`________________________________
`
`BEFORE THE PATENT TRIAL AND APPEAL BOARD
`________________________________
`
`FAMY CARE LIMITED
`Petitioner
`v.
`ALLERGAN, INC.
`Patent Owner
`U.S. Patent No. 8,642,556 B2 to Acheampong et al.
`Issue Date: February 4, 2014
`Title: Methods of Providing Therapeutic Effects Using Cyclosporin Components
`________________________________
`
`Inter Partes Review Trial No. 2017-00570
`________________________________
`
`Petition for Inter Partes Review of U.S. Patent No. 8,642,556
`
`
`Mail Stop "PATENT BOARD"
`Patent Trial and Appeal Board
`U.S. Patent and Trademark Office
`P.O. Box 1450
`Alexandria, VA 22313-1450
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`Petition for Inter Partes Review of U.S. Patent No. 8,642,556 B2
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`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 ’556 PATENT. .................................................. 7
`
`A.
`
`B.
`
`’556 Patent Claims. .......................................................................7
`
`’556 Patent Prosecution History. ...................................................9
`
`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
`
`D. Glonek (EX1009). ...................................................................... 16
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`Petition for Inter Partes Review of U.S. Patent No. 8,642,556 B2
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`IX. CLAIM CONSTRUCTION. ................................................................ 17
`
`A.
`
`B.
`
`C.
`
`D.
`
`E.
`
`“therapeutically effective,” “effective amount,” “overall
`efficacy,” “therapeutic effectiveness” ........................................ 17
`
`“buffer” ....................................................................................... 18
`
`“substantially no detectable concentration” ............................... 18
`
`“adverse events” and “side effects” ........................................... 19
`
`“breaks down” ............................................................................ 20
`
`X.
`
`EXPLANATION OF UNPATENTABILITY GROUNDS. ................ 21
`
`A. Ding ’979 Claim Chart. .............................................................. 21
`
`B.
`
`Ground 1: Claims 1-20 are Unpatentable Under 35 U.S.C. §
`102 by Ding ‘979. ....................................................................... 28
`
`1.
`
`Claims 1-10 and 12-13. .................................................... 28
`
`a.
`b.
`c.
`d.
`e.
`
`Preamble and Dry Eye Efficacy Elements ............ 29
`CsA and Castor Oil Elements ................................ 30
`Additional Composition Elements ........................ 31
`Comparison Elements ............................................ 32
`Ding ’979 taught the entire claimed Composition
`II formulation. ........................................................ 33
`Therapeutic effectiveness ...................................... 35
`f.
`Claim 14. .......................................................................... 37
`
`Claims 15-17. ................................................................... 38
`
`Claims 11 and 18-20. ....................................................... 39
`
`2.
`
`3.
`
`4.
`
`C.
`
`Ground 2: Claims 1-20 Are Unpatentable Under 35 U.S.C. §
`103 in View of Ding ’979 and Sall. ........................................... 40
`
`1.
`
`Claims 1-10 and 12-13. .................................................... 41
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`Petition for Inter Partes Review of U.S. Patent No. 8,642,556 B2
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`a.
`Preamble and Dry Eye Efficacy Elements: ........... 41
`CsA Elements (claims 1 and 13) ........................... 43
`b.
`Castor Oil Elements (independent claims 1 and 13)44
`c.
`Additional Composition Elements: ....................... 47
`d.
`Efficacy. ................................................................. 48
`e.
`Claim 14. .......................................................................... 50
`
`Claims 15-17. ................................................................... 51
`
`Claims 11 and 18-20. ....................................................... 53
`
`2.
`
`3.
`
`4.
`
`D. Ground 3: Claims 14 and 19 Are Unpatentable Under 35 U.S.C.
`§ 103 in View of Ding ‘979, Sall, and Glonek. ......................... 54
`
`E.
`
`F.
`
`Ground 4: Claims 11 and 18-20 Are Unpatentable Under 35
`U.S.C. § 103 in View of Ding ‘979, Sall, and Acheampong. .... 55
`
`Ground 5: Claim 19 is Unpatentable Under 35 U.S.C. § 103 in
`View of Ding ‘979, Sall, Glonek and Acheampong. ................. 57
`
`XI. ALLERGAN’S ALLEGED SECONDARY CONSIDERATIONS DO
`NOT OVERCOME PETITIONER’S STRONG SHOWING OF
`OBVIOUSNESS ................................................................................... 58
`
`A. No Unexpected Results. ............................................................. 61
`
`1.
`
`2.
`
`3.
`
`4.
`
`Schiffman Exhibit B ........................................................ 62
`
`Schiffman Exhibit C/Attar Exhibit B ............................... 67
`
`Schiffman Exhibit D ........................................................ 69
`
`Schiffman Exhibits E and F/Attar Exhibits D and E. ...... 74
`
`B.
`
`Near-Simultaneous Invention. .................................................... 78
`
`XII. CONCLUSION ..................................................................................... 79
`
`XIII. CERTIFICATE OF COMPLIANCE ................................................... 80
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`
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`iii
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`
`
`Exhibit
`1001
`
`EXHIBIT LIST PURSUANT TO 37 C.F.R. § 42.63(e) AND
`TABLE OF ABBREVIATIONS
`
`Description of Exhibit
`U.S. Patent No. 8,642,556 B2 to Acheampong et al., filed August 14,
`2013 (“the ’556 patent”)
`Declaration of Dr. Peter Kador
`Declaration of Dr. Michael A. Lemp
`File history of U.S. Patent No. 8,642,556 to Acheampong et al., filed
`August 14, 2013 (“’556 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
`
`1002
`1003
`1004
`
`1005
`
`1006
`
`1007
`
`1008
`
`1009
`
`1010
`
`1011
`
`1012
`
`1013
`
`1014
`
`1015
`
`iv
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`Petition for Inter Partes Review of U.S. Patent No. 8,642,556 B2
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`1016
`
`1017
`
`1018
`
`1019
`
`1020
`
`1021
`
`1022
`
`1023
`
`1024
`
`1025
`1026
`1027
`1028
`
`1029
`
`1030
`
`Emulsion in the Treatment of Moderate-to-Severe Dry Eye Disease,
`107 OPHTHALMOLOGY 967 (2000) (“Stevenson”)
`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”)
`Stephen C. Pflugfelder et al., The Diagnosis and Management of Dry
`Eye, 19 CORNEA 644 (2000) (“Pflugfelder”)
`1031 Mylan Pharm., Inc. v. Allergan, Inc., IPR2016-01129, 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
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`Petition for Inter Partes Review of U.S. Patent No. 8,642,556 B2
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`Famy Care Limited (“Famy Care” or “Petitioner”) petitions for Inter Partes
`
`Review, seeking cancellation of claims 1-20 of U.S. Patent No. 8,642,556 B2,
`
`which issued on February 4, 2014, to Acheampong et al. (“the ’556 patent”)
`
`(Exhibit (“Ex.”) 1001). PTO records identify Allergan, Inc as the ’556 patent’s
`
`assignee (“Patent Owner”). This Petition demonstrates the reasonable likelihood
`
`that claims 1-20 of the ’556 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
`
`are terminally disclaimed over one another. The patents claim an ophthalmic
`
`emulsion for treating ocular disorders, or conventional methods of administration.
`
`Petitioner has concurrently filed is a Power of Attorney and Exhibit List
`
`pursuant to 37 C.F.R. §§ 42.10(b) and 42.63(e), respectively. The $25,000 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.
`
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`1
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`Petition for Inter Partes Review of U.S. Patent No. 8,642,556 B2
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`I.
`
`INTRODUCTION.
`
`The ’556 patent (EX1001) claims a 0.05% by weight cyclosporine A
`
`(“CsA”) topical ophthalmic emulsion used to treat dry eye disease, which the
`
`specification labels “Composition II.” EX1001, 15:1-13. 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 14). Id., 15:1-
`
`13, 15:65-16:10, 16:46-17:15.
`
`The ’556 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
`
`(0.0625%)
`
`relative
`
`to 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). 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 ¶¶153-
`
`54. 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”, and showed “no difference in toxicity” as
`
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`Petition for Inter Partes Review of U.S. Patent No. 8,642,556 B2
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`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, ¶¶105-
`
`06, 126.
`
`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. EX1004-0205. But Allergan’s unpublished, later-generated pK
`
`and/or population 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, ¶¶183-225.
`
`Consequently, as this Petition explains, the ’556 patent claims are
`
`anticipated and/or obvious on multiple grounds.
`
`1 Petitioner uses “Allergan” to include the individual patent applicants.
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`Petition for Inter Partes Review of U.S. Patent No. 8,642,556 B2
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`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 ’556 patent
`
`(IPR2016-1129), as well as petitions for related Patent Nos. 8,629,111 (IPR2016-
`
`1128), 8,685,930 (IPR2016-01127), 8,633,162 (IPR2016-01130), 8,648,048
`
`(IPR2016-01131), 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. Mylan Pharm., Inc. v. Allergan,
`
`Inc., IPR2016-01129, 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 ’556 patent (IPR2015-01286), as well as petitions for related Patent
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`Petition for Inter Partes Review of U.S. Patent No. 8,642,556 B2
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`Nos. 8,648,048
`
`(IPR2015-01284), 8,633,162
`
`(IPR2015-01278), 8,685,930
`
`(IPR2015-01283), and 8,629,111 (IPR2015-01282).
`
` These petitions were
`
`terminated before institution decisions.
`
`Allergan asserted the ’556 patent and related patents against Petitioner Famy
`
`Care in Allergan, Inc. v. Famy Care Ltd., No. 2:16-cv-401, in the Eastern District
`
`of Texas (EX1023). A complaint asserting the ’556 patent against Petitioner was
`
`served no earlier than April 15, 2016. Petitioner identifies the following pending
`
`actions involving the ’556 patent: Allergan, Inc. v. Teva Pharmaceuticals USA,
`
`Inc., et al., No. 2:15-cv-1455; and Allergan, Inc. v. DEVA Holding AS, No. 2:16-
`
`cv-1447, both in the Eastern District of Texas.
`
`C. Lead and Back-Up Counsel (37 C.F.R. § 42.8(b)(3)).
`
`Back-Up Counsel
`William A. Rakoczy
`Pro hac vice to be filed
`wrakoczy@rmmslegal.com
`Rakoczy Molino Mazzochi Siwik LLP
`6 West Hubbard Street, Suite 500,
`Chicago, Illinois 60654
`Tel.: 312-527-2157
`
`John D. Polivick
`Reg. No. 57,926
`jpolivick@rmmslegal.com
`Rakoczy Molino Mazzochi Siwik LLP
`6 West Hubbard Street, Suite 500
`Chicago, Illinois 60654
`Tel.: 312-527-2157
`
`
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` 5
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`
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`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
`
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`Petition for Inter Partes Review of U.S. Patent No. 8,642,556 B2
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`D.
`
`Service Information (37 C.F.R. § 42.8(b)(4)).
`
`Petitioner consents to service by email at: dmazzochi@rmmslegal.com,
`
`wrakoczy@rmmslegal.com,
`
`jpolivick@rmmslegal.com,
`
`and
`
`FamyCareIPR@rmmslegal.com. Please direct all correspondence regarding this
`
`Petition to counsel at the above addresses.
`
`III. GROUNDS FOR STANDING (37 C.F.R. § 42.104(a)).
`
`Petitioner certifies that the ’556 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 1-20 of the ’556 patent based on the meaningfully distinct grounds set forth
`
`in the table below (and instituted in IPR2016-00129, Paper No. 8 (EX1031) at 18,
`
`22, 23, and 24-25):
`
`Statutory Basis Reference(s)
`Ground Claims
`§ 102
`Ding ’979
`1
`1-20
`§ 103
`Ding ’979 and Sall
`2
`1-20
`3
`14 and 19 § 103
`Ding ’979, Sall, and Glonek
`4
`11, 18-20
`§ 103
`Ding ’979, Sall, and Acheampong
`5
`19
`§ 103
`Ding
`’979,
`Sall, Glonek
`Acheampong
`
`
`
`and
`
` 6
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`Petition for Inter Partes Review of U.S. Patent No. 8,642,556 B2
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`Petitioner sets
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`forth below
`
`its proposed claim constructions and
`
`unpatentability grounds for the ’556 patent. Declarations from technical experts
`
`Peter Kador, Ph.D. (EX1002; EX1032) and Michael Lemp, M.D. (EX1003;
`
`EX1033) accompany this Petition. Petitioner also relies on other exhibits set forth
`
`on the concurrently-filed Exhibit List.
`
`V. OVERVIEW OF THE ’556 PATENT.
`
`A.
`
`’556 Patent Claims.
`
`Independent claim 1 is representative, requiring a first topical ophthalmic
`
`emulsion for treating human eyes comprising by weight: 0.05% CsA; 1.25%
`
`castor oil; polysorbate 80; acrylate/C10-30 alkyl acrylate cross-polymer (“cross-
`
`polymer”); and water. Claim 1’s performance elements require such composition
`
`to be “therapeutically effective” in treating dry eye disease and provide “overall
`
`efficacy substantially equal to a second topical ophthalmic emulsion” comprising
`
`by weight: 0.1% CsA and 1.25% castor oil.
`
`Claims 2-6 and 9-10 require the emulsion to comprise a tonicity or
`
`demulcent agent, specifically glycerine, and/or a buffer, specifically sodium
`
`hydroxide.
`
`Claims 7-8 specify prior art polysorbate 80 (1.0%) and cross-polymer
`
` 7
`
`
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`(0.05%) amounts.
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`Petition for Inter Partes Review of U.S. Patent No. 8,642,556 B2
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`Claim 11 recites that the emulsion produces substantially no detectable
`
`concentration of CsA in the blood.
`
`Claim 12 specifies pH values of 7.2-7.6 for the emulsion of claim 6.
`
`Independent claims 13-15 recite the same emulsion ingredients as in claim 1.
`
`Claim 13 requires the first 0.05% CsA/1.25% castor oil emulsion to “achieve[] at
`
`least as much therapeutic effectiveness” as a second emulsion comprising 0.1%
`
`CsA/1.25% castor oil. Claim 14 requires the first emulsion to “break[] down
`
`more quickly,” thereby reducing vision distortion, as compared to a second
`
`emulsion with 50% as much (0.625%) castor oil. Claim 15 requires the emulsion
`
`to “demonstrate[] a reduction in adverse events” relative to 0.1% CsA/1.25%
`
`castor oil.
`
`Dependent claims 16-17 specify that the adverse events are side effects,
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`namely visual distortion or eye irritation.
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`Like claim 11, claims 18-20 recite that the emulsions of claims 13-15
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`produce “substantially no detectable concentration of cyclosporin A” in the blood.
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`Applying the most detailed claim requirements above for the “first topical
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`ophthalmic emulsion” yields the ’556 patent specification’s “Composition II”; the
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`“second topical emulsion” of claims 1, 13 and 15 includes, e.g., ’556 patent
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`specification “Composition I.” EX1001, 15:1-13, 15:65-18:16; EX1002, ¶153.
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`Petition for Inter Partes Review of U.S. Patent No. 8,642,556 B2
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`B.
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`’556 Patent Prosecution History.
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`U.S. Patent Application No. 13/967,189 (“the ’189 application”) was filed
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`on August 14, 2013, and issued on February 4, 2014 as the ’556 patent. The ’189
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`application was a continuation, via U.S. applications 13/961,808, 11/897,177, and
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`10/927,857 (“the ’857 application,” EX1005), which claimed benefit to U.S.
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`provisional application 60/503,137, filed September 15, 2003.
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`The Examiner did not issue anticipation, but 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 ’556 patent (EX1002, ¶¶46-
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`47)—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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`Petition for Inter Partes Review of U.S. Patent No. 8,642,556 B2
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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 [.]
`EX1005-0435 (emphases added).
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`When prosecuting the ’189 application, Allergan acknowledged its prior
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`admission, but alleged new unexpected results evidence justified patentability over
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`Ding ’979. EX1004-0007. As Section XI discusses, it does not.
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`VI. PERSON OF ORDINARY SKILL IN THE ART.
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`For the ’556 patent, the ordinarily-skilled artisan in the relevant field as of
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`September 15, 20032 would have some combination of: (a) knowledge regarding
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`designing and preparing products intended for ocular administration; and/or (b) the
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`ability to understand results and findings presented or published by others in the
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`field. EX1002, ¶54. Typically this person would have an advanced degree, such
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`as an M.D., or a Ph.D. in organic chemistry, pharmaceutical chemistry, medicinal
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`chemistry, pharmaceutics, physical pharmacy, or a related field, or less education
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`but considerable professional experience in these fields. Id.
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`The ordinarily-skilled artisan typically would work as part of a multi-
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`disciplinary team and draw upon not only his or her own skills, but also take
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`2 The earliest provisional date; Petitioner reserves its priority challenge rights in
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`this or other proceedings.
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`advantage of certain specialized skills of others in the team to solve a given
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`problem. EX1002, ¶55. As of September 15, 2003, the state of the art included the
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`teachings provided by the references discussed in each of the unpatentability
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`grounds set forth below. Additionally, a person of ordinary skill in the art would
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`have been aware of other important information and references relating to dry eye,
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`its causes, and useful treatments. Id.
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`VII. STATE OF THE ART AS OF SEPTEMBER 15, 2003.
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`Prior to September 15, 2003, the art recognized inflammation contributed to
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`certain dry eye diseases. E.g., EX1012-0001-02; EX1003, ¶¶49-59. Dry eye
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`disease was defined as, “a deficiency in either the aqueous or mucin components of
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`the precorneal tear film. The most commonly encountered aqueous-deficient dry
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`eye in the United States is keratoconjunctivitis sicca [KCS] ….” EX1013-0004;
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`EX1002, ¶88; EX1003, ¶49.
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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; EX1002, ¶¶89-90; EX1003, ¶¶50, 54-58. Allergan’s experts
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`conceded during prosecution that “[i]t was known in the art ... that cyclosporin
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`could be administered topically locally to the eye to target and treat dry eye by
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`using cyclosporin A’s immunomodulatory properties[.]” EX1004-0218.
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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, 5:57-63; EX1002, ¶¶95-106. 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. The art recognized that higher castor oil
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`concentrations in a vehicle increased ocular residence time. EX1010, 2:61-65
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`(“relief is limited by the retention time of the administered artificial tear solution in
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`the eye.”), 6:1-8:25, Figs. 2-6 (reporting that castor oil vehicles without CsA were
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`effective in treating KCS), Fig. 7 (showing ocular residence times for 2.5%,
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`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, ¶¶89-90; EX1003, ¶¶52-56.
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`Kunert reported that topical 0.05% CsA emulsions in castor oil significantly
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`decreased lymphocyte activation markers, concluding that this treatment “may help
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`to reduce the pathophysiological factors contributing to the development of KCS.”
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`EX1012-0007; EX1003, ¶52. Turner reported that topical 0.05% CsA emulsions
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`in castor oil decreased inflammation markers in dry eye patients. EX1014-0001;
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`EX1003, ¶52. Stevenson concluded from a Phase 2 dose-ranging trial (0.05%-
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`0.4% CsA emulsions) that 0.05% and 0.10% CsA emulsions were “the most
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`appropriate” because “no additional benefits were observed with the higher
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`concentrations.” EX1015-0001; EX1003, ¶53.
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`Clinical trials conducted before September 2003 showed castor oil provided
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`a “large therapeutic effect” to patients suffering from KCS. E.g., EX1014-0005;
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`EX1015-0007; EX1002, ¶¶100-04; EX1003, ¶¶52-53. This “therapeutic effect of
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`the [castor] oil-in-water vehicle” was “expected, as topical application of certain
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`lipid mixtures can accelerate epidermal barrier recovery after defined barrier
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`insults in mice.” EX1014-0005.
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`Thus, the art well knew 0.05% CsA/castor oil formulations were effective to
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`relieve dry eye disease/KCS. EX1002, ¶¶84-99; EX1003, ¶¶49-59.
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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, ¶¶107-19. It explains CsA behaves “as an
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`immunosuppressant” and for “the enhancement or restoring of lacrimal gland
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`tearing.” EX1006, 1:10-16, 37-39. It teaches topical CsA ophthalmic emulsions to
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`treat KCS. Id., 5:9-12. Claims 7-8 specifically recite emulsions containing 0.05-
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`0.40% CsA, 0.625-5.00% castor oil, 1.00% polysorbate 80, 0.05% Pemulen®,
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`2.20% glycerine, sodium hydroxide, and water and having a pH range of 7.2-7.6.
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`EX1006, 4:4-5, 6:27-42; EX1002, ¶¶107-11; EX1003, ¶¶89-94.
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`Ding ’979 discloses four specific castor oil-based vehicles (Examples 2A-
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`D). EX1006, 4:44-54. Ding ’979’s CsA-containing emulsions in Example 1 used
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`the Example 23 vehicles. EX1006, 4:32-54. Example 1’s emulsions use specific
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`CsA and castor oil percentages across the ranges found in Ding ‘979 claims 7 and
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`8 (0.05% - 0.40% CsA and 0.625% - 5.00% castor oil). Id., 4:32-43, 6:27-42;
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`EX1002, ¶¶112-13.
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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, ¶119.
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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
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`when applied eight times a day for seven days, produced at most “slight to mild
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`discomfort” or “slight hyperemia”; and as between the formulation/vehicle ranges
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`tested, there were “no differences in toxicity” and they had comparable ocular
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`bioavailability. EX1006, 5:15-28; 3:7-9 (compositions of the invention are “non-
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`irritating” and “with high comfort level”).
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`3 Example 2C’s vehicle is identical to the challenged claims’ castor oil vehicle.
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`B.
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`Sall (EX1007).
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`Sall is prior art under 35 U.S.C. § 102(b). EX1002, ¶120; EX1003, ¶¶125-
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`29. Sall describes Patent Owner’s multi-center, randomized, double-masked Phase
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`3 clinical trial assessing the safety and efficacy in KCS treatment of twice-daily
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`topical ophthalmic administration of 0.05% or 0.10% CsA in a castor oil emulsion,
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`compared to the emulsion vehicle without CsA. EX1007-0001-02, 0005-06 (figs.
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`1-4). Sall taught the 0.05% CsA emulsion was safe and effective; was at least as
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`effective as the 0.10% CsA emulsion; and resulted in fewer adverse side effects
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`and CsA blood concentrations below detectible levels. EX1007-0001, 0004-07.
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`Sall compared the 0.05% and 0.10% CsA emulsions to the same control vehicle,
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`and reported trough CsA blood concentrations were undetectable in all 0.05% CsA
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`samples; but quantifiable in six 0.1% CsA samples. EX1007-0002, 0006-07;
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`EX1002, ¶¶120-36; EX1003, ¶¶ 131-38, 160.
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`Sall noted existing palliative dry eye
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`treatments, and deemed
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`its
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`formulations “the first therapeutic treatment specifically for dry eye disease and a
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`significant breakthrough in th