” ................................19
`
`“demonstrates a reduction in adverse events” .............................19
`
`“breaks down” .............................................................................20
`
`X.
`
`EXPLANATION OF UNPATENTABILITY GROUNDS. ................ 21
`
`A. Ding ’979 and Sall Claim Chart. .................................................21
`
`B.
`
`Ground 1: Claims 1-27 Are Unpatentable Under 35 U.S.C.
`§ 103 in View of Ding ‘979 and Sall. .........................................28
`
`1.
`
`2.
`
`3.
`
`4.
`
`5.
`
`6.
`
`7.
`
`Preamble and Dry Eye Efficacy Elements ........................36
`
`Frequency Elements ..........................................................38
`
`CsA Elements ....................................................................38
`
`Castor Oil Elements ..........................................................39
`
`Additional Composition Elements ....................................43
`
`Comparative Elements ......................................................44
`
`CsA Blood Level Elements ...............................................49
`
`C.
`
`Ground 2: Claims 1-27 Are Unpatentable Under 35 U.S.C.
`§ 103 in View of Ding ’979, Sall, and Acheampong. .................52
`
`D. Ground 3: Claims 17-20 Are Unpatentable Under 35
`U.S.C. § 103 in View of Ding ’979, Sall, and Glonek. ...............54
`
`
`
`ii
`
`

`

`Petition for Inter Partes Review of U.S. Patent No. 9,248,191 B2
`
`E.
`
`Ground 4: Claim 20 Is Unpatentable Under 35 U.S.C. §
`103 in View of Ding ’979, Sall, Glonek and Acheampong. .......55
`
`XI. ALLERGAN’S ALLEGED SECONDARY
`CONSIDERATIONS DO NOT OVERCOME PETITIONER’S
`STRONG SHOWING OF OBVIOUSNESS ....................................... 56
`
`A. No Unexpected Results. ..............................................................59
`
`1.
`
`2.
`
`3.
`
`4.
`
`Schiffman Exhibit B .........................................................60
`
`Schiffman Exhibit C/Attar Exhibit B: ..............................65
`
`Schiffman Exhibit D .........................................................68
`
`Schiffman Exhibits E and F/Attar Exhibits D and E ........73
`
`B.
`
`Near-Simultaneous Invention. .....................................................77
`
`XII. CONCLUSION..................................................................................... 78
`
`XIII. CERTIFICATE OF COMPLIANCE ................................................... 79
`
`
`
`
`
`
`
`iii
`
`

`

`Petition for Inter Partes Review of U.S. Patent No. 9,248,191 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. 9,248,191 B2 to Acheampong et al., filed March 21,
`2014 (“the ’191 patent”)
`Declaration of Dr. Peter Kador
`Declaration of Dr. Michael A. Lemp
`File history of U.S. Patent No. 9,248,191 B2 to Acheampong et al.
`(“’191 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. 9,248,191 B2
`
`1016
`
`1017
`
`1018
`
`1019
`
`1020
`
`1021
`
`1022
`
`1023
`
`1024
`
`1025
`
`1026
`1027
`1028
`
`1029
`
`1030
`
`G. Hecht, Ophthalmic Preparations, in REMINGTON: THE SCIENCE
`AND PRACTICE OF PHARMACY 821 (20th ed. 2000) (“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”)
`File history of U.S. Patent No. 8,685,930 B2 to Acheampong et al.
`(“’930 patent FH”)
`File history of U.S. Patent No. 8,629,111 B2 to Acheampong et al.
`(“’111 patent FH”)
`Allergan, Inc.’s Complaint for Patent Infringement, Allergan, Inc. v.
`Famy Care Ltd., No. 2:16-cv-401 (E.D. Tex. Apr. 12, 2016)
`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., IPR2016-01132, 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. 9,248,191 B2
`
`
`Famy Care Limited (“Famy Care” or “Petitioner”) petitions for Inter Partes
`
`Review, seeking cancellation of claims 1-27 of U.S. Patent No. 9,248,191 B2,
`
`which issued on February 2, 2016, to Acheampong et al. (“the ’191 patent”)
`
`(Exhibit (“Ex.”) 1001). PTO records identify Allergan, Inc. as the ’191 patent’s
`
`assignee (“Patent Owner”). This Petition demonstrates the reasonable likelihood
`
`that claims 1-27 of the ’191 patent are unpatentable over the asserted prior art.
`
`Petitioner is filing companion petitions addressing 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
`
`to treat various ocular disorders and/or conventional methods of treatment.
`
`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 by 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
`
`
`
`

`

`Petition for Inter Partes Review of U.S. Patent No. 9,248,191 B2
`
`I.
`
`INTRODUCTION.
`
`The ’191 patent (EX1001) claims conventional methods of administering a
`
`0.05% by weight cyclosporine A (“CsA”) topical ophthalmic emulsion used to
`
`treat dry eye disease, which the specification labels “Composition II.” EX1001,
`
`14:27-37. The claims also include comparative performance elements between the
`
`claimed composition and otherwise-identical formulations containing either 0.1%
`
`by weight CsA, which the specification labels “Composition I”; or 50% less castor
`
`oil (claim 17).
`
`The ’191 patent’s 0.1% CsA Composition I comparator matches Example
`
`1D of Allergan’s Ding ’979 prior art patent. EX1006, 4:31-43. Ding ’979
`
`Example 1E was a 0.05% by weight CsA formulation with 50% less castor oil
`
`(0.625%) relative to Composition II (1.25%). Ding ’979 taught “pharmaceutical
`
`emulsion[s]” encompassing them all. Id., 0004, 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). Example 1’s formulations further used only a 0.04 or 0.08
`
`CsA/castor oil ratio—the claimed Composition II uses 0.04. EX1002, ¶32. Ding
`
`’979 taught preferences narrowing the scope of preferred formulations (EX1006,
`
`3:15-20); uses “for treatment of keratoconjunctivitis sicca (dry eye) syndrome”
`
`(id., 0004, 5:10-12); and that the Example 1A-D formulations shared in vivo
`
`similarities in “ocular bioavailability,” and showed “no difference in toxicity” as
`
` 2
`
`
`
`
`
`

`

`Petition for Inter Partes Review of U.S. Patent No. 9,248,191 B2
`
`CsA and castor oil amounts varied. Id., 0004 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; EX1003 ¶111. Allergan’s published prior art clinical trial data (e.g., EX1007)
`
`confirmed comparable human clinical outcomes for 0.05% and 0.1% CsA
`
`formulations. EX1003, ¶65.
`
`While prosecuting a parent application, Allergan1 admitted that the claimed
`
`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. But Allergan disavowed its admission after creating
`
`purported “unexpected results” showing Composition II was “equally or more
`
`therapeutically effective” than Composition I. EX1024-0249. But Allergan’s
`
`unpublished later-generated pK and/or subpopulation data cannot alter the
`
`ordinarily-skilled artisan’s expectations; and
`
`the comparative performance
`
`attributes were known, inherent and/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, ¶179-220.
`
`Consequently, as this Petition explains, the ’191 patent claims are obvious
`
`on multiple grounds.
`
`
`1 Petitioner uses “Allergan” to include the individual patent applicants.
`
` 3
`
`
`
`
`
`

`

`Petition for Inter Partes Review of U.S. Patent No. 9,248,191 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 ’191 patent
`
`(IPR2016-1132), and petitions for related Patent Nos. 8,629,111 (IPR2016-1128),
`
`8,685,930 (IPR2016-01127), 8,642,556 (IPR2016-01129), 8,633,162 (IPR2016-
`
`01130), and 8,648,048 (IPR2016-01131). On September 9, 2016, Allergan
`
`submitted preliminary responses; on December 8, 2016 the Office instituted inter
`
`partes review on these patents (e.g., Mylan Pharm., Inc. v. Allergan, Inc.,
`
`IPR2016-01132, 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 (IPR2016-1232). Apotex Corp. and Apotex Inc. filed an IPR
`
`petition for U.S. Patent No. 8,648,048 (IPR2015-01284), and petitions for related
`
` 4
`
`
`
`
`
`

`

`Petition for Inter Partes Review of U.S. Patent No. 9,248,191 B2
`
`Patent Nos. 8,633,162 (IPR2015-01278), 8,642,556 (IPR2015-01286), 8,685,930
`
`(IPR2015-01283), and 8,629,111
`
`(IPR2015-01282). These petitions were
`
`terminated before institution decisions.
`
`Allergan asserted the ’191 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. A complaint asserting the ’191 patent against Petitioner was served no
`
`earlier than April 15, 2016. Petitioner identifies the following pending actions
`
`involving the ’191 patent: Allergan, Inc. v. Teva Pharmaceuticals USA, Inc., 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. 9,248,191 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 address.
`
`III. GROUNDS FOR STANDING (37 C.F.R. § 42.104(a)).
`
`Petitioner certifies that the ’191 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 ’191 patent based on the meaningfully distinct grounds set forth
`
`in the table below (see also IPR2016-01132, Paper No. 8, EX1031-0006-07, 0024):
`
`Ground Claims
`1
`1-27
`2
`1-27
`3
`17-20
`4
`20
`
`Statutory Basis Reference(s)
`§ 103
`Ding ’979 and Sall
`§ 103
`Ding ’979, Sall and Acheampong
`§ 103
`Ding ’979, Sall and Glonek
`§ 103
`Ding
`’979,
`Sall, Glonek
`Acheampong
`
`and
`
`
`Petitioner’s proposed claim constructions and unpatentability grounds for
`
`the ’191 patent are set forth 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. 9,248,191 B2
`
`accompany this Petition. Petitioner also relies on other exhibits set forth on the
`
`concurrently filed Exhibit List.
`
`V. OVERVIEW OF THE ’191 PATENT.
`
`A.
`
`’191 Patent Claims.
`
`Independent claims 1, 13, 17, and 21 each require administering twice-daily
`
`a first topical opthalmic emulsion comprising by weight: 0.05% CsA; 1.25% castor
`
`oil; polysorbate 80; acrylate/C10-30 alkyl acrylate cross-polymer (“cross-
`
`polymer”); and water. All claims require a method for treating dry eye disease
`
`(claims 1, 17) or “enhancing” or “restoring” tearing (claims 13, 21). Claims 1 and
`
`13 require a method “therapeutically effective in treating dry eye disease,” and
`
`resulting in “substantially no detectable concentration of [CsA] in the blood”
`
`(claim 1) or “less than about 0.1 ng/ml” of CsA in the blood (claim 13).
`
`Each independent claim includes comparative elements reciting that the
`
`“first topical ophthalmic emulsion” either: “provides overall efficacy substantially
`
`equal to” or “achieves at least as much therapeutic efficacy as” as a “second topical
`
`ophthalmic emulsion” having 0.10% CsA/1.25% castor oil emulsion (claims 1, 13,
`
`and 21); “demonstrates a reduction in adverse events” compared to the “second
`
`topical ophthalmic emulsion” having 0.10% CsA/1.25% castor oil emulsion (claim
`
`21); or “breaks down more quickly in the human eye” than a second emulsion
`
`with only 50% as much castor oil (claim 17).
`
` 7
`
`
`
`
`
`

`

`Petition for Inter Partes Review of U.S. Patent No. 9,248,191 B2
`
`The dependent claims add known percentages of emulsion excipients, pH
`
`values, or performance features.
`
`Applying the most detailed claim requirements for the “first topical
`
`ophthalmic emulsion” ingredients, weight percentage, and pH yields the ‘191
`
`patent’s “Composition II” formulation; the “second topical ophthalmic emulsion”
`
`of claims 1, 13, and 21 encompasses the ‘191 patent’s “Composition I”
`
`formulation. EX1001, 14:25-38, 15:20-18:17; EX1002, ¶¶32, 38-56.
`
`B.
`
`’191 Patent 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 was a continuation, via U.S. applications 13/961,828, 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.
`
`During prosecution of the related ’857 application, Allergan had admitted
`
`that the specification’s Composition II—fully claimed by the ’191 patent (EX1002,
`
`¶¶57-59)—was “squarely within the teachings of Ding [’979]”:
`
`The applicants concede that it would have been obvious to modify
`examples 1A-1E of the Ding reference to arrive at Composition II of
`the present application. The differences are insignificant…. As the
`examiner correctly observes, one of ordinary skill in the art “would
`readily envisage” such a composition, especially in view of Example
`
` 8
`
`
`
`
`
`

`

`Petition for Inter Partes Review of U.S. Patent No. 9,248,191 B2
`
`1B: having selected 0.05% as the concentration of cyclosporin,
`Example 1B (wherein the ratio of cyclosporin to castor oil is 0.04)
`teaches that the concentration of castor oil should be 1.250% (0.05% /
`1.250% = 0.04). The applicants concede that in making this selection
`(0.05% cyclosporin and 1.250% castor oil) there would have been a
`reasonable expectation of success; the differences between Examples
`1A-1E and Composition II are too small to believe otherwise.
`
`The formulation of Composition II is squarely within the teachings
`of the Ding reference, and the Office should disregard any
`statements by the applicants suggesting otherwise.
`
`EX1005-0435 (emphases added).
`
`During prosecution, the Examiner issued obviousness rejections. Allergan
`
`acknowledged its prior admission, but alleged new unexpected results evidence
`
`justified patentability over Ding ’979. In Remarks accompanying the Notice of
`
`Allowance (EX1004-0012), the examiner relied on declarations submitted by Drs.
`
`Schiffman and Attar during the prosecution of U.S. application 13/961,828, which
`
`issued as the ’930 patent. Id. at 0020-21. 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). Id. at 0022. As Section XI discusses, they do not.
`
` 9
`
`
`
`
`
`

`

`Petition for Inter Partes Review of U.S. Patent No. 9,248,191 B2
`
`VI. PERSON OF ORDINARY SKILL IN THE ART.
`
`For the ’191 patent, the ordinarily-skilled artisan in the relevant field as of
`
`September 15, 20032 would 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. Such person typically possessed an advanced degree, e.g., M.D., or Ph.D. in
`
`organic chemistry, pharmaceutical chemistry, medicinal chemistry, pharmaceutics,
`
`physical pharmacy, or related field; or less education but considerable professional
`
`experience in these fields. EX1002, ¶63; EX1003, ¶¶80-81.
`
`The ordinarily-skilled artisan typically worked within a multi-disciplinary
`
`team, drawing upon their own skills or taking advantage of specialized skills of
`
`other team members 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. The ordinarily-skilled artisan would also
`
`have been aware of other important information and references relating to dry eye,
`
`its causes, and useful treatments. EX1002, ¶64; EX1003, ¶82.
`
`
`2 The earliest provisional date; Petitioner reserves its priority challenge rights in
`
`this or other proceedings.
`
`
`
`
`10
`
`

`

`Petition for Inter Partes Review of U.S. Patent No. 9,248,191 B2
`
`VII. STATE OF THE ART AS OF SEPTEMBER 15, 2003.
`
`Before September 15, 2003, the art recognized inflammation contributed to
`
`certain dry eye diseases. E.g., EX1012-0001; EX1003, ¶¶60-70. 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,
`
`¶98; EX1003, ¶60.
`
`Topical ophthalmic administration of CsA, a known anti-inflammatory
`
`agent, significantly reduced inflammation markers associated with dry eye.
`
`EX1012-0001; EX1002, ¶ 99; EX1003, ¶61. Allergan’s experts conceded during
`
`prosecution that “[i]t was known in the art … that cyclosporin could be
`
`administered topically locally to the eye to target and treat dry eye by using
`
`cyclosporin A’s immunomodulatory properties[.]” EX1023-0201.
`
`Castor oil vehicles were used for topical ophthalmic administration of highly
`
`lipophilic drugs, like CsA, requiring formulation in a water-solubilized form.
`
`EX1006, 1:40-44, 3:7-14; EX1010, 5:55-63; EX1002, ¶¶105-16. Methods to
`
`determine optimal oil-to-drug ratios were well established in the art before
`
`September 2003. See generally EX1009. The art recognized that higher castor oil
`
`concentrations 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
`
`11
`
`
`
`

`

`Petition for Inter Partes Review of U.S. Patent No. 9,248,191 B2
`
`the eye”); id., 0011-12, 6:1-8:25; id., 0003-07, Figs. 2-6 (reporting that castor oil
`
`vehicles without CsA were effective in treating KCS); id., 0008, 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, ¶¶63. 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, ¶99; EX1003, ¶¶63-64.
`
`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, ¶¶111-112; EX1003, ¶¶65-67. This “therapeutic effect of
`
`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.
`
`
`
`
`12
`
`

`

`Petition for Inter Partes Review of U.S. Patent No. 9,248,191 B2
`
`Thus, the art well knew 0.05% CsA/castor oil formulations were effective to
`
`relieve dry eye disease/KCS. EX1002, ¶¶97-116; EX1003, ¶¶60-70.
`
`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, ¶¶117-28; EX1003, ¶¶72-75, 100. It explains
`
`CsA behaves “as an immunosuppressant”, and for “the enhancement or restoring
`
`of lacrimal gland tearing.” EX1006, 1:10-16, 37-39. Ding ’979 teaches topical
`
`CsA ophthalmic emulsions to treat KCS. EX1006, 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% 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, 6:27-42; EX1002, ¶¶117-21.
`
`Ding ’979 discloses four specific castor oil-based vehicles (Examples 2A-
`
`D). EX1006, 4:44-54; EX1002, ¶122. Ding ’979’s CsA-containing emulsions in
`
`Example 1 used the Example 23 vehicles. EX1006, 4:32-54. Example 1’s
`
`emulsions use specific CsA and castor oil percentages across the ranges found in
`
`
`3 Example 2C’s vehicle is identical to the vehicle in the challenged claims.
`
`
`
`
`13
`
`

`

`Petition for Inter Partes Review of U.S. Patent No. 9,248,191 B2
`
`Ding ’979 claims 7 and 8 (0.05%-0.40% CsA and 0.625%-5.00% castor oil).
`
`EX1006, 4:32-43; EX1002, ¶123.
`
`Ding ’979 explicitly teaches a “more preferred” CsA to castor oil ratio
`
`range: 0.02-0.12; Example 1’s formulations each had a 0.04 or 0.08 ratio.
`
`EX1006, 3:17-20, 4:31-43; EX1002, ¶123.
`
`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 to rabbit eyes eight times a day for seven days, produced at most
`
`“slight to mild discomfort” or “slight hyperemia”; and there was “no difference in
`
`toxicity” and comparable ocular bioavailability among the formulation/vehicle
`
`ranges tested. Id., 5:15-28; 3:7-9 (compositions are “nonirritating”, “with high
`
`comfort level”).
`
`B.
`
`Sall (EX1007).
`
`Sall is 35 U.S.C. § 102(b) prior art. EX1002, ¶¶129-45; EX1003, ¶100. Sall
`
`describes Patent Owner Allergan’s multi-center, randomized, double-masked
`
`Phase 3 clinical trial assessing the safety and efficacy of a topical ophthalmic
`
`administration comprising 0.05% or 0.10% CsA in castor oil administered twice
`
`daily, compared to the emulsion vehicle without CsA, in increasing tear production
`
`14
`
`
`
`

`

`Petition for Inter Partes Review of U.S. Patent No. 9,248,191 B2
`
`and treating KCS. EX1007-0001-02, 0005-06 (Figs. 1-4). Sall taught the 0.05%
`
`CsA emulsion: (a) was safe and effective; (b) was at least as effective as the 0.10%
`
`CsA emulsion; and (c) yielded fewer adverse side effects, and CsA blood
`
`concentrations below detectible levels. EX1007-0001, 0004-07; EX1002, ¶¶130-
`
`40; EX1003, ¶¶65-66. 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 0.1% CsA samples.
`
`EX1007-0002, 0006-07; EX1002, ¶141; EX1003, ¶153.
`
`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 35 U.S.C. § 102(b) prior art. EX1002, ¶¶145-48; EX1003,
`
`¶162. Acheampong describes Patent Owner Allergan’s study in which CsA
`
`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. No CsA was detected in patients receiving the 0.05% CsA
`
`emulsion. Id., 0004-06.
`
`
`
`
`15
`
`

`

`Petition for Inter Partes Review of U.S. Patent No. 9,248,191 B2
`
`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.
`
`D. Glonek (EX1009).
`
`Glonek, issued Nov. 6, 1996, is 35 U.S.C. § 102(b) prior art. EX1002,
`
`¶¶149-54, EX1003, ¶169. Glonek teaches that “an emulsion over the surface of the
`
`eye is expected to cause blurring. The duration of blur is d