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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`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,
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`v.
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`ALLERGAN, INC.,
`Patent Owner.
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`
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`Patent No. 8,633,162
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`DECLARATION OF WALTER G. CHAMBLISS, PH.D.
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`TEVA - EXHIBIT 1025
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`Filed: January 6, 2017
`
`Filed on behalf of Teva Pharmaceuticals USA, Inc.
`By: Mark D. Schuman
`
`Gary J. Speier
`CARLSON, CASPERS, VANDENBURGH,
`
`
`LINDQUIST & SCHUMAN, P.A.
`
`225 South Sixth Street, Suite 4200
`
`Minneapolis, MN 55402
`
`
`
`UNITED STATES PATENT AND TRADEMARK OFFICE
`
`
`
`BEFORE THE PATENT TRIAL AND APPEAL BOARD
`
`
`
`TEVA PHARMACEUTICALS USA, INC.
`Petitioner,
`
`v.
`
`ALLERGAN, INC.,
`Patent Owner.
`
`
`
`Patent No. 8,633,162
`
`
`
`DECLARATION OF WALTER G. CHAMBLISS, PH.D.
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`TEVA - EXHIBIT 1025
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`TABLE OF CONTENTS
`
`QUALIFICATIONS ....................................................................................... 1
`
`SCOPE OF WORK ......................................................................................... 3
`
`I.
`
`II.
`
`III. OVERVIEW OF THE ‘162 PATENT ........................................................... 4
`
`IV. FILE HISTORY OF THE ‘162 PATENT ....................................................... 8
`
`V. LEGAL STANDARDS ................................................................................ 12
`
`VI. LEVEL OF ORDINARY SKILL AND RELEVANT TIME ...................... 15
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`VII. CLAIM CONSTRUCTION ......................................................................... 17
`
`VIII. THE STATE OF THE ART ......................................................................... 22
`
`IX. ASSERTED REFERENCES DISCLOSE OR SUGGEST EACH OF THE
`CLAIMED FEATURES OF THE ‘162 PATENT ....................................... 31
`
`
`
`GROUND 1. THE TEACHINGS OF DING ’979 AND SALL MAKE
`CLAIMS 1-10, 12-14, 16-20, AND 22-24 OBVIOUS. ............................... 48
`
`GROUND 2. THE TEACHINGS OF DING ’979, SALL, AND
`ACHEAMPONG MAKE CLAIMS 11 AND 21 OBVIOUS. ..................... 65
`
`GROUND 3. THE TEACHINGS OF DING ’979, SALL, AND
`GLONEK MAKE CLAIM 15 OBVIOUS. .................................................. 67
`
`
`X. NO UNEXPECTED RESULTS ................................................................... 70
`
`XI. CONCLUDING STATEMENTS ................................................................. 86
`
`XII. APPENDIX – LIST OF EXHIBITS ............................................................. 88
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`
`
`
`
`i
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`
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`I, Walter G. Chambliss, declare as follows:
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`I. QUALIFICATIONS
`
`
`
`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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`
`
`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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`
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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
`
`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
`
`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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`
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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
`
`which is submitted separately. Ex. 1026.
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`II. SCOPE OF WORK
`
`9.
`
`I understand that a petition is being filed with the United States Patent
`
`and Trademark Office for Inter Partes Review of U.S. Patent No. 8,633,162 (“the
`
`’162 patent,” Ex. 1001). I have been retained by the Petitioner as a technical
`
`expert to provide analysis and opinions regarding the ’162 patent. I have reviewed
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`the ’162 patent and relevant sections of its prosecution history in the United States
`
`Patent and Trademark Office. Ex. 1004. I understand that the ’162 patent is
`
`currently subject to another IPR, Mylan Pharmaceuticals Inc., v. Allergan, Inc.,
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`Case IPR2016-01130 (the “Mylan IPR”). I understand that Petitioner Teva seeks
`
`
`
`3
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`
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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 (IPR2016-01130,
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`Paper 3) and the Declaration of Dr. Mansoor Amiji (IPR2016-01130, 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 ‘162 PATENT
`
`11. The ‘162 patent issued January 21, 2014. The ‘162 patent is entitled
`
`“Methods of Providing Therapeutic Effects using Cyclosporin Components.” The
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`first page of the patent states that an application for the ‘162 patent (U.S.
`
`Application No. 13/967,179, “the ’179 application”) was filed on August 14, 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 ‘162 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 ‘162 patent recites the following:
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`1. A method of treating dry eye disease, the method
`comprising topically administering to the eye of a human in need
`thereof an emulsion at a frequency of twice a day, wherein the
`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 effective at treating
`dry eye disease.
`Ex. 1001, col. 15, ll. 22-30.
`
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`13. Claim 2 depends from claim 1 and recites that the emulsion further
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`comprises a tonicity agent or a demulcent component. Claim 3 further depends
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`from claim 2, and recites that the tonicity agent or demulcent component is
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`glycerine. Claim 4 depends from claim 1, reciting that the emulsion further
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`comprises a buffer; claim 5 further depends from claim 4, and recites that the
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`buffer is sodium hydroxide. Claims 6-9 also depend from claim 1, reciting that the
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`topical ophthalmic emulsion further comprises glycerine and a buffer, that the
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`emulsion comprises polysorbate 80 in an amount of 1.0% by weight, that the
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`
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`5
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`
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`emulsion comprises acrylate/C10-30 alkyl acrylate cross-polymer in an amount of
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`about 0.05% by weight, and that the emulsion further comprises glycerine in an
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`amount of 2.2% by weight and a buffer, respectively. Claim 10 depends from
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`claim 9, reciting that the buffer is sodium hydroxide. Percent values refer to % by
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`weight throughout this declaration unless otherwise indicated.
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`14. Claim 11 depends from claim 1, and recites that when the emulsion
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`is topically administered to the human eye, “the blood of the human has
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`substantially no detectable concentration of cyclosporin A.” Id. at col. 15, ll. 51-
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`53. Claim 12 depends from claim 6, reciting that the emulsion has a pH in the
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`range of about 7.2 to about 7.6. Claims 13 and 14 depend from claim 1, reciting
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`that the emulsion is “as substantially therapeutically effective as” and “achieves at
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`least as much therapeutic effectiveness as,” a similar emulsion comprising
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`cyclosporin A in an amount of 0.1% by weight and castor oil in an amount of
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`1.25% by weight. Id. at col. 15, l. 56 – col. 16, l. 4. Similarly, claim 15 depends
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`from claim 1, reciting that the emulsion breaks down more quickly in the eye of a
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`human, “thereby reducing vision distortion” as compared to a second emulsion that
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`contains only 50% as much castor oil. Id. at col. 16, ll. 5-9. Claim 16 depends
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`from claim 1, reciting that the emulsion, when administered to the human eye,
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`demonstrates “a reduction in adverse events” as compared to a second emulsion
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`comprising 0.1% by weight cyclosporin A and 1.25% castor oil. Id. at col. 16, ll.
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`
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`6
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`
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`10-17. Claim 17 further depends from claim 16, reciting that the adverse events
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`are side effects.
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`15. Claim 18 of the ’162 patent is an independent claim to a method of
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`treatment, and recites the following:
`
`18. A method of reducing side effects in a human being
`treated for dry eye syndrome, the method comprising the step of
`topically administering to the eye of the human in need thereof an
`emulsion at a frequency of twice a day, wherein the emulsion
`comprises:
`cyclosporin A in an amount of about 0.05% by weight;
`castor oil in an amount of 1.25% by weight;
`polysorbate 80 in an amount of about 1.0% by weight;
`acrylate/C10-30 alkyl acrylate cross-polymer in an amount of about
`0.05% by weight;
`a tonicity component or a demulcent component in an amount of
`about 2.2% by weight;
`a buffer; and
`water;
`wherein the topical ophthalmic emulsion has a pH in the range of
`about 7.2 to about 7.6.
`
`Id. at col. 16, ll. 20-36.
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`16. Claims 19-22 depend from claim 18, and recite that the buffer is
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`sodium hydroxide, the tonicity/demulcent component is glycerine, that “when the
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`emulsion is administered to the eye of a human for treating dry eye syndrome, the
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`blood of the human has substantially no detectable concentration of the cyclosporin
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`A,” and that the emulsion is effective in treating dry eye disease. Id. at col. 16, ll.
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`37-46.
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`17. Claim 23 of the ’162 patent is an independent claim to a method for
`7
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`
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`the treatment of keratoconjunctivitis sicca, and recites the following:
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`23. A method of treating dry eye disease, the method
`comprising the step of topically administering to an eye of a human in
`need thereof an emulsion at a frequency of twice a day, the emulsion
`comprising:
`cyclosporin A in an amount of about 0.05% by weight;
`castor oil in an amount of about 1.25% by weight;
`polysorbate 80 in an amount of about 1.0% by weight;
`acrylate/C10-30 alkyl acrylate cross-polymer in an amount of about
`0.05% by weight;
`glycerine in an amount of about 2.2% by weight;
`sodium hydroxide; and
`water; and
`wherein the emulsion is effective in treating dry eye disease.
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`Id. at col. 16, ll. 47-60.
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`Finally, claim 24 depends from claim 23, reciting that the emulsion has a pH in the
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`range of about 7.2 to about 7.6.
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`IV. FILE HISTORY OF THE ‘162 PATENT
`
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`18. As noted above, the instant patent that issued from the ’179
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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 ‘162 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
`8
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`
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`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
`0.04) teaches that the concentration of castor oil should be 1.250%
`(0.05% / 1.250% = 0.04). The applicants concede that in making this
`selection (0.05% cyclosporin and 1.250% castor oil) there would have
`been a reasonable expectation of success; the differences between
`Examples 1A-1E and Composition II are too small to believe otherwise.
`The formulation of Composition II is squarely within the teachings of the
`Ding [’979] reference, and the Office should disregard any statements by
`the applicants suggesting otherwise[.]
`
`Ex. 1005 at 0435.
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`As discussed below, I agree with these statements.
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`19.
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`I have reviewed the content of the ’857 application concurrently with
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`that of the ‘162 patent and find Composition II of the ’857 application to be
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`indistinguishable from the emulsion claimed in the ‘162 patent. A table submitted
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`by the applicant during prosecution of the ’857 application has been included
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`below, and extended to include the emulsion of the ‘162 patent for convenient
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`comparison.
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`
`
`9
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`
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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 ’179 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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`’179 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. The examiner thereafter
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`rejected the claims under 35 U.S.C. § 103 as being obvious over Ding ’979 and for
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`double patenting over Ding ’979. Id. at 0126-43.
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`21. On October 3, 2013, the examiner conducted a telephone interview with four
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`representatives of applicants. Id. at 0194. According to the applicants’ interview
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`summary, the applicants presented “Data demonstrating unexpected results and
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`commercial success of the claimed method” and “Data and information regarding
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`10
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`the claimed method’s satisfaction of a long-felt need.” Id. Applicants’ principal
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`argument was that “the evidence of non-obviousness presented at the interview
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`overcomes the prima facie obviousness rejection.” Id.
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`22. On October 14, 2013, the applicants amended the claims to, among
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`other things, substitute the generic term “acrylate/C10-30 alkyl acrylate cross-
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`polymer” for the trade name Pemulen® and substitute the full term
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`“keratoconjunctivitis sicca” for the acronym “KCS.” Id. at 0189-93. 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, commercial success, and
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`satisfaction of long felt need obtained with the claimed methods and failure of
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`others overcome the prima facie obviousness rejection asserted in the Office
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`Action.” Id. at 0195. The applicants submitted four declarations in support of
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`their assertions: two by Rhett Schiffman, one by Mayassa Attar, and one by Aziz
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`Mottiwala. Specifically, applicants argued, based on one Schiffman declaration
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`(“Schiffman Declaration 1”) and the Attar Declaration that “there are new and
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`unexpected results relative to the prior art.” Id. at 0196 (emphasis in original).
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`The applicants relied on “unexpected results compared to the prior art” in Schirmer
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`Tear Testing and decreased corneal staining, as well as reduction of blurred vision
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`11
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`
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`and decreased use of artificial tears. Id. I discuss Schiffman Declaration 1, as well
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`as the Attar declaration, in Section X below.
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`23. The examiner issued a Notice of Allowance on December 6, 2013. Id.
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`at 0393. The examiner concluded that applicants had failed to demonstrate
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`commercial success or long-felt need. Id. at 0403-05. However, relying on
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`Schiffman Declaration 1 and the Attar Declaration, the examiner concluded that,
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`“the specific combination of 0.05% by weight cyclosporin A with 1.25% by weight
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`castor oil is surprisingly critical for therapeutic effectiveness in the treatment of
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`dry eye or keratoconjunctivitis sicca,” and therefore, “demonstrate[s] surprising
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`and unexpected results.” Id. at 0407.
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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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`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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`12
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`
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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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`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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`13
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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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`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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`14
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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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`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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`
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`15
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`
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`ordinary creativity. I understand that the relevant timeframe for assessing the
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`validity of claims of the ‘162 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 ‘162 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 ‘162 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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`information known in the art relating to dry eye/KCS, its causes and known, useful
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`treatments, whether palliative or therapeutic.
`
`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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`
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`16
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`
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`understand results and findings presented or published by others in the field,
`
`including the publications discussed in this declaration.
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`VII. CLAIM CONSTRUCTION
`
`37.
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`I have been advised that, in the present proceeding, the ‘162 patent
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`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
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`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
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`my analysis throughout this declaration. The ‘162 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 ‘162 patent. I discuss a few terms below and
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`what I understand as constructions of these terms.
`
`38. Claims 4-6, 9-10, 18 and 19 recite that the emulsion of the claimed
`
`method comprises a “buffer,” while claims 5, 10, and 19 recite that “the buffer is
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`sodium hydroxide.” As discussed in the specification, “[t]he pH of the emulsions
`
`can be adjusted in a conventional manner using sodium hydroxide . . .to a
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`physiological pH level.” Ex. 1001, col. 12, ll. 25-27. The specification also notes
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`that “suitable buffer components, for example, and without limitation, phosphates,
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`citrates, acetates, borates and the like and mixtures thereof, may be employed to
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`maintain a suitable pH.” Id. at col. 12, ll. 32-35. Based on the specification of the
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`
`
`17
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`
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`‘162 patent, a person of ordinary skill in the art would understand the term “buffer”
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`to include “sodium hydroxide.”
`
`39. Claims 11 and 21 recite that following administration of the claimed
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`emulsion, “the blood of the human has substantially no detectable concentration of
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`the cyclosporin A.” According to the specification: “Cyclosporin component
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`concentration in blood preferably is determined using a liquid chromatography-
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`mass spectroscopy-mass spectroscopy (LC-MS/MS), which test has a cyclosporin
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`component detection limit of 0.1 ng/ml. Cyclosporin component concentrations
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`below or less than 0.1 ng/ml are therefore considered substantially undetectable.”
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`Ex. 1001, col. 5, l. 64 – col. 6, l. 3. Notably, neither the claims nor the
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`specification discuss the time point at which the blood levels of CsA are measured.
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`A person of ordinary skill in the art could measure blood concentration at either
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`peak or trough levels, e.g., taking blood samples at serial time points, and
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`determining the maximal concentration, or by taking and testing a blood sample
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`just prior to a second administration of the drug to determine the trough level of the
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`drug in the blood. Taking the broadest reasonable construction for the purposes of
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`this proceeding, the phrase “substantially no detectable concentration” of CsA
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`includes CsA blood levels measured at a concentration below 0.1 ng/mL taken at
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`either peak or trough levels.
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`40.
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`Independent claims 1 and 23 state that the emulsion is “effective in
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`18
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`
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`treating dry eye disease.” Dependent claim 22 recites that the emulsion of
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`independent claim 18 is also “effective in treating dry eye disease.” The ’162
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`patent identifies that cyclosporin “acts to enhance or restore lacrimal gland tearing
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`in providing the desired therapeutic effect.” Ex. 1001, col. 9, ll. 14-17. During
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`prosecution, the applicants relied on an increase in tearing as demonstrated by the
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`Schirmer Tear Test to assert unexpected efficacy of the claimed emulsion for
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`treating dry eye disease/KCS. See, e.g., Ex. 1004 at 0200 (arguing that the claimed
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`method was “therapeutically effective for the treatment of dry eye or
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`keratoconjunctivitis sicca . . . according to corneal staining score, Schirmer score,”
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`and other measures). In light of the discussion above and in the context of the
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`specification of the ’162 patent, I understand that an emulsion effective in
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`increasing tear production is an example of an emulsion effective in treating dry
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`eye disease/KCS.
`
`41. Dependent claims 13 and 14 respectively describe the emulsion as
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`being “as substantially therapeutically effective as” and having “at least as much
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`therapeutic effectiveness as” a second emulsion with 0.10% CsA and 1.25% castor
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`oil. The word “therapeutic” means “[r]elating to . . . the treatment, remediating, or
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`curing of a disorder or disease.” Ex. 1022 at 0007. This includes palliative
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`treatments, which focus on remediation of a disease—i.e., they alleviate the
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`symptoms of the disease. Id. at 0004-05. This comports with what the art
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`
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`19
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`
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`recognized as a treatment for dry eye disease/KCS. See Medications for Dry Eye
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`(1999) In PHYSICIANS’ DESK REFERENCE FOR OPHTHALMOLOGY (27th
`
`ed.) Montvale, NJ: PDR Network (“Ophthalmic PDR,” Ex. 1013) at 13 (“Dry eye
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`is treated with artificial tear preparations and ophthalmic lubricants.”) A person of
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`ordinary skill in the art would not understand the phrases “therapeutically
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`effective” or “therapeutic effectiveness” to be limited to treatment of an immune-
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`mediated response sometimes contributing to the condition.
`
`42. Claims 13 and 14 each depend from claim 1, and therefore a person
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`of ordinary skill in the art would understand the phrases “as substantially
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`therapeutically effective as” and “at least as much therapeutic effectiveness as” to
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`refer back to the efficacy recited in claim 1, “effective in treating dry eye disease.”
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`Accordingly, the plain meanings of these terms include “as substantially
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`therapeutically effective in increasing tear production as” and “at least as much
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`therapeutic effectiveness in increasing tear production as.”
`
`43. Claims 16 and 17 respectively recite that the emulsion of the
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`claimed method has fewer “adverse events” relative to a second emulsion, and that
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`the “adverse events” are “side effects.” The specification further refers to adverse
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`events as “e.g. side effects, drug interactions and the like.” Ex. 1001, col. 15, ll. 9-
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`16. The plain meaning of the phrase “side effects” is “A result of a drug or other
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`therapy in addition to or in extension of the desired therapeutic effect; usually but
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`20
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`
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`not necessarily, denoting an undesired effect.” Ex. 1022 at 0006. Accordingly, I
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`understand “adverse events” to include undesirable side effects as well as other
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`negative reactions to the drug. In the context of an agent topically administered to
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`the eye, undesirable side effects commonly include burning, stinging, and gen
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