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`UNITED STATES PATENT AND TRADEMARK OFFICE
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`Case IPR2017-01053
`Patent 8,268,299
`
`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
`
`
`DECLARATION OF GEORGE G. ZHANEL, Ph.D.
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`1
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`ALCON 2025
`Argentum Pharm. LLC v. Alcon Research, Ltd.
`Case IPR2017-01053
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`TABLE OF CONTENTS
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`Case IPR2017-01053
`Patent 8,268,299
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`I.
`
`Introduction ...................................................................................................... 3
`A.
`Background and Qualifications ............................................................. 3
`B. Assignment ............................................................................................ 7
`C.
`The Person of Ordinary Skill in the Art ................................................ 8
`II. Opinions ........................................................................................................... 9
`A.
`The Schneider Patent ............................................................................. 9
`B.
`The Xia Disclosure ................................................................................ 9
`C.
`The POSA Would Have Expected that Compositions
`Combining the Concentrations of Zinc in Xia’s Examples with
`Schneider Formulation A Would Pass Preservative Efficacy
`Testing ................................................................................................. 16
`The POSA Would Not Want to Use a Concentration of Zinc
`that Is Lower than the Concentration Used in Xia Example 18 ......... 19
`The POSA Would Have No Reason to Combine Schneider and
`Xia with Chowhan, and Would Avoid Combining Borate-
`Polyol Complexes with the Claimed Low Concentrations of
`Zinc. ..................................................................................................... 27
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`D.
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`E.
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`2
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`I.
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`
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`I, George G. Zhanel, hereby declare as follows:
`
`Case IPR2017-01053
`Patent 8,268,299
`
`Introduction
`1.
`
`I am over the age of eighteen and am otherwise competent to make
`
`this declaration.
`
`2.
`
`I understand that the Patent Trial and Appeal Board has granted
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`Argentum Pharmaceuticals LLC’s petition to institute this Inter Partes Review
`
`(“IPR”) regarding claims 1-28 of United States Patent No. 8,268,299 (the “’299
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`patent”) on obviousness grounds.
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`A. Background and Qualifications
`3.
`I am currently a Professor in the Department of Medical
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`Microbiology/Infectious Diseases, Max Rady College of Medicine, Rady Faculty
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`of Health Sciences, University of Manitoba, Winnipeg, Canada.
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`4.
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`I received a Ph.D. in Medical Microbiology from the University of
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`Manitoba in 1994 and a Doctor of Pharmacy from the University of Minnesota in
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`1986.
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`5.
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`For approximately the last 30 years, the focus of my work has been
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`antimicrobials and agents with antimicrobial activity.
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`6.
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`I am currently the Chair of the Canadian Antimicrobial Resistance
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`Alliance (CARA) in the Max Rady College of Medicine at the University of
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`Manitoba. I am also the Coordinator of the antimicrobial resistance program in the
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`3
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`
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`Section of Infection Control and Prevention, Department of Internal Medicine at
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`the Health Sciences Centre, Winnipeg, Canada.
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`7.
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`The focus of my research is the study of antimicrobial agents and
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`agents with antimicrobial activity in the treatment and prevention of infectious
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`diseases. Agents with antimicrobial activity include traditional antibiotics used in
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`humans and animals, as well as antiseptics, preservatives, disinfectants, and
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`sterilizers. I gave my first presentation on antimicrobials in 1985 while working
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`toward my Doctor of Pharmacy. In addition, as early as 1985, I began advising
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`clinicians regarding the use and optimization of antimicrobials for the treatment
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`and prevention of infectious diseases, and I began teaching about antimicrobials in
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`1987. The subject of my doctoral thesis in Medical Microbiology, published in
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`1994, was “Cellular and Molecular Evaluation of Fluoroquinolone Resistance in
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`Pseudomonas aeruginosa.”
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`8.
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`By virtue of my education and experience, I am familiar with
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`microorganisms that are likely to grow in liquid pharmaceutical compositions such
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`as ophthalmic solutions, the preservative efficacy standards (“PET”) that
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`pharmaceutical products must meet so as to minimize or inhibit growth of such
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`microorganisms, the testing and evaluation of antimicrobial agents, and the testing
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`and evaluation of the preservative efficacy of pharmaceutical formulations. As
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`
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`4
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`
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`part of my education and experience, I have also prepared numerous
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`pharmaceutical formulations, including topical ophthalmic formulations.
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`9.
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`I currently teach medical students at the University of Manitoba in the
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`first, second, third and fourth years of the Medical curriculum. I also teach internal
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`medicine residents and medical microbiology/infectious diseases postdoctoral
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`fellows. In addition, I teach physician assistants, nurse practitioners, and Masters
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`and Doctoral students in both Medical Microbiology and Clinical Pharmacology,
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`as well as undergraduate students in Science, Pharmacy, Nursing and Medical
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`Technology.
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`10. My work on antimicrobials has led me to serve as a consultant
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`(through advisory boards or otherwise) to many pharmaceutical/biotech
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`companies. These companies include the following companies and/or their
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`affiliates: Abbott, Achaogen, Affinium, Allergan, Astellas, AstraZeneca, Avir,
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`Bayer, Cangene, Cerexa/Forest Labs, Cubist, GlaxoSmithKline, Janssen
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`Ortho/Ortho McNeil, Kane BioTech, Merck, Novexel, Optimer, Paladin Labs,
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`Paratek, Pfizer, Procter & Gamble, Sanofi-Aventis, Sunovion, The Medicines Co.,
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`Tetraphase, Theravance, Triton, Trius, Verity, and Zoetis. As part of my research
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`and consultancy role for these companies, I am routinely called on to provide
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`advice concerning the potential indications for antimicrobials based on a
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`compound’s properties, as well as to make comparative evaluations among
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`5
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`
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`antimicrobials. Specific topics on which I am asked to advise include comparative
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`mechanism of action and resistance, in-vitro activity and factors that influence
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`antimicrobial activity, pharmacokinetics and pharmacodynamics, animal studies
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`including efficacy and toxicity, and clinical uses including indications, adverse
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`effects in humans, drug interactions, the risks versus benefits of antimicrobial
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`treatment and prevention, and pharmacoeconomics. The guidance I provide to
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`companies on scientific matters generally pertains to particular indications and
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`uses for antimicrobial compounds.
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`11.
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`I am frequently consulted by clinical specialists and generalists on
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`matters pertaining to the treatment and prevention of infections, especially
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`antimicrobial resistant infections, including the treatment and prevention of
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`ophthalmic infections. These consultations focus on the selection of specific
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`antimicrobials, dosages, and dosage regimens; risk-benefit analyses of particular
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`antimicrobial treatments; and the monitoring of patients to determine the efficacy
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`and/or toxicity of selected antimicrobial treatments. These consultations range
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`from accompanying physicians to bedside visits to, more commonly, telephone
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`consultations (local or with clinicians from all over the world), hallway discussions
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`and discussions at medical/scientific meetings.
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`12.
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`In formulating my opinions discussed herein, I have relied upon my
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`training, knowledge, and experience, as well as the various materials discussed
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`6
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`
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`herein. I have also considered: (1) Argentum’s Petition for Inter Partes Review;
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`(2) the Declaration of Erning Xia, Ph.D., Ex. 1002; (3) the references cited in Dr.
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`Xia’s declaration; and (4) the transcript of Dr. Xia’s deposition testimony, Ex.
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`2121. A copy of my current curriculum vitae is provided as Exhibit 2026.
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`13.
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`I am being compensated for my time at my usual rate of $500 per
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`hour. My compensation is in no way dependent on the outcome of this proceeding.
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`B. Assignment
`14.
`I have been retained by Williams & Connolly LLP on behalf of Alcon
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`Research, Ltd. (“Alcon”) to serve as an expert witness in these proceedings.
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`15.
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`I have been asked to opine on various issues that I understand to relate
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`to whether the compositions claimed in the ’299 patent would have been obvious
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`to the person of ordinary skill in the art (“POSA”), described in Section I.C below,
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`including issues related to (1) the use of zinc as an antimicrobial agent; (2) the
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`antimicrobial activity of the zinc compositions that are the subject of World
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`Intellectual Property Organization International Patent Application Number
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`2005/097067 A1 (“Xia”), Ex. 1003, (3) the antimicrobial activity of the water-
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`soluble borate-polyol complexes that are the subject of United States Patent
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`Number 6,143,799 (“Chowhan”), Ex. 1004, (4) the antimicrobial activity of
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`hypothetical compositions formulated by combining elements of the zinc
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`compositions that are the subject of Xia with the ophthalmic prostaglandin
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`7
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`compositions that are the subject of United States Patent Number 6,011,062
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`(“Schneider”), Ex. 1007, and (5) the antimicrobial activity of the compositions
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`claimed in the ’299 patent, Ex. 1001.
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`C. The Person of Ordinary Skill in the Art
`16.
`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. With respect to the ’299
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`patent, one technical aspect involved in the inventions described in the patent is the
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`use of antimicrobial agents as preservatives in multi-dose ophthalmic
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`compositions. Accordingly, in my opinion, the hypothetical POSA would have, in
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`addition to other education and experience relevant to the preparation of
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`ophthalmic formulations, (a) education in the area of microbiology, and/or (b)
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`training and/or experience in the area of antimicrobial activity of pharmaceutical
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`formulations and preservative efficacy testing.
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`17.
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`I have considered the definition of the person of ordinary skill in the
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`art provided in the Declaration of Dr. Xia. Ex. 1002 ¶¶ 15-17. The opinions I
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`express herein would not change were that definition applied.
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`18.
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`I have undertaken to determine the knowledge a POSA would have
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`regarding the use of antimicrobial agents as preservatives in multi-dose ophthalmic
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`compositions as of September 21, 2006 (the “priority date”), which I have been
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`advised is the relevant date for making this determination. When I refer to a POSA
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`8
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`in this Declaration, I am referring to a person of ordinary skill in the art as of that
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`date.
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`II. Opinions
`A. The Schneider Patent
`19. Schneider states that it “relates to storage stable, pharmaceutical
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`compositions containing prostaglandins and surfactants.” Ex. 2007, col. 1 ll. 14-
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`17. Schneider discloses ingredients for six example compositions. Id. at col. 7-9.
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`Dr. Xia states that Formulation A in column 9 of Schneider (“Schneider
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`Formulation A”) sets forth the same ingredients as TRAVATAN®. Ex. 1002 ¶ 37.
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`20. The POSA would have understood that the benzalkonium chloride in
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`Schneider Formulation A was that formulation’s primary antimicrobial agent. The
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`POSA would have also known that the EDTA and tromethamine present in that
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`composition have antimicrobial activity, and that their antimicrobial activity was
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`known to be synergistic.
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`21. Schneider does not provide any data about the antimicrobial
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`effectiveness of its compositions, including Schneider Forumulation A.
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`B.
`The Xia Disclosure
`22. Xia states that it “relates to a composition that includes a preservative-
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`effective amount of a soluble zinc compound and has less than a preservative-
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`9
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`effective amount of a primary preservative agent.” Ex. 1003 at 3.1 Xia further
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`provides that, in its preferred embodiment, the composition does not contain any
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`primary preservative agent in addition to zinc. Id. Xia defines “primary
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`preservative agents” to mean “non-zinc containing compounds that derive their
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`preservative activity through a chemical or physiochemical interaction with the
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`microbial organisms.” Id. at 4. The POSA would recognize that there are many
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`such compounds; Xia discloses various classes of such agents, and in particular
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`suggests the use of Polymer JR. Id. at 3. Xia neither refers to nor suggests use of a
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`borate-polyol complex as a preservative system to be combined with zinc.
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`23. According to Dr. Xia, Xia teaches compositions that contain zinc,
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`borate, and propylene glycol. Ex. 1002 ¶ 38. While many of the examples in Xia
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`contain zinc and borate, none of Xia’s examples contain propylene glycol. The
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`sole mention of propylene glycol in the compositions discussed in Xia is as its
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`optional use as a comfort agent. Ex. 1003 at 14. Xia does not suggest that it is
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`advantageous to combine borate, zinc, and propylene glycol rather than borate,
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`1 Citations to page numbers in Exhibit 1003 are to the page numbers in the
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`reference itself, and not to the smaller page numbers added, presumably by
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`Argentum, at the bottom of the pages. This appears to be consistent with Dr. Xia’s
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`practice based on the citations in his declaration, and so I am following his lead.
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`10
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`zinc, or some other comfort agent such as glycerol, nor does it disclose any
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`example formulations that contain all three of those ingredients. It is only with
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`hindsight knowledge of the inventions claimed in the ’299 patent, and their
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`successful use of zinc, borate, and polyols including propylene glycol in a
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`preservative system, that the POSA would have any reason to attach significance to
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`Xia’s mention of propylene glycol.2
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`24. Furthermore, while Xia discloses that zinc may be combined with
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`“primary preservative agents,” nowhere does it suggest that borate, polyol, or
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`borate-polyol complexes are such agents. Nor does it suggest that borate-polyol
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`complexes are relevant to antimicrobial activity, or even refer to borate-polyol
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`complexes at all. The POSA therefore would not understand Xia to disclose
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`compositions that use a zinc-borate-polyol preservative system, or to provide any
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`2 Xia states that it was known as of September 2006 that propylene glycol had
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`antimicrobial activity. Ex. 1002 ¶ 35. But Xia does not cite any reference to
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`support this statement, he does not explain whether propylene glycol has broad or
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`narrow spectrum antimicrobial activity, and he does not explain the concentrations
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`at which propylene glycol has antimicrobial activity and whether it demonstrates
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`synergistic activity with known preservatives or agents with antimicrobial activity.
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`11
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`
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`reason to combine zinc plus borate plus a polyol as a means to improve
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`preservative efficacy.
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`25.
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`In terms of zinc content, Xia states that the Xia invention “teaches
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`self-preserved, antimicrobial ophthalmic compositions containing zinc compounds
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`at concentrations of a ‘minimum of about 0.001 wt.%, about 0.005 wt.%, about
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`0.01 wt.%, or about 0.05 wt.% of a zinc compound per total weight of the
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`composition and/or a maximum of about 1 wt.%, about 0.5 wt.%, about 0.1 wt.%
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`or about 0.05 wt.% of the zinc compound per total weight of the composition.’”
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`Ex. 1002 ¶ 38 (emphasis added) (quoting Ex. 1003 at 5). I disagree.
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`26. Xia discusses two different ways of providing preservative efficacy to
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`a formulation: (1) using zinc ions, without any other preservative agents; and (2)
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`using zinc ions in combination with a “primary” preservative agent, such as a
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`cationic polymer like Polymer JR. Ex. 1003 at 3. Because Xia’s discussion of the
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`minimum concentrations of zinc is part of a general discussion of Xia’s invention
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`and not about formulations using zinc as the lone preservative in particular, and
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`given other prior art concerning the properties of zinc as a preservative agent
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`(discussed further below), the POSA would not understand Xia to suggest that zinc
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`at a concentration of 0.001 wt.% or 0.005 wt.% can provide adequate antimicrobial
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`activity for a formulation to meet PET requirements without a primary preservative
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`agent. Rather, the POSA would understand the lowest concentrations of zinc
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`12
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`disclosed in Xia to be referring to concentrations that may be used in combination
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`with a primary preservative agent (such as a cationic polymer) that can provide
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`broad spectrum antimicrobial activity and therefore can potentially make up for or
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`remedy deficiencies in antimicrobial activity that the POSA would be concerned
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`could result from use of lower concentrations of zinc. In other words, the POSA
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`would understand that the low ends of the zinc concentration ranges (0.001 wt.%
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`or 0.005 wt.%) in Xia were intended for compositions with an additional primary
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`preservative (such as a cationic polymer), not for compositions using zinc alone.
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`27. Regarding the preservative efficacy discussed in the Xia reference, it
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`states that it uses the FDA/ISO 14730 preservative efficacy test, Ex. 1003 at 14,
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`which is one of the standard preservative efficacy tests discussed in the
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`specification of the ’299 patent, see Ex. 1001, col. 7 ll. 46-50. The FDA/ISO
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`14730 test differs in some respects from the USP 27 preservative efficacy test that
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`is referred to in the claims of the ’299 patent, but the differences between the two
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`tests would not be regarded as significant by the POSA. For bacteria, the USP 27
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`test requires a reduction of 1 log (90%) by day 7, 3 logs (99.9%) by day 14, and no
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`increase after day 14; the FDA/ISO 14730 test does not require a measurement at
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`day 7, but like the USP 27 standard requires a reduction of 3 logs (99.9%) by day
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`14. Ex. 1001, col. 7 ll. 33–50. Rather than requiring no increase after day 14, the
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`FDA/ISO standard requires a rechallenge inoculation after the day 14 measurement
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`13
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`is made, and then at least a 3 log reduction from the rechallenge inoculation at day
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`28. Id. For fungi, the USP 27 standard requires no increase in fungi relative to the
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`initial inoculum throughout the 28-day test period; the FDA/ISO standard requires
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`no increase in fungi relative to the initial inoculum at day 14, and no increase
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`relative to the rechallenge inoculum at day 28. Id. The Xia reference defines
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`“preservative-effective amount” as “an amount sufficient to reduce the cell
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`population by three log orders” for each of the five test microorganisms, including
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`the fungi. Ex. 1003 at 4. Xia also sets forth “acceptance criteria” requiring that
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`“bacteria or fungus” be “reduced by at least 3.0 logs at day 14” and, after a
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`rechallenge, “by day 28.” Ex. 1003 at 15. As to fungi, the definitions of
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`“preservative-effective amount” and “acceptance criteria” are more stringent than
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`what the FDA/ISO 14730 test requires. But, the POSA would also note that the
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`formulations with data reported in Tables 4 and 6 of Xia are both described by Xia
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`as “pass[ing] the preservative efficacy test,” Ex. 1003 at 17, 18, and that the PET
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`results reported in Tables 4 and 6 meet the requirements of FDA/ISO 14730, but
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`not the more stringent antifungal requirements articulated in Xia’s definitions of
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`“preservative-effective amount” and “acceptance criteria.” Considering all of these
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`disclosures together, the POSA would understand that when Xia states that a
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`formulation “passed the preservative efficacy test,” but does not report PET data
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`explicitly, it means that the formulation met FDA/ISO 14730 PET criteria as to
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`14
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`
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`both bacteria and fungi. I also understand that Argentum takes the position—
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`consistent with the data reported in Xia—that if Xia states that a formulation
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`“passed the preservative efficacy test,” it means that the formulation meets the
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`FDA/ISO 14730 PET criteria, and accordingly, also meets the USP 27 PET
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`criteria. However, if Xia instead intended the more stringent criteria set forth as
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`“acceptance criteria,” my opinions would not change.3
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`28. Xia provides data regarding the antimicrobial activity of Example
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`compositions in which zinc is used without a primary preservative agent. In
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`particular, each of Examples 8, 16, 17, and 18 of Xia discloses a composition that
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`(a) contains zinc, (b) does not contain a primary preservative agent such as
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`Polymer JR, and (c) passes the preservative efficacy test utilized in the reference.
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`3 If what Xia meant is that its “acceptance criteria” were applied, but a formulation
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`only had to meet those criteria as to bacteria or fungi—but not both—in order to
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`“pass[],” then the POSA would not have an expectation that the formulations Xia
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`describes as “pass[ing]” would pass USP 27 PET, and would still seek to avoid
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`lowering the zinc concentration below the concentrations used in Xia’s examples.
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`Accordingly, regardless of which of these PET criteria Xia applied, the POSA
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`would not have reason to use a concentration of zinc below 0.48 mM or to practice
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`the claimed inventions.
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`15
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`
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`Ex. 1003 at 20-23. The Examples employ, respectively, 3.7 mM (0.05 wt.%), 1.8
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`mM (0.025 wt.%), 0.92 mM (0.0125 wt.%), and 0.48 mM (0.0065 wt.%) of zinc
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`(as zinc chloride), all of which are concentrations that exceed 0.001 wt.% and
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`0.005 wt.% (0.074 mM and 0.37 mM, respectively). Ex. 1002 ¶ 50 (setting forth
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`the value in mM for the 0.001 wt.% and 0.005 wt.% values).
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`29. The POSA would understand Xia to teach that the concentration of
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`zinc employed in any of Examples 8, 16, 17, or 18 was sufficient to meet PET
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`requirements. Ex. 1003 at 22-23 (Table 9 & 11). Given these data and other prior
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`art (discussed further below), however, the POSA would not understand Xia to
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`teach or suggest that any lower concentrations of zinc would do so without the
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`addition of a conventional primary preservative agent.
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`C. The POSA Would Have Expected that Compositions Combining
`the Concentrations of Zinc in Xia’s Examples with Schneider
`Formulation A Would Pass Preservative Efficacy Testing
`
`30.
`
` Dr. Xia opines that the POSA would have been motivated to remove
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`the BAK in Schneider Formulation A and replace it with zinc ions. Ex. 1002 ¶ 47.
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`To the extent Dr. Xia is opining that the only way to create a gentler ophthalmic
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`formulation than Schneider Formulation A was to replace its BAK with zinc, I
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`disagree. The POSA would have been familiar with a variety of different methods
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`for achieving preservative efficacy without using BAK, for example a quaternary
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`ammonium, like polyquaternium-1 or polyquaternium-10, sorbic acid, sodium
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`
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`16
`
`
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`perborate, stabilized oxychloro complex, or a biguanide, instead. Ex. 1001 col. 1
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`ll. 21–23; Ex. 1003 at 5–9. As of 2006, zinc had not been used as a sole
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`preservative in a marketed ophthalmic formulation. Because it lacked a proven
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`track record as a preservative in ophthalmic formulations, the POSA would have
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`had a practical concern about using zinc instead of a tested and proven primary
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`preservative.
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`31. Assuming, however, that the POSA would have been motivated to
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`combine Xia’s teaching regarding zinc ions with Schneider Formulation A, the
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`POSA would have expected to succeed in achieving preservative efficacy by
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`replacing BAK with any of the four zinc ion concentrations disclosed in Xia
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`Examples 8, 16, 17, or 18. The only excipient in Schneider Formulation A that the
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`POSA would expect to have a potentially deleterious effect on the antimicrobial
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`activity of zinc would be EDTA. Xia illustrates EDTA’s effect on the
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`effectiveness of zinc ions by comparing Xia Examples 13-15, which contain
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`EDTA, with Xia Examples 16-18, which do not. However, the POSA would
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`understand from Xia Example 8 that 0.050 wt.% zinc provides sufficient
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`antimicrobial activity to pass preservative efficacy standards even in a formulation
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`that contains 0.050 wt.% EDTA (1:1 ratio of zinc to EDTA)—five times the
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`concentration of EDTA than is present in Schneider Formulation A (0.01% w/v).
`
`
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`17
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`
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`The POSA would also expect the tromethamine in Schneider Formulation A to
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`provide its own intrinsic antimicrobial activity.
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`32. The POSA would therefore expect that simply substituting BAK in
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`Schneider Formulation A with 0.050 wt.% zinc (5:1 ratio of zinc to EDTA) would
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`pass preservative efficacy standards. The POSA would also expect that the
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`concentrations of zinc in Xia Example 16 (0.025 wt.%; 2.5:1 ratio of zinc to
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`EDTA) and Example 17 (0.0125 wt.%; 1.25:1 ratio of zinc to EDTA) would pass
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`preservative efficacy standards, as the ratio of zinc to EDTA would still be greater
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`than in Xia Example 8 (1:1 ratio of zinc to EDTA). As for the concentration of
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`zinc in Xia Example 18 (0.0065 wt.%; 0.65:1 ratio of zinc to EDTA), the POSA
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`would have a reasonable expectation that it, too, would pass PET, particularly
`
`because of the added antimicrobial activity of tromethamine in Schneider
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`Formulation A. If preservative efficacy turned out to be a problem if the
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`concentration of zinc in Xia Example 18 were substituted for the BAK in
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`Schneider Formulation A, the POSA would have no reason to use Example 18’s
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`zinc concentration rather than the higher concentrations in Examples 8, 16, and 17,
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`any of which would be expected to solve any preservative efficacy problem that
`
`arose.
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`
`
`18
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`
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`D. The POSA Would Not Want to Use a Concentration of Zinc that
`Is Lower than the Concentration Used in Xia Example 18
`
`33.
`
`I have been asked to respond to the opinion of Dr. Xia that Xia
`
`suggests the use of a concentration of a zinc compound (and in particular zinc
`
`chloride) as low as 0.001 wt.% to 0.005 wt.% in an ophthalmic formulation. I
`
`disagree with Dr. Xia on this point. As discussed below, the POSA would not
`
`have had a reason to use less zinc than the concentration disclosed in Example 18
`
`of Xia (0.0065 wt.% or 0.48 mM as zinc chloride).
`
`34. While the POSA would understand, based on the data in Xia, that zinc
`
`is potentially effective as a sole preservative at a concentration as low as 0.48 mM
`
`(i.e., the concentration in Xia Example 18), the POSA would have concerns about
`
`attempting to use a lower concentration of zinc, unless the zinc is used in
`
`combination with a primary preservative agent. That is because other data in the
`
`prior art suggested that using zinc concentrations lower than those in Xia’s
`
`working examples would be likely to lead to a loss of preservative efficacy testing,
`
`and would even stimulate bacterial growth.
`
`35.
`
`In a publication by Winslow & Haywood, Ex. 2122, the authors
`
`reported on the effect of various metal cations, including zinc, on the survival of
`
`Escherichia coli, which is one of the types of bacteria used in both USP 27 and the
`
`preservative efficacy test disclosed in Xia. See Ex. 1001, col. 10, ll. 44-55; Ex.
`
`1003 at 14. Winslow reported that when a 0.0005 M (0.5 mM) solution of zinc
`
`
`
`19
`
`
`
`(from zinc chloride) was used, it only partially reduced survival of E. coli, i.e., the
`
`observed bacterial counts were 57% of the control. Ex. 2122 at 54 (Table 2). A
`
`0.001 M (1 mM) zinc solution was required for a 100% lethal effect. Id.
`
`However, when the concentration of zinc was reduced to a 0.00025 M (0.25 mM)
`
`solution—one dilution step below the 0.5 mM zinc solution—bacterial growth
`
`increased to 135% of the control, i.e., the zinc actually stimulated the growth of E.
`
`coli. Id. The POSA would understand from these data that zinc, unlike the vast
`
`majority of agents with antimicrobial activity, is a micronutrient that is essential
`
`for cellular growth and function of organisms. In other words, the POSA would
`
`recognize that use of too low a concentration of zinc could result in the undesirable
`
`outcome of actually promoting growth of organisms rather than inhibiting their
`
`growth, killing them, or achieving complete eradication. Under such
`
`circumstances, the zinc would fail to serve its purpose as a preservative and indeed
`
`would be counterproductive.
`
`36. Winslow also described how concentrations of zinc that inhibited E.
`
`coli growth but did not achieve 100% lethality, such as 0.5 mM, also “tended to
`
`lose their inhibitive power after 48 hours,” which Winslow posited was perhaps a
`
`result of adaptation of the organisms to their zinc solutions. Ex. 2122 at 52. Such
`
`adaptation by the organism would demonstrate to the POSA that the zinc would
`
`begin to have reduced antibacterial activity beginning at 48 hours, as the microbe
`
`
`
`20
`
`
`
`began to adapt to the low zinc concentration. See also Ex. 1005 at 303, 307-12.
`
`The POSA would be particularly concerned with adaptation beginning at such an
`
`early time point, mindful that the USP 27 requirements extend for four weeks—far
`
`longer than 48 hours.
`
`37. The POSA would reach the following conclusions about Winslow’s
`
`data: (a) a 1 mM concentration of zinc resulted in bacterial eradication of E. coli—
`
`which is the desired effect when creating a multi-dose ophthalmic composition,
`
`and in particular is consistent with the goals of preservative efficacy testing, which
`
`generally seeks a reduction of 99.9% (3.0 log10) in the bacterial inoculum (and
`
`ideally complete bacterial eradication); (b) reducing the zinc concentration one
`
`dilution step lower (0.5 mM) only partially reduced survival of E. coli (57% of the
`
`control survived), which is suboptimal as compared to complete bacterial
`
`eradication, and less than the required effect in preservative efficacy testing; (c) at
`
`that same 0.5 mM concentration, the bacteria adapted within 48 hours to this low
`
`zinc concentration, further diminishing the extent of antimicrobial activity; and (d)
`
`reducing the zinc concentration one further dilution step (0.25 mM) actually
`
`stimulated E. coli growth. Ex. 2122 at 54 (Table 2).
`
`38.
`
`In addition, the POSA would understand that a prior art publication by
`
`McCarthy at al. had reported that zinc ions have “little effect against the
`
`troublesome Pseudomonas aeruginosa,” Ex. 2123 at 52, a statement which, based
`
`
`
`21
`
`
`
`on the data in Table 1 of the reference, the POSA would understand applied to
`
`concentrations of up to 50 µg/mL of zinc ions (i.e., 0.76 mM),4 which is more zinc
`
`than the concentration in Xia Example 18.5 P. aeruginosa—another bacteria
`
`included in tests for preservative efficacy, see Ex. 1001, col. 10, ll. 44-55; Ex. 1003
`
`at 14—would be of particular concern to the POSA because, unlike many other
`
`organisms, (a) it is highly virulent and well known as a cause of difficult-to-treat,
`
`potentially sight-threatening ocular infections, see, e.g., Ex 1001, col. 2, ll. 12-19,
`
`and (b) it can thrive in environments with limited nutrients, including an
`
`ophthalmic composition, see, Ex. 2123 at 504 (“The apparent resistance of the
`
`Gram-negative microbial species (Pseudomonas aeruginosa) is not unexpected.
`
`The resistance of this bacterium [P. aeruginosa], especially in organic tissues, is
`
`
`4 This calculation was performed by converting the concentration of zinc ions from
`
`50 µg/mL to 0.05 g/L, dividing that number by the molecular weight of zinc (65.38
`
`g/mol) to obtain a molar concentration, and then multiplying the resulting number
`
`by 1000 to obtain the value in mM.
`
`5 A publication by Zeelie & McCarthy, which is cited in the ’299 patent, Ex. 1001
`
`at 2, provided that the minimum lethal concentration of zinc ions was 1917 x 10-3 g
`
`dm-3, which is even greater than 0.76 mM. Ex. 2124 at 505.
`
`
`
`22
`
`
`
`very well documented. It is a bacterium which can survive on simple inorganic
`
`chemicals, being able to convert them to more elaborate organic requirements.”).
`
`39. Xia provides neither data nor any discussion that addresses the issue
`
`of how low concentrations of zinc can actually promote microbial growth rather
`
`than decrease growth (survival). But based on the data in Winslow, McCarthy, and
`
`Zeelie, the POSA would have had concerns about lowering the zinc concentration
`
`below what was used in Xia Example 18. While t
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