IN THE UNITED STATES PATENT AND TRADEMARK OFFICE
`________________________________
`
`BEFORE THE PATENT TRIAL AND APPEAL BOARD
`________________________________
`
`FAMY CARE LIMITED
`Petitioner
`v.
`ALLERGAN, INC.
`Patent Owner
`________________________________
`
`Patent No. 9,248,191 B2
`________________________________
`
`Declaration of Michael A. Lemp, M.D.
`
`
`
`FAMY CARE - EXHIBIT 1003-0001
`
`

`
`TABLE OF CONTENTS
`
`I.
`
`INTRODUCTION. ........................................................................................... 1
`
`II. QUALIFICATIONS. ........................................................................................ 1
`
`III. SCOPE OF ENGAGEMENT. .......................................................................... 3
`
`IV. SUMMARY OF OPINIONS. ........................................................................... 4
`
`V. THE ’191 PATENT OVERVIEW. .................................................................. 7
`
`A.
`
`B.
`
`The ’191 Patent Specification. .............................................................. 7
`
`The ’191 Patent Claims. ........................................................................ 8
`
`1.
`
`2.
`
`Independent Claims. ................................................................... 8
`
`Dependent Claims. ....................................................................11
`
`C.
`
`’191 Patent File History. .....................................................................14
`
`VI. LEGAL STANDARDS. .................................................................................17
`
`A. Obviousness – 35 U.S.C. § 103. ..........................................................17
`
`VII. STATE OF THE ART AS OF SEPTEMBER 15, 2003. ...............................21
`
`A.
`
`B.
`
`CsA Was A Known Treatment for Dry Eye Disease. .........................21
`
`CsA-in-Castor Oil Emulsions Were Known In The Art. ....................28
`
`VIII. DETAILED BASES FOR OPINIONS. .........................................................31
`
`A.
`
`B.
`
`Person Of Ordinary Skill In The Art. ..................................................31
`
`Claim Construction..............................................................................32
`
`1.
`
`2.
`
`“Substantially No Detectable Concentration Of
`Cyclosporin A.” ........................................................................33
`
`“Therapeutically Effective” “Effective Amount,”
`“Lacrimal Gland Tearing,” “Overall Efficacy
`Substantially Equal To,” “As Much Therapeutic Efficacy
`As.”............................................................................................34
`
`ii
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`FAMY CARE - EXHIBIT 1003-0002
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`3.
`
`4.
`
`“Adverse events.”......................................................................36
`
`“Breaks Down.” ........................................................................37
`
`C.
`
`Comparison Of The Claims Of The ’191 Patent To The Prior
`Art. .......................................................................................................38
`
`1.
`
`Ground 1: Obviousness In View Of Sall And Ding ’979. .......38
`
`a.
`
`Sall and Ding ’979 Teach an Emulsion with 0.05%
`CsA and 1.25% Castor Oil. ............................................40
`
`i.
`
`ii.
`
`0.05% CsA ............................................................46
`
`1.25% Castor Oil ..................................................49
`
`b.
`
`Twice Daily Administration of the 0.05%
`CsA/1.25% Castor Oil Emulsion Taught by Sall
`and Ding ’979 Renders Claims 1-27 Obvious. ...............52
`
`i.
`
`ii.
`
`Preamble Elements I-III .......................................60
`
`Frequency Elements .............................................61
`
`iii.
`
`Formulation Elements ..........................................62
`
`iv. Dry Eye Efficacy Elements ..................................64
`
`v.
`
`vi.
`
`Comparative Efficacy Elements ...........................65
`
`CsA Blood Level Elements ..................................70
`
`vii. All Performance-Related Elements:
`Inherency ..............................................................74
`
`2.
`
`3.
`
`4.
`
`Ground 2: Obviousness Of Claims 1-16, 20, 22 And 27
`In View Of Sall, Ding ’979, And Acheampong. ......................75
`
`Ground 3: Obviousness Of Claims 17-20 In View Of
`Sall, Ding ’979, And Glonek. ...................................................78
`
`Ground 4: Obviousness Of Claim 20 In View Of Sall,
`Ding ’979, Glonek, And Acheampong. ....................................79
`
`iii
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`FAMY CARE - EXHIBIT 1003-0003
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`D.
`
`Secondary Considerations Of Nonobviousness. .................................80
`
`1.
`
`No Unexpected Results. ............................................................86
`
`a.
`
`b.
`
`c.
`
`d.
`
`Schiffman Exhibit B. ......................................................88
`
`Schiffman Exhibit C/Attar Exhibit B. ............................92
`
`Schiffman Exhibit D. ......................................................95
`
`Schiffman Exhibits E and F/Attar Exhibits D and
`E. ...................................................................................100
`
`IX. CONCLUDING STATEMENTS. ................................................................104
`
`iv
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`FAMY CARE - EXHIBIT 1003-0004
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`
`TABLE OF EXHIBITS
`
`Exhibit Description
`
`1001
`
`1002
`
`1003
`
`1004
`
`1005
`
`1006
`
`1007
`
`1008
`
`1009
`
`1010
`
`1011
`
`U.S. Patent No. 9,248,191 B2 to Acheampong et al., filed March 21,
`2014 (“the ’191 patent”)
`
`Declaration of Peter Kador, Ph.D.
`
`Intentionally Blank
`
`File history of U.S. Patent No. 9,248,191 B2 to Acheampong et al.,
`filed March 21, 2014 (“’191 patent FH”)
`
` to
`File history of U.S. Patent Application No. 10/927,857
`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”)
`
`the
`into
`A. Acheampong et al., Cyclosporine Distribution
`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”)
`
`Intraocular Penetration of Topically Applied
`R. Kaswan,
`Cyclosporine, 20 TRANSPL. PROC. 650 (1988) (“Kaswan”)
`
`v
`
`
`FAMY CARE - EXHIBIT 1003-0005
`
`

`
`1012
`
`1013
`
`1014
`
`1015
`
`1016
`
`1017
`
`1018
`
`1019
`
`1020
`
`1021
`
`1022
`
`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”)
`
`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”)
`
`vi
`
`
`FAMY CARE - EXHIBIT 1003-0006
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`

`
`1023
`
`1024
`
`1025
`
`1026
`
`1027
`
`1028
`
`1029
`
`1030
`
`1031
`
`1032
`
`1033
`
`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”)
`
`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
`
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`vii
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`FAMY CARE - EXHIBIT 1003-0007
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`I, Michael A. Lemp, M.D., hereby declare as follows.
`
`I.
`1.
`
`
`INTRODUCTION.
`
`I, Michael A. Lemp, M.D., submit this Declaration on behalf of Famy
`
`Care Limited (“Petitioner”). I understand that Petitioner is filing a petition with
`
`the Patent Trial and Appeal Board (“PTAB”) of the United States Patent and
`
`Trademark Office (“USPTO”) for inter partes review of U.S. Patent No. 9,248,191
`
`B2 (“the ’191 patent”) (EX1001).
`
`2.
`
`
`This Declaration contains my qualifications; my opinions based on
`
`my expertise and my review of the ’191 patent; the factual basis for those opinions;
`
`and data or other information I considered in forming my opinions. The opinions
`
`and facts set forth in this Declaration are based upon information and my analysis
`
`of the ’191 patent, as well as my knowledge and experience in the area of
`
`ophthalmology and treating patients experiencing ophthalmic or ocular conditions
`
`such as dry eye.
`
`II. QUALIFICATIONS.
`Prior to my retirement from clinical practice, I held positions as
`3.
`
`
`Professor and Chairman of the Department of Ophthalmology. I am currently
`
`clinical professor of ophthalmology at Georgetown University School of Medicine
`
`and George Washington University Schools of Medicine. I have served on the
`
`board of directors for the International Society of Refractive Surgery and the
`
`
`
`1
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`FAMY CARE - EXHIBIT 1003-0008
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`International Eye Foundation, the FDA Ophthalmic Devices advisory panel and
`
`currently as Chief Medical Officer of TearLab Corporation, a manufacturer of
`
`diagnostic devices for dry eye disease (“DED”). I am the author of more than 234
`
`scientific papers and six books, including The Dry Eye (1992) and Clinical
`
`Anatomy of the Eye (second edition 1997). I was the Founding Editor–in-Chief of
`
`“The Ocular Surface,” and currently serve as a scientific reviewer for seven
`
`ophthalmic journals. I also organized and chaired the workshops which led to the
`
`publication of The National Eye Institute’s global guidelines for classification and
`
`diagnosis of dry eye in 1995. I have received a number of national and
`
`international awards, including the 1998 Castroviejo Medal, the highest honor in
`
`the field of corneal research for lifetime achievement.
`
`4.
`
`
`I am a 1962 graduate of the Georgetown University School of
`
`Medicine. I completed residency training in ophthalmology at Georgetown
`
`University and a fellowship in corneal and external disease at the Massachusetts
`
`Eye and Ear Infirmary and the Schepens Eye Research Institute—Harvard
`
`University clinical and research facilities ophthalmic. I returned to Washington in
`
`1970 to found the Cornea Service at Georgetown, which I directed for 13 years. In
`
`1983, I was selected to become the professor, chairman, and director of the Center
`
`for Sight at Georgetown University, a post I held until 1992, when I founded
`
`University Ophthalmic Consultants of Washington with my partners.
`
`
`
`2
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`FAMY CARE - EXHIBIT 1003-0009
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` My major areas of research interest have included dry eye, the ocular 5.
`
`surface, corneal and cataract surgery, contact lenses, and laser and other forms of
`
`refractive correction of vision. I have been a visiting professor and lecturer at over
`
`60 universities and organizations in the U.S. and abroad, and have delivered eight
`
`named lectureships.
`
`6.
`
`
`In my clinical practice I have been a consultant managing referred
`
`cases with dry eye disease and other conditions of the ocular surface with both
`
`medication and surgical treatment.
`
`7.
`
`
`Accordingly, I am an expert in the field of ophthalmology and treating
`
`patients experiencing ophthalmic or ocular conditions such as dry eye. Additional
`
`information concerning my education and experience can be found in my
`
`curriculum vitae, a copy of which is attached (EX1033).
`
`III. SCOPE OF ENGAGEMENT.
`I have been retained by Petitioner as a technical expert to consider the
`8.
`
`
`claims of the ’191 patent in relation to the state of the art as of September 15, 2003.
`
`I have also considered the prosecution history of the ’191 patent, including the
`
`purported objective evidence of non-obviousness alleged in the Declarations of
`
`Drs. Rhett M. Schiffman and Mayssa Attar submitted in related applications. (See,
`
`e.g., ’111 patent FH (EX1024_0246-70 (Schiffman Declaration I), 0272-89 (Attar
`
`Declaration)).
`
`
`
`3
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` My opinions and views set forth in this Declaration are based on my 9.
`
`education and training; my experience as a clinician, educator, researcher, and
`
`consultant to government and industry in the field of ophthalmology and treating
`
`patients experiencing ophthalmic or ocular conditions for over 50 years; and on the
`
`materials I have reviewed for this case.
`
`
`
` My time spent on this project is compensated at $500 per hour. My 10.
`
`compensation does not depend in any way on the outcome of Petitioner’s petition
`
`for inter partes review of the ’191 patent. Furthermore, I have no financial interest
`
`in this matter.
`
`IV. SUMMARY OF OPINIONS.
` First, it is my opinion that claims 1-27 of the ’191 patent are obvious 11.
`
`
`in view of, at least, Ding ’979 and Sall. More specifically, Ding ’979 discloses and
`
`teaches each and every element of the formulations recited in the methods claimed
`
`by the ’191 patent—i.e., emulsions with 0.05% cyclosporin A (“CsA”), 1.25%
`
`castor oil, 1.00% polysorbate 80, 0.05% Pemulen® (an acrylate/C10-30 alkyl
`
`acrylate cross-polymer), 2.20% glycerine (a
`
`tonicity agent or demulcent
`
`component), sodium hydroxide (a buffer), water, and having a pH in the range of
`
`7.2 to 7.6—and that these emulsions are safe, efficacious, stable, and comfortable
`
`
`
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`for patients.1 Sall teaches that both 0.05% and 0.10% CsA emulsions in castor oil
`
`are “effective” or “therapeutically effective” in increasing tear production and
`
`treating dry eye disease/KCS when administered twice daily. A person of ordinary
`
`skill in the art would have been motivated from the teachings of Sall to administer
`
`the 0.05% CsA / 1.25% castor oil emulsions taught by Ding ’979 to patients having
`
`dry eye disease/KCS twice daily, and this combination renders the methods recited
`
`by claims 1-27 of the ’191 patent obvious.
`
`12.
`
`
`In addition, the obviousness of the inherent properties recited in the
`
`methods claimed by the ’191 patent are further demonstrated by Acheampong and
`
`Glonek. Acheampong (like Sall) shows that the CsA blood level limitations of the
`
`claims are obvious because it was known in the art at the time of the invention that
`
`0.05% CsA emulsions will produce no detectable concentrations of CsA in the
`
`blood after administration. Glonek shows that the limitations requiring the claimed
`
`emulsion to break down faster and reduce blurring in comparison to a second
`
`emulsion with half as much castor oil are obvious because it was known at the time
`
`of the invention that a less stable oil-in-water emulsion will break down faster and
`
`reduce vision distortion in comparison to a more stable emulsion.
`
`
`
` Second, in my opinion the data presented in Schiffman Declaration I 13.
`
`and the Attar Declaration do not support the conclusion that the ophthalmic
`
`1 Percentages refer to percent by weight unless otherwise noted.
`
`
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`emulsions claimed by the ’191 patent provided unexpectedly superior results over
`
`the closest prior art. Among other reasons, the data relied upon by Drs. Schiffman
`
`and Attar lack the necessary parameters (e.g., raw data values and error rates) to
`
`support a scientific conclusion that the claimed emulsions achieved any superior
`
`results in comparison to the closest prior art that would have been unexpected at
`
`the time of the invention.
`
`
`
` Third, in my opinion the validity of the ’191 patent is not supported 14.
`
`by commercial success and industry praise for RESTASIS™. Ding ’979 taught
`
`and claimed the 0.05% CsA / 1.25% castor oil emulsion that is the subject of the
`
`’191 patent years before the ’191 patent’s priority application was ever filed. The
`
`prior art Ding ’979 patent was listed in the FDA’s Orange Book by Allergan as
`
`covering RESTASIS™. (EX1026; EX1027). Any evidence of commercial
`
`success or industry praise for RESTASIS™ should be attributed to the prior art
`
`Ding ’979 patent, because this evidence lacks a nexus to any novel feature of the
`
`’191 patent claims.
`
`
`
` Fourth, in my opinion, the validity of the ’191 patent is not supported 15.
`
`by long-felt need or failure of others. Ding ’979 satisfied any purported long-felt
`
`need for an emulsion comprising 0.05% CsA, 1.25% castor oil, 1.00% polysorbate,
`
`0.05% Pemulen®, 2.20% glycerine, sodium hydroxide, and water with a pH
`
`between 7.2-7.6 long before the ’191 patent was filed. Moreover, the ’191 patent
`
`
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`concedes that the “compositions may be produced using conventional and well
`
`known methods useful in producing ophthalmic products including oil-in-water
`
`emulsions.” (EX1001, 13:29-31). In my opinion, this admission shows that
`
`Allergan’s purported evidence of other failures is irrelevant and not credible.
`
`V. THE ’191 PATENT OVERVIEW.
`A. THE ’191 PATENT SPECIFICATION.
`
`
` The ’191 patent cover page states that the ’191 patent issued February 16.
`
`2, 2016 to Applicant and Assignee Allergan, Inc., and is entitled “Methods of
`
`Providing Therapeutic Effects using Cyclosporin Components.” (EX1001-0001).
`
`The named inventors are Andrew Acheampong, Diane Tang-Liu, James Chang,
`
`and David Power. (Id.)
`
`
`
` The ’191 patent cover page further states that the application for the 17.
`
`’191 patent—U.S. Patent Application No. 14/222,478 (“the ’478 application”)—
`
`was filed on March 21, 2014, and asserts priority through a series of continuations
`
`to U.S. Patent Application No. 10/927,857 (“the ’857 application”) (see EX1005),
`
`and to U.S. Provisional Patent Application No. 60/503,137, filed on September 15,
`
`2003. (EX1001-0001).
`
`18.
`
`
`I understand that the earliest claimed priority date—September 15,
`
`2003—is a key date relevant to my analysis.
`
`
`
` The ’191 patent is generally directed to methods of treating an eye of 19.
`
`
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`a human or animal with a composition in the form of an emulsion that includes
`
`CsA. (EX1001, Abstract). The ’191 patent is also directed to methods of
`
`providing desired therapeutic effects to humans or animals using compositions
`
`containing CsA. (Id. at 1:20-22).
`
`
`
` The ’191 patent specification acknowledges that the use of CsA and 20.
`
`CsA derivatives to treat ophthalmic conditions was previously known in the art.
`
`(EX1001, 1:28-59). The ’191 patent specification further acknowledges that CsA
`
`oil-in-water emulsions had previously been clinically tested, including emulsions
`
`with castor oil. (Id. at 1:55-59).
`
`THE ’191 PATENT CLAIMS.
`Independent Claims.
`
`B.
`1.
`
`
` The ’191 patent recites 27 claims, including independent claims 1, 13, 21.
`
`17 and 21:
`
`1. A method of treating dry eye disease, the method
`comprising topically administering to a human eye in need
`thereof a first topical ophthalmic emulsion at a frequency of
`twice a day, wherein the first topical ophthalmic emulsion
`comprises cyclosporin A in an amount of about 0.05% by
`weight, polysorbate 80, acrylate/C10-30 alkyl acrylate cross-
`polymer, water, and castor oil in an amount of about 1.25% by
`weight; and
`wherein the method is therapeutically effective in treating
`dry eye disease;
`
`
`
`8
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`FAMY CARE - EXHIBIT 1003-0015
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`
`efficacy
`the method provides overall
`wherein
`substantially equal to administration of a second topical
`ophthalmic emulsion to a human eye in need thereof at a
`frequency of twice a day, the second emulsion comprising
`cyclosporin A in an amount of about 0.1% by weight and castor
`oil in an amount of about 1.25% by weight; and
`wherein the method results in substantially no detectable
`concentration of cyclosporin A in the blood of the human.
`
`
`. . .
`13. A method of enhancing tearing in a human eye, the
`method comprising topically administering to a human eye in
`need thereof a first topical ophthalmic emulsion at a frequency
`of twice a day, wherein the first topical ophthalmic emulsion
`comprises cyclosporin A in an amount of about 0.05% by
`weight, polysorbate 80, acrylate/C10-30 alkyl acrylate cross-
`polymer, water, and castor oil in an amount of about 1.25% by
`weight;
`wherein the method is therapeutically effective in treating
`dry eye disease and wherein the method achieves at least as
`much therapeutic efficacy as administration of a second topical
`ophthalmic emulsion to a human eye in need thereof at a
`frequency of twice a day, the second emulsion comprising
`cyclosporin A in an amount of about 0.1% by weight and castor
`oil in an amount of about 1.25% by weight; and
`wherein the method results in a concentration of
`cyclosporin A in the blood of the human of less than 0.1 ng/ml.
`
`
`
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`. . .
`17. A method of treating dry eye disease, the method
`comprising topically administering to a human eye in need
`thereof a first topical ophthalmic emulsion at a frequency of
`twice a day, wherein the first topical ophthalmic emulsion
`comprises cyclosporin A in an amount of about 0.05% by
`weight, polysorbate 80, acrylate/C10-30 alkyl acrylate cross-
`polymer, water, and castor oil in an amount of about 1.25% by
`weight; and
`wherein the first topical ophthalmic emulsion breaks
`down more quickly in the human eye, once administered to the
`human eye, thereby reducing vision distortion in the human eye
`as compared to a second topical ophthalmic emulsion that
`contains only about 50% as much castor oil as the first topical
`ophthalmic emulsion.
`
`. . .
`21. A method of restoring tearing, the method comprising
`topically administering to a human eye in need thereof a first
`topical ophthalmic emulsion at a frequency of twice a day,
`wherein the first topical ophthalmic emulsion comprises
`cyclosporin A in an amount of about 0.05% by weight,
`polysorbate 80, acrylate/C10-30 alkyl acrylate cross-polymer,
`water, and castor oil in an amount of about 1.25% by weight;
`wherein the method demonstrates a reduction in adverse
`events in the human, compared to administration of a second
`
`
`
`10
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`FAMY CARE - EXHIBIT 1003-0017
`
`

`
`topical ophthalmic emulsion to a human eye in need thereof at a
`frequency of twice a day, the second topical ophthalmic
`emulsion comprising cyclosporin A in an amount of about 0.1%
`by weight and castor oil in an amount of about 1.25% by
`weight; and
`least as much
`the method achieves at
` wherein
`therapeutic efficacy as administration of the second topical
`ophthalmic emulsion to a human in need thereof at a frequency
`of twice a day.
`
`
`
`Dependent Claims.
`
`2.
`
`
` Claims 2-3, depending from claim 1, recite that the emulsion further 22.
`
`comprises a tonicity agent or demulcent component (claim 2), and that the tonicity
`
`agent or demulcent component is glycerine (claim 3).
`
`
`
` Claims 4-5, depending from claim 1, recite that the emulsion further 23.
`
`comprises a buffer (claim 4), and that the buffer is sodium hydroxide (claim 5).
`
`
`
` Claims 6-9, depending from claim 1, recite that: (A) the emulsion 24.
`
`further comprises glycerine and a buffer (claim 6); (B) the emulsion comprises
`
`polysorbate 80 in an amount of about 1.0% by weight (claim 7); (C) the emulsion
`
`comprises acrylate/C10-30 alkyl acrylate cross-polymer in an amount of about
`
`0.05% by weight (claim 8); and (D) the emulsion comprises glycerine in an
`
`amount of about 2.2% by weight, and a buffer (claim 9).
`
`
`
` Claim 10 depends from claim 9 and recites that the buffer is sodium 25.
`
`
`
`11
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`FAMY CARE - EXHIBIT 1003-0018
`
`

`
`hydroxide.
`
`
`
` Claim 11 depends from claim 6 and recites that the emulsion has a pH 26.
`
`in the range of about 7.2 to about 7.6.
`
`
`
` Claim 12 depends from independent claim 1 and recites that no 27.
`
`detectable concentration of CsA in the blood means the concentration is less than
`
`about 0.1 ng/ml.
`
`
`
` Claim 14 depends from independent claim 13 and recites that the 28.
`
`emulsion comprises acrylate/C10-30 alkyl acrylate cross-polymer in an amount of
`
`about 0.05% by weight, polysorbate 80 in an amount of about 1.0% by weight,
`
`glycerine in an amount of about 2.2% by weight, and a buffer.
`
`
`
` Claim 15 depends from claim 14 and recites that the emulsion has a 29.
`
`pH in the range of about 7.2 to about 7.6.
`
`
`
` Claim 16 depends from independent claim 13 and requires that the 30.
`
`method is effective in enhancing lacrimal gland tearing.
`
`
`
` Claim 18 depends from independent claim 17 and recites that the 31.
`
`emulsion comprises acrylate/C10-30 alkyl acrylate cross-polymer in an amount of
`
`about 0.05% by weight, polysorbate 80 in an amount of about 1.0% by weight,
`
`glycerine in an amount of about 2.2% by weight, and a buffer.
`
`
`
` Claim 19 depends from claim 18 and recites that the emulsion has a 32.
`
`pH in the range of about 7.2 to about 7.6.
`
`
`
`12
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`FAMY CARE - EXHIBIT 1003-0019
`
`

`
`
`
` Claim 20 depends from claim 19 and recites that the method results in 33.
`
`a concentration of CsA in the blood of less than about 0.1 ng/ml.
`
`
`
` Claim 22 depends from independent claim 21 and recites that the 34.
`
`method results in a concentration of CsA in the blood of less than about 0.1 ng/ml.
`
`
`
` Claim 23 depends from independent claim 21 and specifies that the 35.
`
`adverse events are selected from the group consisting of visual distortion and eye
`
`irritation.
`
`
`
` Claim 24 depends from independent claim 21 and recites that the 36.
`
`emulsion comprises acrylate/C10-30 alkyl acrylate cross-polymer in an amount of
`
`about 0.05% by weight, polysorbate 80 in an amount of about 1.0% by weight,
`
`glycerine in an amount of about 2.2% by weight, and a buffer.
`
`
`
` Claim 25 depends from claim 24 and recites that the emulsion has a 37.
`
`pH in the range of about 7.2 to about 7.6.
`
`
`
` Claim 26 depends from claim 21 and recites that the method is 38.
`
`effective in restoring lacrimal gland tearing.
`
`
`
` Claim 27 depends from claim 21 and recites that the adverse events 39.
`
`are selected from the group consisting of visual distortion and eye irritation, and
`
`that the method results in a concentration of CsA in the blood of less than about 0.1
`
`ng/ml.
`
`
`
`13
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`FAMY CARE - EXHIBIT 1003-0020
`
`

`
`’191 PATENT FILE HISTORY.
`
`C.
`
`
` As noted above, the ’191 patent asserts to be a continuation of the 40.
`
`’857 application. (EX1001-0001). During prosecution of the ’857 application, the
`
`Applicants expressly admitted that the emulsion—referred to as Composition II
`
`and which remains the emulsion recited in the claims of the ’191 patent—was
`
`squarely within the teachings of U.S. Patent No. 5,474,979 (filed May 17, 1994) to
`
`Ding et al. (“Ding ’979”) (EX1006). The Applicants stated:
`
`The applicants concede that it would have been obvious to modify
`examples 1A-1E of the Ding [’979] reference to arrive at
`Composition II of the present application. The differences are
`insignificant. One need only use the cyclosporin concentration of
`Example 1E (0.05%), the castor oil concentration of Example 1D
`(1.250%), and the remaining ingredients of those examples. As the
`examiner correctly observes, one of ordinary skill in the art “would
`readily envisage” such a composition, especially in view of
`Example 1B: having selected 0.05% as the concentration of
`cyclosporin, Example 1B (wherein the ratio of cyclosporin to castor
`oil is 0.04) teaches that the concentration of castor oil should be
`1.250% (0.05% / 1.250% = 0.04). The applicants concede that in
`making this selection (0.05% cyclosporin and 1.250% castor oil)
`there would have been a reasonable expectation of success; the
`differences between Examples 1A-1E and Composition II are too
`small to believe otherwise. The formulation of Composition II is
`squarely within the teaching of the Ding [’979] reference, and the
`
`
`
`14
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`FAMY CARE - EXHIBIT 1003-0021
`
`

`
`Office should disregard any statements by the applicants suggesting
`otherwise[.]
`
`(’857 application FH (EX1005-0435) (emphasis added)). As discussed below, I
`
`agree with these statements.
`
`41.
`
`
` I have reviewed the ’857 application concurrently with the ’191
`
`patent, and find that the ’857 application Composition II is indistinguishable from
`
`the emulsion claimed in the ’191 patent. In fact, the Applicants submitted a table
`
`(below) during prosecution of the ’857 application comparing the ’857 application
`
`Composition II with Ding ’979. The chart below from the Declaration of Dr.
`
`Kador includes the emulsion claimed in the ’191 patent for comparison.
`
`
`
`’191 Patent
`Composition
`0.05%
`1.25%
`1.00%
`0.05%
`2.20%
`qs
`qs
`7.2-7.6
`0.04
`
`
`
`
`
`(EX1002, ¶58). The ’857 application was ultimately abandoned. (EX1001-0001).
`
`
`
` The Applicants acknowledged 42.
`
`their prior admissions during
`
`prosecution of the ’191 patent, and alleged that evidence supporting the
`
`
`
`15
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`FAMY CARE - EXHIBIT 1003-0022
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`

`
`patentability of the claims had been collected “[s]ince these comments have been
`
`filed.” (EX1004-0803). In remarks accompanying the Notice of Allowance
`
`(EX1004-0012), the Examiner relied on declarations submitted by Drs. Schiffman
`
`and Attar during the prosecution of the parent U.S. Patent Application No.
`
`13,961,828, which issued as U.S. Patent No. 8,685,930 (“the ’930 patent”), to
`
`overcome a potential obviousness rejection in view of Ding ’979. (Id. at 0018-22,
`
`0116).
`
`
`
` The Examiner stated that “the claimed formulations, including 0.05% 43.
`
`by weight cyclosporin A and 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
`
`keratoconjunctivitis sicca (“KCS”). (Id. at 0022).
`
`
`
` During prosecution of the ’930 patent, Applicants specifically argued 44.
`
`that the Schiffman Declaration I and the Attar Declaration show that “the claimed
`
`formulations provided unexpected results compared to the prior art with regards to
`
`two key objective testing parameters for dry eye or keratoconjunctivitis sicca:
`
`Schirmer Tear Testing and decrease in corneal staining, and with regards to
`
`reduction in blurred vision and decreased use of artificial tears.” (EX1023-0192).
`
`
`
` The ’930 patent Notice of Allowance issued on January 24, 2014. 45.
`
`(EX1023-0268).
`
` Relying on the Schiffman Declaration I and the Attar
`
`
`
`16
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`FAMY CARE - EXHIBIT 1003-0023
`
`

`
`Declaration, the Examiner concluded that, “the claimed formulations, including
`
`0.05% by weight cyclosporin A and 1.25% by weight castor oil, demonstrate
`
`surprising and unexpected results” and “[t]hus, the obviousness rejection in view
`
`of Ding et al. [Ding ’979] is rendered moot.” (Id. at 0276-77).
`
`
`
` As discussed in Section VIII.D below, I disagree with the opinions of 46.
`
`Dr. Schiffman and Dr. Attar that the results in the submitted