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`
`UNITED STATES PATENT AND TRADEMARK OFFICE
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`
`BEFORE THE PATENT TRIAL AND APPEAL BOARD
`
`
`APOTEX CORP.,
`Petitioner
`
`v.
`
`ALCON RESEARCH, LTD.,
`Patent Owner.
`
`
`Case IPR2013-00428
`U.S. Patent No. 8,268,299 B2
`
`
`
`
`DECLARATION OF SOUMYAJIT MAJUMDAR, Ph.D.
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`1
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`ALCON 2003
`Apotex Corp. v. Alcon Research, Ltd.
`Case IPR2013-00428
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`

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`
`TABLE OF CONTENTS
`
`
`I.
`
`II.
`
`V.
`
`Introduction ...................................................................................................... 3
`A.
`Background and Qualifications ............................................................. 5
`B.
`The Person of Ordinary Skill in the Art ................................................ 9
`C.
`Construction of Claims ........................................................................ 10
`D.
`Background Regarding Calculations ................................................... 10
`The Disclosures in Xia and Chowhan Would Not Have Rendered
`Obvious the Invention Claimed in the ’299 Patent. ...................................... 12
`Because Xia Solved the Problem Presented, the POSA Would
`A.
`Have Had No Reason to Combine Xia and Chowhan. ....................... 13
`Even if the POSA Sought to Improve Upon Xia, the POSA
`Would Not Have Had Reason to Practice the Claimed
`Invention. ............................................................................................. 15
`Limiting the Concentration of Anionic Species Would Not
`Have Been Obvious to the POSA. ...................................................... 26
`The ’299 Patent’s Propylene Glycol and Sorbitol Limitations
`Would Not Have Been Obvious to the POSA. ................................... 30
`III. The Disclosures in Xia and Chowhan Combined with the Disclosures
`in Gadd Would Not Have Rendered Obvious the Invention Claimed in
`the ’299 Patent. .............................................................................................. 37
`IV. The Disclosures in Xia and Chowhan Combined with the Disclosures
`in the TRAVATAN® Label Would Not Have Rendered Obvious the
`Invention Claimed in the ’299 Patent. ........................................................... 41
`The Disclosures in Xia, Chowhan, Gadd and the TRAVATAN® Label
`Combined Would Not Have Rendered Obvious the Invention Claimed
`in the ’299 Patent. .......................................................................................... 46
`
`B.
`
`C.
`
`D.
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`2
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`I.
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`I, Soumyajit Majumdar, Ph.D., hereby declare as follows:
`
`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.
`
`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 Apotex Corp.
`
`(“Apotex”) to institute this Inter Partes Review (“IPR”) regarding the purported
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`obviousness of claims 1-28 of U.S. Patent No. 8,268,299 (the “’299 patent”). I
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`understand from counsel that the following are the four grounds of obviousness at
`
`issue:
`
`Ground 1: Obviousness of claims 1, 2, 4, 8, 16, 17, and 20 over World
`
`Intellectual Property Organization International Patent Application Number
`
`2005/097067 A1 (“Xia”), APO 1003, and United States Patent No.
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`6,143,799 (“Chowhan”), APO 1004;
`
`Ground 2: Obviousness of claims 1-4, 8, 9, and 13-21 over Xia, Chowhan,
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`and Gadd et al., “Microorganisms and Heavy Metal Toxicity,” Microbial
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`Ecology, 4:303-317 (1978) (“Gadd”), APO 1005;
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`Ground 3: Obviousness of claims 5-7 and 28 over Xia, Chowhan, and the
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`FDA Approved Drug Label for “TRAVATAN® (travoprost ophthalmic
`
`solution) 0.004% sterile” (“TRAVATAN® Label”), APO 1006; and
`3
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`Ground 4: Obviousness of claims 10-12 and 22-28 over Xia, Chowhan,
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`Gadd, and the TRAVATAN® Label.
`
`3.
`
`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
`
`compositions would have been obvious from the perspective of one of ordinary
`
`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”).
`
`4.
`
`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
`
`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
`
`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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`4
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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 twelve 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
`
`Institutes of Health.
`
`6.
`
`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
`
`would have understood, known or concluded as of the priority date.
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`7.
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`I am currently an Associate Professor of Pharmaceutics at the
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`University of Mississippi in Oxford, Mississippi. In addition to my position at the
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`University of Mississippi, I am also a Research Associate Professor at the Research
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`Institute of Pharmaceutical Sciences, and an Associate Director of the Pii Center
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`for Pharmaceutical Technology at the University of Mississippi’s Department of
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`Pharmaceutics. As Associate Director of the Pii Center for Pharmaceutical
`
`Technology, among other things, I help to develop novel ophthalmic formulations.
`
`8.
`
`I received a Ph.D. from the University of Missouri-Kansas City in
`
`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.
`
`9.
`
`Over the years, I have authored and co-authored more than 40 peer-
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`reviewed articles, published in, among other journals: Current Eye Research,
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`Molecular Pharmaceutics, AAPS PharmSci, Clinical Research and Regulatory
`
`Affairs, International Journal of Pharmaceutics, Journal of Ocular Pharmacology
`
`and Therapeutics, Expert Opinion on Drug Delivery, Journal of Ocular
`
`Pharmacology and Therapeutics, Drug Development and Industrial Pharmacy,
`
`Pharmaceutical Research, Drug Metabolism and Disposition, Journal of
`
`Pharmaceutical Sciences, and The Journal of Pharmacy and Pharmacology. I
`
`have also authored two book chapters, both dealing with ophthalmic formulation.
`
`Many of these publications have dealt with the investigation of physical and
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`6
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`chemical stability, complex formation and ionic interactions within ophthalmic
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`formulations.
`
`10.
`
`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,
`
`Journal of Ocular Pharmacology and Therapeutics, Journal of Pharmaceutical
`
`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.
`
`11.
`
`I teach numerous university courses on pharmaceutical sciences,
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`including Basic Pharmaceutics, Industrial Pharmacy, and Advanced
`
`Pharmacokinetics, which covers Biopharmaceutics and Pharmacokinetics. As a
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`professor, I have also advised numerous graduate students, some of whom have
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`received awards and fellowships on the basis of their research.
`
`12.
`
`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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`Award, the American Association of Indian Pharmaceutical Scientists’ AAIPS
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`7
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`(“AAIPS”) Research Award, and the University of Missouri-Kansas City’s School
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`of Graduate Studies Distinguished Dissertation Fellowship Award.
`
`13. My complete curriculum vitae is attached as AL 2004.
`
`14.
`
`I am relying the following documents with respect to the opinions set
`
`forth herein:
`
`Exhibit No. Description
`Apotex’s Petition for Inter Partes Review
`N/A
`Alcon’s Preliminary Response to Apotex’s Petition for Inter
`N/A
`Partes Review
`N/A
`Institution Decision
`APO 1001 United States Patent No. 8,268,299
`APO 1002 Declaration of Michael J. Miller, Ph.D.
`APO 1003 World Intellectual Property Organization International Patent
`Application Number 2005/097067 A1
`APO 1004 United States Patent No. 6,143,799
`APO 1005 Gadd et al., “Microorganisms and Heavy Metal Toxicity,”
`Microbial Ecology, 4:303-317 (1978)
`FDA Approved Drug Label for “TRAVATAN® (travoprost
`ophthalmic solution) 0.004% sterile”
`Transcript, Deposition of Michael J. Miller, Ph.D.
`Declaration of George G. Zhanel, Ph.D.
`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
`United States Patent No. 5,741,817
`United States Patent No. 6,872,705
`
`APO 1006
`AL 2002
`AL 2005
`AL 2048
`AL 2049
`AL 2050
`
`AL 2051
`AL 2052
`AL 2053
`AL 2054
`AL 2055
`
`
`
`8
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`I have also relied on my training and experience and the knowledge and
`
`information available to a person of ordinary skill in the art as of September 21,
`
`2006.
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`15.
`
`I am being compensated for my time at my usual rate of $350 per
`
`hour. My compensation is in no way dependent on the outcome of this IPR.
`
`B.
`16.
`
`The Person of Ordinary Skill in the Art
`
`I understand that the POSA is a hypothetical person who may possess
`
`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
`
`of the ’299 patent, APO 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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`9
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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 Apotex in its Petition, Pet. 7, and in the Declaration of its expert, Dr.
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`Miller, APO 1002 ¶ 15. The opinions I express herein would not change were I to
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`apply Apotex’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 in its Institution Decision ruled that the claim term “self-preserved” as
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`used in the ’299 patent requires “compositions that do not contain a conventional
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`antimicrobial preservative, such as benzalkonium chloride, polyquaternium-1,
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`chlorite, or hydrogen peroxide.” I.D. at 6 (emphasis omitted). I agree with this
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`definition and have applied it in my analysis.
`
`D. Background Regarding Calculations
`21.
`In evaluating the claims of the ’299 patent and the disclosures in the
`
`art, I have made a number of calculations to convert measurements and amounts
`
`from one set of units to another. In particular, I have converted concentrations
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`described as weight percent (wt.%), or percentage weight-by-volume (w/v%) to
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`10
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`millimolar concentrations (mM), and vice versa. At times, I have also made
`
`calculations using concentrations described as percentage weight-by-weight
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`(w/w%).
`
`22.
`
`I have used a standard method for such conversions. To convert
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`w/v% to a millimolar concentration, I begin with the w/v%, which is grams of a
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`particular solute in 100 mL of solution. Next, I multiply this by 10 to reflect grams
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`per liter (L) of solution. I then divide this value by the molecular weight (MW) of
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`the solute, which converts w/v% to molarity (M), meaning moles of solute per liter
`
`of solution (mol / L). Multiplying this molarity by 1,000 provides the millimolar
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`(mM) concentration of the solute. Stated as a formula:
`
`(cid:3436)(cid:4672)(cid:1875)(cid:1874)%(cid:4673)×10(cid:3440)
`×1000=(cid:1865)(cid:1839)
`(cid:1839)(cid:1849)
`molecular weight of 136.29 (cid:3034)(cid:3040)(cid:3042)(cid:3039), to its molar concentration, the conversion would
`(cid:4672)(cid:4674)0.0025×(cid:4672) 1(cid:1859)100 (cid:1865)(cid:1838)(cid:4673)(cid:4675)×10(cid:4673)
`×1000=0.18 (cid:1865)(cid:1839)
`136.29 (cid:1859)/(cid:1865)(cid:1867)(cid:1864)
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`23. For example, to convert 0.0025 w/v% zinc chloride (ZnCl2), with a
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`be as follows:
`
`24. As the terms are used here, the molar concentration of zinc ions in a
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`composition is equal to the molar concentration of the zinc chloride (or other zinc
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`salt having one zinc atom per molecule) added to form the composition. See APO
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`1002 ¶ 20 (Declaration of Apotex’s expert Michael J. Miller, Ph.D.) (“for a zinc
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`salt having one metal atom per molecule, such as ZnCl2, the molar concentration of
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`zinc ions in the claimed compositions is equal to the molar concentration of the
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`zinc salt added to form the concentration”).
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`25. To the extent calculations involve weight-by-weight (w/w%) values,
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`these values can be treated as numerically equal to percentage weight-by-volume
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`(w/v%) in the aqueous compositions at issue here. See APO 1002, 23 n.4.
`
`Weight-by-weight refers to grams of the solute per 100 grams of solution, while
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`weight-by-volume refers to grams of the solute per 100 mL of solution. Although
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`these units are distinct, treating them as identical numerically is appropriate in
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`dilute solutions like the ones at issue here, because the density of such solutions is
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`near 1 (the density of water) and, therefore, 100 mL of solution weighs almost
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`exactly 100 grams. Thus, to convert w/w% to a molar concentration, I treat w/w%
`
`as equivalent to w/v%. I therefore apply the same formula described above with
`
`respect to w/v% to determine the millimolar concentration of the solute.
`
`II. The Disclosures in Xia and Chowhan Would Not Have Rendered
`Obvious the Invention Claimed in the ’299 Patent.
`26. Apotex alleges that all of the claim limitations in the ’299 patent
`
`relating to zinc, borate, sorbitol, propylene glycol, and anionic species would have
`
`been obvious to the POSA over the combination of Xia, see APO 1003, and
`
`Chowhan, see APO 1004. I disagree. For all of the reasons I discuss below, the
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`12
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`claimed invention would not have been obvious to the POSA from the combination
`
`of Xia and Chowhan. The POSA would have had no reason to combine Xia with
`
`Chowhan, and even if the POSA were to combine the references, the POSA would
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`have been led away from the invention claimed in the ’299 patent.
`
`A. Because Xia Solved the Problem Presented, the POSA Would
`Have Had No Reason to Combine Xia and Chowhan.
`27. The POSA would not have had a reason to combine Xia with
`
`Chowhan. I understand that Apotex’s expert, Dr. Miller, characterized the problem
`
`facing the POSA as of the priority date as being that “certain preserved ophthalmic
`
`formulations were potentially toxic or harsh to the eye,” and therefore, that the
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`POSA would have sought to formulate “an acceptable ophthalmic formulation that
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`would limit or eliminate this potential toxicity but still provide for a robust
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`antimicrobial formulation.” AL 2002, 144:19–145:1.
`
`28. The POSA as of September 2006 would have recognized, however,
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`that this problem was already solved by Xia, and the POSA would have had no
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`reason to modify Xia, let alone to combine Xia with Chowhan.
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`29. The POSA would have understood that Xia teaches two methods of
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`preserving an ophthalmic formulation while minimizing eye irritation: (i) the use
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`of zinc alone, and (ii) the use of zinc in combination with a “primary preservative
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`agent,” such as a cationic polymer like Polymer JR. See APO 1003, 3–4.
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`(“Cationic polymers” are sometimes referred to as “polycationic materials.” As
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`used here, both terms refer to the same thing—a type of preservative molecule with
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`multiple cationic functional groups.) Either of these methods, according to Xia,
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`could be used to provide a formulation with sufficient preservative efficacy to pass
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`standard 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 preservative. Each of
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`Examples 16, 17, and 18 of Xia, for example, discloses a composition that (a)
`
`contains only zinc as a preservative, and (b) passes the preservative efficacy test
`
`utilized in the reference. APO 1003, 21–23.
`
`31. Xia teaches, and the POSA would have expected, that these
`
`formulations would not be harsh or irritating to the eye. Xia states as much,
`
`describing how the compositions have “the benefit of being adequately preserved
`
`without having a harsh physiological effect such as irritation or discomfort.” APO
`
`1003, 3, 4.
`
`32. Thus, the POSA who was confronting the problem of formulating a
`
`self-preserved ophthalmic formulation that was not toxic or harsh to the eye would
`
`have recognized that Xia had already solved this problem, and therefore, would not
`
`have had a reason to combine Xia with Chowhan.
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`14
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`B.
`
`Even if the POSA Sought to Improve Upon Xia, the POSA Would
`Not Have Had Reason to Practice the Claimed Invention.
`33. As discussed above, Xia described formulations containing zinc as the
`
`only preservative that satisfy stringent preservative efficacy standards and thus
`
`already solved the problem facing the field posited by Apotex. Even if one were to
`
`assume, however, that the POSA would have been motivated to improve upon the
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`already-acceptable level of preservative efficacy taught by Xia, the POSA would
`
`not have had reason to make the claimed invention. Rather, such a motivation
`
`would have led the POSA away from the invention claimed in the ’299 patent.
`
`34. The POSA, if motivated to improve upon Xia, would have used as the
`
`starting point the example formulations Xia teaches which satisfied the
`
`requirements for preservative efficacy. The lowest concentration of zinc disclosed
`
`in Xia’s examples is in Example 18, which contains a zinc concentration of 0.0065
`
`wt.%. See APO 1003, 16–23. This formulation uses zinc as the only preservative
`
`ingredient. Xia teaches that this formulation possesses sufficient preservative
`
`efficacy to pass standard preservative efficacy tests without any additional
`
`preservative. See APO 1003, 18, 23.
`
`35. Using the method I described above in paragraphs 22–23, the
`
`0.0065 wt.% concentration of zinc chloride in Xia is equivalent to 0.48 mM of zinc
`
`ions:
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`15
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`(cid:4672)(cid:4674)0.0065×(cid:4672) 1(cid:1859)100 (cid:1865)(cid:1838)(cid:4673)(cid:4675)×10(cid:4673)
`136.29 (cid:1859)/(cid:1865)(cid:1867)(cid:1864)
`
`×1000=0.48 (cid:1865)(cid:1839).
`
`36. The concentration of zinc in Example 18 in Xia is the lowest of the
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`three examples in Xia showing sufficient preservative efficacy with formulations
`
`containing only zinc as a preservative agent (Examples 16, 17, and 18).
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`37. The 0.48 mM concentration taught by Xia to provide sufficient
`
`preservative efficacy without the inclusion in the formulation of another
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`preservative agent is higher than the highest concentration of zinc claimed in the
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`’299 patent, i.e., 0.4mM, which is found in claims 1-26. This concentration of
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`0.0065 wt.% is also more than twice the concentration of zinc ions allowed in
`
`claims 27 and 28, which include the limitations of “ionized zinc chloride at a
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`concentration of 0.0025% w/v” and “zinc chloride ionized in the composition at a
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`concentration of 0.0025% w/v,” respectively, each of which requires that 0.0025%
`
`w/v zinc chloride be included in the composition. APO 1001, col.29 l. 17, col.29
`
`ll.39–40. Using the conversion I describe above in paragraphs 22–23, 0.0025%
`
`(cid:4672)(cid:4674)0.0025×(cid:4672) 1(cid:1859)100 (cid:1865)(cid:1838)(cid:4673)(cid:4675)×10(cid:4673)
`136.29 (cid:1859)/(cid:1865)(cid:1867)(cid:1864)
`
`w/v is equivalent to 0.18 mM:
`
`×1000=0.18 (cid:1865)(cid:1839).
`
`
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`38. The POSA would not have had a reason to decrease the concentration
`
`of zinc below the 0.0065 wt.% (0.48mM) disclosed in Xia Example 18. Xia does
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`not provide any data to substantiate the notion that a concentration of zinc lower
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`than the 0.0065 wt.% (0.48 mM) concentration of Example 18 would provide
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`sufficient preservative efficacy in the absence of an additional preservative.
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`39. Xia also does not teach any problem with the concentrations of zinc
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`disclosed in Example 18 or the other formulations disclosed in Xia as satisfying
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`preservative efficacy requirements. There is no suggestion that these
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`concentrations lead to ocular irritation. To the contrary, Xia itself teaches that such
`
`concentrations are not irritating, stating that a “zinc compound alone . . . ha[s] a
`
`preservative effect” and is a “gentle preservative[] relative to known preservatives
`
`and/or antimicrobial agents.” APO 1003, 21. The POSA would have understood
`
`that zinc salts are commonly and safely used as an ophthalmic astringent at
`
`concentrations of around 0.25% w/v, which is many times higher than the highest
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`concentration of zinc chloride used in any of Xia’s examples. AL 2048, 7089
`
`(regulatory determination that zinc sulfate is “generally recognized as safe” at a
`
`concentration of 0.25%). The POSA would therefore have understood from Xia
`
`that formulations containing zinc at the concentrations described in its examples
`
`which satisfy preservative efficacy are not irritating to the eye. Thus, the POSA
`
`would not have had any reason to decrease the amount of zinc below the 0.0065
`
`wt.% (0.48 mM) taught in Xia’s Example 18.
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`17
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`40.
`
`Independent of its examples, Xia lists a broad range of zinc
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`concentrations for use in its two methods—(i) the use of zinc alone, and (ii) the use
`
`of zinc in combination with a “primary preservative agent,” such as a polycationic
`
`material like Polymer JR—that extends “from a minimum of about 0.001 wt.%” or
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`“about 0.005 wt.%.” See APO 1003, 5.
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`41. Using the method described above in paragraphs 22–23, 0.001 wt.% is
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`(cid:4672)(cid:4674)0.001×(cid:4672) 1(cid:1859)100 (cid:1865)(cid:1838)(cid:4673)(cid:4675)×10(cid:4673)
`136.29 (cid:1859)/(cid:1865)(cid:1867)(cid:1864)
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`equivalent to 0.073 mM of zinc ions:
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`×1000=0.073 (cid:1865)(cid:1839).
`
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`For purposes of my analysis, I have used a concentration of 0.074 mM—the same
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`value Dr. Miller used—which, under the circumstances, is an acceptable
`
`approximation (based on a molecular weight of zinc rounded to 136 g/mol).
`
`Whether a value of 0.073 mM or 0.074 mM is used does not affect any of the
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`opinions I express in this declaration. Furthermore, using the same method, 0.005
`
`(cid:4672)(cid:4674)0.005×(cid:4672) 1(cid:1859)100 (cid:1865)(cid:1838)(cid:4673)(cid:4675)×10(cid:4673)
`136.29 (cid:1859)/(cid:1865)(cid:1867)(cid:1864)
`
`wt.% is equivalent to 0.37 mM of zinc ions:
`
`×1000=0.37 (cid:1865)(cid:1839).
`
`
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`42. The disclosure of a “minimum” concentration of “about 0.001 wt.%”
`
`would not have led the POSA to lower the concentration of zinc below the 0.0065
`
`wt.% (0.48 mM) disclosed in Example 18, nor would it have led the POSA to the
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`concentrations claimed in the ’299 patent. Xia teaches both the use of zinc alone,
`
`and the use of zinc in combination with a “primary preservative agent,” such as a
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`cationic polymer like Polymer JR. See APO 1003, 3–4. The POSA would have
`
`recognized, however, that the discussion of a “minimum” concentration of zinc to
`
`use with the invention is a generic disclosure that does not necessarily apply to
`
`each of the two methods taught by Xia. Indeed, the POSA would have been
`
`concerned that the “minimum” concentration of zinc (0.001 wt.%), by itself, could
`
`fail preservative efficacy testing (as discussed below), and Xia does not provide
`
`any data to support the notion that zinc alone (without a “primary preservative
`
`agent”) would satisfy preservative efficacy standards at “about 0.001 wt.%.”
`
`43. Moreover, the POSA would not have wanted to decrease the
`
`concentration of zinc below the 0.0065 wt.% (0.48 mM) level taught by Xia
`
`Example 18, because the POSA would have been concerned about the impact on
`
`preservative efficacy. Xia teaches that 0.48 mM of zinc chloride achieves a
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`preservative-effective level of cytotoxicity with respect to five microorganisms:
`
`three bacteria (S. aureus, P. aeruginosa, and E. coli) and two fungi (C. albicans
`
`and A. niger). See APO 1003, 14, 23 (Example 18). However, as I understand
`
`from the Declaration of Dr. George Zhanel, the POSA would have been concerned
`
`that reducing zinc to a level below 0.48 mM would result in a composition that
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`could fail preservative efficacy with respect to at least E. coli and P. aeruginosa,
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`and even risk stimulating bacterial growth. AL 2005 ¶¶ 26–30.
`
`44. Accordingly, the POSA would have understood that the lowest
`
`concentrations of zinc disclosed in Xia are intended for use in the second method
`
`which Xia teaches—the use of zinc in combination with a “primary preservative
`
`agent” such as a cationic polymer like Polymer JR. The “primary preservative
`
`agent” would provide antimicrobial activity and would be expected to compensate
`
`for any diminished antimicrobial activity that could come with using lesser
`
`concentrations of zinc.
`
`45. The POSA, however, would not have expected Chowhan’s borate-
`
`polyol complexes to make up for any diminished antimicrobial activity that could
`
`come with using a concentration of zinc that is less than 0.48 mM, and therefore,
`
`would not have looked to combine Chowhan with Xia. There is no suggestion in
`
`Xia or Chowhan that using borate-polyol complexes with zinc would have the
`
`same effects in terms of the formulation’s overall antimicrobial preservation, as
`
`combining zinc with the cationic polymers, like Polymer JR, specifically taught by
`
`Xia. Furthermore, as discussed below, the POSA would have had particular
`
`reasons not to select a borate-polyol complex given the suggestion in Chowhan
`
`that it will not enhance antibacterial activity. See infra ¶¶ 46–47. Thus, the POSA
`
`would not have expected that Chowhan would overcome any diminished
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`antimicrobial effectiveness that could come with a decrease in the concentration of
`
`zinc. This understanding would have led the POSA away from a combination of
`
`Xia with Chowhan. The POSA would have recognized that Chowhan teaches that
`
`borate-polyol complexes have antimicrobial activity with respect to fungi,
`
`particularly with respect to organisms such as A. niger. See APO 1004, col. 2 ll.5–
`
`10, col. 9 ll.12–63. In contrast, however, the POSA would not have understood
`
`Chowhan to teach that borate-polyol complexes are effective against bacteria. Not
`
`only is there no specific disclosure in Chowhan that borate-polyol complexes have
`
`antimicrobial activity against bacteria specifically, but Chowhan contains no data
`
`showing that the borate-polyol complexes it teaches have an appreciable impact on
`
`bacterial populations.
`
`46. The only antimicrobial data in Chowhan are found in Examples 10,
`
`11, and 12. Examples 11 and 12 do not contain data regarding bacteria at all; they
`
`simply provide data highlighting that borate-polyol complexes can provide
`
`enhanced antimicrobial activity with respect to the fungus A. niger. Example 10 of
`
`Chowhan does provide bacterial data, but these data do not show antibacterial
`
`activity of borate-polyol complexes. Example 10 compared two formulations, one
`
`which contained a borate-polyol complex and one that did not. No improvement in
`
`efficacy was shown with respect to bacteria in the formulation containing a borate-
`
`polyol complex as compared to the formulation without a borate-polyol complex.
`
`21
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`See APO 1004, col. 8 l.45–col. 9 l.65. For these reasons, Chowhan would not have
`
`provided the POSA with an expectation that borate-polyol complexes, if combined
`
`with a concentration of zinc that was less than the amount in Xia Example 18,
`
`would restore any loss in antibacterial activity that could result from such a
`
`reduced concentration of zinc.
`
`47. For all of these reasons, the POSA would not have combined Xia with
`
`Chowhan. Indeed, if the POSA were motivated to use an amount of zinc different
`
`from that used in Xia Example 18, the POSA would have had reason to increase
`
`the concentration of zinc. The POSA would not have expected that increasing the
`
`concentration of zinc above the amount in Xia Example 18 would lead to irritation
`
`or other harsh effects in the eye, given the concentrations disclosed in Xia’s
`
`examples are many times lower than the concentrations known at that time to be
`
`safe for use in the eye. AL 2048, 7089. The POSA would also have recognized
`
`that Xia itself teaches that its ophthalmic compositions have “the benefit of being
`
`adequately preserved without having a harsh physiological effect such as irritation
`
`or discomfort caused by at least some traditional preservative agents.” APO 1003,
`
`3.
`
`48. Nonetheless, even if the POSA were motivated to decrease the
`
`amount of zinc in the formulations disclosed in Xia’s examples, the POSA would
`
`still not have arrived at the claimed invention because the POSA would have had
`
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`no reason to combine Xia with the borate-polyol system taught by Chowhan (as
`
`discussed above).
`
`49. Furthermore, Xia itself teaches that a less-than-preservative-effective
`
`amount of polycationic material, such as Polymer JR, can be used “in conjunction
`
`with a soluble zinc compound” in order to improve its antimicrobial activity. APO
`
`1003,