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. 8,648,048 B2 to Acheampong et al.
`Issue Date: February 11, 2014
`Title: Methods of Providing Therapeutic Effects Using Cyclosporin Components
`________________________________
`
`Inter Partes Review Trial No. 2017-00566
`________________________________
`
`Petition for Inter Partes Review of U.S. Patent No. 8,648,048
`
`
`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. 8,648,048 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 ’048 PATENT. .................................................. 7
`
`A.
`
`B.
`
`’048 Patent Claims. ....................................................................... 7
`
`’048 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). ..............................................................16
`
`D. Glonek (EX1009). .......................................................................16
`
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`Petition for Inter Partes Review of U.S. Patent No. 8,648,048 B2
`
`IX. CLAIM CONSTRUCTION. ................................................................ 17
`
`A.
`
`B.
`
`C.
`
`D.
`
`E.
`
`“substantially
`amount,”
`“effective
`“effective,”
`therapeutically effective as,” and “as much therapeutic
`effectiveness as” ..........................................................................17
`
`“buffer” ........................................................................................19
`
`“substantially no detectable concentration” ................................19
`
`“adverse events” and “side effects” ............................................20
`
`“breaks down” .............................................................................20
`
`X.
`
`EXPLANATION OF UNPATENTABILITY GROUNDS. ................ 21
`
`A. Ding ’979 and Sall Claim Chart. .................................................21
`
`B.
`
`Ground 1: Claims 1-23 Are Unpatentable Under 35 U.S.C.
`§ 103 in View of Ding ’979 and Sall. .........................................29
`
`1.
`
`2.
`
`3.
`
`4.
`
`5.
`
`6.
`
`7.
`
`Preamble and Dry Eye Efficacy Elements ........................37
`
`Frequency Elements ..........................................................39
`
`CsA Elements ....................................................................39
`
`Castor Oil Elements ..........................................................40
`
`Additional Composition Elements ....................................44
`
`Comparative Elements ......................................................45
`
`CsA Blood Level Elements ...............................................50
`
`C.
`
`Ground 2: Claims 11 and 21 Are Unpatentable Under 35
`U.S.C. § 103
`in View of Ding
`’979, Sall, and
`Acheampong. ...............................................................................53
`
`D. Ground 3: Claim 15 is Unpatentable Under 35 U.S.C. §
`103 in View of Ding ’979, Sall, and Glonek. .............................55
`
`
`
`ii
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`Petition for Inter Partes Review of U.S. Patent No. 8,648,048 B2
`
`XI. ALLERGAN’S ALLEGED SECONDARY
`CONSIDERATIONS DO NOT OVERCOME PETITIONER’S
`STRONG SHOWING OF OBVIOUSNESS ....................................... 56
`
`A. No Unexpected Results. ..............................................................60
`
`1.
`
`2.
`
`3.
`
`4.
`
`Schiffman Exhibit B .........................................................61
`
`Schiffman Exhibit C/Attar Exhibit B: ..............................66
`
`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
`
`
`
`
`
`
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`iii
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`Petition for Inter Partes Review of U.S. Patent No. 8,648,048 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. 8,648,048 B2 to Acheampong et al., filed August 14,
`2013 (“the ’048 patent”)
`Declaration of Dr. Peter Kador
`Declaration of Dr. Michael A. Lemp
`File history of U.S. Patent No. 8,648,048 to Acheampong et al., filed
`August 14, 2013 (“’048 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
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`

`

`Petition for Inter Partes Review of U.S. Patent No. 8,648,048 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., IPR2016-01131, 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
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`

`

`Petition for Inter Partes Review of U.S. Patent No. 8,648,048 B2
`
`
`Famy Care Limited (“Famy Care” or “Petitioner”) petitions for Inter Partes
`
`Review, seeking cancellation of claims 1-23 of U.S. Patent No. 8,648,048 B2,
`
`which issued on February 11, 2014, to Acheampong et al. (“the ’048 patent”)
`
`(Exhibit (“Ex.”) 1001). PTO records identify Allergan, Inc. as the ’048 patent’s
`
`assignee (“Patent Owner”). This Petition demonstrates the reasonable likelihood
`
`that claims 1-23 of the ’048 patent are unpatentable over the asserted prior art.
`
`Peteitioner has filed companion petitions to address related patents that are
`
`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 have concurrently filed a Power of Attorney and Exhibit List
`
`pursuant to 37 C.F.R. §§ 42.10(b) and 42.63(e), respectively. The $26,800 fee
`
`required under 37 C.F.R. § 42.15(a) has been paid from Deposit Account 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. 8,648,048 B2
`
`I.
`
`INTRODUCTION.
`
`The ’048 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,
`
`14:20-30. Claims 13-16 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” (claims 13,
`
`14, 16); or 50% less castor oil (claim 15). See id., 14:20-30, 15:15-16:57.
`
`The ’048 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 ¶156. 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 “no difference in toxicity” as CsA and
`
` 2
`
`
`
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`

`

`Petition for Inter Partes Review of U.S. Patent No. 8,648,048 B2
`
`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, ¶59.
`
`During a parent application’s prosecution, 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.
`
`Allergan disavowed its admission after creating purported “unexpected
`
`results” that Composition II was “equally or more therapeutically effective” than
`
`Composition I. EX1004-0253. 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 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, ¶¶170-212.
`
`Consequently, as this Petition explains, the claims of the ’048 patent are
`
`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. 8,648,048 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 ’048 patent
`
`(IPR2016-1131), as well as 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 9,248,191 (IPR2016-01132). 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., IPR2016-01131, 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 the ’048 patent (IPR2015-01284), as well as petitions for related Patent
`
` 4
`
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`
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`

`

`Petition for Inter Partes Review of U.S. Patent No. 8,648,048 B2
`
`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 ’048 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 ’048 patent against Petitioner was
`
`served no earlier than April 15, 2016. Petitioner identifies the following pending
`
`actions involving the ’048 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. 8,648,048 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 ’048 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 1-23 of the ’048 patent based on the meaningfully distinct grounds set forth
`
`in the table below (and instituted in Mylan Pharm., Inc. v. Allergan, Inc., IPR2016-
`
`01131, Paper No. 8 (P.T.A.B. Dec. 8, 2016), EX1031-0006, 0022):
`
`Statutory Basis Reference(s)
`Ground Claims
`§ 103
`Ding ’979 and Sall
`1
`1-23
`2
`11 and 21 § 103
`Ding ’979, Sall, and Acheampong
`3
`15
`§ 103
`Ding ’979, Sall, and Glonek
`
`
`Petitioner’s proposed claim constructions and unpatentability grounds for
`
`the ’048 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. 8,648,048 B2
`
`M.D. (EX1003; EX1033). The petitioner further relies on other Exhibits set forth
`
`on the concurrently-filed Exhibit List.
`
`V. OVERVIEW OF THE ’048 PATENT.
`
`A.
`
`’048 Patent Claims.
`
`Independent claim 1 recites a method of increasing tear production in the
`
`eye of a human, comprising administering twice-daily a topical ophthalmic
`
`emulsion comprising by weight: 0.05% CsA; 1.25% castor oil; polysorbate 80;
`
`acrylate/C10-30 alkyl acrylate cross-polymer (“cross-polymer”); and water.
`
`Claims 2-6 and 9-10 further recite a tonicity or demulcent agent, specifically
`
`glycerine, and/or a buffer, specifically sodium hydroxide. Claim 12 specifies pH
`
`values for the emulsion of claim 6, which comprises glycerine and a buffer.
`
`Claims 7-8 are dependent claims that specify known weight percentages of
`
`polysorbate 80 and cross-polymer, respectively. Claim 11 recites that when the
`
`emulsion is administered to the eye substantially no detectable blood concentration
`
`of CsA results.
`
`Claims 13-14 and 16-17 respectively compare the therapeutic efficacy or
`
`adverse events of the claimed emulsion verses one with 0.10% CsA. Claim 15
`
`compares the breakdown rate of the claimed with a second emulsion containing
`
`half as much castor oil.
`
` 7
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`

`Petition for Inter Partes Review of U.S. Patent No. 8,648,048 B2
`
`Independent claim 18 recites a method of treating KCS using an emulsion
`
`comprising by weight: 0.05% CsA; 1.25% castor oil; 1.0% polysorbate 80; 0.05%
`
`cross-polymer; 2.2% tonicity/demulcent component (e.g., glycerin); buffer; water;
`
`and pH 7.2-7.6. The claim 18 method is recited as “effective in treating” KCS.
`
`Dependent claims 19-21 further specify sodium hydroxide as the buffer and
`
`glycerine as the tonicity/demulcent agent, and that the blood of the human has
`
`substantially no detectable concentration of CsA.
`
`Independent claim 22 recites a method comprising twice-daily administering
`
`to the eye of a human having KCS an emulsion comprising by weight: 0.05% CsA;
`
`1.25% castor oil; 1.0% polysorbate 80; 0.05% cross-polymer; 2.2% glycerin;
`
`sodium hydroxide; and water. The claim 22 method is recited as “effective in
`
`increasing tear production.” Dependent claim 23 recites a pH range of 7.2-7.6.
`
`Applying the most detailed claim requirements for the first “emulsion”
`
`ingredients, weight percentage and pH yields
`
`the ‘048 patent’s specific
`
`“Composition II” formulation; the “second topical emulsion” of claims 13-14 and
`
`16 encompasses the ’048 patent’s “Composition I” formulation. EX1001, 14:20-
`
`30, 15:15-16:57; EX1002, ¶¶38-51, 155.
`
`B.
`
`’048 Patent Prosecution History.
`
`U.S. Patent Application No. 13/967,168 (“the ’168 application”) was filed
`
`on August 14, 2013, and issued on February 11, 2014 as the ’048 patent. The ’168
`
` 8
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`

`Petition for Inter Partes Review of U.S. Patent No. 8,648,048 B2
`
`application was a continuation, via U.S. applications 13/961,835, 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.
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`During prosecution, the Examiner issued obviousness rejections. During
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`prosecution of
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`the related ’857 application, Allergan admitted
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`that
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`the
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`specification’s Composition II—fully claimed by the ’048 patent (EX1002, ¶52)—
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`was “squarely within the teachings of Ding [’979]”:
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`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.
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`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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`Petition for Inter Partes Review of U.S. Patent No. 8,648,048 B2
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`In Remarks accompanying a Notice of Allowance (EX1004-0468), the
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`Examiner relied on declarations submitted by Drs. Schiffman and Attar during the
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`prosecution of U.S. application 13/961,828, which issued as the ’930 patent, in
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`withdrawing the obviousness rejection in view of Ding ’979. Id., 0473. The
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`Examiner stated that “the specific combination of 0.05% by weight cyclosporin A
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`with 1.25% by weight castor oil is surprisingly critical for therapeutic effectiveness
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`in the treatment of dry eye or keratoconjunctivitis sicca,” and therefore,
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`“demonstrate[s] surprising and unexpected results.” Id. As Section XI below
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`discusses, they do not. EX1002, ¶¶52-58; EX1003, ¶¶34-40.
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`VI. PERSON OF ORDINARY SKILL IN THE ART.
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`For the ’048 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. Such person typically possessed an advanced degree, e.g., M.D., or Ph.D. in
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`organic chemistry, pharmaceutical chemistry, medicinal chemistry, pharmaceutics,
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`2 The earliest provisional date; Petitioner reserves its priority challenge rights in
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`this or other proceedings.
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`Petition for Inter Partes Review of U.S. Patent No. 8,648,048 B2
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`physical pharmacy, or related field; or less education but considerable professional
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`experience in these fields. EX1002, ¶60; EX1003, ¶75.
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`The ordinarily-skilled artisan typically worked within a multi-disciplinary
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`team, and drew upon their skills; or would take advantage of certain specialized
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`skills of other team members to solve a given problem. As of September 15, 2003,
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`the state of the art included the teachings provided by the references discussed in
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`each of the unpatentability grounds set forth below. Additionally, the ordinarily-
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`skilled artisan would have been aware of other important information and
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`references relating to dry eye, its causes, and useful treatments. EX1002, ¶61,
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`EX1003, ¶76.
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`VII. STATE OF THE ART AS OF SEPTEMBER 15, 2003.
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`Before September 15, 2003, that the art recognized inflammation contributed
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`to certain dry eye diseases. E.g., EX1012-0001; EX1002, ¶¶93-100; EX1003,
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`¶¶54-64. 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 [KCS].”
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`EX1013-0004; EX1003, ¶54.
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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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`EX1012-0001, 1489; EX1002, ¶¶93-100. Allergan’s experts conceded during
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`Petition for Inter Partes Review of U.S. Patent No. 8,648,048 B2
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`prosecution that “[i]t was known in the art … that cyclosporin could be
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`administered topically locally to the eye to target and treat dry eye by using
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`cyclosporin A’s immunomodulatory properties.” EX1004-0262.
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`Castor oil vehicles were used for topical ophthalmic administration of highly
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`lipophilic drugs, like CsA, that must be formulated in a water-solubilized form.
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`EX1006, 1:40-44, 3:7-14; EX1010, 5:55-63; EX1002, ¶¶100-11. Methods to
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`determine optimal oil-to-drug ratios were well established in the art prior to
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`September 2003. See generally EX1009; EX1002. The art recognized that higher
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`castor oil concentrations in a vehicle increased ocular residence time. EX1010,
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`2:61-65 (“relief is limited by the retention time of the administered artificial tear
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`solution in the eye.”), id., 0011-12, 6:1-8:25, id., 0003-07, Figs. 2-6 (reporting that
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`castor oil vehicles without CsA were effective in treating KCS), id., 0008, Fig. 7
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`(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, ¶94-111; EX1003, ¶57. Kunert
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`reported that topical 0.05% CsA emulsions in castor oil significantly decreased
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`lymphocyte activation markers, concluding that this treatment “may help to reduce
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`the pathophysiological factors contributing to the development of KCS.” EX1012-
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`0007. Turner reported that topical 0.05% CsA emulsions in castor oil decreased
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`inflammation markers in dry eye patients. EX1014-0001, 492. Stevenson
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`Petition for Inter Partes Review of U.S. Patent No. 8,648,048 B2
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`concluded from a Phase 2 dose-ranging trial (0.05%-0.4% CsA emulsions) that
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`0.05% and 0.10% CsA emulsions were “the most appropriate” because “no
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`additional benefits were observed with the higher concentrations.” EX1015-0001;
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`EX1003, ¶¶57-59.
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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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`492, 496; EX1015-0007; EX1002, ¶106; EX1003, ¶¶60-61. This “therapeutic
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`effect of the [castor] oil-in-water vehicle” was “expected, as topical application of
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`certain lipid mixtures can accelerate epidermal barrier recovery after defined
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`barrier insults in mice.” EX1014-0005, 496.
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`Thus, the art well knew 0.05% CsA/castor oil formulations were effective to
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`relieve dry eye disease/KCS. EX1002, ¶¶93-111; EX1003, ¶¶54-62.
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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. EX1002, ¶¶112-23; EX1003, ¶94. It explains CsA
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`behaves “as an immunosuppressant”, and for “the enhancement or restoring of
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`lacrimal gland tearing.” EX1006, 1:10-16, 37-39; EX1002, ¶113. It teaches topical
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`CsA ophthalmic emulsions to treat KCS. EX1006, 5:9-12; EX1002, ¶113;
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`EX1003, ¶¶65-69. Claims 7-8 specifically recite emulsions containing 0.05-0.40%
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`Petition for Inter Partes Review of U.S. Patent No. 8,648,048 B2
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`CsA, 0.625-5.00% castor oil, 1.00% polysorbate 80, 0.05% Pemulen®
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` (an
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`acrylate/C10-30 alkyl acrylate cross-polymer), 2.20% glycerine, sodium
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`hydroxide, and water and having a pH range of 7.2-7.6. EX1006, 6:27-41;
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`EX1002, ¶¶115-16; EX1003, ¶¶67-69.
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`Ding ’979 discloses four specific castor oil-based vehicles (Examples 2A-
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`D). EX1006, 4:44-54; EX1002, ¶117. Ding ’979’s CsA-containing emulsions in
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`Example 1 used the Example 23 vehicles. EX1006, 4:32-54; EX1002, ¶112.
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`Example 1’s emulsions use specific CsA and castor oil percentages across the
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`ranges found in Ding ’979 claims 7 and 8 (0.05%-0.40% CsA and 0.625%-5.00%
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`castor oil). EX1006, 4:32-43; EX1002, ¶118.
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`Ding ’979 explicitly teaches a “more preferred” range for CsA to castor oil
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`ratio: 0.02-0.12; Example 1’s specific formulations each had only a 0.04 or 0.08
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`ratio. EX1006, 3:17-20, 4:31-43; EX1002, ¶118.
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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.”
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`EX1006, 5:9-14. Ding ’979 reports that the Examples 1A-D formulations, even
`
`when applied eight times a day for seven days to rabbit eyes, produced at most
`
`
`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. 8,648,048 B2
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`“slight to mild discomfort” or “slight hyperemia”; and as between the
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`formulation/vehicle ranges tested, there were “no difference in toxicity” and they
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`had comparable ocular bioavailability. Id., 0004-05, 5:15-28; 3:7-9 (invention’s
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`compositions are “nonirritating” and “with high comfort level”); EX1002, ¶121.
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`B.
`
`Sall (EX1007).
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`Sall is 35 U.S.C. § 102(b) prior art. EX1002, ¶¶124-39; EX1003, ¶94. Sall
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`describes Patent Owner Allergan’s multi-center, randomized, double-masked
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`Phase 3 clinical trial assessing the safety and efficacy (in increasing tear
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`production and treating KCS) of twice-daily topical ophthalmic administration of
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`0.05% or 0.10% CsA in a castor oil emulsion, compared to the emulsion vehicle
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`without CsA. EX1007-0001-02, 0005-06 (Figs. 1-4). Sall taught the 0.05% CsA
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`emulsion was safe and effective, was at least as effective as the 0.10% CsA
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`emulsion; and resulted in fewer adverse side effects, and in CsA blood
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`concentrations below detectible levels. EX1007-0001, 0004-07; EX1002, ¶¶125-
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`26, EX1003, ¶59. Sall compared the 0.05% and 0.10% CsA emulsions to the same
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`control vehicle, and reported trough CsA blood concentrations were undetectable
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`in all 0.05% CsA samples; but quantifiable in six 0.1% CsA samples. EX1007-
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`0002, 0006-07; EX1002, ¶127-36; EX1003, ¶¶59-60.
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`Sall noted existing palliative dry eye
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`treatments, and deemed
`
`its
`
`formulations “the first therapeutic treatment specifically for dry eye disease and a
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`Petition for Inter Partes Review of U.S. Patent No. 8,648,048 B2
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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, ¶¶140-43;
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`EX1003, ¶156. Acheampong describes a Patent Owner study in which CsA