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`UNITED STATES PATENT AND TRADEMARK OFFICE
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`Case IPR2017-01053
`Patent 8,268,299
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`BEFORE THE PATENT TRIAL AND APPEAL BOARD
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`ARGENTUM PHARMACEUTICALS LLC,
`Petitioner
`
`v.
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`ALCON RESEARCH, LTD.,
`Patent Owner
`
`
`Case IPR2017-01053
`Patent 8,268,299
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`DECLARATION OF SOUMYAJIT MAJUMDAR, Ph.D.
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`1
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`ALCON 2023
`Argentum Pharm. LLC v. Alcon Research, Ltd.
`Case IPR2017-01053
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`Case IPR2017-01053
`Patent 8,268,299
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`I. 
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`II. 
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`E. 
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`2. 
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`
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`TABLE OF CONTENTS
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`Introduction ...................................................................................................... 4 
`A. 
`Background and Qualifications ............................................................. 6 
`B. 
`The Person of Ordinary Skill in the Art .............................................. 10 
`C. 
`Construction of Claims ........................................................................ 11 
`D. 
`Background Regarding Calculations ................................................... 11 
`The Disclosures in Schneider, Xia, and Chowhan Would Not Have
`Rendered Obvious the Invention Claimed in the ’299 Patent. ...................... 14 
`A. 
`Schneider ............................................................................................. 14 
`B.  Xia ....................................................................................................... 15 
`C. 
`Chowhan .............................................................................................. 19 
`D. 
`Because Xia Solved the Problem Presented, the POSA Would
`Have Had No Reason to Combine Schneider with Xia ...................... 21 
`Even Assuming the POSA Combined Schneider with Xia, the
`POSA Would Not Have Had Reason to Practice the Claimed
`Invention .............................................................................................. 24 
`The POSA would reasonably expect that the combined
`1. 
`Schneider/Xia formulation would pass preservative
`efficacy testing. ......................................................................... 24 
`The POSA would not have been motivated to reduce the
`concentration of zinc below the levels disclosed in Xia’s
`Examples to the levels claimed in the ’299 patent. .................. 28 
`Even if the POSA were to decrease the concentration of
`zinc below 0.48 mM, the POSA would have included a
`conventional preservative in the solution. ................................ 30 
`Even if the POSA were to decrease the concentration of
`zinc below that in Xia’s Example 18, the POSA would
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`3. 
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`4. 
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`F. 
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`Case IPR2017-01053
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`Patent 8,268,299
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`not have been motivated to modify the Schneider/Xia
`formulation with Chowhan ....................................................... 34 
`Limiting the Concentration of Anionic Species Would Not
`Have Been Obvious to the POSA. ...................................................... 38 
`The ’299 Patent’s Propylene Glycol and Sorbitol Limitations
`Would Not Have Been Obvious to the POSA. ................................... 44 
`The pH Limitations in the ’299 Patent Would Not Have Been
`Obvious to the POSA. ......................................................................... 52 
`III.  The Disclosures in Schneider, Xia and Chowhan Combined with the
`Disclosures in Gadd Would Not Have Rendered Obvious the
`Invention Claimed in the ’299 Patent. ........................................................... 56 
`IV.  The Disclosures in Schneider, Xia and Chowhan Combined with the
`Disclosures in the TRAVATAN® Label Would Not Have Rendered
`Obvious the Invention Claimed in the ’299 Patent. ...................................... 61 
`The Disclosures in Schneider, Xia, Chowhan, Gadd and the
`TRAVATAN® Label Combined Would Not Have Rendered Obvious
`the Invention Claimed in the ’299 Patent. ..................................................... 62 
`
`G. 
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`H. 
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`V. 
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`3
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`I.
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`I, Soumyajit Majumdar, Ph.D., hereby declare as follows:
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`Case IPR2017-01053
`Patent 8,268,299
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`INTRODUCTION
`1.
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`I am over the age of eighteen, and am otherwise competent to make
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`this declaration.
`
`2.
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`I have been informed by counsel for Alcon Research, Ltd. (“Alcon”)
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`that the Patent Trial and Appeal Board has granted the petition of Argentum
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`Pharmaceuticals LLC (“Argentum”) to institute this Inter Partes Review (“IPR”)
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`regarding the purported obviousness of claims 1–28 of U.S. Patent No. 8,268,299
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`(the “’299 patent”). I understand from counsel that the following are the four
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`grounds of obviousness at issue:
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`Ground 1: Obviousness of claims 1, 2, 4–8, 16, 17, and 20 over World
`
`Intellectual Property Organization International Patent Application Number
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`2005/097067 A1 (“Xia”), Ex. 1003, United States Patent No. 6,011,062
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`(“Schneider”), Ex. 1007, and United States Patent No. 6,143,799
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`(“Chowhan”), Ex. 1004;
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`Ground 2: Obviousness of claim 28 over Xia, Schneider, Chowhan, and the
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`FDA Approved Drug Label for “TRAVATAN® (travoprost ophthalmic
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`solution) 0.004% sterile” (“TRAVATAN® Label”), Ex. 1006;
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`Patent 8,268,299
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`Ground 3: Obviousness of claims 1–23, 25, and 26 over Xia, Schneider,
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`Chowhan, and Gadd et al., “Microorganisms and Heavy Metal Toxicity,”
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`Microbial Ecology, 4:303–317 (1978) (“Gadd”), Ex. 1005;
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`Ground 4: Obviousness of claims 24, 27, and 28 over Xia, Schneider,
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`Chowhan, Gadd, and the TRAVATAN® Label.
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`3.
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`I have been retained as an expert witness to opine as to various
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`aspects of the compositions claimed in the ’299 patent, including whether those
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`compositions would have been obvious from the perspective of one of ordinary
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`skill in the art (“POSA”) as of the priority date, which I have been asked to assume
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`by counsel to be September 21, 2006 (“priority date”).
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`4.
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`I have been informed by counsel for Alcon that an obviousness
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`analysis involves a review of the scope and content of the prior art, the differences
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`between the prior art and the claims at issue, the level of ordinary skill in the
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`pertinent art, and “objective indicia of non-obviousness,” such as long-felt need
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`and commercial success. In particular, I have been advised that, for an invention to
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`be regarded as “obvious,” the POSA must have had a reason to modify the prior art
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`or to combine one or more prior art references in a manner that would yield the
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`claimed invention. I have also been informed that, for a claim to be obvious, the
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`POSA must have a reasonable expectation of success with respect to the claimed
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`invention. I have analyzed each of those questions, except that I understand that
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`other experts for Alcon will address objective evidence of nonobviousness.
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`A. Background and Qualifications
`5.
`I am an expert in the area of drug delivery, formulation, and
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`disposition, in particular ocular drug delivery, formulation, and disposition. I have
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`more than fourteen years of experience, in addition to my graduate studies and
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`research, in the fields of topical ophthalmic formulation, ocular penetration, drug
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`delivery, and disposition. I have performed and become familiar with numerous
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`experiments involving stability, solubility, ionic interactions within ophthalmic
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`formulations, complex formation, and the influence of formulation on preservative
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`efficacy. My recent research activities have focused primarily on the development
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`of drug delivery methods to enhance ocular bioavailability of poorly permeating
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`compounds. In this research, I focus on, among other things, biopharmaceutical
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`and pharmacokinetic considerations, and formulation design. My ocular drug
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`delivery research is and has been supported by funding received from the National
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`Eye Institute and National Institute of General Medical Sciences of the National
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`Institutes of Health.
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`6.
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`Based on my education, background, experience, and expertise, I am
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`qualified to provide an opinion as to what a person of ordinary skill in the art
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`would have understood, known or concluded as of the priority date.
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`Patent 8,268,299
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`I am currently an Associate Dean for Research and Graduate
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`7.
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`Programs and Professor of Pharmaceutics and Drug Delivery at the University of
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`Mississippi in Oxford, Mississippi. In addition to my position at the University of
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`Mississippi, I am also a Research Professor at the Research Institute of
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`Pharmaceutical Sciences, and served as an Associate Director of the Pii Center for
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`Pharmaceutical Technology at the University of Mississippi’s Department of
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`Pharmaceutics. As Associate Director of the Pii Center for Pharmaceutical
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`Technology, among other things, I help to develop novel ophthalmic formulations.
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`8.
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`I received a Ph.D. from the University of Missouri-Kansas City in
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`Pharmaceutical Sciences and Pharmacology. Prior to receiving a Ph.D., I worked
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`for Sandoz India Ltd. and Novartis Enterprises Pvt. Ltd., formulating drugs. In
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`those roles, I formulated multiple topical ophthalmic formulations.
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`9.
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`Over the years, I have authored and co-authored 70 peer-reviewed
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`articles, published in, among other journals: Current Eye Research, Molecular
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`Pharmaceutics, AAPS PharmSci, Clinical Research and Regulatory Affairs,
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`International Journal of Pharmaceutics, Journal of Ocular Pharmacology and
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`Therapeutics, Expert Opinion on Drug Delivery, Journal of Ocular Pharmacology
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`and Therapeutics, Drug Development and Industrial Pharmacy, Pharmaceutical
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`Research, Drug Metabolism and Disposition, Journal of Pharmaceutical Sciences,
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`and The Journal of Pharmacy and Pharmacology. I have also authored two book
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`Patent 8,268,299
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`chapters, both dealing with ophthalmic formulation. Many of these publications
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`have dealt with the investigation of physical and chemical stability, complex
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`formation and ionic interactions within ophthalmic formulations.
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`10.
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`In addition to writing and publishing numerous articles, I am also a
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`reviewer (by invitation) for numerous journals, including: Current Eye Research,
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`Expert Opinion on Drug Delivery, International Journal of Pharmaceutics,
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`Journal of Ocular Pharmacology and Therapeutics, Journal of Pharmaceutical
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`Sciences, and Molecular Pharmaceutics. In this role, I have reviewed manuscripts
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`submitted by other scientists relating to ophthalmic pharmaceuticals and
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`pharmacology. I also keep myself familiar with the latest research in the field of
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`ophthalmic pharmaceuticals and pharmacology through attending and presenting at
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`scientific conference and academic symposia, and reading scientific literature.
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`11.
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`I have taught numerous university courses on pharmaceutical
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`sciences, including Basic Pharmaceutics, Industrial Pharmacy, and Advanced
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`Pharmacokinetics, which covers Biopharmaceutics and Pharmacokinetics. As a
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`professor, I also advise numerous graduate students, some of whom have received
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`awards and fellowships on the basis of their research.
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`12.
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`I have received numerous awards and honors for my work as a
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`researcher and a teacher. These awards include the University of Mississippi’s
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`Pharmaceutical Sciences Teacher of the Year and its Faculty Research Fellowship
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`Case IPR2017-01053
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`Patent 8,268,299
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`Award, the American Association of Indian Pharmaceutical Scientists’ AAIPS
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`(“AAIPS”) Research Award, the University of Missouri-Kansas City’s School of
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`Graduate Studies Distinguished Dissertation Fellowship Award, and the Lipid-
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`based Drug Delivery Outstanding Researcher Award 2014 from the Lipid based
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`drug delivery focus group, American Association of Pharmaceutical Scientists.
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`13. My complete curriculum vitae is attached as Ex. 2024.
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`14.
`
`I am relying the following documents with respect to the opinions set
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`forth herein:
`
`Exhibit No. Description
`Argentum’s Petition for Inter Partes Review
`N/A
`N/A
`Institution Decision
`Ex. 1001
`United States Patent No. 8,268,299
`Ex. 1002
`Declaration of Erning Xia, Ph.D.
`Ex. 1003 World Intellectual Property Organization International Patent
`Application Number 2005/097067 A1
`Ex. 1004
`United States Patent No. 6,143,799
`Gadd et al., “Microorganisms and Heavy Metal Toxicity,”
`Ex. 1005
`Microbial Ecology, 4:303–317 (1978)
`FDA Approved Drug Label for “TRAVATAN® (travoprost
`ophthalmic solution) 0.004% sterile”
`Declaration of George G. Zhanel, Ph.D.
`The Merck Index, An Encyclopedia of Chemicals, Drugs, and
`Biologicals (13th ed. 2001), Merck Research Laboratories, 1810
`53 Fed. Reg. 7076 (Mar. 4, 1988)
`U.S. Pharmacopeia 23 (1995)
`Remington: The Science and Practice of Pharmacy (20th ed.
`2000)
`Final Report on the Safety Assessment of Polyquaternium-10,
`7 J. of the Am. College of Toxicology 347 (1988)
`United States Patent No. 5,336,508
`United States Patent No. 5,393,491
`
`Ex. 1006
`Ex. 2025
`Ex. 2031
`Ex. 2032
`Ex. 2033
`Ex. 2034
`
`Ex. 2035
`Ex. 2036
`Ex. 2037
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`9
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`United States Patent No. 5,741,817
`United States Patent No. 6,872,705
`Transcript, Deposition of Erning Xia, Ph.D.
`
`Ex. 2038
`Ex. 2039
`Ex. 2121
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`Case IPR2017-01053
`Patent 8,268,299
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` have also relied on my training and experience and the knowledge and
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` I
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`information available to a person of ordinary skill in the art as of September 21,
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`2006.
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`15.
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`I am being compensated for my time at my usual rate of $350 per
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`hour. My compensation is in no way dependent on the outcome of this IPR.
`
`B.
`16.
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`The Person of Ordinary Skill in the Art
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`I understand that the POSA is a hypothetical person who may possess
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`the combined skills of more than one actual person. I have formed an opinion as
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`to the qualifications of the person of ordinary skill in the art to whom the invention
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`of the ’299 patent, Ex. 1001, is directed, as is applicable to my opinions as
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`expressed in this Declaration.
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`17.
`
`In my opinion, the POSA would have had expertise in the
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`development and preservation of ophthalmic formulations. The POSA would have
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`had at least the equivalent of a master’s degree in pharmacy, pharmaceutical
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`sciences, pharmaceutics, chemistry, or a related field, with at least a few years of
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`experience in the development of ophthalmic formulations. The POSA would also
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`have had education in the field of microbiology and/or training or experience in the
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`area of antimicrobial activity of pharmaceutical formulations and preservative
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`efficacy testing, or the ability to consult with microbiologists with such experience.
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`18.
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`I have considered the definition of the person of ordinary skill in the
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`art offered by Argentum in its Petition, Pet. at 7, and in the Declaration of its
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`expert, Dr. Xia, Ex. 1002 ¶¶ 15–17. The opinions I express herein would not
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`change were I to apply Argentum’s definition.
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`19.
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`I have undertaken to determine the knowledge the POSA would have
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`had as of September 21, 2006, which I was asked to assume as the earliest priority
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`date of the ’299 patent. When I refer to the POSA in this Declaration, I am
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`referring to a person of ordinary skill in the art as of that date.
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`C. Construction of Claims
`20. For purposes of this declaration, I have been advised by counsel that
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`the Board for purposes of its Institution Decision found that the claim term “self-
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`preserved” as used in the ’299 patent requires “compositions that do not contain a
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`conventional antimicrobial preservative, such as [benzalkonium chloride],
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`polyquaternium-1, chlorite, or hydrogen peroxide.” I.D. at 7–8. I agree with this
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`definition and have applied it in my analysis.
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`D. Background Regarding Calculations
`21.
`In evaluating the claims of the ’299 patent and the disclosures in the
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`art, I have made a number of calculations to convert measurements and amounts
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`from one set of units to another. In particular, I have converted concentrations
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`described as percent weight-by-volume (% w/v)1 to millimolar concentrations
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`(mM).
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`22.
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`I have used a standard method for such conversions. A concentration
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`expressed as % w/v refers to the number of grams of a particular solute per 100 mL
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`of solution. I multiply this by 10 to reflect grams per liter (L) of solution. I then
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`divide this value by the molecular weight (MW) of the solute, which converts
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`% w/v to molarity (M), meaning moles of solute per liter of solution (mol / L).2
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`Multiplying this molarity by 1,000 provides the millimolar (mM) concentration of
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`the solute. Stated as a formula: (cid:3436)(cid:4672)(cid:1875)(cid:1874)%(cid:4673)(cid:3400)10(cid:3440)
`(cid:1839)(cid:1849)
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`(cid:3400)1000(cid:3404)(cid:1865)(cid:1839)
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`1 The same unit is sometimes expressed as “w/v%” or “weight percent by volume,”
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`or some similar variation. There is no difference among these terms. In addition,
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`when terms like “weight percent” or simply “%” are used, the skilled artisan would
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`determine from context whether percent weight-by-volume is meant or whether
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`some other term, such as percent weight-by-weight (“%w/w”) is intended.
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`2 Thus, 1 mM is equal to 1 millimole per liter (which can also be written 1 mmol /
`L).
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`23. For example, to convert 0.0025% w/v zinc chloride (ZnCl2), with a
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`molecular weight of 136.29 (cid:3034)(cid:3040)(cid:3042)(cid:3039), see Ex. 2031 at 1810, to its molar concentration,
`(cid:4672)(cid:4674)0.0025(cid:4672) 1(cid:1859)100 (cid:1865)(cid:1838)(cid:4673)(cid:4675)(cid:3400)10(cid:4673)
`(cid:3400)1000(cid:3404)0.18 (cid:1865)(cid:1839)
`136.29 (cid:1859)/(cid:1865)(cid:1867)(cid:1864)
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`the conversion would be as follows:
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`24. As the terms are used here, the molar concentration of zinc ions in a
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`solution is equal to the molar concentration of the zinc chloride (or other zinc salt
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`having one zinc atom per molecule) added to form the solution. See Ex. 1002 ¶ 22
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`(Declaration of Argentum’s expert Erning Xia, Ph.D.) (“for a zinc salt having one
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`metal atom per molecule, such as ZnCl2, the molar concentration of zinc ions in the
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`claimed compositions is equal to the molar concentration of the zinc salt added to
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`form the composition”).
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`25. To the extent calculations involve weight-by-weight values (typically
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`expressed as “% w/w” or “w/w%”), these values can be treated as numerically
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`equal to percentage weight-by-volume values (% w/v) in the aqueous compositions
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`at issue here, as I note that Dr. Xia agrees. See Ex. 1002 at 27 n.4. Weight-by-
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`weight refers to grams of the solute per 100 grams of solution, while weight-by-
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`volume refers to grams of the solute per 100 mL of solution. Although these units
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`are distinct and the values are not precisely identical, the density of the aqueous
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`compositions discussed here is very close to 1 g/mL (the density of water) and,
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`therefore, 100 mL of solution weighs almost exactly 100 grams. Thus, to convert
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`w/w% to a molar concentration, I treat w/w% as equivalent to % w/v. I therefore
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`apply the same formula described above with respect to % w/v to determine the
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`millimolar concentration of the solute.
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`II. The Disclosures in Schneider, Xia, and Chowhan Would Not Have
`Rendered Obvious the Invention Claimed in the ’299 Patent.
`26. Argentum alleges that all of the claim limitations in the ’299 patent
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`relating to zinc, borate, sorbitol, propylene glycol, anionic species, and pH would
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`have been obvious to the POSA over the combination of Schneider, see Ex. 2007,
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`Xia, see Ex. 1003, and Chowhan, see Ex. 1004. I disagree. For all of the reasons I
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`discuss below, the claimed invention would not have been obvious to the POSA
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`from the combination of Schneider, Xia, and Chowhan. The POSA would have
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`had no reason to combine Schneider with Xia or Chowhan, much less to combine
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`all three of Schneider, Xia, and Chowhan. And even if the POSA were to combine
`
`Schneider, Xia, and Chowhan, the POSA would have been led away from the
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`invention claimed in the ’299 patent.
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`A.
`Schneider
`27. Schneider “relates to storage stable, pharmaceutical compositions
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`containing prostaglandins and surfactants.” Ex. 2007, col. 1 ll.14–17. The
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`invention disclosed in Schneider was that polyethoxylated caster oils unexpectedly
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`enhance the chemical stability of prostaglandins, which have low solubility in
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`water and are generally unstable. Id., col. 1 ll. 21–22, col. 1 ll. 54–56.
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`28. Schneider discloses six formulations it describes as representative of
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`the invention. Each of the six formulations contains mannitol as its tonicity-
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`adjusting agent at concentrations of 4.25% w/v or greater, and no other polyol. See
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`id., col. 7 l. 65–col. 9 l. 42. One of these six compositions—formulation A in
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`Example 2 (column 9) of Schneider (“Schneider Formulation A”)—contains the
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`same ingredients as TRAVATAN®. Ex. 1002 ¶ 37. Schneider Formulation A
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`contains: travoprost (0.004% w/v); a polyethoxylated castor oil known as HCO40
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`(0.5% w/v); tromethamine (0.12% w/v); boric acid (0.3% w/v); mannitol (4.6%
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`w/v); edetate disodium (a salt of EDTA) (0.01% w/v); and BAK (0.015% w/v).
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`Ex. 1007 col. 9 ll. 26–42. The pH of Schneider Formulation A was adjusted to 6 ±
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`0.2. The only ingredient in Schneider Formulation A that the POSA would expect
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`to potentially have a deleterious effect on the antimicrobial activity of zinc would
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`be EDTA.
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`B. Xia
`29. Xia teaches the preservation of ophthalmic compositions through the
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`use of “a preservative-effective amount of a soluble zinc compound and . . . less
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`than a preservative-effective amount of a primary preservative agent, preferably no
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`primary preservative agent.” Ex. 1003 at 3. The POSA would have understood
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`that Xia teaches two methods of preserving an ophthalmic formulation while
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`minimizing eye irritation: (i) the use of zinc alone, and (ii) the use of zinc in
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`combination with a “primary preservative agent,” such as a cationic polymer like
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`polyquaternium-10 (Polymer JR). See Ex. 1003, 3–4. (“Cationic polymers” are
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`sometimes referred to as “polycationic materials.” As used here, both terms refer
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`to the same thing—a type of preservative molecule with multiple cationic
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`functional groups.) Either of these methods, according to Xia, could be used to
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`provide a formulation with sufficient preservative efficacy to pass standard
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`preservative efficacy tests.
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`30. The POSA would also have recognized that Xia discloses multiple
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`ophthalmic formulations that are self-preserved, that is, they satisfy preservative
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`efficacy standards but do not contain a conventional primary preservative.
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`Example 8 of Xia, for example, discloses a composition that contains zinc and
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`EDTA, and passes the preservative efficacy test used by Xia. Ex. 1003 at 20–22.
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`The POSA would not have considered EDTA to be a conventional primary
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`preservative, but would have understood that it possessed antimicrobial activity.
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`See, e.g., Ex. 1003 at 20. In addition, each of Examples 16, 17, and 18 of Xia
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`discloses a composition that (a) contains only zinc as a preservative, and (b) passes
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`the preservative efficacy test used by Xia. Ex. 1003 at 21–23. None of Xia’s
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`example formulations contain polyol. See id. at 14–23.
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`31. The lowest concentration of zinc disclosed in Xia’s examples is in
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`Example 18, which contains a zinc concentration of 0.0065 wt.%. See Ex. 1003 at
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`23. Using the method I described above in paragraphs 22–23, the 0.0065 wt.%
`
`(cid:4672)(cid:4674)0.0065(cid:4672) 1(cid:1859)100 (cid:1865)(cid:1838)(cid:4673)(cid:4675)(cid:3400)10(cid:4673)
`136.29 (cid:1859)/(cid:1865)(cid:1867)(cid:1864)
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`concentration of zinc chloride in Xia is equivalent to 0.48 mM of zinc ions:
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`(cid:3400)1000(cid:3404)0.48 (cid:1865)(cid:1839).
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`32. Xia teaches that this formulation possesses sufficient preservative
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`efficacy to pass standard preservative efficacy tests without any additional
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`conventional preservative. See Ex. 1003 at 21, 23. Xia does not, however, provide
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`any data to suggest that a concentration of zinc lower than 0.0065 wt.% would
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`provide sufficient preservative efficacy in the absence of an additional
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`conventional preservative.
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`33. Xia teaches that Examples 8, 16, 17, and 18, along with all the other
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`compositions disclosed in Xia, would not be harsh or irritating to the eye. Indeed,
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`Xia states expressly that its compositions have “the benefit of being adequately
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`preserved without having a harsh physiological effect such as irritation or
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`discomfort.” Ex. 1003 at 3, 4.
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`34. Xia does not provide the POSA with any reason not to use Polymer
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`JR as a preservative. To the contrary, Xia teaches that Polymer JR would be
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`“useful, based on the present teachings, in the present invention”; that formulations
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`containing zinc and Polymer JR “are gentle preservatives relative to known
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`preservatives and/or antimicrobial agents”; and that far from leading to eye
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`irritation, Polymer JR is “an active agent for the treatment of dry eye.” Ex. 1003 at
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`5, 7, 21.
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`35. Xia also does not provide the POSA with any reason not to use the
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`concentrations of zinc disclosed in Example 18 or the other formulations disclosed
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`in Xia as satisfying preservative efficacy requirements. There is no suggestion, for
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`example, that these concentrations lead to ocular irritation. To the contrary, Xia
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`itself teaches that such concentrations are not irritating, stating that a “zinc
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`compound alone . . . ha[s] a preservative effect” and is a “gentle preservative[]
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`relative to known preservatives and/or antimicrobial agents.” Ex. 1003 at 21.
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`36. Xia further teaches that anionic substances are compatible with its
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`disclosed formulations. According to Xia, “anionic surfactants” and
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`“polyquaternium polymers . . . [which] preferably include[] an ophthalmologically
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`suitable anionic organic or inorganic counterion” “are suitable for use in the
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`present invention.” Ex. 1003 at 5, 13. Further, all of Xia’s example formulations
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`contain sodium chloride as a tonicity-adjusting agent. See Ex. 1003 at 16–19, 22–
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`23. All but one example formulations contain sodium chloride at a concentration
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`of 0.220 wt% (37.6 mM), and the exception includes an even greater concentration
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`(0.450 wt%., or 77 mM).3 See id. The POSA would understand that sodium
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`chloride dissociates into sodium cations and chloride anions when added to an
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`aqueous solution.
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`C. Chowhan
`37. Chowhan teaches that borate-polyol complexes in ophthalmic
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`compositions can enhance the antimicrobial efficacy of antimicrobial agents
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`against fungi “such as A. niger.” Ex. 1004 col. 2, ll. 4–12.
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`38. Chowhan discloses a broad genus of “preferred” polyols that might
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`potentially be combined to form these borate-polyol complexes: “sugars, sugar
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`alcohols and sugar acids, including, but not limited to: mannitol, glycerin,
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`propylene glycol and sorbitol.” Id. col. 3 ll. 4–6. Chowhan teaches mannitol and
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`glycerin as “[e]specially preferred polyols,” of which the “most preferred is
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`mannitol.” Id. col. 3 ll. 7–9. Indeed, Chowhan’s examples all teach the use of
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`either mannitol or glycerin, many at concentrations of 2.0% w/v or greater. See id.
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`cols. 5–10.
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`3 Conversions from wt.% to millimolar concentration were performed using the
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`same formula described above, and is based on a molar mass of NaCl equal to
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`58.44 g/mol. See Ex. 1002 at 40 n.11.
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`39. Although Chowhan discloses that propylene glycol and sorbitol are
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`“preferred” polyols, none of Chowhan’s examples uses sorbitol, and only one uses
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`propylene glycol (in combination with mannitol). See id.
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`40. Chowhan does not suggest that the choice or concentration of polyols
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`will have an impact on preservative efficacy. Although Chowhan suggests polyols
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`might be mixed when it states that borate-polyol complexes may be formed by
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`mixing borate with “polyol(s)”, Chowhan does not teach any reason to mix
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`polyols. See Ex. 1004 col. 3 ll. 10–12. Chowhan’s only example containing two
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`polyols contains such a high concentration of one polyol (propylene glycol; 10%)
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`that the POSA would not understand its inclusion in the formulation to have been
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`for the purpose of forming borate-polyol complexes. See id. col. 7 ll. 10–30.
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`Likewise, Chowhan teaches a total polyol concentration range of 0.5 to 6.0%, but
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`does not suggest particular concentrations of particular polyols within that range.
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`Id. col. 3 ll. 42–45.
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`41. Moreover, Chowhan contains no data showing that borate-polyol
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`complexes have an appreciable impact on bacterial populations. The only
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`antimicrobial data in Chowhan are found in Examples 10, 11, and 12. Examples
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`11 and 12 do not contain data regarding bacteria at all; they simply provide data
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`illustrating that borate-polyol complexes can provide enhanced antimicrobial
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`activity with respect to the fungus A. niger. Example 10 of Chowhan does provide
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`bacterial data, but these data do not show antibacterial activity of borate-polyol
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`complexes. Example 10 compared two formulations, one which contained a
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`borate-polyol complex and one that did not. No improvement in efficacy was
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`shown with respect to bacteria in the formulation containing a borate-polyol
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`complex as compared to the formulation without a borate-polyol complex; the
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`efficacy difference that the POSA would understand this Example to be illustrating
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`relates, rather, to “certain organisms, such as A. niger”—i.e., to fungi. Ex. 1004
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`col. 8 l. 45–col. 9 l. 65.
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`D. Because Xia Solved the Problem Presented, the POSA Would
`Have Had No Reason to Combine Schneider with Xia
`42. Argentum alleges that the POSA “would have been motivated to
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`combine Xia and Schneider in order to improve Schneider’s ophthalmic
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`formulation containing a glaucoma agent by removing a source of toxicity,
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`discomfort, and irritation to the eye—BAC.”4 Ex. 1002 ¶ 47; Pet. at 14. “A POSA
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`would therefore have been motivated to replace the [BAK] with zinc ions as
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`suggested by Xia.” Ex. 1002 ¶ 47. I disagree for two reasons.
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`43. First, the POSA’s motivation was broader than merely formulating a
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`prostaglandin analogue composition that was less toxic than the formulations in
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`Schneider. Rather, the POSA was motivated to create multi-dose ophthalmic
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`formulations that employed preservative systems that were less toxic than
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`4 “BAC” and “BAK” are both accepted abbreviations for benzalkonium chloride.
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`traditional preservatives and yet passed preservative efficacy standards such as the
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`U.S. Pharmacopeia guidelines. Dr. Xia apparently agrees. Ex. 1002 ¶ 33 (“Well
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`before 2006, there had been significant movement in the field of ophthalmic
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`preservation away from the use of ‘traditional’ chemical preservative strategies
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`that were less harsh to the eye.”).
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`44. Accordingly, the POSA with that broader motivation would not use as
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`a starting point a patent narrowly focused on “prostaglandin compositions.”
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`Instead, the POSA would have been motivated to do what Dr. Xia himself did,
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`which was to develop a basic BAK-free multi-use ophthalmic formulation that
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`could be used as a vehicle for a variety of different active ingredients. Xia, for
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`example, describes its compositions as potentially including “glaucoma agents,
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`such as beta-blockers, muscarinics and carbonic anhydrase inhibitors;
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`dopaminergic agonists and antagonists; anti-infectives; non-steroidal and steroidal
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`anti-inflammatories, prostaglandins; proteins; growth factors and anti-allergics.”
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`Ex. 1003 at 12.
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`45. Second, even if the POSA were to use Schneider as a starting point for
`
`making a new formulation, and thus started out with the composition of Schneider,
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`the