UNITED STATES PATENT AND TRADEMARK OFFICE
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`BEFORE THE PATENT TRIAL AND APPEAL BOARD
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`MYLAN PHARMACEUTICALS INC.,
`Petitioner
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`v.
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`ALLERGAN, INC.,
`Patent Owner
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`1
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`Case IPR2016-01128
`Patent 8,629,111
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`DECLARATION OF THORSTEINN LOFTSSON, PH.D.
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`ALL 2025
`MYLAN PHARMACEUTICALS V. ALLERGAN
`IPR2016-01128
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`Case IPR2016-01128
`Attorney Docket No: 13351-0008IP2
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`I, Thorsteinn Loftsson, Ph.D., declare as follows:
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`I.
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`Experience and Qualifications
`1.
`I graduated in 1972 with a degree in Pharmacy from the University of
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`Iceland. I then received a M.Sc. in Pharmacy from the University of Copenhagen
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`in 1975. Next, I attended the University of Kansas as a Fulbright Fellow, obtaining
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`an M.S. in 1978 and a Ph.D. in 1979, both in Pharmaceutical Chemistry. My Ph.D.
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`thesis related to drug delivery systems and methods.
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`2.
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`Following my studies, I joined the faculty of the University of Iceland
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`in 1979. I first served as an Assistant Professor (1979-1983), then as an Associate
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`Professor (1983-1985), and I am now a Professor of Physical Pharmacy, which I
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`have been since 1986. I have also been employed at the College of Pharmacy at
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`the University of Florida as an Adjust Associate Professor (1980-1987) and as an
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`Adjunct Professor (1987-2011).
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`3.
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`Over the years, I have worked on many different ophthalmic and other
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`drug formulations. For example, I have worked on the ophthalmic drug
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`loteprednol etabonate, currently on the market, and two drugs now in phase II
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`studies, dexamethasone and dorzolamide. I also have experience in changing
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`delivery mechanisms, changing the membranes, changing the drug molecules, and
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`changing drug concentrations. My experience includes working with the ocular
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`penetration enhancer cyclodextrin and working with prodrugs to change drug
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`Case IPR2016-01128
`Attorney Docket No: 13351-0008IP2
`penetration. I have also worked with and published on research involving
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`cyclodextrin-based aqueous cyclosporin A (CsA) eye drop formulations. I have
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`studied the effects of various solubilizers on CsA solubility in aqueous eye drop
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`media, the permeation of CsA through membranes, the chemical stability of CsA
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`in aqueous solutions, and the interactions of CsA with various cyclodextrins. I
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`note that each formulation poses unique challenges such as the drugs’
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`physicochemical properties (i.e. solubility, chemical stability, physical stability,
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`lipophilicity, molecular weight and molecular structure) and the type of eye drop
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`formulation (i.e. aqueous versus non-aqueous, instant release versus sustained
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`release, single phase [e.g., aqueous solution or oil solution] versus disperse phase
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`[e.g., microsuspension, nanosuspension, emulsion or microsuspension]).
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`4.
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`In addition, I have authored more than 200 publications, including
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`journal articles, textbook chapters and case reports, many of which focus on
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`formulation of ophthalmic formulations and ophthalmic drug delivery systems, as
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`well as two textbooks one on drug stability and drug stabilization and the other one
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`on drug pharmacokinetics.
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`5.
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`I am a member of a number of professional organizations including
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`the American Chemical Society (Division of Medicinal Chemistry), the American
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`Association of Pharmaceutical Scientists for which I am a Fellow, the European
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`Case IPR2016-01128
`Attorney Docket No: 13351-0008IP2
`Federation of Pharmaceutical Science, the Icelandic Pharmacists Association, the
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`Icelandic Biochemical Society and Societas Scientiarum Islandica.
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`6.
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`I also serve or have served on the editorial boards for the Journal of
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`Pharmaceutical Sciences, the Journal of Pharmacy and Pharmacology, the Journal
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`of Drug Delivery Science and Technology, the International Journal of
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`Pharmaceutics, the European Journal of Pharmaceutical Sciences, Drug Stability
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`and Die Pharmazie. Currently I am the Review Editor of the International Journal
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`of Pharmaceutics.
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`7.
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`In addition, I have served on numerous advisory boards. For example,
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`I currently serve or have previous served on boards for Pharmatec, Inc. (Scientific
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`Advisory Board), Cyclops ehf., Oculis ehf. and Lipid Pharmaceuticals ehf.
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`8.
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`Over the course of my career, I have received several honors and
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`awards, including for example, a Fulbright Fellowship, two NATO Awards, a
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`Faculty Research Award for the University of Iceland Faculty of Medicine, an
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`International Scholarship from the Nagai Foundation Tokyo, a Fellow for the
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`American Association of Pharmaceutical Scientists, a Thomson Reuters Highly
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`Cited Researcher, a member of Thomson Reuters’ list of the World’s Most
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`Influential Scientific Minds and the Asa Wright Prize. In 2016, I received the
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`AAPS Research Achievement Award in Physical Pharmacy and
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`Biopharmaceutics.
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`Case IPR2016-01128
`Attorney Docket No: 13351-0008IP2
`A more thorough summary of my education, employment, honors,
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`9.
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`fellowships, memberships, lectures and publications is provided in my CV, which
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`is attached to this declaration as Exhibit A.
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`II.
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`Scope of Work
`10.
`I understand that the United States Patent Trial and Appeal Board
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`(“PTAB”) has instituted inter partes review of U.S. Patent Nos. 8,629,111,
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`8,633,162, 8,642,556, 8,648,048, 8,685,930 and 9,248,191 (collectively “the
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`patents-in-suit”). (IPR2016-01128, -01130, -01129, -01131, -01127 and -01132,
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`respectively). I have been engaged in the present matter by counsel to provide my
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`independent analysis of the issues raised in the petitions for inter partes review of
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`the patents-in-suit.
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`11.
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`I am being compensated for my work at the rate of $400 per hour. My
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`compensation does not in any way depend on the outcome the litigation or the inter
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`partes reviews.
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`12.
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`In writing this Declaration, I have reviewed the patents-in-suit
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`assigned to Allergan, Inc. and the declaration submitted by Dr. Amiji in this
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`proceeding.1 I have also considered the following: my own knowledge and
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`experience in the field of ophthalmic formulation, including my work experience
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`1 I note the specifications of the patents-in-suit are seemingly identical.
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`Case IPR2016-01128
`Attorney Docket No: 13351-0008IP2
`with cyclosporin and oil-in-water ophthalmic emulsions and the state of the art as
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`of the priority date of the patents-in-suit. In arriving at my opinions, I have also
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`reviewed and considered other documents, a complete list of which are included as
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`Exhibit B to my declaration.
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`III. Level of Ordinary Skill at the Relevant Time
`13.
`I understand that Petitioner asserts that a person of ordinary skill in
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`the art would likely have had “some combination of: (a) experience formulating
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`pharmaceutical products; (b) experience designing and preparing drug emulsions
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`intended for topical ocular administration; and (c) the ability to understand results
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`and findings presented or published by others in the field.” Paper 8 (citing Ex.
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`1002 ¶ 36). “Petitioner further contends that this person typically would have an
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`advanced degree, such as a medical degree, or a Ph.D. in organic chemistry,
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`pharmaceutical chemistry, medicinal chemistry, pharmaceutics, physical
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`pharmacy, or a related field, or less education but considerable professional
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`experience in these fields.” Id. (citing Ex. 1002 ¶ 35).
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`14.
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`I understand the PTAB has adopted Petitioner’s definition of the level
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`of ordinary skill in the art in IPR2016-01132 and IPR2016-01130. (IPR2016-
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`01132 Paper 8, at 7; IPR2016-00130 Paper 8, at 7-8). As of 2002-2003, I had at
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`least these qualifications of a person of skill in the art. I have applied this
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`definition of a person of ordinary skill in the art while conducting my analysis.
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`Case IPR2016-01128
`Attorney Docket No: 13351-0008IP2
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`IV. Claim Construction
`15.
`I understand that in the context of the inter partes review of U.S.
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`Patent Nos. 8,629,111, the PTAB has construed the term “therapeutically
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`effective” to encompass both palliative and curative treatments of dry eye disease.
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`(IPR2016-01128 Paper 8, at 6-8). I have applied this definition in my analysis.
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`16.
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`I further understand that the PTAB has determined it was unnecessary
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`to expressly construe any other claim terms at this time. (Id. at 8-9). As such, I
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`have interpreted other claim terms according to their ordinary and accustomed
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`meaning as would be understood by one of ordinary skill in the art.
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`V.
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`Background
`17. Ophthalmic formulation is a difficult task, and a formulator considers
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`many things when designing an ophthalmic formulation. The drug must possess
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`sufficient solubility in the formulation to prevent drug precipitation during storage
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`and handling, and remain both physically and chemically stable during the shelf-
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`life of the drug product. For example, the pH of a formulation must be adjusted to
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`allow for minimal drug degradation and sufficient drug solubility. Solubilizers,
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`such as surfactants and complexing agents, along with preservatives may be added.
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`However, the formulation must also be designed so that it is comfortable enough to
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`be used in the eye.
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`Case IPR2016-01128
`Attorney Docket No: 13351-0008IP2
`18. A formulator must also consider potential interactions between the
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`drug and any other components of the formulation, which can be hard to predict.
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`For example, buffer salts are known to catalyze degradation of drugs in aqueous
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`solutions (i.e. general base and general acid catalysis of drug degradation), and
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`polymers are known to form complexes with drugs that can hamper their
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`absorption through biological membranes.
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`19. The topical application of a drug to the eye presents several
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`challenges. When a drop (35 to 50 μL) is applied to the eye, the eye drop is mixed
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`with tear fluid and dispersed over the eye surface through blinking. Then the
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`majority of the eye drop is drained from the eye surface, returning the solution
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`volume to the normal resident tear volume of about 7 μL. While the pre-ocular
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`solution volume remains constant, drug concentration decreases due to dilution by
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`tear turnover and corneal and noncorneal absorption.
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`20. Cyclosporin A (“CsA”) is a hydrophobic immune-modulating anti-
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`inflammatory drug that is particularly challenging to deliver as a treatment for dry
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`eye disease. Systemic CsA is generally not considered for the treatment of ocular
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`pathologies because of severe systemic adverse effects, such as nephrotoxicity and
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`hypertension. Agarwal & Rupenthal, at 2 (EX. 2011). Therefore, delivery of CsA
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`to the eye must be done topically.
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`Case IPR2016-01128
`Attorney Docket No: 13351-0008IP2
`21. CsA has relatively high hydrophobicity and low aqueous solubility,
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`making it “not merely difficult but practically impossible to prepare a
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`pharmaceutical composition containing cyclosporin dissolved in an aqueous
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`medium.” Ding et al., U.S. 5,474,979 (EX. 1006), 1:42-44; Lallemand et al., at 2
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`(EX. 2014). The solubility of cyclosporin in water is between 20 μg/mL to 30
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`μg/mL. Ding et al., U.S. 5,474,979 (EX. 1006), 1:45-46.
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`22. Attempts to improve the aqueous solubility of CsA have included the
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`use of surfactants and/or penetration enhancers, but their use in ophthalmic
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`applications is limited by their high irritation potential because these molecules
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`typically function by comprising the integrity of the ocular tissues. Agarwal &
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`Rupenthal, at 2 (EX. 2011).
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`23. Formulations incorporating CsA as oily solutions have also been
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`prepared. However, oily solutions limit the bioavailability of CsA due to the
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`separation of CsA from the solution as a solid immediately after it comes into
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`contact with the aqueous environment of the eye. Ding et al., U.S. 5,474,979 (EX.
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`1006), 1:49-53. Oils can also irritate the eye. Lallemand et al., at 2 (EX. 2014).
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`Ding et al. reports “it is well known that castor oil is irritating to sensitive tissues
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`such as the eye.” Ding ’607 (EX. 1010), at 5:17-21. In addition, there is evidence
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`of increased ocular toxicity after frequent use, with blurring of vision also
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`commonly observed because of the high viscosity of the carrier oil. Agarwal &
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`Case IPR2016-01128
`Attorney Docket No: 13351-0008IP2
`Rupenthal, at 2 (EX. 2011); Ding et al., U.S. 5,474,979 (EX. 1006), 2:5-7 (“[I]f
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`oily preparations containing cyclosporin are applied directly to the eyes, irritation
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`or a clouding of visual field may result.”).
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`24. Other efforts to deliver CsA involve using micelles, liposomes, and
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`nanoparticles. Ding et al., U.S. 5,474,979 (EX. 1006), 2:11-38; Lallemand et al., at
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`2-5 (EX. 2014). These formulations suffer from poor stability, surface toxicity,
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`short corneal surface half-life, and poor scalability. Lallemand et al., at 2-5 (EX.
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`2014); Agarwal & Rupenthal, at 4-5 (EX. 2011).
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`25. As described in Ding et al., U.S. Patent No. 5,474,979, Allergan chose
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`to formulate ophthalmic treatments of CsA using an oil-in-water emulsion. Ding et
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`al., U.S. 5,474,979 (EX. 1006), 3:6-28. Emulsions are the mixture of two or more
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`liquids in which one is present as droplets of microscopic size, distributed
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`throughout the other.
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`26. Oil-in-water emulsions are complex, multi-component formulations
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`that require scientific understanding of interfacial properties of chemicals (i.e. not
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`only surfactants but that of other pharmaceutical excipients and the drug itself),
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`phase distribution of drug molecules, aggregation and micellar formation, and the
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`physical stability of emulsions. As a result, oil-in-water emulsions for use in the
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`eye present particularly difficult formulation challenges. For example, an
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`indispensable component of an emulsion system is an emulsifier (i.e. the surfactant
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`Case IPR2016-01128
`Attorney Docket No: 13351-0008IP2
`forming the emulsion), but the majority of known emulsifiers are highly irritating
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`to the eyes. In addition, because emulsions are often opaque and viscous, they can
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`cause blurred vision when applied to the eye. Glonek et al., U.S. 5,578,586 (EX.
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`1009), 6:35. Moreover, the eye will naturally remove oil-based vehicles more
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`quickly than aqueous vehicles, further complicating the challenge of using
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`emulsions to treat eye diseases. Lallemand et al., at 2 (EX. 2014). For all of these
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`reasons, before the approval of RESTASIS®, there were no prescription oil-in-
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`water emulsions for ophthalmic use on the market in the United States.
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`27. Oil-in-water emulsions containing CsA are particularly challenging
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`from a formulation perspective. CsA emulsions need to balance the predisposition
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`of CsA, as a lipophilic molecule, to remain in the oil component of an emulsion,
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`with CsA’s propensity to undergo conformational changes and crystallize out of
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`solution. Ding et al., U.S. 5,474,979 (EX. 1006), at 2:42-45. In both
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`circumstances, the bioavailability of CsA is reduced.
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`28. For at least these reasons, the delivery of CsA to the eye is extremely
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`challenging from the perspective of a formulator.
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`VI. RESTASIS®
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`(cid:38)(cid:68)(cid:86)(cid:72)(cid:3)(cid:44)(cid:51)(cid:53)(cid:21)(cid:19)(cid:20)(cid:25)(cid:16)(cid:19)(cid:20)(cid:20)(cid:21)(cid:27)(cid:3)
`(cid:36)(cid:87)(cid:87)(cid:82)(cid:85)(cid:81)(cid:72)(cid:92)(cid:3)(cid:39)(cid:82)(cid:70)(cid:78)(cid:72)(cid:87)(cid:3)(cid:49)(cid:82)(cid:29)(cid:3)(cid:3)(cid:20)(cid:22)(cid:22)(cid:24)(cid:20)(cid:16)(cid:19)(cid:19)(cid:19)(cid:27)(cid:44)(cid:51)(cid:21)(cid:3)
`Attorney Docket No: 13351-0008IP2
`(cid:21)(cid:28)(cid:17)(cid:3) (cid:53)(cid:40)(cid:54)(cid:55)(cid:36)(cid:54)(cid:44)(cid:54)(cid:138)(cid:3)(cid:76)(cid:86)(cid:3)(cid:68)(cid:81)(cid:3)(cid:82)(cid:83)(cid:75)(cid:87)(cid:75)(cid:68)(cid:79)(cid:80)(cid:76)(cid:70)(cid:3)(cid:72)(cid:80)(cid:88)(cid:79)(cid:86)(cid:76)(cid:82)(cid:81)(cid:3)(cid:70)(cid:82)(cid:81)(cid:87)(cid:68)(cid:76)(cid:81)(cid:76)(cid:81)(cid:74)(cid:3)(cid:19)(cid:17)(cid:19)(cid:24)(cid:8)(cid:3)(cid:38)(cid:86)(cid:36)(cid:3)(cid:76)(cid:81)(cid:3)(cid:68)(cid:3)
`RESTASIS® is an ophthalmic emulsion containing 0.05% CsA in a
`29.
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`Case IPR2016-01128
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`(cid:20)(cid:17)(cid:21)(cid:24)(cid:8)(cid:3)(cid:70)(cid:68)(cid:86)(cid:87)(cid:82)(cid:85)(cid:3)(cid:82)(cid:76)(cid:79)(cid:3)(cid:89)(cid:72)(cid:75)(cid:76)(cid:70)(cid:79)(cid:72)(cid:17)(cid:21)(cid:3)(cid:3)(cid:53)(cid:40)(cid:54)(cid:55)(cid:36)(cid:54)(cid:44)(cid:54)(cid:138)(cid:3)(cid:47)(cid:68)(cid:69)(cid:72)(cid:79)(cid:3)(cid:11)(cid:40)(cid:59)(cid:17)(cid:3)(cid:21)(cid:19)(cid:19)(cid:27)(cid:12)(cid:15)(cid:3)(cid:68)(cid:87)(cid:3)(cid:22)(cid:16)(cid:23)(cid:17)(cid:3)(cid:3)(cid:53)(cid:40)(cid:54)(cid:55)(cid:36)(cid:54)(cid:44)(cid:54)(cid:138)(cid:3)
`1.25% castor oil vehicle.2 RESTASIS® Label (EX. 2008), at 3-4. RESTASIS®
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`(cid:90)(cid:68)(cid:86)(cid:3)(cid:87)(cid:75)(cid:72)(cid:3)(cid:73)(cid:76)(cid:85)(cid:86)(cid:87)(cid:3)(cid:41)(cid:39)(cid:36)(cid:16)(cid:68)(cid:83)(cid:83)(cid:85)(cid:82)(cid:89)(cid:72)(cid:71)(cid:3)(cid:82)(cid:83)(cid:75)(cid:87)(cid:75)(cid:68)(cid:79)(cid:80)(cid:76)(cid:70)(cid:3)(cid:72)(cid:80)(cid:88)(cid:79)(cid:86)(cid:76)(cid:82)(cid:81)(cid:17)(cid:3)(cid:3)(cid:47)(cid:68)(cid:79)(cid:79)(cid:72)(cid:80)(cid:68)(cid:81)(cid:71)(cid:3)(cid:72)(cid:87)(cid:3)(cid:68)(cid:79)(cid:17)(cid:15)(cid:3)(cid:68)(cid:87)(cid:3)(cid:20)(cid:20)(cid:3)(cid:11)(cid:40)(cid:59)(cid:17)(cid:3)
`was the first FDA-approved ophthalmic emulsion. Lallemand et al., at 11 (EX.
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`(cid:21)(cid:19)(cid:20)(cid:24)(cid:12)(cid:17)(cid:3)(cid:3)(cid:53)(cid:40)(cid:54)(cid:55)(cid:36)(cid:54)(cid:44)(cid:54)(cid:138)(cid:3)(cid:76)(cid:86)(cid:3)(cid:179)(cid:76)(cid:81)(cid:71)(cid:76)(cid:70)(cid:68)(cid:87)(cid:72)(cid:71)(cid:3)(cid:87)(cid:82)(cid:3)(cid:76)(cid:81)(cid:70)(cid:85)(cid:72)(cid:68)(cid:86)(cid:72)(cid:3)(cid:87)(cid:72)(cid:68)(cid:85)(cid:3)(cid:83)(cid:85)(cid:82)(cid:71)(cid:88)(cid:70)(cid:87)(cid:76)(cid:82)(cid:81)(cid:3)(cid:76)(cid:81)(cid:3)(cid:83)(cid:68)(cid:87)(cid:76)(cid:72)(cid:81)(cid:87)(cid:86)(cid:3)(cid:90)(cid:75)(cid:82)(cid:86)(cid:72)(cid:3)
`2015). RESTASIS® is “indicated to increase tear production in patients whose
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`(cid:87)(cid:72)(cid:68)(cid:85)(cid:3)(cid:83)(cid:85)(cid:82)(cid:71)(cid:88)(cid:70)(cid:87)(cid:76)(cid:82)(cid:81)(cid:3)(cid:76)(cid:86)(cid:3)(cid:83)(cid:85)(cid:72)(cid:86)(cid:88)(cid:80)(cid:72)(cid:71)(cid:3)(cid:87)(cid:82)(cid:3)(cid:69)(cid:72)(cid:3)(cid:86)(cid:88)(cid:83)(cid:83)(cid:85)(cid:72)(cid:86)(cid:86)(cid:72)(cid:71)(cid:3)(cid:71)(cid:88)(cid:72)(cid:3)(cid:87)(cid:82)(cid:3)(cid:82)(cid:70)(cid:88)(cid:79)(cid:68)(cid:85)(cid:3)(cid:76)(cid:81)(cid:73)(cid:79)(cid:68)(cid:80)(cid:80)(cid:68)(cid:87)(cid:76)(cid:82)(cid:81)(cid:3)
`tear production is presumed to be suppressed due to ocular inflammation
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`(cid:68)(cid:86)(cid:86)(cid:82)(cid:70)(cid:76)(cid:68)(cid:87)(cid:72)(cid:71)(cid:3)(cid:90)(cid:76)(cid:87)(cid:75)(cid:3)(cid:78)(cid:72)(cid:85)(cid:68)(cid:87)(cid:82)(cid:70)(cid:82)(cid:81)(cid:77)(cid:88)(cid:81)(cid:70)(cid:87)(cid:76)(cid:89)(cid:76)(cid:87)(cid:76)(cid:86)(cid:3)(cid:86)(cid:76)(cid:70)(cid:70)(cid:68)(cid:17)(cid:180)(cid:3)(cid:3)(cid:53)(cid:40)(cid:54)(cid:55)(cid:36)(cid:54)(cid:44)(cid:54)(cid:138)(cid:3)(cid:47)(cid:68)(cid:69)(cid:72)(cid:79)(cid:3)(cid:11)(cid:40)(cid:59)(cid:17)(cid:3)(cid:21)(cid:19)(cid:19)(cid:27)(cid:12)(cid:15)(cid:3)(cid:68)(cid:87)(cid:3)(cid:20)(cid:17)(cid:3)(cid:3)
`associated with keratoconjunctivitis sicca.” RESTASIS® Label (EX. 2008), at 1.
`
`(cid:53)(cid:40)(cid:54)(cid:55)(cid:36)(cid:54)(cid:44)(cid:54)(cid:138)(cid:3)(cid:90)(cid:68)(cid:86)(cid:3)(cid:87)(cid:75)(cid:72)(cid:3)(cid:73)(cid:76)(cid:85)(cid:86)(cid:87)(cid:15)(cid:3)(cid:68)(cid:81)(cid:71)(cid:3)(cid:85)(cid:72)(cid:80)(cid:68)(cid:76)(cid:81)(cid:86)(cid:3)(cid:87)(cid:75)(cid:72)(cid:3)(cid:82)(cid:81)(cid:79)(cid:92)(cid:15)(cid:3)(cid:82)(cid:83)(cid:75)(cid:87)(cid:75)(cid:68)(cid:79)(cid:80)(cid:76)(cid:70)(cid:3)(cid:73)(cid:82)(cid:85)(cid:80)(cid:88)(cid:79)(cid:68)(cid:87)(cid:76)(cid:82)(cid:81)(cid:3)(cid:76)(cid:81)(cid:71)(cid:76)(cid:70)(cid:68)(cid:87)(cid:72)(cid:71)(cid:3)
`RESTASIS® was the first, and remains the only, ophthalmic formulation indicated
`
`(cid:87)(cid:82)(cid:3)(cid:76)(cid:81)(cid:70)(cid:85)(cid:72)(cid:68)(cid:86)(cid:72)(cid:3)(cid:87)(cid:72)(cid:68)(cid:85)(cid:3)(cid:83)(cid:85)(cid:82)(cid:71)(cid:88)(cid:70)(cid:87)(cid:76)(cid:82)(cid:81)(cid:3)(cid:76)(cid:81)(cid:3)(cid:71)(cid:85)(cid:92)(cid:3)(cid:72)(cid:92)(cid:72)(cid:3)(cid:83)(cid:68)(cid:87)(cid:76)(cid:72)(cid:81)(cid:87)(cid:86)(cid:17)(cid:3)(cid:3)Id(cid:17)(cid:3)(cid:3)(cid:3)
`to increase tear production in dry eye patients. Id.
`
`(cid:22)(cid:19)(cid:17)(cid:3) (cid:58)(cid:75)(cid:76)(cid:79)(cid:72)(cid:3)(cid:86)(cid:72)(cid:72)(cid:78)(cid:76)(cid:81)(cid:74)(cid:3)(cid:41)(cid:39)(cid:36)(cid:3)(cid:68)(cid:83)(cid:83)(cid:85)(cid:82)(cid:89)(cid:68)(cid:79)(cid:3)(cid:73)(cid:82)(cid:85)(cid:3)(cid:53)(cid:40)(cid:54)(cid:55)(cid:36)(cid:54)(cid:44)(cid:54)(cid:138)(cid:3)(cid:73)(cid:82)(cid:85)(cid:3)(cid:87)(cid:75)(cid:72)(cid:3)(cid:87)(cid:85)(cid:72)(cid:68)(cid:87)(cid:80)(cid:72)(cid:81)(cid:87)(cid:3)(cid:82)(cid:73)(cid:3)
`30. While seeking FDA approval for RESTASIS® for the treatment of
`
`(cid:71)(cid:85)(cid:92)(cid:3)(cid:72)(cid:92)(cid:72)(cid:15)(cid:3)(cid:36)(cid:79)(cid:79)(cid:72)(cid:85)(cid:74)(cid:68)(cid:81)(cid:3)(cid:70)(cid:82)(cid:81)(cid:71)(cid:88)(cid:70)(cid:87)(cid:72)(cid:71)(cid:3)(cid:87)(cid:90)(cid:82)(cid:3)(cid:80)(cid:88)(cid:79)(cid:87)(cid:76)(cid:70)(cid:72)(cid:81)(cid:87)(cid:72)(cid:85)(cid:15)(cid:3)(cid:85)(cid:68)(cid:81)(cid:71)(cid:82)(cid:80)(cid:76)(cid:93)(cid:72)(cid:71)(cid:15)(cid:3)(cid:71)(cid:82)(cid:88)(cid:69)(cid:79)(cid:72)(cid:16)(cid:80)(cid:68)(cid:86)(cid:78)(cid:72)(cid:71)(cid:3)(cid:51)(cid:75)(cid:68)(cid:86)(cid:72)(cid:3)(cid:22)(cid:3)
`dry eye, Allergan conducted two multicenter, randomized, double-masked Phase 3
`
`(cid:70)(cid:79)(cid:76)(cid:81)(cid:76)(cid:70)(cid:68)(cid:79)(cid:3)(cid:87)(cid:85)(cid:76)(cid:68)(cid:79)(cid:86)(cid:3)(cid:87)(cid:72)(cid:86)(cid:87)(cid:76)(cid:81)(cid:74)(cid:3)(cid:87)(cid:75)(cid:72)(cid:3)(cid:72)(cid:73)(cid:73)(cid:76)(cid:70)(cid:68)(cid:70)(cid:92)(cid:3)(cid:68)(cid:81)(cid:71)(cid:3)(cid:86)(cid:68)(cid:73)(cid:72)(cid:87)(cid:92)(cid:3)(cid:82)(cid:73)(cid:3)(cid:70)(cid:92)(cid:70)(cid:79)(cid:82)(cid:86)(cid:83)(cid:82)(cid:85)(cid:76)(cid:81)(cid:3)(cid:82)(cid:83)(cid:75)(cid:87)(cid:75)(cid:68)(cid:79)(cid:80)(cid:76)(cid:70)(cid:3)(cid:72)(cid:80)(cid:88)(cid:79)(cid:86)(cid:76)(cid:82)(cid:81)(cid:86)(cid:3)
`clinical trials testing the efficacy and safety of cyclosporin ophthalmic emulsions
`
`(cid:76)(cid:81)(cid:3)(cid:83)(cid:68)(cid:87)(cid:76)(cid:72)(cid:81)(cid:87)(cid:86)(cid:3)(cid:90)(cid:76)(cid:87)(cid:75)(cid:3)(cid:80)(cid:82)(cid:71)(cid:72)(cid:85)(cid:68)(cid:87)(cid:72)(cid:3)(cid:87)(cid:82)(cid:3)(cid:86)(cid:72)(cid:89)(cid:72)(cid:85)(cid:72)(cid:3)(cid:71)(cid:85)(cid:92)(cid:3)(cid:72)(cid:92)(cid:72)(cid:3)(cid:71)(cid:76)(cid:86)(cid:72)(cid:68)(cid:86)(cid:72)(cid:17)(cid:3)(cid:3)(cid:55)(cid:75)(cid:72)(cid:3)(cid:83)(cid:82)(cid:82)(cid:79)(cid:72)(cid:71)(cid:3)(cid:85)(cid:72)(cid:86)(cid:88)(cid:79)(cid:87)(cid:86)(cid:3)(cid:82)(cid:73)(cid:3)(cid:87)(cid:75)(cid:72)(cid:86)(cid:72)(cid:3)
`in patients with moderate to severe dry eye disease. The pooled results of these
`
`(cid:70)(cid:79)(cid:76)(cid:81)(cid:76)(cid:70)(cid:68)(cid:79)(cid:3)(cid:87)(cid:85)(cid:76)(cid:68)(cid:79)(cid:86)(cid:3)(cid:90)(cid:72)(cid:85)(cid:72)(cid:3)(cid:83)(cid:88)(cid:69)(cid:79)(cid:76)(cid:86)(cid:75)(cid:72)(cid:71)(cid:3)(cid:69)(cid:92)(cid:3)(cid:54)(cid:68)(cid:79)(cid:79)(cid:3)(cid:72)(cid:87)(cid:3)(cid:68)(cid:79)(cid:17)(cid:3)(cid:3)(cid:54)(cid:68)(cid:79)(cid:79)(cid:3)(cid:72)(cid:87)(cid:3)(cid:68)(cid:79)(cid:17)(cid:15)(cid:3)(cid:68)(cid:87)(cid:3)(cid:25)(cid:22)(cid:20)(cid:16)(cid:22)(cid:23)(cid:3)(cid:11)(cid:40)(cid:59)(cid:17)(cid:3)(cid:20)(cid:19)(cid:19)(cid:26)(cid:12)(cid:17)(cid:3)
`clinical trials were published by Sall et al. Sall et al., at 631-34 (EX. 1007).
`
`(cid:22)(cid:20)(cid:17)(cid:3) (cid:55)(cid:75)(cid:72)(cid:3)(cid:51)(cid:75)(cid:68)(cid:86)(cid:72)(cid:3)(cid:22)(cid:3)(cid:87)(cid:85)(cid:76)(cid:68)(cid:79)(cid:86)(cid:3)(cid:76)(cid:81)(cid:89)(cid:82)(cid:79)(cid:89)(cid:72)(cid:71)(cid:3)(cid:87)(cid:75)(cid:72)(cid:3)(cid:83)(cid:68)(cid:85)(cid:68)(cid:79)(cid:79)(cid:72)(cid:79)(cid:3)(cid:68)(cid:86)(cid:86)(cid:72)(cid:86)(cid:86)(cid:80)(cid:72)(cid:81)(cid:87)(cid:3)(cid:82)(cid:73)(cid:3)(cid:82)(cid:76)(cid:79)(cid:16)(cid:76)(cid:81)(cid:16)(cid:90)(cid:68)(cid:87)(cid:72)(cid:85)(cid:3)
`31.
`The Phase 3 trials involved the parallel assessment of oil-in-water
`
`(cid:72)(cid:80)(cid:88)(cid:79)(cid:86)(cid:76)(cid:82)(cid:81)(cid:86)(cid:3)(cid:70)(cid:82)(cid:81)(cid:87)(cid:68)(cid:76)(cid:81)(cid:76)(cid:81)(cid:74)(cid:3)(cid:19)(cid:17)(cid:19)(cid:24)(cid:8)(cid:3)(cid:38)(cid:86)(cid:36)(cid:3)(cid:76)(cid:81)(cid:3)(cid:68)(cid:3)(cid:70)(cid:68)(cid:86)(cid:87)(cid:82)(cid:85)(cid:3)(cid:82)(cid:76)(cid:79)(cid:3)(cid:89)(cid:72)(cid:75)(cid:76)(cid:70)(cid:79)(cid:72)(cid:3)(cid:68)(cid:81)(cid:71)(cid:3)(cid:19)(cid:17)(cid:20)(cid:19)(cid:8)(cid:3)(cid:38)(cid:86)(cid:36)(cid:3)(cid:76)(cid:81)(cid:3)(cid:68)(cid:3)(cid:70)(cid:68)(cid:86)(cid:87)(cid:82)(cid:85)(cid:3)
`emulsions containing 0.05% CsA in a castor oil vehicle and 0.10% CsA in a castor
`
`(cid:3)(cid:3)(cid:3)(cid:3)(cid:3)(cid:3)(cid:3)(cid:3)(cid:3)(cid:3)(cid:3)(cid:3)(cid:3)(cid:3)(cid:3)(cid:3)(cid:3)(cid:3)(cid:3)(cid:3)(cid:3)(cid:3)(cid:3)(cid:3)(cid:3)(cid:3)(cid:3)(cid:3)(cid:3)(cid:3)(cid:3)(cid:3)(cid:3)(cid:3)(cid:3)(cid:3)(cid:3)(cid:3)(cid:3)(cid:3)(cid:3)(cid:3)(cid:3)
`(cid:21)(cid:3)(cid:55)(cid:75)(cid:72)(cid:3)(cid:20)(cid:17)(cid:21)(cid:24)(cid:8)(cid:3)(cid:70)(cid:68)(cid:86)(cid:87)(cid:82)(cid:85)(cid:3)(cid:82)(cid:76)(cid:79)(cid:3)(cid:89)(cid:72)(cid:75)(cid:76)(cid:70)(cid:79)(cid:72)(cid:3)(cid:76)(cid:81)(cid:70)(cid:79)(cid:88)(cid:71)(cid:72)(cid:86)(cid:3)(cid:20)(cid:17)(cid:21)(cid:24)(cid:8)(cid:3)(cid:70)(cid:68)(cid:86)(cid:87)(cid:82)(cid:85)(cid:3)(cid:82)(cid:76)(cid:79)(cid:15)(cid:3)(cid:20)(cid:17)(cid:19)(cid:19)(cid:8)(cid:3)(cid:83)(cid:82)(cid:79)(cid:92)(cid:86)(cid:82)(cid:85)(cid:69)(cid:68)(cid:87)(cid:72)(cid:3)(cid:27)(cid:19)(cid:15)(cid:3)
`2 The 1.25% castor oil vehicle includes 1.25% castor oil, 1.00% polysorbate 80,
`
`(cid:19)(cid:17)(cid:19)(cid:24)(cid:8)(cid:3)(cid:68)(cid:70)(cid:85)(cid:92)(cid:79)(cid:68)(cid:87)(cid:72)(cid:18)(cid:38)(cid:20)(cid:19)(cid:16)(cid:22)(cid:19)(cid:3)(cid:68)(cid:79)(cid:78)(cid:92)(cid:79)(cid:3)(cid:68)(cid:70)(cid:85)(cid:92)(cid:79)(cid:68)(cid:87)(cid:72)(cid:3)(cid:70)(cid:85)(cid:82)(cid:86)(cid:86)(cid:16)(cid:83)(cid:82)(cid:79)(cid:92)(cid:80)(cid:72)(cid:85)(cid:3)(cid:11)(cid:72)(cid:17)(cid:74)(cid:17)(cid:3)(cid:51)(cid:72)(cid:80)(cid:88)(cid:79)(cid:72)(cid:81)(cid:138)(cid:3)(cid:55)(cid:53)(cid:16)(cid:21)(cid:15)(cid:3)
`0.05% acrylate/C10-30 alkyl acrylate cross-polymer (e. g. Pemulen® TR-2,
`
`(cid:38)(cid:68)(cid:85)(cid:69)(cid:82)(cid:80)(cid:72)(cid:85)(cid:3)(cid:20)(cid:22)(cid:23)(cid:21)(cid:12)(cid:15)(cid:3)(cid:21)(cid:17)(cid:21)(cid:19)(cid:8)(cid:3)(cid:74)(cid:79)(cid:92)(cid:70)(cid:72)(cid:85)(cid:76)(cid:81)(cid:15)(cid:3)(cid:19)(cid:17)(cid:22)(cid:28)(cid:26)(cid:8)(cid:3)(cid:86)(cid:82)(cid:71)(cid:76)(cid:88)(cid:80)(cid:3)(cid:75)(cid:92)(cid:71)(cid:85)(cid:82)(cid:91)(cid:76)(cid:71)(cid:72)(cid:15)(cid:3)(cid:68)(cid:81)(cid:71)(cid:3)(cid:28)(cid:24)(cid:8)(cid:3)(cid:83)(cid:88)(cid:85)(cid:76)(cid:73)(cid:76)(cid:72)(cid:71)(cid:3)
`Carbomer 1342), 2.20% glycerin, 0.397% sodium hydroxide, and 95% purified
`
`(cid:90)(cid:68)(cid:87)(cid:72)(cid:85)(cid:17)(cid:3)(cid:3)(cid:49)(cid:39)(cid:36)(cid:3)(cid:21)(cid:20)(cid:16)(cid:19)(cid:21)(cid:22)(cid:3)(cid:11)(cid:40)(cid:59)(cid:17)(cid:3)(cid:21)(cid:19)(cid:19)(cid:20)(cid:12)(cid:15)(cid:3)(cid:87)(cid:69)(cid:79)(cid:17)(cid:22)(cid:17)(cid:22)(cid:17)(cid:21)(cid:17)(cid:20)(cid:16)(cid:20)(cid:17)(cid:3)
`water. NDA 21-023 (EX. 2001), tbl.3.3.2.1-1.
`
`(cid:3)
`
`(cid:20)(cid:21)(cid:3)
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`12
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`Case IPR2016-01128
`Attorney Docket No: 13351-0008IP2
`oil vehicle for the treatment of dry eye. Sall et al., at 632 (EX. 1007). The safety
`
`and efficacy of these formulations were compared to a control castor oil vehicle.
`
`Sall et al., at 631-34 (EX. 1007). Sall et al. reports the CsA/castor oil vehicle
`
`formulations were administered to separate groups of patients twice a day, and
`
`various measurements were tracked and recorded over the course of the study. Sall
`
`et al., at 632-33 (EX. 1007).
`
`32. Sall et al. does not disclose the specific composition of the
`
`formulations used in the Phase 3 clinical trials, other than noting the amount of
`
`CsA (0.05% or 0.1%) in each formulation. Sall et al., at 631-34 (EX. 1007). Thus,
`
`skilled artisans reviewing Sall et al. would not know the amount of castor oil in
`
`each formulation, including the control castor oil vehicle formulation. The shared
`
`specification of the patents-in-suit discloses the amount of castor oil present in the
`
`formulations used in the Phase 3 studies. Acheampong et al., U.S. 8,629,111 (EX.
`
`1001), 14:25-41. The specification states Composition I (0.1% CsA/ 1.25% castor
`
`oil vehicle) and Composition II (0.05% CsA/1.25% castor oil vehicle) were used in
`
`the “Phase 3, double-masked, randomized, parallel group study for the treatment of
`
`dry eye disease.” Acheampong et al., U.S. 8,629,111 (EX. 1001), 14:25-41. I
`
`have reproduced this section of the specification below:
`
`
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`13
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`Case IPR2016-01128
`Attorney Docket No: 13351-0008IP2
`
`
`
`Id.
`
`33. The results of Allergan’s Phase 3 clinical trials confirm the specific
`
`formulation of 0.05% CsA in a 1.25% castor oil vehicle acts differently than a
`
`formulation of 0.1% CsA in a 1.25% castor oil vehicle and is critical for increasing
`
`tear production in patients with dry eye. Specifically, Figure 2 of Sall et al.,
`
`reports the change from baseline in categorized Schirmer values measured with
`
`anesthesia for patients who received (a) 0.05% CsA in a castor oil vehicle, (b)
`
`0.1% CsA in a castor oil vehicle, or (c) the castor oil vehicle control formulation
`
`after 3 and 6 months of treatment. While it is now know that all three formulations
`
`in this study contained 1.25% castor oil vehicle, as discussed above, skilled
`
`artisans would not have known the precise composition of the formulations at the
`
`time of the study.
`
`34. The data demonstrate that the 0.05% CsA formulation resulted in a
`
`statistically significant change in tear production compared to 1.25% castor oil
`14
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`Case IPR2016-01128
`Attorney Docket No: 13351-0008IP2
`vehicle control formulation at month 3 whereas the 0.1% CsA formulation did not
`
`demonstrate a statistically significant change compared to the vehicle control
`
`formulation. Id. At month 6, the 0.05% CsA formulation increased tear
`
`production to a greater extent than the 0.10% CsA formulation. Id.
`
`
`
`Id.
`
`35.
`
`I further note the data also demonstrate the 1.25% castor oil vehicle
`
`control formulation decreased tear production at months 3 and 6, which indicates
`
`the 1.25% castor oil vehicle is not responsible for the therapeutic effects of
`
`Restasis® in restoring tear production and treating dry eye.
`
`36. To the extent Dr. Amiji suggests a 0.05% CsA/1.25% castor oil
`
`vehicle formulation and 0.1% CsA/1.25% castor oil vehicle formulation both
`
`
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`15
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`Case IPR2016-01128
`Attorney Docket No: 13351-0008IP2
`“satisfy the concentration threshold for therapeutic efficacy,” suggesting “any
`
`increased delivery [of CsA to the eye] is immaterial” for effectiveness, I disagree.
`
`Amiji Decl’n (EX. 1002), ¶ 145. If this was true, then the 0.1% CsA/1.25% castor
`
`oil vehicle formulation should have been at least as effective, when compared to
`
`the castor oil vehicle control, as the 0.05% CsA/1.25% castor oil vehicle
`
`formulation at increasing tear production after both three and six months of
`
`treatment. However, the data from Sall Figure 2 demonstrate this is not the case.
`
`The 0.1% CsA/1.25% castor oil vehicle for