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`Paper No.
`Filed: January 6, 2017
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`Filed on behalf of Teva Pharmaceuticals USA, Inc.
`By: Mark D. Schuman
`
`Gary J. Speier
`CARLSON, CASPERS, VANDENBURGH,
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`
`LINDQUIST & SCHUMAN, P.A.
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`225 South Sixth Street, Suite 4200
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`Minneapolis, MN 55402
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`
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`UNITED STATES PATENT AND TRADEMARK OFFICE
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`
`
`BEFORE THE PATENT TRIAL AND APPEAL BOARD
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`
`
`TEVA PHARMACEUTICALS USA, INC.
`Petitioner,
`
`v.
`
`ALLERGAN, INC.,
`Patent Owner.
`
`
`
`Patent No. 8,685,930
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`
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`DECLARATION OF WALTER G. CHAMBLISS, PH.D.
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`TEVA - EXHIBIT 1026
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`
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`TABLE OF CONTENTS
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`QUALIFICATIONS ....................................................................................... 1
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`SCOPE OF WORK ......................................................................................... 3
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`I.
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`II.
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`III. OVERVIEW OF THE ’930 PATENT ........................................................... 4
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`IV. FILE HISTORY OF THE ’930 PATENT ....................................................... 7
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`V. LEGAL STANDARDS ................................................................................ 10
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`VI. LEVEL OF ORDINARY SKILL AND RELEVANT TIME ...................... 14
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`VII. CLAIM CONSTRUCTION ......................................................................... 15
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`VIII. THE STATE OF THE ART ......................................................................... 19
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`IX. ASSERTED REFERENCES DISCLOSE OR SUGGEST EACH OF THE
`CLAIMED FEATURES OF THE ’930 PATENT ....................................... 28
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`A. Brief Overview of the Asserted References ....................................... 28
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`B. Detailed Analysis of the Claims ......................................................... 43
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`
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`GROUND 1. EACH OF CLAIMS 1-36 IS ANTICIPATED BY
`DING ’979 .................................................................................................... 43
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`GROUND 2. THE TEACHINGS OF DING ’979 AND SALL MAKE
`CLAIMS 1-10, 12-22, 24-34, AND 36 OBVIOUS. .................................... 51
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`GROUND 3. THE TEACHINGS OF DING ’979, SALL, AND
`ACHEAMPONG MAKE CLAIMS 11, 23, AND 35 OBVIOUS. .............. 60
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`X. NO UNEXPECTED RESULTS ................................................................... 63
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`XI. CONCLUDING STATEMENTS ................................................................. 78
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`XII. APPENDIX – LIST OF EXHIBITS ............................................................. 80
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`
`
`i
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`I, Walter G. Chambliss, declare as follows:
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`I. QUALIFICATIONS
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`
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`1. My name is Walter Chambliss. I received a B.S. in Pharmacy in
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`1977, an M.S. in Pharmaceutics in 1980, and a Ph.D. in Pharmaceutics in 1982
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`from the University of Mississippi.
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`
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`2.
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`I worked for seventeen years in research and development in the
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`pharmaceutical industry at G.D. Searle, Bristol-Myers and Schering-Plough, where
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`I was involved in formulation development and/or process development of over
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`300 products. I was Vice President of Research and Development for the
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`HealthCare Products Division of Schering-Plough for five years.
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`
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`3.
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`For the past seventeen years, I have been a Professor of Pharmaceutics
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`at the University of Mississippi, where I teach graduate courses in pharmaceutics.
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`I am also a Research Professor in the Research Institute of Pharmaceutical
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`Sciences where I am responsible for managing pharmaceutical development
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`projects. In addition, I am the Director of Technology Management and oversee
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`the technology transfer activities for the University.
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`
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`4.
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`I provide broad research and development consulting to the
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`pharmaceutical industry, and have been an invited speaker in the areas of
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`formulation and product development.
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`1
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`5.
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`I have authored or co-authored over twenty publications in the field of
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`pharmaceutical development, including a book chapter concerning delivery of
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`pharmaceutical products to the eye, and I am a co-inventor of a U.S. patent.
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`6.
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`I am a member of numerous technical societies, including the
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`Academy of Pharmaceutical Research and Sciences of the American Pharmacists
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`Association, and the American Association of Pharmaceutical Scientists. I am also
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`a member of Rho Chi, a national professional honor society. I am a Past President
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`of the Academy of Pharmaceutical Research and Sciences, and previously served
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`as a member of the Board of Trustees of the American Pharmacists Association. I
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`received the Distinguished Alumni Award from the University of Mississippi
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`School of Pharmacy, and have served on several external scientific advisory boards
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`of profit and non-profit organizations. I am also a Fellow of the Academy of
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`Pharmaceutical Research and Science of the American Pharmacists Association
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`and the American Association of Indian Pharmaceutical Scientists. I served on the
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`International Steering Committee for the 2nd, 3rd and 4th Editions of the
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`Handbook of Pharmaceutical Excipients and wrote monographs for excipients
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`included in several editions.
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`
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`7.
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`I was responsible for the formulation development of numerous oil-
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`based and water-based formulations at Bristol-Myers and Schering-Plough
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`including formulations designed to be administered to the eye. A majority of these
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`2
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`formulations were oil-in-water emulsions for topical administration consisting of
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`the active pharmaceutical ingredient(s) dispersed or dissolved in oil. I have
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`significant experience in the use of polymers, including acrylate/C10-30 alkyl
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`acrylate cross-polymer, and surfactants, including polysorbate 80, as inactive
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`ingredients in oil-in-water emulsion formulations. In addition, I have significant
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`experience in the selection of other inactive ingredients commonly used in oil-in-
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`water emulsion formulations including tonicity agents, demulcents, pH adjusting
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`agents, and buffers.
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`8. A summary of my education, experience, publications, awards and
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`honors, patents, publications, and presentations is provided in my CV, a copy of
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`which is submitted separately. Ex. 1027.
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`II. SCOPE OF WORK
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`9.
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`I understand that a petition is being filed with the United States Patent
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`and Trademark Office for Inter Partes Review of U.S. Patent No. 8,685,930 (“the
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`’930 patent,” Ex. 1001). I have been retained by the Petitioner as a technical
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`expert to provide analysis and opinions regarding the ’930 patent. I have reviewed
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`the ’930 patent and relevant sections of its prosecution history in the United States
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`Patent and Trademark Office. Ex. 1004. I understand that the ’930 patent is
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`currently subject to another IPR, Mylan Pharmaceuticals Inc., v. Allergan, Inc.,
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`Case IPR2016-01127 (the “Mylan IPR”). I understand that Petitioner Teva seeks
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`3
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`to become a party to the Mylan IPR. I have reviewed the materials submitted with
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`the petition filed in the Mylan IPR, including the petition itself (IPR2016-01127,
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`Paper 3) and the Declaration of Dr. Mansoor Amiji (IPR2016-01127, Exhibit
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`1002). I have also reviewed and considered other documents such as the relevant
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`prior art, and cite them herein. For convenience, documents cited in this
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`declaration are listed in the Appendix in Section XII. I note that I agree in all
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`material respects with the analysis and opinions set forth by the petitioner Mylan’s
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`expert, Dr. Amiji, in the declaration that was submitted in the Mylan IPR and share
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`the same opinions below. Because my independent analysis of the claims and
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`prior art led to the same conclusions as Dr. Amiji, coupled with the fact that the
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`Petitioner Teva is seeking to become a party to the Mylan IPR, I have incorporated
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`below Dr. Amiji’s opinions and characterizations as my own.
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`10.
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`I am compensated at the rate of $800 per hour for non-testifying time
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`spent on this case and $1,000 per hour for time spent testifying at deposition or
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`trial. I have no financial interest in the outcome of this matter.
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`III. OVERVIEW OF THE ’930 PATENT
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`11. The ’930 patent issued April 1, 2014. The ’930 patent is entitled
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`“Methods of Providing Therapeutic Effects using Cyclosporin Components.” The
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`first page of the patent states that an application for the ’930 patent (U.S.
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`Application No. 13/961,828, “the ’828 application”) was filed on August 7, 2013
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`4
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`and claims priority through a series of continuations to U.S. Application No.
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`10/927,857 (“the ’857 application,” Ex. 1005), and thereby to U.S. Provisional
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`Patent Application No. 60/503,137, filed on September 15, 2003.
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`12. The ’930 patent is generally directed to pharmaceutical compositions
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`of cyclosporin A (referred to herein as “CsA”) for the treatment of ocular
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`disorders.
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`Claim 1 of the ’930 patent recites the following:
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`1. A topical ophthalmic emulsion for treating an eye of a human
`having keratoconjunctivitis sicca, wherein the topical ophthalmic emulsion
`comprises cyclosporin A in an amount of about 0.05% by weight,
`polysorbate 80, acrylate/C10-30 alkyl acrylate cross-polymer, water, and
`castor oil in an amount of about 1.25% by weight; and wherein the topical
`ophthalmic emulsion is therapeutically effective in treating
`keratoconjunctivitis sicca.
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`Ex. 1001, col. 14, ll. 41-48.
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`13. Claims 2-4 either directly or indirectly depend from claim 1 and recite
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`that the emulsion further comprises a tonicity agent or demulcent component, that
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`the tonicity agent or demulcent component is glycerine, and that the emulsion of
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`claim 1 further comprises a buffer. Claim 5 depends from claim 4, reciting that the
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`buffer is sodium hydroxide. Claims 6-9 depend from claim 1, reciting that the
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`emulsion comprises glycerine and a buffer, that the emulsion comprises
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`polysorbate 80 in an amount of about 1.0% by weight, that the emulsion comprises
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`acrylate/C10-30 alkyl acrylate cross-polymer in an amount of about 0.05% by
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`5
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`weight, and that the emulsion comprises glycerine in an amount of about 2.2% by
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`weight, water, and a buffer, respectively. Claim 10 depends from claim 9, and
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`recites that the buffer is sodium hydroxide. Claim 11 also depends from claim 1,
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`and recites that after administration of the emulsion to a human eye, the human’s
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`blood has substantially no detectable concentration of CsA. Percent values refer to
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`% by weight throughout this declaration unless otherwise indicated. Claim 12
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`depends from claim 6, reciting that the emulsion has a pH in the range of about 7.2
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`to about 7.6.
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`14. Claim 13 of the ’930 patent is an independent claim, which recites the
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`same emulsion as in claim 1:
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`13. A topical ophthalmic emulsion for treating an eye of a
`human, wherein the topical ophthalmic emulsion comprises
`cyclosporin A in an amount of 0.05% by weight, polysorbate 80,
`acrylate/C10-30 alkyl acrylate cross-polymer, water, and castor oil in
`an amount of about 1.25% by weight; and wherein the first topical
`ophthalmic emulsion is therapeutically effective in treating dry eye
`disease.
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`Id. at col. 15, ll. 14-21.
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`15. Claims 14-24 depend directly or indirectly from independent claim
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`13, and recite the same limitations as in claims 2-12, discussed above.
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`16. Claim 25 of the ’930 patent is also an independent claim, which
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`recites the same emulsion as in independent claims 1 and 13:
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`25. A topical ophthalmic emulsion for increasing tear
`production in the eye of a human having keratoconjunctivitis sicca,
`6
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`
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`wherein the topical ophthalmic emulsion comprises cyclosporin A in
`an amount of 0.05% by weight, polysorbate 80, acrylate/C10-30 alkyl
`acrylate cross-polymer, water, and castor oil in an amount of about
`1.25% by weight; and wherein the topical ophthalmic emulsion is
`therapeutically effective in increasing tear production in the eye of the
`human having keratoconjunctivitis sicca.
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`Id. at col. 16, ll. 4-14.
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`17. Finally, claims 26-36 depend directly or indirectly from independent
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`claim 25, and recite the same limitations as in claims 2-12 and 14-24, discussed
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`above.
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`IV. FILE HISTORY OF THE ’930 PATENT
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`18. As noted above, the instant patent that issued from the ’828
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`application resulted from continuations of the ’857 application. During
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`prosecution of the ’857 application, the applicant expressly admitted that the
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`emulsion, referred to as Composition II, and which remains the emulsion recited in
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`the claims of the ’930 patent, was squarely within the teachings of U.S. Patent No.
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`5,474,979 (filed May 17, 1994) to Ding et al. (“Ding ’979,” Ex. 1006). The
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`applicant stated:
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`The applicants concede that it would have been obvious to modify
`examples 1A-1E of the Ding [’979] reference to arrive at Composition II
`of the present application. The differences are insignificant. One need
`only use the cyclosporin concentration of Example 1E (0.05%), the castor
`oil concentration of Example 1D (1.250%), and the remaining ingredients
`of those examples. As the examiner correctly observes, one of ordinary
`skill in the art “would readily envisage” such a composition, especially in
`view of Example 1B: having selected 0.05% as the concentration of
`cyclosporin, Example 1B (wherein the ratio of cyclosporin to castor oil is
`7
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`0(
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`bETDt
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`Ex. 10005 at 0435.
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`0.04) teachees that the concentrattion of cas
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`tor oil shouuld be 1.2550%
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`00.05% / 1.2250% = 0.004). The appplicants cconcede th
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`at in makinng this
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`castor oil)) there wouuld have
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`seelection (00.05% cyclosporin annd 1.250%
`f success;
`een
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`been a reasoonable exppectation o
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`the differeences betw
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`Examples 11A-1E and Compositiion II are ttoo small too believe ootherwise.
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`The formulation of Coompositionn II is squaarely withinn the teachhings of thee
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`Ding [’979]] referencee, and the OOffice shouuld disregaard any stattements byy
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`hhe applicannts suggestting otherwwise[.]
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`As discuussed beloow, I agree with thesee statementts.
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`19.
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`I havve reviewedd the conteent of the ’
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`857 appliccation conccurrently wwith
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`that of tthe ’930 paatent and fiind Compoosition II oof the ’857
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`applicatioon to be
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`indistinguishable from the emmulsion cllaimed in tthe ’930 paatent. A taable submittted
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`by the aapplicant dduring prosecution of f the ’857 aapplicationn has been iincluded
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`below, aand extendded to incluude the emmulsion of tthe ’930 paatent for coonvenient
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`comparison.
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`8
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`Ex. 1005 at 0434 (right-most column added). The ’857 application was ultimately
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`abandoned. Ex. 1004 at 0002.
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`20. As mentioned above, the ’828 application resulted from a series of
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`continuations from the abandoned ’857 application. Id. During prosecution of the
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`’828 application, the applicants acknowledged their prior admissions, stating that
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`they had been collecting evidence to support the patentability of the claims “[s]ince
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`these comments have been filed.” Ex. 1004 at 0007.
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`21. On December 4, 2013, the examiner conducted a telephone interview.
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`Id. at 0190. According to the applicants’ interview summary, the applicants
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`“proposed presenting data and evidence to support the patentability of the pending
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`claims in the form of declarations.” Id.
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`22. On October 23, 2013, the applicants amended the claims to, among
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`other things, substitute the generic term “acrylate/C10-30 alkyl acrylate
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`crosspolymer” for the trade name Pemulen® and substitute the full term
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`“keratoconjunctivitis sicca” for the acronym “KCS.” Id. at 0185-89. The
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`applicants stated without elaboration that “a prima facie case of obviousness
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`cannot be properly established against the pending claims,” but based their
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`argument on their assertion that “the unexpected results obtained from the claimed
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`formulations successfully rebut any prima facie case of obviousness and support
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`the patentability of the pending claims.” Id. at 0196. The applicants submitted
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`9
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`four declarations in support of their assertions: two by Rhett Schiffman, one by
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`Mayassa Attar, and one by Aziz Mottiwala. Specifically, applicants argued, based
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`on one Schiffman declaration (“Schiffman Declaration 1”) and the Attar
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`Declaration that “there are new and unexpected results relative to the prior
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`art.” Id. at 0192 (emphasis in original). The applicants relied on “unexpected
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`results compared to the prior art” in Schirmer Tear Testing and decreased corneal
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`staining, as well as reduction of blurred vision and decreased use of artificial tears.
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`Id. I discuss Schiffman Declaration 1, as well as the Attar declaration, in Section
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`X below.
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`23. The examiner issued a Notice of Allowance on January 28, 2014. Id.
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`at 0268. Relying on Schiffman Declaration 1 and the Attar Declaration, the
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`examiner concluded that, “the specific combination of 0.05% by weight
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`cyclosporin A with 1.25% by weight castor oil is surprisingly critical for
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`therapeutic effectiveness in the treatment of dry eye or keratoconjunctivitis sicca,”
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`and therefore, “demonstrate[s] surprising and unexpected results.” Id. at 0276.
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`24. As set forth in detail throughout this declaration, I disagree with the
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`opinions of Dr. Schiffman and Dr. Attar that the results in the submitted
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`declarations were unexpected or surprising.
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`V. LEGAL STANDARDS
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`25.
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`I understand that a claim is not patentable under 35 U.S.C. § 102, for
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`10
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`
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`lack of novelty, if each and every element of the claim is described, either
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`expressly or inherently, in a single prior art reference.
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`26.
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`I have been informed that a claimed invention is not patentable under
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`35 U.S.C. § 103, for obviousness, if the differences between the invention and the
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`prior art are such that the subject matter as a whole would have been obvious at the
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`time the invention was made to “a person having ordinary skill in the art” to which
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`the subject matter of the invention pertains. I understand that “a person of ordinary
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`skill in the art” is a hypothetical person who is presumed to have known the
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`relevant art at the time of the invention. As discussed above, I understand that
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`prior art for the purpose of this declaration includes references that were published
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`at least before September 15, 2003.
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`27.
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`I have been instructed that, a determination of obviousness requires
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`inquiries into (i) the scope and content of the art when the invention was made; (ii)
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`the differences between the art and the claims at issue; (iii) the level of ordinary
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`skill in the pertinent art when the invention was made; and, to the extent they exist,
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`any secondary considerations.
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`28.
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`I understand that a claim can be found to be obvious if all the claimed
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`elements were known in the prior art and one skilled in the art could have
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`combined the elements as claimed by known methods with no change in their
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`11
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`respective functions, and the combination would have yielded nothing more than
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`predictable and expected results to one of ordinary skill in the art.
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`29.
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`I understand that improper hindsight must not be used when
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`comparing the prior art to the invention for obviousness. Thus, a conclusion of
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`obviousness must be firmly based on the knowledge and skill of a person of
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`ordinary skill in the art at the time the invention was made.
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`30.
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`I have been informed that obviousness may also be shown by
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`demonstrating that it would have been obvious to modify what is taught in a single
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`piece of prior art to create the patented invention. I understand that obviousness
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`may be demonstrated by showing that it would have been obvious to combine the
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`teachings of more than one item of prior art. I understand that in order for a
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`combination of references or teachings to render the claimed invention obvious,
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`there must be some supporting rationale for combining the cited references or
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`teachings as proposed.
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`31.
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`I am informed that the following are examples of principles that may
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`indicate that it would have been obvious to combine multiple teachings, resulting
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`in the claimed combination, if the claimed combination involves: (i) the
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`combination of prior art elements according to known methods to yield predictable
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`results; (ii) the simple substitution of one known element for another to obtain
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`predictable results; (iii) the use of a known technique to improve similar methods
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`12
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`or products in the same way; (iv) the application of a known technique to a known
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`method or product ready for improvement to yield predictable results; (v) the
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`application of a technique or approach that would have been “obvious to try” (e.g.,
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`choosing from a finite number of identified, predictable solutions, with a
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`reasonable expectation of success); (vi) predictable variations of a known work in
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`one field of endeavor prompted for use in either the same field or a different field
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`based on design incentives or other market forces; or (vii) some teaching,
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`suggestion, or motivation in the prior art that would have led one of ordinary skill
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`to modify the prior art reference or to combine prior art reference teachings to
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`arrive at the claimed invention.
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`32.
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`I also understand that “secondary considerations” may be weighed
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`against evidence of obviousness where appropriate.
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`33.
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`I understand that such secondary considerations, where in evidence,
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`may include: (i) commercial success of a product due to the merits of the claimed
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`invention; (ii) a long-felt, but unsatisfied need for the invention; (iii) failure of
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`others to find the solution provided by the claimed invention; (iv) deliberate
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`copying of the invention by others; (v) unexpected results achieved by the
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`invention; (vi) praise of the invention by others skilled in the art; (vii) lack of
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`independent simultaneous invention within a comparatively short space of time;
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`and (viii) teaching away from the invention in the prior art. Secondary
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`13
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`considerations are relevant where there is a nexus between the evidence and the
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`claimed invention.
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`VI. LEVEL OF ORDINARY SKILL AND RELEVANT TIME
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`34.
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`I have been advised that “a person of ordinary skill in the relevant
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`field” is a hypothetical person who is presumed to have known the relevant art at
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`the time of the invention. A person of ordinary skill in the art is also a person of
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`ordinary creativity. I understand that the relevant timeframe for assessing the
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`validity of claims of the ’930 patent for the purposes of this declaration is assumed
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`to be September 15, 2003, the earliest alleged priority date of the application that
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`led to the ’930 patent. Unless otherwise specifically noted, all of my opinions
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`expressed herein regarding a person of ordinary skill in the art apply to a person of
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`ordinary skill in the art as of September 15, 2003.
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`35. By virtue of my education, experience, and training, I am familiar
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`with the level of skill in the art of the ’930 patent prior to September 15, 2003. In
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`my opinion, a person of ordinary skill in the relevant field as of September 15,
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`2003 would typically have an advanced degree, such as a medical degree, or a
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`Ph.D. inorganic chemistry, pharmaceutical chemistry, medicinal chemistry,
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`pharmaceutics, physical pharmacy, or a related field, or could have less education
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`but considerable professional experience in one or more of these fields.
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`Additionally, a person of ordinary skill in the art would have been aware of the
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`14
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`
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`information known in the art relating to dry eye/KCS, its causes and known, useful
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`treatments, whether palliative or therapeutic.
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`36.
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`In particular, one of ordinary skill in the art would likely have some
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`combination of the following skills and experience: (i) experience formulating
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`pharmaceutical products; (ii) experience designing and preparing drug
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`formulations intended for topical ocular administration; (iii) the ability to
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`understand results and findings presented or published by others in the field,
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`including the publications discussed in this declaration.
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`VII. CLAIM CONSTRUCTION
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`37.
`
`I have been advised that, in the present proceeding, the ’930 patent
`
`claims are to be given their broadest reasonable interpretation in view of the
`
`specification. I also understand that, absent some reason to the contrary, claim
`
`terms are typically given their ordinary and accustomed meaning as would be
`
`understood by one of ordinary skill in the art. I have followed these principles in
`
`my analysis throughout this declaration. The ’930 patent provides definitions for
`
`certain claim terms. In my opinion, these definitions are conventional. Certain
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`claim terms are not defined in the ’930 patent. I discuss a few terms below and
`
`what I understand as constructions of these terms.
`
`38. Claims 4-6, 9-10, 16-18, 21-22, 28-30 and 33-34 recite that the
`
`claimed emulsion comprises a “buffer,” while claims 5, 10, 17, 22, 29, and 34
`
`
`
`15
`
`
`
`recite that “the buffer is sodium hydroxide.” As discussed in the specification,
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`“[t]he pH of the emulsions can be adjusted in a conventional manner using sodium
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`hydroxide . . .to a physiological pH level.” Ex. 1001, col. 11, ll. 44-46. The
`
`specification also notes that “suitable buffer components, for example, and without
`
`limitation, phosphates, citrates, acetates, borates and the like and mixtures thereof,
`
`may be employed to maintain a suitable pH.” Id. at col. 11, ll. 51-54. Based on
`
`the specification of the ’930 patent, a person of ordinary skill in the art would
`
`understand the term “buffer” to include “sodium hydroxide.”
`
`39. Claims 11, 23, and 35 recite that following administration of the
`
`claimed emulsion, “the blood of the human has substantially no detectable
`
`concentration of the cyclosporin A.” According to the specification: “Cyclosporin
`
`component concentration in blood preferably is determined using a liquid
`
`chromatography-mass spectroscopy-mass spectroscopy (LC-MS/MS), which test
`
`has a cyclosporin component detection limit of 0.1 ng/ml. Cyclosporin component
`
`concentrations below or less than 0.1 ng/ml are therefore considered substantially
`
`undetectable.” Ex. 1001, col. 5, ll. 27-33. Notably, neither the claims nor the
`
`specification discuss the time point at which the blood levels of CsA are measured.
`
`40. A person of ordinary skill in the art could measure blood
`
`concentration at either peak or trough levels, e.g., taking blood samples at serial
`
`time points, and determining the maximal concentration, or by taking and testing a
`
`
`
`16
`
`
`
`blood sample just prior to a second administration of the drug to determine the
`
`trough level of the drug in the blood. Taking the broadest reasonable construction
`
`for the purposes of this proceeding, the phrase “substantially no detectable
`
`concentration” of CsA includes CsA blood levels measured at a concentration
`
`below 0.1 ng/mL taken at either peak or trough levels.
`
`41. Claims 1, 13, and 25 recite that the claimed emulsion is “effective in
`
`treating keratoconjunctivitis sicca,” “effective in treating dry eye,” and “effective
`
`in increasing tear production,” respectively. The ’930 patent equates KCS with dry
`
`eye disease (Ex. 1001, col. 2, ll. 62-65, “The present invention is particularly
`
`effective in treating dry eye syndrome. Cyclosporin has been found as effective in
`
`treating immune mediated keratoconjunctivitis sicca (KCS or dry eye disease).”)
`
`and characterizes KCS as “an absolute or partial deficiency in aqueous tear
`
`production.” Id. at col. 3, ll. 2-5; see also STEDMAN’S MEDICAL
`
`DICTIONARY 27TH EDITION (M.B. Pugh ed. 2000) (“Stedman’s,” Ex. 1022) at
`
`0003 (KCS is an “inflammation of the conjunctive and of the cornea” that is
`
`“associated with decreased tears” and is a synonym of dry eye syndrome).
`
`42. During prosecution, the applicants relied on an increase in tearing as
`
`demonstrated by the Schirmer Tear Test to assert unexpected efficacy of the
`
`claimed emulsion for treating dry eye disease/KCS. See, e.g., Ex. 1004 at 0195
`
`(arguing that the claimed emulsion was “therapeutically effective for the treatment
`
`
`
`17
`
`
`
`of dry eye or[KCS] . . . according to corneal staining score, Schirmer score,” and
`
`other measures). In light of the discussion above and in the context of the
`
`specification of the ’930 patent, I understand that an emulsion effective in
`
`increasing tear production is an example of an emulsion effective in treating dry
`
`eye disease/KCS.
`
`43. Independent claims 1, 13, and 25 recite the phrase “therapeutically
`
`effective.” The word “therapeutic” means “[r]elating to . . . the treatment,
`
`remediating, or curing of a disorder or disease.” Ex. 1022 at 0007. This includes
`
`palliative treatments, which focus on remediation of a disease—i.e., they alleviate
`
`the symptoms of the disease. Id. at 0004-05.
`
`44. This comports with what the art recognized as a treatment for dry eye
`
`disease/KCS. See Medications for Dry Eye (1999) In PHYSICIANS’ DESK
`
`REFERENCE FOR OPHTHALMOLOGY (27th ed.) Montvale, NJ: PDR Network
`
`(“Ophthalmic PDR,” Ex. 1013) at 13 (“Dry eye is treated with artificial tear
`
`preparations and ophthalmic lubricants.”) A person of ordinary skill in the art
`
`would not understand the phrases “therapeutically effective” or “therapeutic
`
`effectiveness” to be limited to treatment of an immune-mediated response
`
`sometimes contributing to the condition.
`
`45.
`
`I have followed these definitions in my analysis throughout this
`
`declaration.
`
`
`
`18
`
`
`
`VIII. THE STATE OF THE ART
`
`46. Below I describe some of the relevant aspects of what was generally
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`known in the art as of September 15, 2003.
`
`47. CsA, a well-known immunosuppressant, has been utilized for decades
`
`in the treatment of inflammatory diseases such as psoriasis and rheumatoid
`
`arthritis, as well as in the prevention of transplant rejection. K. Kunert et al.,
`
`Analysis of Topical Cyclosporine Treatment of Patients with Dry Eye Syndrome
`
`118 ARCH. OPHTHALMOL. 1489 (2000) (“Kunert,” Ex. 1012). In the 1990’s,
`
`CsA was administered topically for the treatment of dry eye disease/KCS, “a
`
`deficiency in either the aqueous or mucin components of the precorneal tear film.
`
`The most commonly encountered aqueous deficient dry eye in the United States is
`
`keratoconjunctivitis sicca [KCS].” Ex. 1013 at13. Regarding CsA-based
`
`ophthalmic preparations, Kunert teaches: “Topical CsA has been used as treatment
`
`of ocular conditions such as vernal keratoconjunctivitis, corneal transplants,
`
`corneal ulcers, and herpetic stromal keratitis.” Ex. 1012 at 1490. Kunert further
`
`teaches, “Clinical trials with this drug have shown improvement in various
`
`objective measures of KCS such as corneal staining and Schirmer test values.” Id.
`
`48. These clinical trials evaluated the efficacy and safety of various CsA
`
`emulsions by measuring changes in the levels of inflammatory markers in patients’
`
`eyes (e.g. cytokines) and objective clinical criteria for diagnosis of moderate-to-
`
`
`
`19
`
`
`
`severe KCS (e.g. Schirmer tear test and corneal staining). Ex. 1012; see also, K.
`
`Turner et al., Interleukin-6 Levels in the Conjunctival Epithelium of Patients with
`
`Dry Eye Disease Treated with Cyclosporine Ophthalmic Emulsion 19 CORNEA
`
`492 (2000) (“Turner,” Ex. 1014); D. Stevenson et al., Efficacy and Safety of
`
`Cyclosporin A Ophthalmic Emulsion in the Treatment of Moderate-to-severe Dry
`
`Eye Disease 107 OPHTHALMOL. 967 (2000) (“Stevenson,” Ex. 1015). From
`
`these trials it was established that the maximal therapeutic effect for the topical
`
`treatment of dry eye disease/KCS was obtained at 0.05% and 0.10% CsA. Ex. 1015
`
`at 967.
`
`49. As the efficacy of CsA for the treatment of dry eye disease/KCS had
`
`been established prior to September 15, 2003, CsA-based pharmaceuticals were
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`prescribed for ophthalmic administration. Ex. 1013 at 18. As described in the
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`“Cyclosporine” section of the PDR for Ophthalmology: “This potent
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`immunosuppressant has a high degree of selectivity for T lymphocytes. Available
`
`under the trade name Sandimmune, it has been used in a 2% topical solution
`
`asprophylaxis against rejection in high-risk, penetrating keratoplasty and for the
`
`treatment of severe vernal conjunctivitis resistant to more conventional therapy,
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`ligneous conjunctivitis unresponsive to other topical therapy, and noninfectious
`
`peripheral
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