`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 Peter Kador, Ph.D.
`
`FAMY CARE - EXHIBIT 1002-0001
`
`

`

`TABLE OF CONTENTS
`
`I.
`
`INTRODUCTION. ........................................................................................... 1
`
`II. QUALIFICATIONS. ........................................................................................ 1
`
`III. SCOPE OF ENGAGEMENT. .......................................................................... 5
`
`IV. SUMMARY OF OPINIONS. ........................................................................... 7
`V. THE ’048 PATENT OVERVIEW. ................................................................17
`
`A. The ’048 Patent Specification. ....................................................................17
`
`B. The ’048 Patent Claims. ..............................................................................19
`
`1. Independent Claims. ...................................................................................19
`
`2. Composition Dependent Claims. ................................................................20
`
`3. “Efficacy”and “Comparative Efficacy” Dependent Claims .......................22
`4. “Substantially No Detectable Concentration of CsA” Dependent Claims. 22
`
`C.
`
`’048 Patent File History. .............................................................................23
`
`VI. THE PERSON OF ORDINARY SKILL IN THE ART. ...............................27
`
`VII. CLAIM CONSTRUCTION. ..........................................................................28
`
`A.
`B.
`
`C.
`
`D.
`
`E.
`
`“Buffer” .......................................................................................................29
`“Substantially No Detectable Concentration Of The Cyclosporin A.” .......29
`
`“Effective Amount,” “Substantially Therapeutically Effective As,” and “As
`Much Therapeutic Effectiveness As” .........................................................31
`
`“Adverse Events” and “Side Effects” .........................................................33
`
`“Breaks Down” ............................................................................................34
`
`VIII. LEGAL STANDARDS. .................................................................................35
`
`A. Anticipation – 35 U.S.C. § 102. ..................................................................35
`
`B. Obviousness – 35 U.S.C. § 103. ..................................................................35
`
`IX. DISCLOSURES, KNOWLEDGE & INFORMATION AVAILABLE IN
`THE ART AS OF SEPTEMBER 15, 2003. ...................................................39
`A. State of the Art Generally. ...........................................................................39
`
`1. CsA Was a Known Treatment for Dry Eye Disease. ..................................39
`
`2. CsA-in-Castor Oil Emulsions Were Known In the Art. .............................43
`
`B. Ding ’979. ....................................................................................................49
`
`C.
`
`Sall. ..............................................................................................................55
`
`ii
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`

`

`D. Acheampong. ...............................................................................................63
`
`E. Glonek .........................................................................................................65
`
`X. DETAILED ANALYSIS OF THE ’048 PATENT CLAIMS. .......................67
`
`A. Ground 1: ’048 patent Claims 1-23 Are Obvious In View Of Ding ’979 and
`Sall...............................................................................................................68
`1. Claims 1-23. ................................................................................................68
`
`2. Reasonable Expectation of Success. .........................................................109
`
`B. Ground 2: ’048 Patent Claims 11 And 21 Are Obvious In View Of Ding
`’979, Sall, and Acheampong. ....................................................................110
`
`C. Ground 3: ’048 Patent Claim 15 Is Obvious In View Of Ding ’979, Sall
`and Glonek. ...............................................................................................113
`
`XI. SECONDARY CONSIDERATIONS OF NONOBVIOUSNESS. .............116
`
`XII. CONCLUDING STATEMENTS. ................................................................120
`
`iii
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`FAMY CARE - EXHIBIT 1002-0003
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`

`

`TABLE OF EXHIBITS
`
`Exhibit
`
`Description
`
`1001 U.S. Patent No. 8,648,048 B2 to Acheampong et al. (“the ’048 patent)
`
`1002
`
`Intentionally Blank
`
`1003 Declaration of Dr. Michael A. Lemp
`
`1004
`
`1005
`
`File history of U.S. Patent No. 8,648,048 to Acheampong et al., filed
`August 14, 2013 (“’048 patent FH”)
`
`File history of U.S. Patent Application No. 10/927,857 to Acheampong
`et al., filed August 27, 2004 (“’857 application FH”)
`
`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”)
`
`1008 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”)
`
`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 R. Kaswan, Intraocular Penetration of Topically Applied 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”)
`
`iv
`
`FAMY CARE - EXHIBIT 1002-0004
`
`

`

`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 REMINGTON’S 20TH EDITION: THE SCIENCE AND PRACTICE OF
`PHARMACY (A. Gennaro ed. 2003) (“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 944, 1300, 1548, 1634, 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)
`
`v
`
`FAMY CARE - EXHIBIT 1002-0005
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`

`

`1024 APPROVED DRUG PRODUCTS WITH THERAPEUTIC EQUIVALENCE
`EVALUATIONS (34th ed. 2014) (Excerpts)
`
`1025
`
`Intentionally Blank
`
`1026
`
`7/30/2003 Allergan Correspondence to FDA regarding RESTASIS™
`
`1027 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 Curriculum Vitae of Dr. Peter Kador
`
`1033 Curriculum Vitae of Dr. Michael A. Lemp
`
`
`
`vi
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`FAMY CARE - EXHIBIT 1002-0006
`
`

`

`I, Peter Kador, declare as follows:
`
`I.
`
`
`1.
`
`INTRODUCTION.
`
`I, Peter Kador, Ph.D., submit this declaration on behalf of Famy Care
`
`Limited (“Petitioner”). I understand that Petitioner is filing a petition with the
`
`United States Patent and Trademark Office (“USPTO”) for inter partes review of
`
`U.S. Patent No. 8,648,048 (“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
`
`pharmaceutical formulations.
`
`II. QUALIFICATIONS.
`
`
`3.
`
`I received a B.A. degree in Chemistry from Capital University,
`
`Columbus, Ohio in 1972 and a Ph.D. in Medicinal Chemistry from the Ohio State
`
`University in 1976.
`
`
`4.
`
`After graduation, I received a Staff Fellowship to the National Eye
`
`Institute (“NEI”), National Institutes of Health, in Bethesda, Maryland.
`
`
`5.
`
`I was promoted to tenured Research Chemist (GS 13) in 1979,
`
`becoming the youngest member, at the age of 29, of the permanent research staff
`
`
`
`1
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`FAMY CARE - EXHIBIT 1002-0007
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`

`

`of the NEI.
`
`
`6.
`
`Six years later, I became the Head of the Section of Molecular
`
`Pharmacology in the Laboratory of Mechanisms of Ocular Diseases and in 1989 I
`
`was promoted to a GS 15, the university equivalent of a full tenured Professor.
`
`
`7.
`
`In 1991, I was named Chief of the newly established Laboratory of
`
`Ocular Therapeutics.
`
`
`8.
`
`After over 25 years of service, I retired from the National Institutes of
`
`Health and service to the Federal Government.
`
`
`9.
`
`For the last fourteen years, I have served as tenured Professor in the
`
`College of Pharmacy and hold appointments in the Department of Ophthalmology
`
`at the University of Nebraska Medical Center (“UNMC”), the School of Veterinary
`
`Medicine and Biomedical Sciences at the University of Nebraska Lincoln, and the
`
`Department of Ophthalmology, Xijing Hospital, Fourth Military Medical
`
`University, Xi’an, People’s Republic of China.
`
`
`10.
`
`I have also started Therapeutic Vision, Inc., a startup company, where
`
`I am the President and CEO.
`
` My professional activities include being Executive Vice-President of
`11.
`
`the National Foundation for Eye Research and serving as President (2004-2011)
`
`and currently as treasurer of the Association for Ocular Pharmacology and
`
`Therapeutics (AOPT).
`
`
`
`2
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`FAMY CARE - EXHIBIT 1002-0008
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`

`
`12.
`
`I have served as a consultant on cataract drug development to Shojin
`
`Research Associates, on ocular toxicology to Merck and Co. (2001-2006), Eli Lilly
`
`and Company (2007-2009) and Johnson and Johnson Company (2009-2010).
`
`
`
` From 2000-2006, I served on the Expert Committee on Ophthalmic 13.
`
`Drugs for the U.S. Pharmacopeia on the Scientific Advisory Board of Encore
`
`Vision (2007-2010) and Merz Pharmaceuticals GmbH (2011-2012).
`
`
`14.
`
`I am also currently Scientific Advisor to Aventix Animal Health.
`
`
`15.
`
`I have also organized or co-organized over 34 National and
`
`International Workshops and Conferences and presented over 67 invited papers
`
`both nationally and internationally. I have lectured in Europe, Russia, Turkey,
`
`Japan, Korea, China, New Zealand, Australia, Canada, and Argentina.
`
`
`
` Throughout my 40 year career, I have been recognized both nationally 16.
`
`and internationally for my research accomplishments. International awards include
`
`the Rohto Foundation Cataract Research Award, the Alcon Foundation Research
`
`Award, the Kinoshita Lectureship, and the Ernst H. Bárány Prize in Ocular
`
`Pharmacology. Other awards include the Distinguished Scientist Award of the
`
`University of Nebraska Medical Center, the Alumni Achievement Award of
`
`Capital University, the Jack Beal Post baccalaureate Alumni Achievement Award
`
`from
`
`the Ohio State University College of Pharmacy,
`
`and
`
`the
`
`Bundesverdienstkreuz am Bande (Federal Cross of Merit) from the German
`
`
`
`3
`
`FAMY CARE - EXHIBIT 1002-0009
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`

`

`Federal Government.
`
`
`17.
`
`I am also a Fellow of the American Association of Pharmaceutical
`
`Scientists, and the Association for Research in Vision and Ophthalmology.
`
`
`
` As a recognized leader in eye research, I have published extensively 18.
`
`(over 228 publications, 315 abstracts, and 8 patents) on many aspects of ocular
`
`diseases and their treatment.
`
`
`
` My research areas include studies on the enzyme aldose reductase, its 19.
`
`inhibitors, and their role in the development of ocular diabetic complications,
`
`studies on age-related cataracts and anti-cataract agents; the development of
`
`diabetic retinopathy and its treatment; and the use of MRI and NMR spectroscopy
`
`as a non-invasive tool for eye research.
`
`
`20.
`
`I have developed and characterized a number of animal models
`
`including mice (mice with age-related cataracts and a diabetic transgenic mouse
`
`retinopathy model), rats (radiation, diabetic and galactosemic), and dogs, including
`
`the establishment of the galactose-fed dog as the only animal model that
`
`demonstrates both clinical as well as histological retinal changes associated with
`
`diabetic retinopathy that are similar to man. I have designed and synthesized
`
`multifunctional antioxidants to treat age-related degenerative diseases of the eye
`
`that include age-related macular degeneration and neural tissues.
`
`
`21.
`
`In addition to my research, I have developed a graduate course on
`
`
`
`4
`
`FAMY CARE - EXHIBIT 1002-0010
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`

`

`Ocular Research and Drug Development, and I teach an elective course on Ocular
`
`Diseases and their Treatment to Pharmacy students. Both courses include lectures
`
`on ocular drug delivery.
`
`
`22.
`
`I also have direct experience in the formulation, development and
`
`commercialization of topical ophthalmic formulations. This experience was
`
`obtained in the development of the aldose reductase inhibitor (ARI) Kinostat® (2-
`
`MS), covered by US Patent No 8,158,667 and nutraceutical eye formulation
`
`covered by U.S. Patent No. 9,173,915. I am the sole inventor of the ’915 patent and
`
`a co-inventor of the ’667 patent. The patented formulation is currently sold as
`
`Optixcare® Eye Health, which is an antioxidant eye drop that maintains tear flow in
`
`dry eye. I am further involved in continued development of such topical
`
`ophthalmic formulations for human treatment.
`
`
`
` Additional information about my professional and educational 23.
`
`experience, and other background information, is described in my curriculum vitae
`
`(EX1032).
`
`III. SCOPE OF ENGAGEMENT.
`
`
`24.
`
`I have been retained by Petitioner as a technical expert to offer my
`
`analysis and opinions relating to the ’048 patent, as well as various issues related to
`
`pharmaceutical formulations as they relate to the ’048 patent and to other topics
`
`relevant to the subject matter of the ’048 patent, as discussed in more detail below.
`
`
`
`5
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`FAMY CARE - EXHIBIT 1002-0011
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`

`
`25.
`
`I have reviewed the ’048 patent and relevant sections of its
`
`prosecution history before the USPTO. (EX1004). I have also reviewed and
`
`considered various other documents in arriving at my opinions, and cite them in
`
`this Declaration. For convenience, documents cited in this Declaration are listed in
`
`the above Table of Exhibits.
`
` My opinions and views set forth in this Declaration are based on my
`26.
`
`education and training; my experience at the NEI and as an educator, researcher,
`
`and consultant at UNMC in the areas of pharmaceutical sciences for 40 years; and
`
`on the materials I have reviewed for this case.
`
`
`27.
`
`I have been asked to consider the level of education, skill set and
`
`training possessed by persons of ordinary skill in the field relevant to the ’048
`
`patent as of September 15, 2003.
`
`
`28.
`
`I have also been asked to consider, from the perspective of the person
`
`of ordinary skill in the art as of September 15, 2003, whether the ’048 patent
`
`claims were anticipated and/or obvious to one of ordinary skill in the art at that
`
`time.
`
`
`29.
`
`I have formed certain opinions on these issues, which are set forth in
`
`detail below.
`
`
`
` My time spent on this project is compensated at $425 per hour. My 30.
`
`compensation does not depend in any way on the outcome of Petitioner’s petition
`
`
`
`6
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`

`

`for inter partes review of the ’048 patent. Furthermore, I have no financial interest
`
`in this matter.
`
`IV. SUMMARY OF OPINIONS.
`
`
`31.
`
`In this declaration, I consider the ’048 patent’s claimed methods and
`
`topical ophthalmic emulsions in relation to the state of the art before September 15,
`
`2003, including but not limited to the prior art references Ding ’979 (EX1006), Sall
`
`(EX1007), Acheampong (EX1008), and Glonek (EX1009). I also considered the
`
`prosecution history of the ’048 patent (EX1004) and related applications
`
`(EX1005), as well as the Declaration of Famy Care’s clinician Michael A. Lemp,
`
`M.D. (“Lemp Declaration”) (EX1003). In my analysis of the prior art, I focused
`
`on how the art developed, and what was known, preferred, guided, reasoned and/or
`
`reasonably expected by the person of ordinary skill in the art, and did so without
`
`regard to the ’048 patent or the Allergan patents which belong to the same family
`
`as the ’048 patent.
`
`
`
` Based on my review of the materials identified in connection with this 32.
`
`Declaration, together with my knowledge, education and experience, it is my
`
`opinion that as of September 15, 2003:
`
` Claims 1-23 of the ’048 patent are directed to methods of treating dry eye
`
`disease/KCS requiring twice daily administration of topical ophthalmic
`
`emulsions comprising several components known in the art, including 0.05%
`
`
`
`7
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`

`cyclosporine A (“CsA”) and 1.25% castor oil. The claims also include
`
`comparative performance elements between the claimed composition and
`
`otherwise-identical formulations containing either 0.1% by weight CsA or
`
`50% less castor oil.
`
` Applying all of the most detailed requirements for the claimed “emulsion”
`
`ingredients, weight percentage and pH yields the specific formulation
`
`presented as “Composition II” in the ’048 patent’s specification.
`
` GROUND 1: Claims 1-23 are obvious in view of the CsA-in-castor oil
`
`emulsions taught by Ding ’979 and the safety and efficacy taught for 0.05%
`
`CsA-in-castor oil emulsions by Sall.
`
`o Ding ’979 discloses topical ophthalmic castor oil-in-water emulsions
`
`for the treatment of dry eye disease or keratoconjunctivitis sicca
`
`containing CsA with identical excipients at identical concentrations to
`
`those in the ’048 patent’s claimed emulsions.
`
`o The specific combination of 0.05% CsA and 1.25% castor oil is the
`
`only difference between Composition II claimed by the ’048 patent
`
`and Ding ’979 Examples 1D (0.1% CsA, 1.25% castor oil) and 1E
`
`(0.05% CsA, 0.625% castor oil). A person of ordinary skill in the art
`
`would understand that the ratios of CsA to castor oil in Example 1 are
`
`
`
`8
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`

`0.04 and 0.08; Composition II of the ’048 patent merely applies the
`
`0.04 ratio to the 0.05% CsA formulation. All of these species fall
`
`within claim 8’s “pharmaceutical emulsion”; and Ding ’979’s stated
`
`preferences.
`
`o A person of ordinary skill in the art would have understood that claim
`
`8 of Ding ’979 discloses a fully operational invention across the full
`
`range of the genus for the use taught for the formulations, notably dry
`
`eye disease.
`
`o Ding ’979 teaches that Examples 1A-1D were found to deliver
`
`therapeutic levels of CsA in ocular bioavailability studies, and reports
`
`no meaningful differences in ocular bioavailability, toxicity, or
`
`irritability. Ding ’979 emphasizes the importance of CsA to castor oil
`
`ratios, and a person of ordinary skill in the art would have looked to
`
`Examples 1A-1D and recognized that they had CsA to castor oil ratios
`
`of 0.04 and 0.08.
`
`o The application of the 0.04 CsA to castor oil ratio taught by Ding ’979
`
`(Example 1B) to the lowest concentration of CsA (0.05%) specified in
`
`Ding ’979 claim 8 also results in an emulsion with 0.05% CsA and
`
`1.25% castor oil.
`
`
`
`9
`
`FAMY CARE - EXHIBIT 1002-0015
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`

`o An emulsion with 0.05% CsA and 1.25% castor oil would have
`
`therefore have been obvious to one of ordinary skill in the art from the
`
`teachings of Ding ’979.
`
`o The specific CsA and castor oil amounts of 0.05% and 1.25% are not
`
`critical to the operability of the invention of Ding ’979 claim 8. A
`
`person of ordinary skill in the art would have expected a 0.05% CsA
`
`emulsion within the range of CsA to castor oil ratios of Ding ’979
`
`Examples 1A-1D (0.04 or 0.08) to have substantially the same
`
`functionality in treating dry eye disease consistent with the Example 1
`
`bioavailability and toxicity teachings.
`
`o Allergan’s prior art clinical trial data published by Sall confirmed
`
`comparable human clinical outcomes for 0.05% and 0.1% CsA
`
`formulations. Sall reports the results of Phase 3 clinical trials
`
`involving the parallel assessment of the efficacy and safety of 0.05%
`
`and 0.10% CsA-in-castor oil emulsions. Sall concluded that both the
`
`0.05% and the 0.10% CsA emulsions were safe and effective in the
`
`treatment of moderate to severe dry eye disease when administered
`
`twice daily, yielding improvements in both objective and subjective
`
`measures.
`
`
`
`10
`
`FAMY CARE - EXHIBIT 1002-0016
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`

`

`o Sall teaches toward using 0.05% CsA-in-castor oil emulsions for the
`
`treatment of dry eye disease/KCS and twice-daily administration. Sall
`
`shows that the 0.05% emulsion achieved a statistically significant
`
`improvement over vehicle in more clinical markers than the 0.10%
`
`emulsion, that the 0.05% emulsion numerically reduced side effects,
`
`and that the 0.05% emulsion never resulted in any detectable blood
`
`levels of CsA. Sall also teaches that castor oil has substantial
`
`palliative effects, including increased ocular residence time and
`
`prevention of tear evaporation.
`
`o Sall’s teachings would have motivated a person of ordinary skill in the
`
`art to make and use the 0.05% CsA and 1.25% castor oil emulsion
`
`taught by Ding ’979 to treat patients with dry eye/KCS. The person of
`
`ordinary skill in the art looking for a 0.05% CsA formulation would
`
`readily find Ding ’979 Example 1E. Such person would also see Ding
`
`Example 1 used only two CsA/castor oil ratios, of 0.04 or 0.08. Both
`
`would have been obvious to try (indeed, Ding ’979 had already
`
`prepared Example 1E, 0.08 ratio).
`
`o Given Sall’s teachings that castor oil itself could have a palliative
`
`effect, a person of ordinary skill in the art would have had a reason;
`
`
`
`11
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`FAMY CARE - EXHIBIT 1002-0017
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`

`been motivated to; and in fact preferred the higher castor oil
`
`concentration of 1.25% castor oil. A person of ordinary skill in the art
`
`would have reasonably expected the higher castor oil concentration to
`
`increase the emulsions residence time on the eye and decrease tear
`
`evaporation.
`
`o A person of ordinary skill in the art would have reasonably expected
`
`that the emulsions having 0.05% CsA and 1.25% castor oil taught by
`
`Ding ’979: are therapeutically effective in increasing tear production
`
`and treating dry eye disease/KCS when administered twice daily;
`
`produce substantially no detectable concentration of CsA in the blood
`
`when administered twice daily; have therapeutic efficacy that is
`
`substantially equal to, or at least as much as, a second emulsion
`
`having 0.1% CsA and 1.25% castor oil; and, tend to reduce adverse
`
`events and side effects in comparison to 0.1% CsA emulsions.
`
`o Moreover, a person of ordinary skill in the art at the time of the
`
`invention would have known, or reasonably expected, that decreasing
`
`the castor oil concentration in the 0.05% CsA emulsions taught by
`
`Ding ’979 from 1.25% to 0.625% increases the stability of the
`
`emulsion on the eye. A person of ordinary skill in the art would have
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`known that more stable emulsions take longer to differentiate into
`
`separate layers on the eye and tend to have a longer duration of
`
`blurring.
`
` GROUND 2: Claims 11 and 21 of the ’048 patent would have been obvious to
`
`a person of ordinary skill in the art in view of Ding ’979, Sall and
`
`Acheampong.
`
`o Claims 11 and 21 require the “emulsion” to produce “substantially no
`
`detectable concentration” of CsA in the blood when administered.
`
`o Should Allergan argue that the person of ordinary skill in the art
`
`would not have reasonably expected this intrinsic property of the CsA
`
`being delivered, Acheampong gives the person of ordinary skill in the
`
`art a reasonable expectation that this is, in fact, an intrinsic property of
`
`the emulsions recited in claims 11 and 21 of the ’048 patent.
`
`o Separately, Acheampong provides a further reason to pursue the
`
`0.05% CsA formulation.
`
`o Like Sall, Acheampong reports that 0.05% CsA emulsions produce no
`
`detectable concentration of CsA in the blood at both trough and peak
`
`time points.
`
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`o A person of ordinary skill in the art would have looked to
`
`Acheampong in evaluating the formulations disclosed in Ding ’979, in
`
`view of the motivation provided by Sall, because a person of ordinary
`
`skill in the art would consider the safety of the topical ophthalmic
`
`emulsion. Acheampong guides the person of ordinary skill in the art
`
`towards the use of the 0.05% CsA formulation given the absence of
`
`systemic toxicity risks due to CsA blood levels.
`
` Ground 3: Claim 15 of the ’048 patent would have been obvious to a person
`
`of ordinary skill in the art in view of Ding ’979, Sall, and Glonek.
`
`o Claims 15 recites that the “emulsion” breaks down more quickly on
`
`the eye and reduces vision distortion in comparison to an emulsion
`
`with half as much castor oil. To the extent Allergan argues this
`
`phenomenon would not have been known to the person of ordinary
`
`skill in the art as part of such person’s general knowledge and
`
`understanding, Glonek teaches this intrinsic property of the claimed
`
`emulsions.
`
`o A person of ordinary skill in the art also would have known that the
`
`Sall and Ding ’979 formulations were topical ophthalmic
`
`formulations; if the person of ordinary skill had any concerns about
`
`
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`the effect of increasing the castor oil levels within Ding’s Example 1E
`
`(0.05% CsA, 0.625% castor oil) to the 0.05% CsA, 1.25% castor oil
`
`levels in patients, such person would have looked to Glonek in
`
`evaluating the formulations disclosed in Ding ’979, in view of the
`
`motivation provided by Sall, because Glonek teaches the impact of
`
`increasing oil concentration in oil-in-water emulsions for the
`
`treatment of dry eye.
`
`o Glonek teaches that the duration of blurring for an emulsion is
`
`dependent upon the time required for an emulsion to differentiate and
`
`form separate layers. A person of ordinary skill in the art would have
`
`understood that decreasing the oil concentration in an emulsion (while
`
`holding the surfactant concentration constant) increases the stability
`
`and duration of blurring for an emulsion. Increasing the oil
`
`concentration in an emulsion reduces the duration of blurring for an
`
`emulsion after topical application—hence, the person of ordinary skill
`
`in the art would have reasonably expected this same phenomenon to
`
`occur in the 0.05% CsA/1.25% castor oil formulation as compared to
`
`a formulation with only half as much castor oil, i.e., 0.625%.
`
` I have reviewed the Lemp Declaration, and I agree with Dr. Lemp’s
`
`
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`opinions concerning secondary considerations. Reasons include:
`
`o I agree with Dr. Lemp that the data presented by the Applicants
`
`during prosecution do not support the conclusion that the ’048
`
`patent’s claimed emulsions provide unexpected results over the
`
`closest prior art. I further agree with Dr. Lemp that the data presented
`
`by the Applicants lacks the necessary parameters (e.g., raw data
`
`values and error rates) to support a scientific conclusion that the
`
`claimed emulsions achieved any superior results.
`
`o I agree with Dr. Lemp that the validity of the ’048 patent is not
`
`supported 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
`
`o I agree with Dr. Lemp that the validity of the ’048 patent is not
`
`
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`supported by long-felt need or failure of others. Ding ’979 satisfied
`
`any purported long-felt need for an emulsion comprising, e.g., 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. The person of ordinary skill in
`
`the art faced no manufacturing concerns, since the ’048 patent itself
`
`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). All of these
`
`emulsions fall within the scope of Ding ’979 claim 8, which Ding
`
`’979 stated could be used for treatment of dry eye disease. In my
`
`opinion, this admission shows that 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 33.
`
`11, 2014 to Applicant and Assignee Allergan, Inc., and is entitled “Methods of
`
`Providing Therapeutic Effects using Cyclosporin Components.” The named
`
`inventors are Andrew Acheampong, Diane D. Tang-Liu, James N. Chang, and
`
`David F. Power. (EX1001, Cover).
`
`
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` The ’048 patent cover page further states that the application for the
`34.
`
`’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 continuations
`
`to U.S. Patent Application No. 10/927,857 (“the ’857 application”) (EX1005), and
`
`to U.S. Provisional Patent Application No. 60/503,137, filed on September 15,
`
`2003. (EX1001, Cover).
`
`
`35.
`
`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 36.
`
`a human or animal with a composition in the form of an emulsion that includes
`
`cyclosporin. (EX1001, Abstract). The ’048 patent is also directed to methods of
`
`providing desired therapeutic effects to humans or animals using compositions
`
`containing cyclosporin. (Id. at 1:18-20).
`
`
`
` The ’048 patent specification acknowledges that the use of CsA and 37.
`
`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).