UNITED STATES PATENT AND TRADEMARK OFFICE
`
`
`BEFORE THE PATENT TRIAL AND APPEAL BOARD
`
`
`
`AREGENTUM PHARMACEUTICALS LLC,
`Petitioner,
`
`v.
`
`ALLERGAN, INC.,
`Patent Owner.
`
`
`
`Patent No. 8,629,111
`
`
`
`DECLARATION OF DILEEP BHAGWAT, PH.D.
`
`
`
`
`
`
`
`ARGENTUM - EX. 1002, p. 001
`
`
`
`
`BEFORE THE PATENT TRIAL AND APPEAL BOARD
`
`
`
`AREGENTUM PHARMACEUTICALS LLC,
`Petitioner,
`
`v.
`
`ALLERGAN, INC.,
`Patent Owner.
`
`
`
`Patent No. 8,629,111
`
`
`
`DECLARATION OF DILEEP BHAGWAT, PH.D.
`
`
`
`
`
`
`
`ARGENTUM - EX. 1002, p. 001
`
`
`
`
`
`I.
`
`II.
`
`TABLE OF CONTENTS
`
`QUALIFICATIONS ........................................................................................ 2
`
`SCOPE OF WORK .......................................................................................... 4
`
`III. OVERVIEW OF THE ’111 PATENT .............................................................. 5
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`IV. FILE HISTORY OF THE ’111 PATENT ........................................................ 8
`
`V.
`
`LEGAL STANDARDS ................................................................................. 12
`
`VI. LEVEL OF ORDINARY SKILL AND RELEVANT TIME ......................... 15
`
`VII. CLAIM CONSTRUCTION .......................................................................... 17
`
`VIII. THE STATE OF THE ART ........................................................................... 21
`
`IX. ASSERTED REFERENCES DISCLOSE OR SUGGEST
`EACH OF THE CLAIMED FEATURES OF THE ’111
`PATENT ........................................................................................................ 30
`
`GROUND 1. EACH OF CLAIMS 1-27 IS ANTICIPATED BY DING
`’979 ........................................................................................................... 46
`
`GROUND 2. THE TEACHINGS OF DING ’979 AND SALL MAKE
`CLAIMS 1-27 OBVIOUS. ............................................................................. 55
`
`GROUND 3. THE TEACHINGS OF DING ’979, SALL, AND
`ACHEAMPONG MAKE CLAIMS 11 AND 16 OBVIOUS. .................................. 63
`
`X. NO UNEXPECTED RESULTS .................................................................... 66
`
`XI. CONCLUDING STATEMENTS .................................................................. 83
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`XII. APPENDIX – LIST OF EXHIBITS .............................................................. 85
`
`
`
`i
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`ARGENTUM - EX. 1002, p. 002
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`
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`I.
`
`I, Dileep Bhagwat, declare as follows:
`
`QUALIFICATIONS
`1.
`My name is Dileep Bhagwat. Since 2013 I have worked as a Sr.
`
`Pharmaceutical Consultant and CEO of WPDC, LLC which focuses on consulting
`
`on Pharmaceutical (Formulation) Development, Quality, Clinical and global
`
`Regulatory filings. Over these past four years, I have personally consulted for
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`U.S., Swiss, European, Japanese, and Israeli companies. I spent over 5 months in
`
`Basel, Switzerland working on a consulting project for a large Swiss company.
`
`2.
`
`I received a B.S. (Pharmacy) degree from Bombay University, India;
`
`a M.S. and Ph.D. (Industrial Pharmacy) degrees from St. John’s University New
`
`York where I was inducted into the Rho Chi Pharmaceutical Honor Society. I also
`
`have a management (MBA) degree in International Business from Pace University,
`
`New York.
`
`3.
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`I have worked in the Pharmaceutical Industry for over 35 years (of
`
`which 25 years were in management positions) in Pharmaceutical Research and
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`Development, Quality, Manufacturing, Regulatory Affairs. I have worked on many
`
`dosage forms, for example Solid/liquid oral (Immediate released/controlled
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`release), sub-lingual, intra-nasal, Topicals (patches/creams/lotions/gels/
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`emulsions), injectables, Metered Dose Inhalers and in multiple therapeutic areas
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`(e.g. Oncology, Pain, Dermatology, GI, CNS, cardiovascular).
`
`2
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`ARGENTUM - EX. 1002, p. 003
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`4.
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`I am an inventor on 16 issued U.S. patents plus many international
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`patents. I have made many poster and podium presentations at various
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`pharmaceutical and medical conferences including at the American Association of
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`Pharmaceutical Scientists (AAPS), American Pain Society (APS), European
`
`Hematology Association, American Society of Hematology (ASH), Controlled
`
`Release Society.
`
`5.
`
`From 2004 to 2012 I worked at EpiCept Corporation (as part of the
`
`management team reporting to the CEO) as Sr. Vice President, Pharmaceutical
`
`Development. I was responsible for all aspects of drug product development
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`(Phase I – III) and GMP manufacturing/commercialization/supply chain of pain
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`and oncology compounds in the EpiCept pipeline. I was responsible for QA and
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`global Regulatory CMC submissions for NDA, NDS and MAA.
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`6.
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`From 1999 to 2004 I worked at Bradley Pharmaceuticals as Chief
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`Scientific Officer reporting to the CEO and responsible for all scientific activities
`
`at the company. I was responsible for Product development, Operations Dept.
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`(manufacturing and supply chain), setting up and managing a Clinical program,
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`Regulatory and Quality Assurance and compliance.
`
`7.
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`From 1994 to 1999 I worked at TIMERx Technologies as Vice
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`President, Pharmaceutical R & D, reporting to the President. I organized and
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`modernized the R & D efforts of PENWEST’s emerging Oral Controlled Release
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`3
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`ARGENTUM - EX. 1002, p. 004
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`
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`business. When Penwest Pharmaceuticals was created by merging the TIMERx
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`and Mendell (excipient) businesses, I served as Vice President, Scientific
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`Development and Regulatory Affairs leading the development and licensing of
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`Penwest’s oral controlled release technology. From 1979 to 1994 I worked at
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`Purdue Frederick Research Center in various capacities in Pharmaceutical R & D
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`leading to Assistant Director in the Pharmaceutical Development Division. Prior to
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`that I worked for Hoechst Pharmaceutical, India in manufacturing.
`
`8.
`
`A summary of my education, experience, awards and honors, patents
`
`is provided in my CV, a copy of which is submitted separately. Ex. 1003.
`
`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. 8,629,111
`
`(“the ’111 patent,” Ex. 1001). I have been retained by the Petitioner as a technical
`
`expert to provide analysis and opinions regarding the ’111 patent. I have reviewed
`
`the ’111 patent and relevant sections of its prosecution history in the United States
`
`Patent and Trademark Office. Ex. 1004. I have also reviewed and considered
`
`various other documents in arriving at my opinions, and cite them in this
`
`declaration. For convenience, documents cited in this declaration are listed in the
`
`Appendix in Section XII.
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`4
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`ARGENTUM - EX. 1002, p. 005
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`10.
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`I am compensated at the rate of $275/hour for my work. I have no
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`financial interest in the outcome of this matter.
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`III. OVERVIEW OF THE ’111 PATENT
`11.
`The ’111 patent issued January 14, 2014. The ’111 patent is entitled
`
`“Methods of Providing Therapeutic Effects using Cyclosporin Components.” The
`
`first page of the patent states that an application for the ’111 patent (U.S.
`
`Application No. 13/967,163, “the ’163 application”) was filed on August 14, 2013
`
`and claims priority through a series of continuations to U.S. Application No.
`
`10/927,857 (“the ’857 application,” Ex. 1005), and thereby to U.S. Provisional
`
`Patent Application No. 60/503,137, filed on September 15, 2003.
`
`12.
`
`The ‘111 patent is generally directed to pharmaceutical compositions
`
`of cyclosporin A (referred to herein as “CsA”) for the treatment of ocular disorders.
`
`Claim 1 of the ’111 patent recites the following:
`
`A topical ophthalmic emulsion for treating an eye of a human
`comprising 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
`cyclosporin A is the only peptide present in the topical emulsion.
`Ex. 1001, col. 15, ll. 14-20.
`13.
`Claims 2-4 either directly or indirectly depend from claim 1 and
`
`recite that the emulsion further comprises a tonicity agent or demulcent
`
`component, that the tonicity agent or demulcent component is glycerine, and that
`
`5
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`ARGENTUM - EX. 1002, p. 006
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`
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`the emulsion of claim 1 further comprises a buffer. Claim 5 depends from claim 4,
`
`reciting that the buffer is sodium hydroxide. Claims 6-9 depend from claim 1,
`
`reciting that the emulsion comprises glycerine and a buffer, that the emulsion
`
`comprises polysorbate 80 in an amount of about 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 comprises glycerine in an amount of about
`
`2.2% by weight, water, and a buffer, respectively. Percent values refer to % by
`
`weight throughout this declaration unless otherwise indicated. Claim 10 depends
`
`from claim 9, and recites that the buffer is sodium hydroxide. Claim 11 also
`
`depends from claim 1, and recites that after administration of the emulsion to a
`
`human eye, the human’s blood has substantially no detectable concentration of
`
`CsA. Claim 12 depends from claim 6, reciting that the emulsion has a pH in the
`
`range of about 7.2 to about 7.6.
`
`14.
`
`Claim 13 of the ‘111 patent is an independent claim, which narrows
`
`the formulation presented in claim 1, reciting the following:
`
`13. A topical ophthalmic emulsion for treating an eye of a human,
`wherein the topical ophthalmic 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;
`
`6
`
`ARGENTUM - EX. 1002, p. 007
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`
`
`
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`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 and wherein cyclosporin A is the only peptide
`present in the total ophthalmic emulsion.
`Id. at col. 15, l. 52 to col. 16, l. 6.
`15.
`Claims 14-17 depend from claim 13, and recite that the buffer is
`
`sodium hydroxide, the tonicity component is glycerine, that “when the topical
`
`ophthalmic emulsion is administered to an eye of a human, the blood of the human
`
`has substantially no detectable concentration of the cyclosporin A,” and that the
`
`emulsion is effective in treating keratoconjunctivitis sicca. Id. at col. 16, ll. 7-19.
`
`16.
`
`Claim 18 of the ’111 patent is an independent claim to a more narrow
`
`formulation, and recites the following:
`
`18. A topical ophthalmic emulsion for treating an eye of a human,
`the topical ophthalmic 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
`
`7
`
`ARGENTUM - EX. 1002, p. 008
`
`
`
`
`
`wherein cyclosporin A is the only peptide present in the topical
`ophthalmic emulsion.
`Id. at col. 16, ll. 20-31.
`Dependent claim 19 recites that the emulsion of claim 18 has a pH in the range of
`about 7.2 to about 7.6.
`17.
`Finally, claims 20-27 all depend from one of independent claims 1,
`
`13, or 18, and recite that the claimed emulsion is therapeutically effective in
`
`treating dry eye, therapeutically effective in treating keratoconjunctivitis sicca, or
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`is therapeutically effective in increasing tear production.
`
`IV. FILE HISTORY OF THE ’111 PATENT
`18. As noted above, the instant patent that issued from the ‘163
`
`application resulted from continuations of the ’857 application. During prosecution
`
`of the ’857 application, the applicant expressly admitted that the emulsion, referred
`
`to as Composition II, and which remains the emulsion recited in the claims of the
`
`’111 patent, was squarely within the teachings of U.S. Patent No. 5,474,979 (filed
`
`May 17, 1994) to Ding et al. (“Ding ’979,” Ex. 1006). The 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”
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`8
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`ARGENTUM - EX. 1002, p. 009
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`
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`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.
`19.
`I have reviewed the content of the ’857 application concurrently with
`
`that of the ’111 patent and find Composition II of the ’857 application to be
`
`indistinguishable from the emulsion claimed in the ’111 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 ’111 patent for convenient
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`comparison.
`
`9
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`ARGENTUM - EX. 1002, p. 010
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`
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`Ex. 1005 at 0434 (right-most column added). The ’857 application was ultimately
`abandoned. Ex. 1004 at 0002.
`20. As mentioned above, the ’163 application resulted from a series of
`
`continuations from the abandoned ’857 application. Id. During prosecution of the
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`’163 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
`
`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 0170-89.
`
`21. On October 3, 2013, the examiner conducted an interview with four
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`representatives of applicants. Id. at 0234. 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 formulation” and “Data and information
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`10
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`ARGENTUM - EX. 1002, p. 011
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`regarding the claimed formulation’s satisfaction of a long-felt need.” Id.
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`Applicants’ principal argument was that “the evidence of non-obviousness
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`presented at the interview overcomes the prima facie obviousness rejection.” Id.
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`22. On October 23, 2013, the applicants amended the claims to, among
`
`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 0230-33. The
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`applicants stated without elaboration that “the prima facie case of obviousness has
`
`not been 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 formulations 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 0235. The applicants submitted four declarations in support of their
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`assertions: two by Rhett Schiffman, one by Mayassa Attar, and one by Aziz
`
`Mottiwala. Specifically, applicants argued, based on one Schiffman declaration
`
`(“Schiffman Declaration 1”) and the Attar Declaration that “there are new and
`
`unexpected results relative to the prior art.” Id. at 0236 (emphasis in original).
`
`The applicants relied on “unexpected results compared to the prior art” in Schirmer
`
`Tear Testing and decreased corneal staining, as well as reduction of blurred vision
`
`11
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`ARGENTUM - EX. 1002, p. 012
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`
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`and decreased use of artificial tears. Id. I discuss Schiffman Declaration 1, as well
`
`as the Attar declaration, in Section X below.
`
`23.
`
`The examiner issued a Notice of Allowance on November 21, 2013.
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`Id. at 0428. The examiner concluded that applicants had failed to demonstrate
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`commercial success or long-felt need. Id. at 0439-41. 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 0443.
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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
`
`declarations were unexpected or surprising.
`
`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
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`12
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`ARGENTUM - EX. 1002, p. 013
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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
`
`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 prior
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`art for the purpose of this declaration includes references that were published at
`
`least before September 15, 2003.
`
`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;
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`(ii) the differences between the art and the claims at issue; (iii) the level of ordinary
`
`skill in the pertinent art when the invention was made; and, to the extent they exist,
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`any secondary considerations.
`
`28.
`
`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
`
`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
`
`ordinary skill in the art at the time the invention was made.
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`13
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`ARGENTUM - EX. 1002, p. 014
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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.
`
`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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`14
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`ARGENTUM - EX. 1002, p. 015
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`
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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
`
`to modify the prior art reference or to combine prior art reference teachings to
`
`arrive at the claimed invention.
`
`32.
`
`I also understand that “secondary considerations” may be weighed
`
`against evidence of obviousness where appropriate.
`
`33.
`
`I understand that such secondary considerations, where in evidence,
`
`may include: (i) commercial success of a product due to the merits of the claimed
`
`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
`34.
`I have been advised that “a person of ordinary skill in the relevant
`
`field” is a hypothetical person who is presumed to have known the relevant art at
`
`the time of the invention. A person of ordinary skill in the art is also a person of
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`15
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`ARGENTUM - EX. 1002, p. 016
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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 ’111 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
`
`led to the ’111 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.
`
`35.
`
`By virtue of my education, experience, and training, I am familiar
`
`with the level of skill in the art of the ’111 patent prior to September 15, 2003. In
`
`my opinion, a person of ordinary skill in the relevant field as of September 15,
`
`2003 would typically have an advanced degree, such as a medical degree, or a
`
`Ph.D. in organic chemistry, pharmaceutical chemistry, medicinal chemistry,
`
`pharmaceutics, physical pharmacy, or a related field, or could have less education
`
`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
`
`information known in the art relating to dry eye/KCS, its causes and known, useful
`
`treatments, whether palliative or therapeutic.
`
`36.
`
`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
`
`16
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`ARGENTUM - EX. 1002, p. 017
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`
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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
`37.
`I have been advised that, in the present proceeding, the ’111 patent
`
`claims are to be given their broadest reasonable interpretation in view of the
`
`specification. I also understand that, absent some reason to the contrary, claim
`
`terms are typically given their ordinary and accustomed meaning as would be
`
`understood by one of ordinary skill in the art. I have followed these principles in
`
`my analysis throughout this declaration. The ’111 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 ’111 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, and 13-14 recite that the claimed emulsion
`
`comprises a “buffer,” while claims 5, 10, and 14 recite that “the buffer is sodium
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`hydroxide.” As discussed in the specification, “[t]he pH of the emulsions can be
`
`adjusted in a conventional manner using sodium hydroxide . . . to a physiological
`
`pH level.” Ex. 1001, col. 12, ll. 17-19. The specification also notes that “suitable
`
`buffer components, for example, and without limitation, phosphates, citrates,
`
`acetates, borates and the like and mixtures thereof, may be employed to maintain a
`
`suitable pH.” Id. at col. 12, ll. 24-27. Based on the specification of the ’111
`
`17
`
`ARGENTUM - EX. 1002, p. 018
`
`
`
`
`
`patent, a person of ordinary skill in the art would understand the term “buffer” to
`
`include “sodium hydroxide.”
`
`39.
`
`Claims 11 and 16 recite that following administration of the claimed
`
`emulsion, “the blood of the human has substantially no detectable concentration of
`
`the cyclosporin A.” According to the specification: “Cyclosporin component
`
`concentration in blood preferably is determined using a liquid chromatography-
`
`mass spectroscopy-mass spectroscopy (LC-MS/MS), which test has a cyclosporin
`
`component detection limit of 0.1 ng/ml. Cyclosporin component concentrations
`
`below or less than 0.1 ng/ml are therefore considered substantially undetectable.”
`
`Ex. 1001, col. 5, l. 65 – col. 6, l. 4. Notably, neither the claims nor the specification
`
`discuss the time point at which the blood levels of CsA are measured. A person of
`
`ordinary skill in the art could measure blood concentration at either peak or trough
`
`levels, e.g., taking blood samples at serial time points, and determining the
`
`maximal concentration, or by taking and testing a blood sample just prior to a
`
`second administration of the drug to determine the trough level of the drug in the
`
`blood. Taking the broadest reasonable construction for the purposes of this
`
`proceeding, the phrase “substantially no detectable concentration” of CsA includes
`
`CsA blood levels measured at a concentration below 0.1 ng/mL taken at either
`
`peak or trough levels.
`
`18
`
`ARGENTUM - EX. 1002, p. 019
`
`
`
`
`
`40. Dependent claims 20, 23, and 25 recite that the emulsion of
`
`independent claims 1, 13, and 18, respectively, are “therapeutically effective in
`
`treating dry eye.” Dependent claims 21 and 26 recite that the emulsion of
`
`independent claims 1 and 18, respectively, are “therapeutically effective in treating
`
`keratoconjunctivitis sicca.” Dependent claim 17 recites that the emulsion of
`
`independent claim 13 is also “effective in treating keratoconjunctivitis sicca.”
`
`Dependent claims 22, 24, and 27 recite that the emulsion of independent claims 1,
`
`13, and 18, respectively are “therapeutically effective in increasing tear
`
`production.”
`
`41.
`
`The ‘111 patent equates KCS with dry eye disease (Ex. 1001, col. 2,
`
`ll. 64-66, “The present invention is particularly effective in treating dry eye
`
`syndrome. Cyclosporin has been found as effective in treating immune mediated
`
`keratoconjunctivitis sicca (KCS or dry eye disease)”) and characterizes KCS as “an
`
`absolute or partial deficiency in aqueous tear production.” Id. at col. 3, ll. 3-5; see
`
`also Stedman’s Medical Dictionary 27th Edition (M.B. Pugh ed. 2000)
`
`(“Stedman’s,” Ex. 1022) at 0003 (KCS is an “inflammation of the conjunctive and
`
`of the cornea” that is “associated with decreased tears” and is a synonym of dry
`
`eye syndrome).
`
`42. During prosecution, the applicants relied on an increase in tearing as
`
`demonstrated by the Schirmer Tear Test to assert unexpected efficacy of the
`
`19
`
`ARGENTUM - EX. 1002, p. 020
`
`
`
`
`
`claimed emulsion for treating dry eye disease/KCS. See, e.g., Ex. 1004 at 0240
`
`(arguing that the claimed emulsion was “therapeutically effective for the treatment
`
`of dry eye or keratoconjunctivitis sicca . . . according to corneal staining score,
`
`Schirmer score,” and other measures). In light of the discussion above and in the
`
`context of the specification of the ‘111 patent, I understand that an emulsion
`
`effective in increasing tear production is an example of an emulsion effective in
`
`treating dry eye disease/KCS.
`
`43. Dependent claims 19-27 recite that the emulsion is “therapeutically
`
`effective.” The word “therapeutic” means “[r]elating to . . . the treatment,
`
`remediating, or curing of a disorder or disease.” Ex. 1022 at 0007. This includes
`
`palliative treatments, which focus on remediation of a disease—i.e., they alleviate
`
`the symptoms of the disease. Id. at 0004-05.
`
`44.
`
`This comports with what the art recognized as a treatment for dry eye
`
`disease/KCS. See Medications for Dry Eye (1999) in Physicians’ Desk Reference
`
`for Ophthalmology (27th ed.) Montvale, NJ: PDR Network (“Ophthalmic PDR,”
`
`Ex. 1013) at 13 (“Dry eye is treated with artificial tear preparations and ophthalmic
`
`lubricants.”) A person of ordinary skill in the art would not understand the phrases
`
`“therapeutically effective” or “therapeutic effectiveness” to be limited to treatment
`
`of an immune-mediated response sometimes contributing to the condition.
`
`20
`
`ARGENTUM - EX. 1002, p. 021
`
`
`
`
`
`45.
`
`I have followed these definitions in my analysis throughout this
`
`declaration.
`
`VIII. THE STATE OF THE ART
`46.
`Below I describe some of the relevant aspects of what was generally
`
`known in the art as of September 15, 2003.
`
`47.
`
`CsA, a well-known immunosuppressant, has been utilized for
`
`decades in the treatment of inflammatory diseases such as psoriasis and rheumatoid
`
`arthritis, as well as in the prevention of transplant rejection. K. Kunert et al.,
`
`Analysis of Topical Cyclosporine Treatment of Patients with Dry Eye Syndrome
`
`118 ARCH OPHTHAMOL. 1489 (2000) (“Kunert,” Ex. 1012). In the 1990’s, CsA was
`
`administered topically for the treatment of dry eye disease/KCS, “a deficiency in
`
`either the aqueous or mucin components of the precorneal tear film. The most
`
`commonly encountered aqueous-deficient dry eye in the United States is
`
`keratoconjunctivitis sicca [KCS].” Ex. 1013 at 13. Regarding CsA-based
`
`ophthalmic preparations, Kunert teaches: “Topical CsA has been used as treatment
`
`of ocular conditions such as vernal keratoconjunctivitis, corneal transplants,
`
`corneal ulcers, and herpetic stromal keratitis.” Ex. 1012 at 1490. Kunert further
`
`teaches, “Clinical trials with this drug have shown improvement in various
`
`objective measures of KCS such as corneal staining and Schirmer test values.” Id.
`
`21
`
`ARGENTUM - EX. 1002, p. 022
`
`
`
`
`
`48.
`
`These clinical trials evaluated the efficacy and safety of various CsA
`
`emulsions by measuring changes in the levels of inflammatory markers in patients’
`
`eyes (e.g. cytokines) and objective clinical criteria for diagnosis of moderate-to-
`
`severe KCS (e.g. Schirmer tear test and corneal staining). Ex. 1012; see also, K.
`
`Turner et al., Interleukin-6 Levels in the Conjunctival Epithelium of Patients with
`
`Dry Eye Disease Treated with Cyclosporine Ophthalmic Emulsion 19 Cornea 492
`
`(2000) (“Turner,” Ex. 1014); D. Stevenson et al., Efficacy and Safety of
`
`Cyclosporin A Ophthalmic Emulsion in the Treatment of Moderate-to-severe Dry
`
`Eye Disease 107 Ophthalmology 967 (2000) (“Stevenson,” Ex. 1015). From these
`
`trials it was established that the maximal therapeutic effect for the topical treatment
`
`of dry eye disease/KCS was obtained at 0.05% and 0.10% CsA. Ex. 1015 at 967.
`
`49. As the efficacy of CsA for the treatment of dry eye disease/KCS had
`
`been established prior to September 15, 2003, CsA-based pharmaceuticals were
`
`prescribed for ophthalmic administration. Ex. 1013 at 18. As described in the
`
`“Cyclosporine” section of the PDR for Ophthalmology: “This potent
`
`immunosuppressant has a high degree
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