UNITED STATES PATENT AND TRADEMARK OFFICE
`
`BEFORE THE PATENT TRIAL AND APPEAL BOARD
`
`ARGENTUM PHARMACEUTICALS, LLC
`Petitioner
`
`v.
`
`ALCON RESEARCH LIMITED
`Patent Owner
`
`U.S. Patent No. 8,268,299
`
`Inter Partes Review Case No. Unassigned
`
`DECLARATION OF ERNING XIA, Ph.D.
`
`Exhibit 1002
`ARGENTUM
`
`000001
`
`
`
`BEFORE THE PATENT TRIAL AND APPEAL BOARD
`
`ARGENTUM PHARMACEUTICALS, LLC
`Petitioner
`
`v.
`
`ALCON RESEARCH LIMITED
`Patent Owner
`
`U.S. Patent No. 8,268,299
`
`Inter Partes Review Case No. Unassigned
`
`DECLARATION OF ERNING XIA, Ph.D.
`
`Exhibit 1002
`ARGENTUM
`
`000001
`
`
`
`TABLE OF CONTENTS
`Introduction ....................................................................................................... 2
`I.
`II. My Background and Qualifications .................................................................. 4
`III.
`List of Documents I Considered in Formulating My Opinion ......................... 7
`IV.
`Person of Ordinary Skill in the Art ................................................................... 8
`V.
`The ’299 Patent Specification ......................................................................... 10
`VI.
`The Claims of the ’299 patent and Claim Construction ................................. 11
`VII. State of the Art as of September 21, 2006 ...................................................... 15
`VIII. Summary Chart of Analysis Over the Art ...................................................... 23
`IX.
`The Basis of my Analysis with Respect to Obviousness ............................... 23
`X. Ground 1: Xia in view of Schneider and Chowhan ........................................ 24
`XI. Ground 2: Xia in view of Schneider, the Travatan Label, and Chowhan ...... 57
`XII. Ground 3: Xia in view of Schneider, Chowhan and Gadd ............................. 64
`XIII. Ground 4: Xia in view of Schneider, the Travatan Label, Chowhan, and Gadd
`.......................................................................................................................111
`XIV. Secondary Considerations of Nonobviousness ............................................125
`
`i
`
`000002
`
`
`
`I, Erning Xia, Ph.D., hereby declare as follows.
`
`I.
`
`Introduction
`
`1.
`
`I am over the age of eighteen (18) and otherwise competent to
`
`make this declaration.
`
`2.
`
`I have been retained as an expert witness on behalf of
`
`ARGENTUM PHARMACEUTICALS, LLC., (“ARGENTUM”) for the above-
`
`captioned inter partes review (“IPR”). I am being compensated for my time by
`
`the hour in preparing this declaration, but my compensation is not tied to the
`
`outcome of this matter.
`
`3.
`
`I understand that this Declaration accompanies a petition for IPR
`
`involving U.S. Patent No. 8,268,299 (“the ’299 patent”), Ex. 1001, which
`
`resulted from U.S. Application No. 11/858,781 (“the ’781 application”), filed on
`
`September 20, 2007, and alleging an earliest priority date of September 21, 2006.
`
`4.
`
`The ’299 patent names Bhagwati P. Kabra, Masood A. Chowhan,
`
`L. Wayne Schneider and Wesley Wehsin Han as inventors. The ’299 patent
`
`issued on September 18, 2012, from the ’781 application. I further understand
`
`that, according to the United States Patent and Trademark Office (“USPTO”)
`
`records, the ’299 patent is currently assigned to Alcon Research Limited
`
`(“Alcon” or “the patentee”).
`
`2
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`000003
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`
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`5.
`
`In preparing this Declaration, I have reviewed the ’299 patent and
`
`considered each of the documents cited herein, in light of general knowledge in
`
`the art. In formulating my opinions, I have relied upon my experience, education
`
`and knowledge in the relevant art. In formulating my opinions, I have also
`
`considered the viewpoint of a person of ordinary skill in the art (“POSA”), i.e., a
`
`person of ordinary skill in the field of ophthalmic drug formulations and
`
`antimicrobial preservation of such compositions, defined further below in
`
`Section IV. Throughout this declaration, in rendering my opinion, I have
`
`considered what the viewpoint of a POSA would have been prior to September
`
`21, 2006, the filing date of U.S. Provisional Patent Application No. 60/826,529,
`
`to which the challenged ’299 patent claims priority.
`
`3
`
`000004
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`
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`II. My Background and Qualifications
`
`6.
`
`I am an expert in the field of ophthalmic drug formulation and
`
`antimicrobial preservation of such formulations, and I have been an expert in this
`
`field since prior to 2006. I am presently employed by Fulcrum International
`
`Technologies, Inc. I obtained a Bachelor of Science degree in Pharmacy from
`
`Nanjing College of Pharmacy in 1982, a Master of Science degree in
`
`Biopharmaceuticals from China Pharmaceutical University in 1985, and a Ph.D.
`
`in Pharmaceutics from the University of Iowa in 1995.
`
`7.
`
`I was an Assistant Professor and Research Associate for the College
`
`of Pharmacy at the China Pharmaceutical University from August 1985 to
`
`December 1987, a Research Associate at Illinois State University from January
`
`1988 to December 1989, and a Research and Teaching Assistant for the
`
`University of Iowa, College of Pharmacy from 1990 to 1995. After receiving my
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`Ph.D. in Pharmaceutics, I held the positions of Senior Formulation Process
`
`Scientist and Principal Formulation Process Scientist with Bausch & Lomb in
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`Rochester, NY from 1995-1999 and 1999-2001, respectively. I subsequently held
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`the positions of Senior Principal Formulation Process Scientist from 2001-2004,
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`Research Fellow from 2004-2005, and Site Leader/Research Fellow from 2006-
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`2008 at Bausch & Lomb.
`
`8.
`
`I have served as Program Director and Research Fellow at Valeant
`
`4
`
`000005
`
`
`
`
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`Pharmaceuticals in Rochester, NY from 2009-2013. I currently hold the position
`
`of Distinguished Research Fellow and Chief Technology Officer (“CTO”) at
`
`Fulcrum International Technologies, Inc. (“Fulcrum”) and have served in this
`
`position since September of 2013.
`
`9.
`
`I have experience formulating topical ophthalmic products for
`
`treating dry eye, including products that decrease the evaporation of natural tears
`
`and products that increase tear production. While serving as CTO at Fulcrum, I
`
`helped develop a water-soluble based nutritional product for eye fatigue called 7-
`
`Hours™. Previously, I led Vision Care research initiatives as Program Director at
`
`Valeant Pharmaceuticals and dry eye
`
`initiatives and dry eye portfolio
`
`management as a Research Fellow at Bausch & Lomb in Rochester, NY. Also,
`
`while at Bausch & Lomb, my colleagues and I often consulted with physicians to
`
`determine the current ophthalmic needs in the market, and then made efforts to
`
`meet those needs.
`
`10.
`
`I have received several honors in my career, including the Bausch &
`
`Lomb In Focus Recognition in 2010, the Bausch & Lomb CSO Innovation Award
`
`in 2007, the National Award for Science Spectrum Trailblazer in 2005, and the
`
`National Emerald Award for Career Achievement in Industry in 2004.
`
`11.
`
`During my nearly 30 years of experience in topical ophthalmic drug
`
`5
`
`000006
`
`
`
`
`
`formulation, I have authored or co-authored 36 scientific articles. I am also a
`
`named inventor on 110 U.S. patents and patent applications. Each publication,
`
`patent, and patent application is listed in my curriculum vitae, Ex. 1015.
`
`12.
`
`Examples of patents and patent applications on which I am an
`
`inventor include:
`
`“Composition and Method for Inhibiting Uptake of Biguanide Disinfectants
`by Poly(Ethylene),” WO 2003/011350; U.S. Pat. No. 6,514,528;
`
`“Compositions with Enhanced Antimicrobial Efficacy against E. coli,” WO
`2004/030709; U.S. Pat. No. 7,067,479;
`
`“Antimicrobial Composition and Uses Thereof,” WO 2005/115485; U.S.
`Pat. No. 7,632,869;
`
`“Stability Enhancement of Solutions Containing Antimicrobial Agents,”
`WO 2005/053757;
`
`“Zinc Preservative Composition and Method of Use,” WO 2005/097067
`
`“Compositions with Enhanced Antimicrobial Efficacy against
`Acanthamoebae,” WO 2004/030710
`
`“Pharmaceutical Formulations Comprising Polyanionic Materials And Zinc
`Based Preservatives,” WO 2007/106723;
`
`“Gentle Preservative Composition for Self-Preserving Solutions,” WO
`2005/053759;
`
`“Gentle Preservative Composition,” WO 2006/007219;
`
`“Topical Preservative Compositions,” WO 2007/002780
`
`6
`
`000007
`
`
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`13.
`
`Accordingly, I am an expert in the field of topical ophthalmic drug
`
`formulation and antimicrobial preservation of such formulations. My full
`
`background is detailed in my curriculum vitae, Ex. 1015.
`
`III. List of Documents I Considered in Formulating My Opinion
`
`14.
`
`In formulating my opinion, I have considered the documents cited
`
`herein, including the following documents:
`
`Exhibit
`#
`
`Description
`
`1004
`
`1006
`
`1007
`
`1001 Kabra et al., U.S. Patent No. 8,268,299, “Self Preserved Aqueous
`Pharmaceutical Compositions” (filed September 20, 2007; issued
`September 18, 2012)
`1003 Xia et al., WO 2005/097067, “Zinc Preservative Composition and
`Method of Use” (filed March 24, 2005; published October 20,
`2005)
`Chowhan et al., U.S. Patent No. 6,143,799, “Use of Borate-Polyol
`Complexes in Ophthalmic Compositions” (filed July 2, 1998;
`issued November 7, 2000)
`1005 Gadd et al., “Microorganisms and Heavy Metal Toxicity,”
`Microbial Ecology, 4:303-317 (1978)
`FDA Approved Drug Label “TRAVATAN® (travoprost ophthalmic
`solution) 0.004% Sterile” (2001)
`Schneider et al., U.S. Patent No. 6,011, 062, “Storage-Stable
`Prostaglandin Compositions” (filed February 9, 1999; issued January 4,
`2000)
`File history of U.S. Patent No. 8,268,299
`Joint Claim Construction Statement dated 7/18/2014 in Alcon
`Research, Ltd. v. Mylan Pharmaceuticals, Inc. C.A. No.
`1:13-cv-01332-SLR
`File history of U.S. Patent No. 8,323,630
`File history of U.S. Patent No. 8,388,941
`
`1008
`1009
`
`1010
`1011
`
`7
`
`000008
`
`
`
`Exhibit
`#
`
`Description
`
`1012
`
`1013
`
`Sheftel, “Indirect Food Additives and Polymers: Migration
`and Toxicology,” p. 422 (2000)
`The European Agency for the Evaluation of Medicinal Products,
`Veterinary Medicines Evaluation Unit, “Polyoxyl Castor Oil, Polyoxyl
`Hydrogenated Castor Oil Summary Report” (1999)
`“Antimicrobial Effectiveness Testing,” in The United States
`Pharmacopeia 27: The National Formulary 22, pp. 2148-2150 (2004)
`Curriculum Vitae of Erning Xia, Ph.D.
`FORM 6-K, SECURITIES AND EXCHANGE COMMISSION, For
`the month of May 2002, ALCON, INC.
`The Merck Index, An Encyclopedia of Chemicals, Drugs, and
`Biologicals, 13th Ed., (2001), Merck Research Laboratories, 5767, 8797,
`9842.
`1019 Kabara and Orth “Chapter 1, Principles for Product Preservation”,
`Preservative-Free and Self-Preserving Cosmetics and Drugs, Principles
`and Practice, (1997) Marcel Dekker, New York.
`Patent Owner Alcon Research, Ltd.’s Response, IPR2013-00428, Paper
`30.
`
`1014
`
`1015
`1016
`
`1017
`
`1020
`
`IV.
`
`Person of Ordinary Skill in the Art
`
`15.
`
`I understand that a person of ordinary skill in the art (“POSA”) is
`
`a hypothetical person who is presumed to be aware of all of the pertinent art and
`
`is a person of ordinary creativity. A POSA with respect to topical eye
`
`formulations would have had knowledge of the scientific literature regarding
`
`ophthalmic formulations, development of ophthalmic formulations, antimicrobial
`
`preservation of such formulations, and strategies for inhibiting microbial growth,
`
`including knowledge of a wide array of excipients suitable for use in ophthalmic
`
`formulations and their properties, as of September 2006.
`
`8
`
`000009
`
`
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`16.
`
`With respect to the subject matter of the ’299 patent, a POSA
`
`typically would have had: (i) a Pharm. D. or Ph.D. in chemistry, biochemistry,
`
`pharmaceutics, or in a related field in the biological or chemical sciences, and
`
`have at least about two years of experience in the development of ophthalmic
`
`formulations for agents used to treat ocular diseases, including antimicrobial
`
`preservation of such formulations; or (ii) a Master's degree in chemistry,
`
`biochemistry, pharmaceutics, or in a related field in the biological or chemical
`
`sciences, and have at least about five years of experience in the development of
`
`ophthalmic formulations used to treat ocular diseases, including antimicrobial
`
`preservation of such formulations; or (iii) a bachelor’s degree in pharmacy,
`
`chemistry, biochemistry, pharmaceutics, or in a related field in the biological or
`
`chemical sciences, and have at least about 10 years of experience in the
`
`development of ophthalmic formulations used to treat ocular diseases, including
`
`antimicrobial preservation of such formulations. The POSA would have an
`
`understanding of preservative-free and self-preserving ophthalmic formulations
`
`as well as ingredients and combinations of such ingredients suitable for
`
`generating preservative-free and self-preserving ophthalmic formulations. These
`
`descriptions are approximate, and a higher level of education or specific skill
`
`might make up for less experience, and vice-versa.
`
`17.
`
`A POSA typically would work as part of a multidisciplinary team
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`9
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`000010
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`
`
`
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`and draw upon not only his or her own skills, but also take advantage of certain
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`specialized skills of others in the team to solve a given problem. For example, a
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`microbiologist having experience with bacteria and fungi that can contaminate
`
`ophthalmic formulations and a clinician having experience in treating disorders
`
`of the eye, such as glaucoma, with topical pharmaceuticals, may also be part of
`
`the team.
`
`18.
`
`I believe that I would qualify as a person of at least ordinary skill
`
`in the art as of September 21, 2006.
`
`V.
`
`The ’299 Patent Specification
`19. The ’299 patent is directed to multi-dose, self-preserved ophthalmic
`
`compositions. Ex. 1001, Abstract. The ’299 patent states that such compositions
`
`provide sufficient antimicrobial activity to satisfy USP preservative efficacy
`
`requirements without the use of “conventional” anti-microbial preservative
`
`agents. Ex. 1001, Abstract. The ’299 patent alleges that such compositions are
`
`“effectively preserved by a balanced ionic buffer system containing zinc ions at a
`
`concentration of 0.04 to 0.9 mM, preferably 0.04 to 0.4 mM. Id. The ’299
`
`specification continues that “the compositions also contain borat [sic] or, most
`
`preferably, one or more borate/polyol complexes.” Id. Additionally, the ’299
`
`patent states that “limiting the amount of divalent metals other than zinc and the
`
`amount of ionized salts present has also been determined to be important to
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`10
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`000011
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`
`
`
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`maximize the anti-microbial activity of the balanced buffer systems.” Id.
`
`VI. The Claims of the ’299 patent and Claim Construction
`20.
`I understand that terms of the claims are to be given their broadest
`
`reasonable interpretation as understood by a POSA in light of the language of the
`
`claims and specification of the ’299 patent. For my analysis of the meaning of
`
`claim 1 and the other claims of the ’299 patent, I have been asked to assume that
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`the term “comprising” allows for and does not exclude other components from the
`
`claimed compositions.
`
`21. Claim 1 of the ’299 patent is directed to:
`A multi-dose, self-preserved ophthalmic composition,
`comprising:
`zinc ions at a concentration of 0.04 to 0.4 mM; and
`borate and polyol, the borate being present in the
`composition at a concentration of 0.1 to 2.0% w/v and
`the polyol being present in the composition at a
`concentration of 0.25 to 2.5% w/v,
`the
`in
`the polyol comprising propylene glycol
`composition at a concentration of 0.25 to 1.25% w/v
`and sorbitol in the composition at a concentration of
`0.05 to 0.5% w/v; wherein:
`(i) the composition has a concentration of anionic
`species less than 15 mM; and
`(ii) the composition exhibits sufficient antimicrobial
`activity to allow the composition to satisfy USP 27
`preservative efficacy requirements.
`
`
`
`22. Zinc ions at a concentration of. “Zinc ions at a concentration of”
`
`as used in the ’299 patent encompasses the concentration of zinc salts such as
`
`11
`
`000012
`
`
`
`
`
`zinc chloride (ZnCl2), zinc sulfate, zinc acetate, and zinc carbonate used to
`
`prepare the claimed composition. Ex. 1001, 4:54-56. Complete dissociation of
`
`zinc salts into zinc ions is presumed in aqueous compositions at relevant salt
`
`concentrations because zinc salts are highly soluble in water. Ex. 1012. Thus,
`
`for a zinc salt having one metal atom per molecule, such as ZnCl2, the molar
`
`concentration of zinc ions in the claimed compositions is equal to the molar
`
`concentration of the zinc salt added to form the composition. In other words,
`
`there is a 1 to 1 ratio of zinc ions to ZnCl2 molecules.
`
`23. The ’299 patent states:
`
`[t]he pharmaceutical compositions of the present
`invention contain zinc ions at a concentration of 0.04 to
`0.9 millimoles/liter (“mM”), preferably 0.04 to 0.4 mM
`and most preferably 0.1 to 0.4 mM. The zinc ions are
`preferably provided in the form of zinc chloride, at a
`concentration of 0.0005 [0.04 mM1] to 0.012 [0.9 mM]
`percent by weight/volume (“w/v %”), preferably
`0.0005 [0.04 mM] to 0.005 [0.4 mM] w/v % and most
`preferably 0.001 [0.1 mM] to 0.005 [0.4 mM] w/v %.
`
`Ex. 1001, 4:41-53.2
`
`24. Claims 24 and 28 recite concentrations of “zinc chloride ionized,”
`
`and claim 27 recites a concentration of “ionized zinc chloride.” These terms are
`
`not used in the specification of the ’299 patent and were not explicitly defined
`
`
`
`
`
`
`
`
`1 The method for conversion of w/v% to molarity is shown below.
`
`2 All citations to U.S. Patents are shown as column number : line numbers.
`
`12
`
`000013
`
`
`
`
`
`during prosecution of the ’299 patent. Because zinc chloride is not an ionized
`
`compound in ophthalmic compositions, but rather dissociates to zinc ions and
`
`chloride ions, a POSA would have understood that the terms “zinc chloride
`
`ionized” and “ionized zinc chloride” refers to the concentration of zinc ions in
`
`the composition.
`
`25. Polyol. The ’299 patent defines “polyol” as including:
`
`any compound having at least one hydroxyl group on
`each of two adjacent carbon atoms that are not in trans
`configuration relative to each other. Ex. 1001, 6:19-22.
`
`This construction is consistent with that agreed to by Alcon in its litigation over
`
`the ’299 patent with Mylan. See Ex. 1009, 1. The ’299 patent goes on to
`
`explain that
`
`polyols can be linear or cyclic, substituted or
`unsubstituted, or mixtures thereof, so long as the
`resultant complex is water soluble and pharmaceutically
`acceptable. Examples of such compounds include:
`sugars, sugar alcohols, sugar acids and uronic acids.
`Preferred polyols are sugars, sugar alcohols and sugar
`acids, including, but not limited to: mannitol, glycerin,
`xylitol, sorbitol and propylene glycol. Ex. 1001, 6:22-28.
`
`
`
`
`
`
`
`
`
`26. The ’299 patent states that preferred polyols are mannitol, glycerin,
`
`xylitol, sorbitol and propylene glycol. A POSA would understand that one
`
`polyol could be substituted for another polyol due to their structural similarities.
`
`27. Self-preserved ophthalmic composition. The specification of the
`
`13
`
`000014
`
`
`
`’299 patent discusses the meaning of “self-preserved” in the art at 3:10-19, and
`
`notes that “[t]he compositions of the present invention, which do not contain a
`
`conventional antimicrobial preservative, are referred to herein as being ‘self-
`
`preserved.’” Ex. 1001, 3:27-29. The ’299 specification does not define
`
`“conventional antimicrobial preservative,” but identifies BAC, polyquaternium-
`
`1, chlorite, and hydrogen peroxide to be conventional preservatives. A POSA
`
`would therefore understood a “self-preserved ophthalmic composition” to refer
`
`to “an ophthalmic composition
`
`that does not contain a conventional
`
`antimicrobial preservative such as BAC, polyquaternium-1, chlorite, and
`
`hydrogen peroxide.” Patent Owner has essentially agreed, stating that a “self-
`
`preserved ophthalmic composition” refers to an ophthalmic composition that
`
`does not contain a conventional antimicrobial preservative, yet is preserved from
`
`microbial contamination.” Ex. 1009, 1.
`
`28. Anionic species. The specification of the ’299 patent does not
`
`specifically define the term “anionic species”. However, based on the disclosure
`
`of the ’299 patent, a POSA would have understood that “anionic species” refers
`
`to ions having a negative charge. Generally, in aqueous solutions, ions are the
`
`result of dissolution of ionic compounds, such as salts. However the term
`
`anionic species can encompass any element or molecule that is negatively
`
`charged in solution. This construction is consistent with that agreed to by Alcon
`
`14
`
`000015
`
`
`
`
`
`in its litigation over the ’299 patent with Mylan. See Ex. 1009, 1. (Joint Claim
`
`Construction Statement dated 7/18/2014 in Alcon Research, Ltd. v. Mylan
`
`Pharmaceuticals, Inc. C.A. No. 1:13-cv-01332-SLR).
`
`29. Does not contain multivalent buffering anions or metal cations
`
`other than zinc. The specification of the ’299 patent states that “’substantially
`
`free of multivalent buffering anions’ means that the composition either does not
`
`contain any multivalent buffering anions or contains an amount of said anions that
`
`does not inhibit the ability of the composition to satisfy specified preservative
`
`efficacy standards, e.g., “USP, EP or JP.” Ex. 1001, 5:22-27.
`
`30.
`
`Therefore, based on the definition of “substantially free of
`
`multivalent buffering anions in the ‘299 patent, a POSA would likewise
`
`understand the claim term "does not contain multivalent buffering anions or
`
`metal cations other than zinc”
`
`to encompass a composition containing
`
`multivalent buffering anions or metal cations other than zinc, so long as the
`
`composition also meets specified preservative efficacy standards.
`
`31.
`
`Any term I have not expressly defined above, I have given its plain
`
`and ordinary meaning under a broadest reasonable claim construction.
`
`VII. State of the Art as of September 21, 2006
`32. Many multi-dose ophthalmic formulations were known before 2006.
`
`Ex. 1003, 1. One such formulation was Alcon’s own Travatan® product, which
`
`15
`
`000016
`
`
`
`
`
`contained 0.004% w/w travoprost (also known as fluprostenol isopropyl ester) in
`
`an aqueous solution having a pH of about 6 ± 0.2. The formulation includes a
`
`polyethoxylated hydrogenated castor oil known as HCO-40 (indicating an
`
`average of 40 ethylene oxide subunits), boric acid, mannitol, tromethamine,
`
`EDTA disodium, and benzalkonium chloride (BAC). Ex. 1006, 1; see also Ex.
`
`1007, Example 2, Formulation A. Travoprost is a synthetic prostaglandin ester,
`
`and Travatan®
`
`is
`
`indicated for
`
`treatment of glaucoma-induced ocular
`
`hypertension. Id. A single drop of Travatan® is administered into the affected
`
`eye(s) on a daily basis using a multi-dose dispensing bottle. Id.
`
`33. One issue associated with multi-dose ophthalmics is contamination
`
`by bacteria and fungi. As of September 21, 2006, a variety of strategies were
`
`known in the art for preserving ophthalmic formulations and preventing
`
`microbial contamination. Ex. 1003, 1. Chief among such strategies was the
`
`addition of chemical preservative agents. Id. However, the use of such chemical
`
`preservative agents was known to be harsh to the eye and cause eye irritation in
`
`patients. Ex. 1003, 1. Well before 2006, there had been significant movement in
`
`the field of ophthalmic preservation away from the use of “traditional” chemical
`
`preservatives and toward preservative strategies that were less harsh to the eye.
`
`Ex. 1004, 1:49-56. However, such alternative strategies necessarily still needed
`
`to satisfy the U.S. Pharmacopeia guidelines required for multi-dose ophthalmic
`
`16
`
`000017
`
`
`
`products.
`
`34.
`
`To maximize self-preservation and meet U.S. Pharmacopeia
`
`guidelines while maintaining the therapeutic efficacy and comfort of ophthalmic
`
`solutions for the patient, multi-function ingredients having some preservative
`
`activity are typically incorporated into ophthalmic formulations. One of the
`
`most common is the use of buffers for maintaining pH that also boost the
`
`antimicrobial properties of the composition. Well known buffers that exhibit
`
`preservative activity include boric acid/borate buffers and buffers incorporating
`
`tromethamine, which is tris-(hydroxymethyl)-aminomethane (a.k.a. TRIS). Ex.
`
`1017, 9842. Lowering the pH of an ophthalmic solution from neutral to acid
`
`(e.g., from about 7 to 6 or lower) also improves preservative activity. Ex. 1019,
`
`4. Both techniques are employed in Travatan® itself, which incorporates a boric
`
`acid/tromethamine buffer system at a pH of about 6. Ex. 1006, 1.
`
`35.
`
`Tonicity agents are added to ophthalmic solutions to match the
`
`tonicity (concentration of solutes that won’t cross a cell membrane) of the
`
`solution to that of the eye. For example, 0.9% NaCl is isotonic with cells of the
`
`eye. Ex. 1003, 10. Both charged species such as salts and uncharged species
`
`such as alcohols may be used as tonicity agents. Ex. 1007, 7:21-25. Certain
`
`tonicity agents also exhibit antimicrobial activity. Propylene glycol is one such
`
`17
`
`000018
`
`
`
`
`
`agent, and it is also a demulcent. Id.; Ex. 1018; Ex. 1003, ¶ [0054]. Boric acid is
`
`another; in addition to being a buffering agent and a preservative, it can be used
`
`to adjust the tonicity of an ophthalmic solution.
`
`36.
`
`As of 2006, one effective strategy for self-preservation involved the
`
`use of borate polyol complexes as an antimicrobial for ophthalmic formulations.
`
`Ex. 1004, Abstract. A second strategy known as of 2006 involved the use of zinc
`
`ions. Ex. 1003. Both zinc ions and borate-polyol complexes were known to be
`
`safe for ocular administration and were known to have antimicrobial activity. Ex.
`
`1004, 2:15-23 and 1003, 3. Furthermore, both zinc ions and borate-polyol
`
`complexes were known to potentiate the activity of other antimicrobial agents,
`
`thereby reducing or eliminating the need for traditional chemical preservatives
`
`that could be harsh to the eye. Ex. 1003, 1-3; 1004, 1:49-2:13; and 1004, 1:49-55.
`
`In fact, Alcon employed a borate-polyol complex (boric acid, mannitol) in its
`
`FDA-approved ophthalmic product, Travatan®, along with other components
`
`having anti-microbial activity such as BAC, tromethamine, and EDTA. Ex. 1006,
`
`1. Exemplary relevant art that was published before September 21, 2006 includes
`
`the references described below.
`
`37. Schneider. Schneider is U.S. Patent No. 6,011,062, issued on
`
`January 4, 2000. Schneider claims priority as a continuation–in-part to U.S.S.N.
`
`18
`
`000019
`
`
`
`
`
`09/033,748, filed 2/24/1998, now abandoned, which is a continuation-in-part of
`
`U.S. Patent No. 5,849,792, which is a division of U.S. Patent No. 5,631,287.
`
`Schneider is listed on the Travatan® Label (as are its parent patents) and
`
`discloses storage stable ophthalmic formulations of prostaglandin esters. Ex.
`
`1007, 2:8-14. Formulation A of Example 2 (reproduced in the table below)
`
`discloses a topically administrable ophthalmic formulation containing the same
`
`ingredients as Travatan. Ex. 1007, 9:20-42. Compound 32 in the table refers to
`
`1R-[1α(Z),2β(1E,3R*),3α,5α]-7-[3,5-dihydroxy-2-[3-hydroxy-4-[3-
`
`(trifluoromethyl)phenoxy]-1-butenyl]cyclopentyl]-5-heptenoic
`
`acid,
`
`1-
`
`methylethyl ester, which is an alternative chemical name for isopropyl (Z)-7-
`
`[(1R,2R,3R,5S)-3,5-dihydroxy-2-[(1E,3R)-3-hydroxy-4-[(α,α,α-trifluoro-m-
`
`tolyl)oxy]-1-butenyl]cyclopentyl]-5-heptenoate, which the TRAVATAN label
`
`indicates is the same chemical compound as travoprost. Ex. 1006, 1. As noted
`
`above, HCO-40 is a polyethoxylated ester of hydrogenated castor oil and is used
`
`to enhance the stability of prostaglandin in the ophthalmic formulation. Ex.
`
`1007, 6:44-49. The pH of Formulation A is given as 6 ± 0.2, which a POSA
`
`would understand to disclose formulations having a pH from 5.8 to 6.2. This
`
`understanding is confirmed by claim 8 of Schneider which lists the same
`
`ingredients in the same amounts as Formulation A, but explicitly specifies the
`
`pH as 5.8-6.2. The only anionic species contained in Formulation A are the
`
`19
`
`000020
`
`
`
`
`
`borate polyol-complex and edetate. Id., 9:20-42. Formulation A also lacks
`
`multivalent cations. Id.
`
`Ingredient
`
`Compound 32*
`
`Formulation A
`%w/v
`0.001-0.005
`
`PEG-40 hydrogenated castor oil 0.5
`
`Tromethamine
`
`Boric acid
`
`Mannitol
`
`Edetate Disodium
`
`Benzalkonium chloride
`
`NaOH/HCl
`
`Purified Water
`
`0.12
`
`0.3
`
`4.6
`
`0.01
`
`0.015
`
`q.s. to pH 6 ± 0.2
`
`q.s. to 100%
`
`* preferably 1R-[1α(Z),2β(1E,3R*),3α,5α]-7-[3,5-dihydroxy-2-[3-
`
`hydroxy-4-[3-(trifluoromethyl)phenoxy]-1-butenyl]cyclopentyl]-5-
`
`heptenoic acid, 1-methylethyl ester
`
`38. Xia.
`
` Xia is International Application Publication No. WO
`
`2005/097067 filed on March 24, 2005 and claiming priority to U.S. Application
`
`No. 10/812,543 filed on March 29, 2004. Xia was published on October 20,
`
`2005 and is entitled “Zinc Preservative Composition and Method of Use.” Xia
`
`20
`
`000021
`
`
`
`
`
`teaches self-preserved, antimicrobial ophthalmic compositions containing zinc
`
`compounds at concentrations of a “minimum of about 0.001 wt.%, about 0.005
`
`wt.%, about 0.01 wt.% or about 0.05 wt.% of a zinc compound per total weight
`
`of the composition and/or a maximum of about 1 wt.%, about 0.5 wt.%, about
`
`0.1 wt.% or about 0.05 wt.% of the zinc compound per total weight of the
`
`composition.” Ex. 1003, 5. Xia also teaches compositions containing borate (Ex.
`
`1003, 12) and the polyol propylene glycol. Ex. 1003, 14. Xia discloses that its
`
`self-preserved compositions may include therapeutic agents such as glaucoma
`
`agents and specifically mentions prostaglandins as a therapeutic agent that may
`
`be included. Ex. 1003, 12.
`
`39. Chowhan. Chowhan is U.S. Patent No. 6,143,799. Chowhan
`
`issued on November 7, 2000. Chowhan teaches self-preserved ophthalmic
`
`compositions containing “borate-polyol complexes which have surprisingly been
`
`found to have increased antimicrobial activity as compared to boric acid or its
`
`salts. . . .” Ex. 1004, 2:6-9. Chowhan teaches adding boric acid as part of a
`
`borate-polyol complex (Ex. 1004, 2:15-16), the borate-polyol complex in an
`
`amount between about 0.5 to about 6.0 percent by weight (wt %), preferably
`
`between from about 1.0 to about 2.5 wt %. Ex. 1004, 3:43-46. Chowhan also
`
`teaches the use of sorbitol and propylene glycol as a preferred polyols in borate-
`
`polyol complexes. Ex. 1004, 3:5-6. Chowhan teaches that the ratio of borate to
`
`21
`
`000022
`
`
`
`
`
`polyol in the complex can be between about 1:0.1 and about 1:10. Ex. 1004,
`
`3:15-17. Chowhan also teaches that formulations it discloses meet the
`
`preservative efficacy requirements of the British Pharmacopeia, which is
`
`generally more stringent in its requirements than those of USP 27.
`
`40. Gadd. Gadd is a publication from the journal Microbial Ecology
`
`entitled “Microorganisms and Heavy Metal Toxicity.” Gadd was published in
`
`1978. Gadd discloses that anions are able to reduce metal toxicity to
`
`microorganisms by causing otherwise toxic metals to precipitate out of solution.
`
`Gadd also discloses zinc as a metal that is toxic to microorganisms. As such, a
`
`POSA reading Gadd would have known that limiting anion concentrations is an
`
`important part of preserving antimicrobial efficacy of zinc containing compositions
`
`by avoiding precipitation of zinc out of the solution.
`
`41.
`
`Travatan Label. The Travatan Label was published in 2001 (Ex.
`
`1006), the year of the U.S. launch of Travatan as shown by Alcon’s SEC filing
`
`dated May 15, 2002 (Ex. 1016). The Travatan Label indicates that the synthetic
`
`prostaglandin analogue travoprost is useful for treating glaucoma when used at a
`
`concentration of 0.004% in a sterile, self-preserved, multi-dose solution. The
`
`Travatan Label indicates that inactive ingredients in the product are “polyoxyl 40
`
`hydrogenated castor oil, tromethamine, boric acid, mannitol, edetate disodium,
`
`sodium hydroxide and/or hydrochloric acid (to adjust pH) and purified water.”
`
`22
`
`000023
`
`
`
`
`
`Ex. 1006, 1. The composition described in the Travatan Label must have met the
`
`USP 27 requirements because it was a multi-dose ophthalmic composition
`
`approved for use in patients in the U.S.
`
`VIII. Summary Chart of Analysis Over the Art
`
`
`
`Ground
`
`References
`
`Claims
`
`1. Obviousness Xia in view of Schneider and Chowhan 1, 2, 4-8, 16, 17, 20
`
`2. Obviousness Xia in view of Schneider, the
`Travatan® Label, and Chowhan
`3. Obviousness Xia in view of Schneider, Chowhan,
`and Gadd
`4. Obviousness Xia in view of Schneider, the
`Travatan® Label, Chowhan, and Gadd
`
`28
`
`1-23, 25-26
`
`24, 27-28
`
`IX. The Basis of my Analysis with Respect to Obviousness
`
`42.
`
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