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. 8,648,048 B2
`________________________________
`
`Declaration of Michael A. Lemp, M.D.
`
`FAMY CARE - EXHIBIT 1003-0001
`
`

`
`TABLE OF CONTENTS
`
`I.
`
`II.
`
`INTRODUCTION. .......................................................................................... 1
`
`QUALIFICATIONS. ....................................................................................... 1
`
`III.
`
`SCOPE OF ENGAGEMENT. ......................................................................... 3
`
`IV. SUMMARY OF OPINIONS. .......................................................................... 4
`
`V.
`
`THE ’048 PATENT OVERVIEW. ................................................................. 7
`
`A.
`
`B.
`
`The ’048 Patent Specification. .............................................................. 7
`
`The ’048 Patent Claims. ........................................................................ 8
`
`1.
`
`2.
`
`3.
`
`4.
`
`Independent Claims. ................................................................... 8
`
`“Formulation” Dependent Claims. ...........................................10
`
`“Efficacy” and “Comparative Efficacy” Dependent
`Claims. ......................................................................................11
`
`“Substantially No Detectable Concentration of CsA”
`Dependent Claims. ....................................................................11
`
`C.
`
`’048 Patent File History. .....................................................................12
`
`VI. LEGAL STANDARDS. ................................................................................15
`
`A. Obviousness – 35 U.S.C. § 103. ..........................................................15
`
`VII. STATE OF THE ART AS OF SEPTEMBER 15, 2003. ..............................20
`
`A.
`
`B.
`
`CsA Was A Known Treatment for Dry Eye Disease. .........................20
`
`CsA-in-Castor Oil Emulsions Were Known In The Art. ....................26
`
`VIII. DETAILED BASES FOR OPINIONS. ........................................................30
`
`A.
`
`B.
`
`Person Of Ordinary Skill In The Art. ..................................................30
`
`Claim Construction..............................................................................31
`
`ii
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`FAMY CARE - EXHIBIT 1003-0002
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`
`1.
`
`2.
`
`3.
`
`4.
`
`“Substantially No Detectable Concentration Of [The]
`Cyclosporin A.” ........................................................................31
`
`“Effective,” “Effective Amount,” “Lacrimal Gland
`Tearing,” “Overall Efficacy Substantially Equal To,” “As
`Much Therapeutic Efficacy As.” ..............................................32
`
`“Adverse Events” and “Side Effects.” ......................................34
`
`“Breaks Down.” ........................................................................36
`
`C.
`
`Comparison of the Claims of the ’048 Patent to the Prior Art. ...........37
`
`1.
`
`Ground 1: Obviousness In View Of Sall And Ding ’979. .......37
`
`a.
`
`Sall and Ding ’979 Teach an Emulsion with 0.05%
`CsA and 1.25% Castor Oil. ............................................38
`
`i.
`
`ii.
`
`0.05% CsA ............................................................44
`
`1.25% Castor Oil ..................................................47
`
`b.
`
`Twice Daily Administration of the 0.05%
`CsA/1.25% Castor Oil Emulsion Taught by Sall
`and Ding ’979 Renders Claims 1-23 Obvious. ...............51
`
`i.
`
`ii.
`
`Preamble Elements. ..............................................59
`
`Frequency Elements. ............................................60
`
`iii.
`
`Formulation Elements. .........................................61
`
`iv. Dry Eye Efficacy Elements. .................................62
`
`v.
`
`vi.
`
`Comparative Efficacy Elements. ..........................63
`
`CsA Blood Level Elements. .................................68
`
`vii. All Performance-Related Elements:
`Inherency ..............................................................73
`
`2.
`
`Ground 2: Obviousness Of Claims 11 And 21 In View
`Of Sall, Ding ’979, And Acheampong. ....................................73
`
`iii
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`FAMY CARE - EXHIBIT 1003-0003
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`
`3.
`
`Ground 3: Obviousness Of Claim 15 In View Of Sall,
`Ding ’979, And Glonek. ............................................................76
`
`D.
`
`Secondary Considerations of Nonobviousness. ..................................78
`
`1.
`
`No Unexpected Results. ............................................................84
`
`a.
`
`b.
`
`c.
`
`d.
`
`Schiffman Exhibit B. ......................................................86
`
`Schiffman Exhibit C/Attar Exhibit B. ............................90
`
`Schiffman Exhibit D. ......................................................93
`
`Schiffman Exhibits E and F/Attar Exhibits D and
`E. .....................................................................................98
`
`IX. CONCLUDING STATEMENTS ................................................................102
`
`iv
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`FAMY CARE - EXHIBIT 1003-0004
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`
`TABLE OF EXHIBITS
`
`Exhibit Description
`
`1001 U.S. Patent No. 8,648,048 B2 to Acheampong et al., filed August 14,
`2013 (“the ’048 patent”)
`
`1002 Declaration of Peter Kador, Ph.D.
`
`1003
`
`1004
`
`1005
`
`Intentionally Blank
`
`File history of U.S. Patent No. 8,648,048 to Acheampong et al., filed
`August 14, 2013 (“’048 patent FH”)
`
` to
`File history of U.S. Patent Application No. 10/927,857
`Acheampong et al., filed August 27, 2004 (“’857 application FH”)
`
`1006 U.S. Patent No. 5,474,979 to Ding et al., filed May 17, 1994 (“Ding
`’979”)
`
`1007 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
`1008 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”)
`
`1009 U.S. Patent No. 5,578,586 to Glonek et al., filed February 4, 1994
`(“Glonek”)
`
`1010 U.S. Patent No. 5,981,607 to Ding et al., filed January 20, 1998
`(“Ding ’607”)
`
`1011
`
`Intraocular Penetration of Topically Applied
`R. Kaswan,
`Cyclosporine, 20 TRANSPL. PROC. 650 (1988) (“Kaswan”)
`
`1012 K. Kunert et al., Analysis of Topical Cyclosporine Treatment of
`Patients with Dry Eye Syndrome, 118 ARCH OPHTHALMOL 1489
`(2000) (“Kunert”)
`
`v
`
`
`FAMY CARE - EXHIBIT 1003-0005
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`

`
`1013
`
`PHYSICIANS’ DESK REFERENCE FOR OPHTHALMOLOGY 13-18 (Medical
`Economics Co., 27th ed. 1999) (“Ophthalmic PDR”)
`
`1014 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”)
`
`1015 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”)
`
`1016 G. Hecht, Ophthalmic Preparations, in REMINGTON: THE SCIENCE
`AND PRACTICE OF PHARMACY 821 (20th ed. 2000) (“Remington”)
`
`1017
`
`E. Goto et al., Low-Concentration Homogenized Castor Oil Eye
`Drops for Noninflamed Obstructive Meibomian Gland Dysfunction,
`109 OPHTHALMOLOGY 2030 (2002) (“Goto”)
`
`1018 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”)
`
`1019
`
`C. Vieira et al., Effect of Ricinoleic Acid in Acute and Subchronic
`Experimental Models of Inflammation, 9 MEDIATORS INFLAMMATION
`223 (2000) (“Vieira”)
`
`1020
`
`R. Murphy, The Once and Future Treatment of Dry Eye, REVIEW OF
`OPTOMETRY ONLINE (Feb. 15, 2000) (“Murphy”)
`
`1021 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”)
`
`1022
`
`STEDMAN’S MEDICAL DICTIONARY 585, 944, 958, 1300, 1548, 1634,
`1788, 1821 (27th ed. 2000) (“Stedman’s”)
`
`1023 Allergan, Inc.’s Complaint for Patent Infringement, Allergan, Inc. v.
`Famy Care Ltd., No. 2:16-cv-401 (E.D. Tex. Apr. 12, 2016)
`
`vi
`
`
`FAMY CARE - EXHIBIT 1003-0006
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`

`
`1024 APPROVED DRUG PRODUCTS WITH THERAPEUTIC EQUIVALENCE
`EVALUATIONS (34th ed. 2014) (Excerpts)
`
`1025
`
`1026
`
`1027
`
`Intentionally Blank
`
`7/30/2003 Allergan Correspondence to FDA regarding RESTASIS™
`
`RESTASIS Orange Book Listing (dated Jan. 12, 2015)
`
`1028 U.S. Patent No. 6,635,654 B1 to Chang et al., filed January 9, 2003
`(“the ’654 patent”)
`
`1029 U.S. Patent No. 6,984,628 B2 to Bakhit et al., filed July 15, 2003
`(“the ’628 patent”)
`
`1030
`
`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)
`
`1032
`
`1033
`
`Curriculum Vitae of Dr. Peter Kador
`
`Curriculum Vitae of Dr. Michael A. Lemp
`
`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. 8,648,048
`
`B2 (“the ’048 patent”) (EX1001).
`
`2.
`
`
`This Declaration contains my qualifications; my opinions based on
`
`my expertise and my review of the ’048 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 ’048 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. 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 ’048 patent in relation to the state of the art as of September 15, 2003.
`
`I have also considered the prosecution history of the ’048 patent, and the purported
`
`objective evidence of non-obviousness alleged in the Declarations of Drs. Rhett M.
`
`Schiffman and Mayssa Attar. (EX1004-0260-84 (“Schiffman Declaration I”),
`
`0286-303 (“Attar Declaration”), 0315-428 (“Schiffman Declaration II”)).
`
`
`
` My opinions and views set forth in this Declaration are based on my 9.
`
`
`
`3
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`FAMY CARE - EXHIBIT 1003-0010
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`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 ’048 patent. Furthermore, I have no financial interest
`
`in this matter.
`
`IV. SUMMARY OF OPINIONS.
` First, it is my opinion that claims 1-23 of the ’048 patent are obvious 11.
`
`
`in view of, at least, Ding ’979 and Sall. More specifically, Ding ’979 teaches each
`
`and every element of the formulations recited in the methods claimed by the ’048
`
`patent—i.e., emulsions with 0.05% cyclosporin A (“CsA”), 1.25% castor oil, 1.0%
`
`polysorbate 80, 0.05% Pemulen® (an acrylate/C10-30 alkyl acrylate cross-
`
`polymer), 2.2% 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 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
`
`
`1 Percentages refer to percent by weight unless otherwise indicated.
`
`
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`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 1-23 of the ’048 patent obvious.
`
`12.
`
`
`In addition, the obviousness of the inherent properties recited in the
`
`methods claimed by the ’048 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
`
`emulsions claimed by the ’048 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
`
`
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`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 ’048 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
`
`’048 patent years before the ’048 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 ’048 patent
`
`claims.
`
`
`
` Fourth, in my opinion, the validity of the ’048 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 ’048 patent was filed. Moreover, the ’048 patent concedes
`
`that the “compositions may be produced using conventional and well known
`
`methods useful
`
`in producing ophthalmic products
`
`including oil-in-water
`
`emulsions.” (EX1001, 13:20-22). In my opinion, this admission shows that
`
`
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`Allergan’s purported evidence of other failures is irrelevant and not credible.
`
`V. THE ’048 PATENT OVERVIEW.
`A. THE ’048 PATENT SPECIFICATION.
`
`
` The ’048 patent cover page states that the ’048 patent issued February 16.
`
`11, 2014 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 D. Tang-Liu, James N.
`
`Chang, and David F. Power. (Id.)
`
`
`
` The ’048 patent cover page further states that the application for the 17.
`
`’048 patent—U.S. Patent Application No. 13/967,168 (“the ’168 application”)—
`
`was filed on August 14, 2013, and asserts priority through a series of continuation
`
`applications 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 ’048 patent is generally directed to methods of treating an eye of 19.
`
`a human or animal with a composition in the form of an emulsion that includes
`
`CsA. (EX1001, Abstract). The ’048 patent is also directed to methods of
`
`providing desired therapeutic effects to humans or animals using compositions
`
`
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`7
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`containing CsA. (Id. at 1:18-20).
`
`
`
` The ’048 patent specification acknowledges that the use of CsA and 20.
`
`CsA derivatives to treat ophthalmic conditions was previously known in the art.
`
`(EX1001, 1:26-57). The ’048 patent specification further acknowledges that CsA
`
`oil-in-water emulsions had previously been clinically tested, including emulsions
`
`with castor oil. (Id. at 1:53-57).
`
`THE ’048 PATENT CLAIMS.
`Independent Claims.
`
`B.
`1.
`
`
` The ’048 patent recites 23 claims, including independent claims 1, 18, 21.
`
`and 22:
`
`1. A method of increasing tear production in the eye of a
`human, the method comprising topically administering to the
`eye of the human in need thereof an emulsion at a frequency of
`twice a day, wherein the 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 topical ophthalmic emulsion is effective in
`increasing tear production.
`
`. . .
`
`18. A method of treating keratoconjunctivitis sicca, the
`method comprising the step of topically administering to an eye
`of a human in need thereof an emulsion at a frequency of twice
`
`
`
`8
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`FAMY CARE - EXHIBIT 1003-0015
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`
`a day, the emulsion comprising:
`cyclosporin A in an amount of about 0.05% by weight;
`castor oil in an amount of about 1.25% by weight;
`polysorbate 80 in an amount of about 1.0% by weight;
`acrylate/C10-30 alkyl acrylate cross-polymer
`in an
`amount of about 0.05% by weight;
`a tonicity component or a demulcent component in an
`amount of about 2.2% by weight;
`a buffer; and
`water;
`treating
`in
`effective
`is
`emulsion
`the
`wherein
`keratoconjunctivitis sicca and wherein the topical ophthalmic
`emulsion has a pH in the range of about 7.2 to about 7.6.
`. . .
`
`22. A method comprising:
`administering an emulsion topically to the eye of a
`human having keratoconjunctivitis sicca at a frequency of twice
`a day, wherein the emulsion comprises:
`cyclosporin A in an amount of about 0.05% by weight;
`castor oil in an amount of about 1.25% by weight;
`polysorbate 80 in an amount of about 1.0% by weight;
`acrylate/C10-30 alkyl acrylate cross-polymer
`in an
`amount of about 0.05% by weight;
`glycerine in an amount of about 2.2% by weight;
`sodium hydroxide; and
`water; and
`
`
`
`9
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`FAMY CARE - EXHIBIT 1003-0016
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`

`
`wherein the emulsion is effective in increasing tear
`production in the human having keratoconjunctivitis sicca.
`
`
`
`“Formulation” 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 directly from claim 9 (and indirectly from claim 1) 25.
`
`and recites that the buffer is sodium hydroxide.
`
`
`
` Claim 12 depends directly from claim 6 (and indirectly from claim 1) 26.
`
`and recites that the emulsion has a pH in the range of about 7.2 to about 7.6.
`
`
`
` Claims 19-20 depend from independent claim 18 and require that the 27.
`
`buffer is sodium hydroxide (claim 19), and that the tonicity component or the
`
`
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`10
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`demulcent component is glycerine (claim 20).
`
`
`
` Claim 23 depends from independent claim 22 and requires that the 28.
`
`emulsion has a pH in the range of about 7.2 to about 7.6.
`
`“Efficacy” and “Comparative Efficacy” Dependent Claims.
`
`3.
`
`
` Claim 13 depends from claim 1 and requires that the emulsion is as 29.
`
`substantially therapeutically effective as a second emulsion comprising about 0.1%
`
`CsA and 1.25% castor oil.
`
`
`
` Claim 14 depends from claim 1 and requires that the emulsion 30.
`
`achieves at least as much therapeutic effectiveness as a second emulsion
`
`comprising about 0.1% CsA and 1.25% castor oil.
`
`
`
` Claim 15 depends from claim 1 and requires that the emulsion breaks 31.
`
`down more quickly in the eye after administration than a second emulsion that
`
`contains only 50% as much castor oil.
`
`
`
` Claim 16 depends from claim 1 and requires that the emulsion 32.
`
`demonstrates a reduction in adverse events in comparison to a second emulsion
`
`comprising about 0.1% CsA and 1.25% castor oil. Claim 17 depends from claim
`
`16 and restricts the adverse events to side effects.
`
`4.
`
`“Substantially No Detectable Concentration of CsA”
`Dependent Claims.
`
`
`
` Claims 11 (depending from claim 1) and 21 (depending from claim 33.
`
`18) recite that when the emulsion is administered to an eye of a human in an
`
`
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`11
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`effective amount in increasing tear production/treating dry eye “the blood of the
`
`human has substantially no detectable concentration of [the] cyclosporin A.”
`
`’048 PATENT FILE HISTORY.
`
`C.
`
`
` As noted above, the ‘048 patent asserts to be a continuation of the 34.
`
`’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 ’048 patent—was
`
`squarely within the teachings of U.S. Patent No. 5,474,979 to Ding et al., filed May
`
`17, 1994 (“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
`
`
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`small to believe otherwise. The formulation of Composition II is
`squarely within the teaching of the Ding [’979] reference, and the
`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.
`
`35.
`
`
`I have reviewed the ’857 application concurrently with the ’048
`
`patent, and find that the ’857 application Composition II is indistinguishable from
`
`the emulsion claimed in the ’048 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 ’048 patent for comparison.
`
`
`
`
`
`‘048 patent
`Composition
`0.05%
`1.25%
`1.00%
`0.05%
`2.20%
`qs
`qs
`7.2-7.6
`
`0.04
`
`
`
`
`
`
`(EX1002, ¶53). The ’857 application was ultimately abandoned. (EX1001-0001).
`
`
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`
`
` Applicants acknowledged their prior admissions during prosecution of 36.
`
`the ‘048 patent, and alleged that evidence supporting the patentability of the claims
`
`had been collected “[s]ince these comments have been filed.” (EX1004-0007).
`
`The pending claims were rejected by the Examiner under 35 U.S.C. § 103 in view
`
`of Ding ’979. (Id. at 0178-83).
`
`
`
` The Applicants’ written summary of an October 3, 2013 examiner 37.
`
`interview states that the “Applicants presented data demonstrating unexpected
`
`results, commercial success, and satisfaction of a long felt need of the claimed
`
`methods.” (EX1004-01246). The Applicants argued that “the evidence of non-
`
`obviousness presented at the interview overcomes the prima facie obviousness
`
`rejection.” (Id.)
`
`
`
` Four declarations were submitted to the USPTO in support of these 38.
`
`arguments: declarations from Dr. Rhett Schiffman (“Schiffman Declaration I”) and
`
`Dr. Mayssa Attar (the “Attar Declaration”) concerning surprising and unexpected
`
`results; and declarations from Aziz Mottiwala (the “Mottiwala Declaration”) and
`
`Dr. Rhett Schiffman (“Schiffman Declaration II”) concerning commercial success
`
`and satisfaction of a long-felt need. (EX1004-0260-84 (Schiffman Declaration I),
`
`0286-303 (Attar Declaration), 0305-13 (Mottiwala Declaration), 0315-428
`
`(Schiffman Declaration II)). Schiffman Declaration I and the Attar Declaration
`
`assert that “the claimed methods, including administration of a formulation with
`
`
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`0.05% 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
`
`keraconjunctivitis sicca) and improved visual blurring and reduced artificial tear
`
`use as compared to the prior art . . . .” (Id. at 0253).
`
`
`
` As discussed in Section VIII.D below, I disagree with the opinions of 39.
`
`Dr. Schiffman and Dr. Attar that the results in the submitted declarations were
`
`unexpected or surprising.
`
`
`
` The Examiner issued a Notice of Allowance on December 2, 2013. 40.
`
`(EX1004-0461). The Examiner stated that Applicants had failed to demonstrate
`
`commercial success or long-felt need. (Id. at 0469-71). However, relying on
`
`Schiffman Declaration I and the Attar 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 herein withdrawn.”
`
`(Id. at 0473).
`
`VI. LEGAL STANDARDS.
`A. OBVIOUSNESS – 35 U.S.C. § 103.
`I have been informed and understand that a person cannot obtain a
`
`41.
`
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`patent if his or her invention would have been obvious to a person of ordinary skill
`
`
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`in the field of the invention at the time of the invention.
`
`42.
`
`
`I have been informed that a patent is invalid as obvious “if the
`
`differences between the subject matter sought to be patented and the prior art are
`
`such that the subject matter as a whole would have been obvious at the time the
`
`invention was made to a person having ordinary skill in the art.”
`
`43.
`
`
`In evaluating obviousness, I have been asked to consider: (1) the
`
`scope and content of the prior art; (2) what the level of ordinary skill in the art was
`
`at the time the invention was made; (3) if there are any perceived differences
`
`between the prior art and the asserted claims and whether the differences involve a
`
`modification that would have been beyond the existing knowledge, or ordinary
`
`creativity, to the person of ordinary skill in the art (in other words, were not
`
`obvious to the person of ordinary skill), and to provide my opinions on the reasons
`
`why the person of ordinary skill would have had a reason or motivation or other
`
`suggestion to make these modifications; and (4) any secondary considerations of
`
`non-obviousness (also known as objective indicia of non-obviousness).
`
`44.
`
`
`I have been informed and understand that in analyzing the question of
`
`obviousness, it is improper to use hindsight reconstruction, and that one cannot use
`
`the patent as a road map for selecting and combining items of prior art. I have
`
`been informed and understand that the relevant question is what a person of
`
`ordinary skill in the art would have understood at the time the invention was made.
`
`
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`45.
`
`
`I have been informed and understand that the combination of familiar
`
`elements according to known methods is likely to be obvious when it does no more
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`than yield predictabl