`
`Paper No.
`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
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`Minneapolis, MN 55402
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`
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`UNITED STATES PATENT AND TRADEMARK OFFICE
`
`
`
`BEFORE THE PATENT TRIAL AND APPEAL BOARD
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`
`
`TEVA PHARMACEUTICALS USA, INC.
`Petitioner,
`
`v.
`
`ALLERGAN, INC.,
`Patent Owner.
`
`
`
`Patent No. 9,248,191
`
`
`
`DECLARATION OF WALTER CHAMBLISS, PH.D.
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`TEVA - EXHIBIT 1026
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`
`
`TABLE OF CONTENTS
`
`QUALIFICATIONS ....................................................................................... 1
`
`SCOPE OF WORK ......................................................................................... 4
`
`I.
`
`II.
`
`III. OVERVIEW OF THE ‘191 PATENT ........................................................... 5
`
`IV. FILE HISTORY OF THE ‘191 PATENT ..................................................... 10
`
`V. LEGAL STANDARDS ................................................................................ 13
`
`VI. LEVEL OF ORDINARY SKILL AND RELEVANT TIME ...................... 16
`
`VII. CLAIM CONSTRUCTION ......................................................................... 17
`
`VIII. THE STATE OF THE ART ......................................................................... 22
`
`IX. ASSERTED REFERENCES DISCLOSE OR SUGGEST EACH OF THE
`CLAIMED FEATURES OF THE ‘191 PATENT ....................................... 31
`
`A.
`
`B. Detailed Analysis of the Claims ......................................................... 48
`
`Brief Overview of the Asserted References ....................................... 31
`
`
`
`
`
`
`
`GROUND 1. THE TEACHINGS OF DING ’979 AND SALL MAKE
`CLAIMS 1-16 AND 21-27 OBVIOUS. ........................................................ 49
`
`GROUND 2. THE TEACHINGS OF DING ‘979, SALL, AND
`ACHEAMPONG MAKE CLAIMS 1-16 AND 21-27 OBVIOUS. ............. 67
`
`GROUND 3. THE TEACHINGS OF DING ‘979, SALL, AND
`GLONEK MAKE CLAIMS 17-21 OBVIOUS. ........................................... 69
`
`GROUND 4. THE TEACHINGS OF DING ‘979, SALL,
`ACHEAMPONG AND GLONEK MAKE CLAIM 20 OBVIOUS. ........... 73
`
`
`X. NO UNEXPECTED RESULTS ................................................................... 75
`
`XI. CONCLUDING STATEMENTS ................................................................. 91
`i
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`
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`XII. APPENDIX – LIST OF EXHIBITS ............................................................. 93
`
`
`
`
`ii
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`
`
`I, Walter G. Chambliss, declare as follows:
`
`I. QUALIFICATIONS
`
`
`
`1. My name is Walter Chambliss. I received a B.S. in Pharmacy in
`
`1977, an M.S. in Pharmaceutics in 1980, and a Ph.D. in Pharmaceutics in 1982
`
`from the University of Mississippi.
`
`
`
`2.
`
`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
`
`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.
`
`
`
`3.
`
`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
`
`Sciences where I am responsible for managing pharmaceutical development
`
`projects. In addition, I am the Director of Technology Management and oversee
`
`the technology transfer activities for the University.
`
`
`
`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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`
`
`3
`
`
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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.
`
`
`
`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
`
`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
`
`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
`
`Handbook of Pharmaceutical Excipients and wrote monographs for excipients
`
`included in several editions.
`
`
`
`7.
`
`I was responsible for the formulation development of numerous oil-
`
`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
`
`
`
`4
`
`
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`formulations were oil-in-water emulsions for topical administration consisting of
`
`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
`
`acrylate cross-polymer, and surfactants, including polysorbate 80, as inactive
`
`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
`
`agents, and buffers.
`
`8. A summary of my education, experience, publications, awards and
`
`honors, patents, publications, and presentations is provided in my CV, a copy of
`
`which is submitted separately. Ex. 1027.
`
`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. 9,248,191 (“the
`
`‘191 patent,” Ex. 1001). I have been retained by the Petitioner as a technical
`
`expert to provide analysis and opinions regarding the ’191 patent. I have reviewed
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`the ‘191 patent and relevant sections of its prosecution history in the United States
`
`Patent and Trademark Office. Ex. 1004. I understand that the ‘191 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
`
`
`
`5
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`
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`to become a party to the Mylan IPR. I have reviewed the materials submitted with
`
`the petition filed in the Mylan IPR, including the petition itself (IPR2016-01132,
`
`Paper 3) and the Declaration of Dr. Mansoor Amiji (IPR2016-01132, Exhibit
`
`1002). I have also reviewed and considered other documents such as the relevant
`
`prior art, and cite them herein. For convenience, documents cited in this
`
`declaration are listed in the Appendix in Section XII. I note that I agree in all
`
`material respects with the analysis and opinions set forth by the petitioner Mylan’s
`
`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
`
`prior art led to the same conclusions as Dr. Amiji, coupled with the fact that the
`
`Petitioner Teva is seeking to become a party to the Mylan IPR, I have incorporated
`
`below Dr. Amiji’s opinions and characterizations as my own.
`
`10.
`
`I am compensated at the rate of $800 per hour for non-testifying time
`
`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.
`
`III. OVERVIEW OF THE ‘191 PATENT
`
`11. The ‘191 patent issued February 11, 2014. The ‘191 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 ‘191 patent (U.S.
`
`Application No. 14/222,478, “the ’478 application”) was filed on March 21, 2014
`
`
`
`6
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`
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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.
`
`12. The ‘191 patent is generally directed to methods of treatment of
`
`ocular disorders using pharmaceutical compositions of cyclosporin A (referred to
`
`herein as “CsA”). Claim 1 of the ‘191 patent recites the following:1
`
`1. A method of treating dry eye disease, the method comprising topically
`administering to a human eye in need thereof a first topical ophthalmic
`emulsion at a frequency of twice a day, wherein the first 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;
`wherein the method is therapeutically effective in treating dry eye
`disease;
`wherein the method provides overall efficacy substantially equal to
`administration of a second topical ophthalmic emulsion to a human eye
`in need thereof at a frequency of twice a day, the second emulsion
`comprising cyclosporin A in an amount of about 0.1% by weight and
`castor oil in an amount of about 1.25% by weight; and
`wherein the method results in substantially no detectable
`concentration of cyclosporin A in the blood of the human.
`
`Ex. 1001, col. 15, ll. 20-38.
`
`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
`
`
`1 Claim 1 of the patent as published recites “cyclosporin A in an amount of about
`005% by weight.” On February 16, 2016, a request was filed for a certificate of
`correction, including a request to replace “005%” with “0.05%.” Ex. 1004 at 0006.
`In my analysis, I assume that claim 1 is intended to recite “0.05%.”
`
`
`
`
`7
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`
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`from claim 2, and recites that the tonicity agent or demulcent component is
`
`glycerine. Claim 4 depends from claim 1, reciting that the emulsion further
`
`comprises a buffer; claim 5 further depends from claim 4, and recites that the
`
`buffer is sodium hydroxide. Claims 6-9 also depend from claim 1, reciting that the
`
`topical ophthalmic emulsion further comprises glycerine and a buffer, that the
`
`emulsion comprises polysorbate 80 in an amount of 1.0% by weight, that the
`
`emulsion comprises acrylate/C10-30 alkyl acrylate cross-polymer in an amount of
`
`about 0.05% by weight, and that the emulsion further comprises glycerine in an
`
`amount of 2.2% by weight and a buffer, respectively. Claim 10 depends from
`
`claim 9, reciting that the buffer is sodium hydroxide. Claim 11 depends from
`
`claim 6 and recites that the emulsion has a pH in the range of about 7.2 to about
`
`7.6.2 Percent values refer to % by weight throughout this declaration unless
`
`otherwise indicated. Claim 12 depends from claim 1, reciting that the
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`“substantially no detectable concentration” of CsA in the blood means that the
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`concentration of CsA in the blood is “less than about 0.1 ng/ml.” Id. at col. 15, l.
`
`67.
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`14. Claim 13 of the ’191 patent is an independent claim to a method of
`
`treatment and recites the following:
`
`
`2 The certificate of correction mentioned in footnote 1 includes a request to make
`claim 11 depend on claim 6 instead of claim 2. Ex. 1004 at 0006. Regardless of
`whether claim 11 depends from claim 2 or 6, my conclusions remain the same.
`8
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`
`
`
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`13. A method of enhancing tearing in a human eye, the method
`comprising topically administering to a human eye in need thereof a first
`topical ophthalmic emulsion at a frequency of twice a day, wherein the
`first 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;
`wherein the method is therapeutically effective in treating dry eye
`disease and wherein the method achieves at least as much therapeutic
`efficacy as administration of a second topical ophthalmic emulsion to a
`human eye in need thereof at a frequency of twice a day, the second
`emulsion comprising cyclosporin A in an amount of about 0.1% by
`weight and castor oil in an amount of about 1.25% by weight; and
`wherein the method results in a concentration of cyclosporin A in
`the blood of the human of less than about 0.1 ng/ml.
`
`Ex. 1001, col. 16, ll. 1-20.
`
`15. Claims 14 and 16 depend from claim 13, and further recite that the
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`emulsion comprises acrylate/C10-30 alkyl acrylate cross-polymer in an amount of
`
`about 0.05% by weight, polysorbate 80 in an amount of about 1.0% by weight,
`
`glycerine in an amount of about 2.2% by weight and a buffer, and that the method
`
`is effective in enhancing lacrimal gland tearing. Claim 15 depends from claim 14
`
`and further recites the emulsion has a pH range from about 7.2 to about 7.6.
`
`16. Claim 17 of the ’191 patent is an independent claim to a method of
`
`treatment and recites the following:
`
`17. A method of treating dry eye disease, the method
`comprising topically administering to a human eye in need thereof a first
`topical ophthalmic emulsion at a frequency of twice a day wherein the
`first 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
`9
`
`
`
`
`
`weight; and
`Wherein the first topical ophthalmic emulsion breaks down more
`quickly in the human eye, once administered to the human eye, thereby
`reducing visual distortion in the human eye as compared to a second
`topical ophthalmic emulsion that contains only about 50% as much castor
`oil as the first topical ophthalmic emulsion.
`
`Ex. 1001, col. 16, ll. 33-46.
`
`17. Claim 18 depends from claim 17, and recites that the emulsion further
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`comprises acrylate/C10-30 alkyl acrylate cross-polymer in an amount of about
`
`0.05% by weight, polysorbate 80 in an amount of about 1.0% by weight, glycerine
`
`in an amount of about 2.2% by weight and a buffer. Claim 19 depends from claim
`
`18 and further recites that the emulsion has a pH in the range of about 7.2 to about
`
`7.6. Claim 20 recites that the method of claim 19 results in a CsA blood
`
`concentration of less than about 0.1 ng/ml.
`
`18. Claim 21 of the ’191 patent is an independent claim to a method of
`
`treatment and recites the following:
`
`22. A method of restoring tearing, the method comprising
`topically administering to a human eye in need thereof a first topical
`ophthalmic emulsion at a frequency of twice a day, wherein the first
`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;
`wherein the method demonstrates a reduction in adverse events in
`the human compared to administration of a second topical ophthalmic
`emulsion to a human in need thereof at a frequency of twice a day, the
`second topical ophthalmic emulsion comprising cyclosporin A in an
`amount of about 0.1% by weight and castor oil in an amount of about
`1.25% by weight; and
`
`
`
`10
`
`
`
`wherein the method achieves at least as much therapeutic efficacy
`as administration of the second topical ophthalmic emulsion to a human
`in need thereof at a frequency of twice a day.
`
`Id. at col. 16, l. 60 – col. 17, l. 11.
`
`19. Claims 22-24 depends from claim 21, reciting that the method results
`
`in a blood CsA concentration of less than 0.1 ng/ml, that the adverse events are
`
`selected from the group consisting of visual distortion and eye irritation, and that
`
`the emulsion further comprises acrylate/C10-30 alkyl acrylate cross-polymer in an
`
`amount of about 0.05% by weight, polysorbate 80 in an amount of about 1.0% by
`
`weight, glycerine in an amount of 2.2% by weight, and a buffer. Claim 25 depends
`
`from claim 24 and recites that the emulsion has a pH in the range of about 7.2 to
`
`about 7.6. Finally, claims 26 and 27 depend from claim 21 and recite that the
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`method is effective in restoring lacrimal gland tearing and that the adverse events
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`are selected from the group consisting of visual distortion and eye irritation and the
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`CsA blood concentration is less than about 0.1 ng/ml following emulsion
`
`administration.
`
`IV. FILE HISTORY OF THE ’191 PATENT
`
`20. As noted above, the instant patent that issued from the ’478
`
`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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`
`
`11
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`
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`the claims of the ‘191 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:
`
`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
`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.
`
`As discussed below, I agree with these statements.
`
`21.
`
`I have reviewed the content of the ’857 application concurrently with
`
`that of the ‘191 patent and find Composition II of the ’857 application to be
`
`indistinguishable from the emulsion claimed in the ‘191 patent. A table submitted
`
`by the applicant during prosecution of the ’857 application has been included
`
`below, and extended to include the emulsion of the ‘191 patent for convenient
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`comparison.
`
`
`
`12
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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 0797.
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`22. As mentioned above, the ’478 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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`’478 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 0803. The examiner thereafter
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`rejected the claims for non-statutory double patenting over U.S. Patent Nos.
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`8,648,048; 8,629, 111; 8,633,162; 8,642,556; and 8,685,930. Id. at 0153-54.
`
`23. The examiner issued a Notice of Allowance on December 18, 2015.
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`Id. at 0116, relying on declarations submitted during the prosecution of parent U.S.
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`Patent Application No. 13/961,828, which issued as the 8,685,930 patent. During
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`prosecution of the ’828 application, the examiner concluded that, “the specific
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`
`
`13
`
`
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`combination of 0.05% by weight cyclosporin A with 1.25% by weight castor oil is
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`surprisingly critical for therapeutic effectiveness in the treatment of dry eye or
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`keratoconjunctivitis sicca,” and therefore, “demonstrate[s] surprising and
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`unexpected results.” Id. at 0022; see also Ex. 1026 (’930 file history) at 0276.
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`24. As set forth in detail throughout this declaration, I disagree with the
`
`opinions of Dr. Schiffman and Dr. Attar that the results in the submitted
`
`declarations were unexpected or surprising.
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`V. LEGAL STANDARDS
`
`
`25.
`
`I understand that a claim is not patentable under 35 U.S.C. § 102, for
`
`lack of novelty, if each and every element of the claim is described, either
`
`expressly or inherently, in a single prior art reference.
`
`26.
`
`I have been informed that a claimed invention is not patentable under
`
`35 U.S.C. § 103, for obviousness, if the differences between the invention and the
`
`prior art are such that the subject matter as a whole would have been obvious at the
`
`time the invention was made to “a person having ordinary skill in the art” to which
`
`the subject matter of the invention pertains. I understand that “a person of ordinary
`
`skill in the art” is a hypothetical person who is presumed to have known the
`
`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
`
`at least before September 15, 2003.
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`
`
`14
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`
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`27.
`
`I have been instructed that, a determination of obviousness requires
`
`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.
`
`I understand that a claim can be found to be obvious if all the claimed
`
`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
`
`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.
`
`I understand that improper hindsight must not be used when
`
`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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`
`
`15
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`
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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.
`
`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
`
`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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`
`
`16
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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.
`
`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 ‘191 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 ‘191 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.
`
`
`
`17
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`
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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 ‘191 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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`2003would 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.
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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.
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`I have been advised that, in the present proceeding, the ‘191 patent
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`claims are to be given their broadest reasonable interpretation in view of the
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`specification. I also understand that, absent some reason to the contrary, claim
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`
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`18
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`
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`terms are typically given their ordinary and accustomed meaning as would be
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`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 ‘191 patent provides definitions for
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`certain claim terms. In my opinion, these definitions are conventional. Certain
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`claim terms are not defined in the ‘191 patent. I discuss a few terms below and
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`what I understand as constructions of these terms.
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`38. Claims 4-6, 9, 10, 18, and 24 recite that the emulsion of the claimed
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`method comprises a “buffer,” while claims 5 and 10 recite that “the buffer is
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`sodium hydroxide.” As discussed in the specification, “[t]he pH of the emulsions
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`can be adjusted in a conventional manner using sodium hydroxide . . .to a
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`physiological pH level.” Ex. 1001, col. 12, ll. 15-27. 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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`‘191 patent, a person of ordinary skill in the art would understand the term “buffer”
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`to include “sodium hydroxide.”
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`39. Claims 1 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.” Claims 12, 13, 20, 22, and 27 recite that the method results in
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`a CsA blood concentration of less than about 0.1 ng/mL. According to the
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`
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`19
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`
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`specification: “Cyclosporin component concentration in blood preferably is
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`determined using a liquid chromatography-mass spectroscopy-mass spectroscopy
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`(LC-MS/MS), which test has a cyclosporin component detection limit of 0.1 ng/ml.
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`Cyclosporin component concentrations below or less than 0.1 ng/ml are therefore
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`considered substantially undetectable.” Ex. 1001, col. 5, ll. 57-63. Notably,
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`neither the claims nor the specification discuss the time point at which the blood
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`levels of CsA are measured. A person of ordinary skill in the art could measure
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`blood concentration at either peak or trough levels, e.g., taking blood samples at
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`serial time points, and determining the maximal concentration, or by taking and
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`testing a blood sample just prior to a second administration of the drug to
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`determine the trough level of the drug in the blood. Taking the broadest reasonable
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`construction for the purposes of this proceeding, the phrase “substantially no
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`detectable concentration” of CsA includes CsA blood levels measured at a
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`concentration below 0.1 ng/mL taken at either peak or trough levels.
`
`40.
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`Independent claims 1 and 13 state the method is “therapeutically
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`effective in treating dry eye disease.” Claim 16 depends from claim 13 and recites
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`that the method is effective in enhancing lacrimal gland tearing. The patent states
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`that “it is believed that, in certain embodiments of the present invention, the
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`cyclosporine component acts to enhance or restore lacrimal gland tearing in
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`providing the desired therapeutic effect.” Ex. 1001, col. 9, ll. 13-16. Consistent
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`
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`20
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`
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`with this statement, dependent claim 26 recites that the method is effective in
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`restoring lacrimal gland tearing. As lacrimal glands are tear glands, and tears are
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`simply “the fluid secreted by the lacrimal glands,” the plain meaning of “lacrimal
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`gland tearing” is “tearing.” Ex. 1022 at 0008-09.
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`41. Additionally, as dry eye disease/KCS involves the drying of the eye,
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`“associated with decreased tears,” enhancing tearing in a patient suffering from dry
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`eye/KCS would constitute restoration of tearing in that patient. Id. at 0003. In
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`light of the discussion above and in the context of the specification of the ’191
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`patent, I understand that an emulsion effective in increasing tear production is an
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`example of an emulsion effective in enhancing and restoring lacrimal gland tearing
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`and in treating dry eye disease.
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`42. Claim 1 further recites that the method “provides overall efficacy
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`substantially equal to” a method involving the administration of a second emulsion
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`containing 0.1% CsA and 1.25% castor oil. Claims 13 and 21 recite that the
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`method “achieves at least as much therapeutic efficacy as” the method of
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`administering this second emulsion. The word “therapeutic” means “[r]elating to .
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`. . the treatment, remediating, or curing of a disorder or disease.” Ex. 1022 at
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`0007. This includes palliative treatments, which focus on remediation of a
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`disease—i.e., they alleviate the symptoms of the disease. Id. at 0004-05. This
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`comports with
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