Filed on behalf of Akorn Inc.
`By: Michael R. Dzwonczyk
`
`Azy S. Kokabi
`
`Sughrue Mion, PLLC
`
`2100 Pennsylvania Ave., NW
`
`Washington, DC 20037
`
`Telephone: 202-293-7060
`
`Facsimile: 202-293-7860
`
`email:
`mdzwonczyk@sughrue.com
`
`
` akokabi@sughrue.com
`
`
`
`IN THE UNITED STATES PATENT AND TRADEMARK OFFICE
`__________________
`
`BEFORE THE PATENT TRIAL AND APPEAL BOARD
`__________________
`
`AKORN INC.
`Petitioner
`
`v.
`
`ALLERGAN, INC.
`Patent Owner
`__________________
`
`Case No. IPR2017-00596
`Patent No. 8,629,111
`__________________
`
`DECLARATION OF MANSOOR AMIJI, PH.D.
`
`
`
`
`
`EXHIBIT 1002
`
`

`
`TABLE OF CONTENTS
`TABLE OF CONTENTS
`
`
`
`I.
`
`QUALIFICATIONS ........................................................................................... 1
`QUALIFICATIONS ......................................................................................... .. 1
`
`II.
`
`SCOPE OF WORK ............................................................................................ 3
`SCOPE OF WORK .......................................................................................... ..3
`
`III. OVERVIEW OF THE ’111 PATENT .................................................................... 3
`III.
`OVERVIEW OF THE ’ 111 PATENT .................................................................. ..3
`
`IV. FILE HISTORY OF THE ’111 PATENT ................................................................ 6
`IV.
`FILE HISTORY OF THE ’ 1 1 1 PATENT .............................................................. ..6
`
`V.
`
`LEGAL STANDARDS ..................................................................................... 10
`LEGAL STANDARDS ................................................................................... .. 10
`
`VI. LEVEL OF ORDINARY SKILL AND RELEVANT TIME ........................................ 13
`VI.
`LEVEL OF ORDINARY SKILL AND RELEVANT TIME ...................................... .. 13
`
`VII. CLAIM CONSTRUCTION ................................................................................ 14
`VII.
`CLAIM CONSTRUCTION .............................................................................. .. 14
`
`VIII. THE STATE OF THE ART................................................................................ 18
`VIII.
`THE STATE OF THE ART .............................................................................. .. 18
`
`IX. ASSERTED REFERENCES DISCLOSE OR SUGGEST EACH OF THE
`ASSERTED REFERENCES DISCLOSE OR SUGGEST EACH OF THE
`CLAIMED FEATURES OF THE ’111 PATENT .................................................... 25
`CLAIMED FEATURES OF THE ’ 111 PATENT .................................................. ..25
`
`
`
`
`
`
`
`GROUND 1. EACH OF CLAIMS 1-27 IS ANTICIPATED BY DING
`GROUND 1. EACH OF CLAIMS 1-27 IS ANTICIPATED BY DING
`’979 ............................................................................................................ 40
`’979 .......................................................................................................... ..40
`
`GROUND 2. THE TEACHINGS OF DING ’979 AND SALL MAKE
`GROUND 2. THE TEACHINGS OF DING ’97 9 AND SALL MAKE
`CLAIMS 1-10, 12-15, AND 17-27 OBVIOUS. ................................................... 48
`CLAIMS 1-10, 12-15, AND 17-27 OBVIOUS .................................................. ..48
`
`GROUND 3. THE TEACHINGS OF DING ’979, SALL, AND
`GROUND 3. THE TEACHINGS OF DING ’979, SALL, AND
`ACHEAMPONG MAKE CLAIMS 11 AND 16 OBVIOUS. ..................................... 56
`ACHEAMPONG MAKE CLAIMS 11 AND 16 OBVIOUS. ................................... ..5 6
`
`X. NO UNEXPECTED RESULTS ........................................................................... 58
`NO UNEXPECTED RESULTS ......................................................................... ..58
`
`XI. CONCLUDING STATEMENTS .......................................................................... 72
`XI.
`CONCLUDING STATEMENTS ........................................................................ ..7 2
`
`XII. APPENDIX – LIST OF EXHIBITS ..................................................................... 74
`XII.
`APPENDIX — LIST OF EXHIBITS ................................................................... ..74
`
`
`
`i
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`

`
`I, Mansoor Amiji, declare as follows:
`
`I.
`
`QUALIFICATIONS
`
`1.
`
`My name is Mansoor Amiji. I am currently the Bouvé College
`
`Distinguished Professor in the Department of Pharmaceutical Sciences in the
`
`School of Pharmacy at Northeastern University. I have been a member of the
`
`faculty at Northeastern since 1993. I am also an affiliate faculty member in the
`
`Departments of Chemical Engineering and Biomedical Engineering within the
`
`College of Engineering at Northeastern, as well as a Distinguished Adjunct
`
`Professor within the Faculty of Pharmacy at King Abdulaziz University.
`
`2.
`
`I received a B.S. in Pharmacy from Northeastern University in
`
`1988, and a Ph.D. in Pharmaceutics/Biomaterials Science from Purdue University
`
`in 1992. I have also conducted research as a Senior Research Scientist at the
`
`Columbia Research Laboratories in Madison, Wisconsin, as well as served as a
`
`Visiting Research Scholar in the Department of Chemical Engineering at MIT.
`
`3.
`
`My current research focuses on the development of biocompatible
`
`materials from natural and synthetic polymers, target-specific drug and gene
`
`delivery systems for cancer and infectious diseases, and nanotechnology
`
`applications for medical diagnosis, imaging and therapy. I have extensive
`
`experience with pharmaceutical formulations, including oil-in-water emulsions
`
`containing various types of oils, including castor oil, as well as with sterile
`
`formulations and dosage forms for use in the eye. I have also taught courses on the
`
`development and characterization of ophthalmic formulations to undergraduate
`
`pharmacy and graduate students.
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`

`
`4.
`
`I have had extensive experience in the development and
`
`characterization of lipid-based drug delivery systems, including oil-in-water
`
`emulsion formulations intended for parenteral and oral administration. I have also
`
`worked on emulsion formulations that are targeted to different parts of the body,
`
`including the brain.
`
`5.
`
`My research has been funded by such organizations as the National
`
`Institute of Health (NIH) and the National Science Foundation (NSF), as well as
`
`other government agencies and foundations. I also serve, or have served, on the
`
`editorial board of thirteen peer-reviewed journals such as Drug Design:
`
`Development and Therapy, Expert Opinion on Drug Delivery, Pharmaceutical
`
`Formulations and Quality, and Tissue Barriers. I have also served as a reviewer
`
`for 39 peer-reviewed journals including Science, Angewandte Chemie
`
`International Edition, European Journal of Pharmaceutical Sciences, Journal of
`
`Pharmaceutical Sciences, and Nature Communications.
`
`6.
`
`I have authored or co-authored more than 200 peer-reviewed
`
`journal articles. I have also authored 43 book chapters and been listed as an
`
`inventor on 16 patents and patent applications. I have given over 170 invited
`
`seminars at scientific symposia and educational institutions.
`
`7.
`
`I have received numerous honors and awards, including my 2014
`
`induction into the College of Fellows at the Controlled Release Society,
`
`appointment as an Honorary Member in the Phi Lambda Sigma Pharmacy
`
`Leadership Society, a fellowship as well as the Meritorious Manuscript Award
`
`
`
`-2-
`
`

`
`from the American Association of Pharmaceutical Sciences, and the Eurand Award
`
`for Outstanding Research in Oral Drug Delivery.
`
`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. 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.
`
`10.
`
`I am compensated at the rate of $870/hour for my work. I have no
`
`financial interest in the outcome of this matter.
`
`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.
`
`
`
`-3-
`
`

`
`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:
`1.
`human comprising cyclosporin A in an amount of about 0.05% by
`
`A topical ophthalmic emulsion for treating an eye of a
`
`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
`
`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
`
`
`
`-4-
`
`

`
`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;
`
`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 – 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.
`
`
`
`-5-
`
`

`
`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
`
`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
`
`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
`
`
`
`-6-
`
`

`
`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”
`
`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
`
`
`
`-7-
`
`

`
`below, and extended to include the emulsion of the ’111 patent for convenient
`
`comparison.
`
`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
`
`’163 application, the applicants acknowledged their prior admissions, stating that
`
`they had been collecting evidence to support the patentability of the claims “[s]ince
`
`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
`
`double patenting over Ding ’979. Id. at 0170-89.
`
`21.
`
`On October 3, 2013, the examiner conducted an interview with four
`
`representatives of applicants. Id. at 0234. According to the applicants’ interview
`
`
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`-8-
`
`

`
`summary, the applicants presented “Data demonstrating unexpected results and
`
`commercial success of the claimed formulation” and “Data and information
`
`regarding the claimed formulation’s satisfaction of a long-felt need.” Id.
`
`Applicants’ principal argument was that “the evidence of non-obviousness
`
`presented at the interview overcomes the prima facie obviousness rejection.” Id.
`
`22.
`
`On October 23, 2013, the applicants amended the claims to, among
`
`other things, substitute the generic term “acrylate/C10-30 alkyl acrylate cross-
`
`polymer” for the trade name Pemulen® and substitute the full term
`
`“keratoconjunctivitis sicca” for the acronym “KCS.” Id. at 0230-33. The applicants
`
`stated without elaboration that “the prima facie case of obviousness has not been
`
`properly established against the pending claims,” but based their argument on their
`
`assertion that “the unexpected results, commercial success, and satisfaction of long
`
`felt need obtained with the claimed formulations and failure of others overcome
`
`the prima facie obviousness rejection asserted in the Office Action.” Id. at 0235.
`
`The applicants submitted four declarations in support of their 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 and
`
`decreased use of artificial tears. Id. I discuss Schiffman Declaration 1, as well as
`
`the Attar declaration, in Section X below.
`
`
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`-9-
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`

`
`23.
`
`The examiner issued a Notice of Allowance on November 21, 2013.
`
`Id. at 0428. The examiner concluded that applicants had failed to demonstrate
`
`commercial success or long-felt need. Id. at 0439-41. However, relying on
`
`Schiffman Declaration 1 and the Attar Declaration, the examiner concluded that,
`
`“the specific combination of 0.05% by weight cyclosporin A with 1.25% by weight
`
`castor oil is surprisingly critical for therapeutic effectiveness in the treatment of
`
`dry eye or keratoconjunctivitis sicca,” and therefore, “demonstrate[s] surprising
`
`and unexpected results.” Id. at 0443.
`
`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.
`
`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
`
`
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`

`
`understand that prior 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; (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,
`
`any secondary considerations.
`
`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
`
`combined the elements as claimed by known methods with no change in their
`
`respective functions, and the combination would have yielded nothing more than
`
`predictable and expected results to one of ordinary skill in the art.
`
`29.
`
`I understand that improper hindsight must not be used when
`
`comparing the prior art to the invention for obviousness. Thus, a conclusion of
`
`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.
`
`30.
`
`I have been informed that obviousness may also be shown by
`
`demonstrating that it would have been obvious to modify what is taught in a single
`
`piece of prior art to create the patented invention. I understand that obviousness
`
`may be demonstrated by showing that it would have been obvious to combine the
`
`teachings of more than one item of prior art. I understand that in order for a
`
`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
`
`teachings as proposed.
`
`31.
`
`I am informed that the following are examples of principles that
`
`may indicate that it would have been obvious to combine multiple teachings,
`
`resulting in the claimed combination, if the claimed combination involves: (i) the
`
`combination of prior art elements according to known methods to yield predictable
`
`results; (ii) the simple substitution of one known element for another to obtain
`
`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
`
`method or product ready for improvement to yield predictable results; (v) the
`
`application of a technique or approach that would have been “obvious to try” (e.g.,
`
`choosing from a finite number of identified, predictable solutions, with a
`
`reasonable expectation of success); (vi) predictable variations of a known work in
`
`one field of endeavor prompted for use in either the same field or a different field
`
`based on design incentives or other market forces; or (vii) some teaching,
`
`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
`
`
`
`-12-
`
`

`
`others to find the solution provided by the claimed invention; (iv) deliberate
`
`copying of the invention by others; (v) unexpected results achieved by the
`
`invention; (vi) praise of the invention by others skilled in the art; (vii) lack of
`
`independent simultaneous invention within a comparatively short space of time;
`
`and (viii) teaching away from the invention in the prior art. Secondary
`
`considerations are relevant where there is a nexus between the evidence and the
`
`claimed invention.
`
`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
`
`ordinary creativity. I understand that the relevant timeframe for assessing the
`
`validity of claims of the ’111 patent for the purposes of this declaration is assumed
`
`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
`
`expressed herein regarding a person of ordinary skill in the art apply to a person of
`
`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
`
`
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`-13-
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`

`
`but considerable professional experience in one or more of these fields.
`
`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
`
`combination of the following skills and experience: (i) experience formulating
`
`pharmaceutical products; (ii) experience designing and preparing drug
`
`formulations intended for topical ocular administration; (iii) the ability to
`
`understand results and findings presented or published by others in the field,
`
`including the publications discussed in this declaration.
`
`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
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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 ’111 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 ’111 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.
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`Claims 4-6, 9-10, and 13-14 recite that the claimed emulsion
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`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
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`adjusted in a conventional manner using sodium hydroxide . . . to a physiological
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`pH level.” Ex. 1001, col. 12, ll. 17-19. The specification also notes that “suitable
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`buffer components, for example, and without limitation, phosphates, citrates,
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`acetates, borates and the like and mixtures thereof, may be employed to maintain a
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`suitable pH.” Id. at col. 12, ll. 24-27. Based on the specification of the ’111 patent,
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`a person of ordinary skill in the art would understand the term “buffer” to include
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`“sodium hydroxide.”
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`39.
`
`Claims 11 and 16 recite that following administration of the
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`claimed emulsion, “the blood of the human has substantially no detectable
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`concentration of the cyclosporin A.” According to the specification: “Cyclosporin
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`component concentration in blood preferably is determined using a liquid
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`chromatography-mass spectroscopy-mass spectroscopy (LC-MS/MS), which test
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`has a cyclosporin component detection limit of 0.1 ng/ml. Cyclosporin component
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`concentrations below or less than 0.1 ng/ml are therefore considered substantially
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`undetectable.” Ex. 1001, col. 5, l. 65 – col. 6, l. 4. Notably, neither the claims nor
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`the specification discuss the time point at which the blood levels of CsA are
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`measured. A person of ordinary skill in the art could measure blood concentration
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`at either 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.
`
`Dependent claims 20, 23, and 25 recite that the emulsion of
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`independent claims 1, 13, and 18, respectively, are “therapeutically effective in
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`treating dry eye.” Dependent claims 21 and 26 recite that the emulsion of
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`independent claims 1 and 18, respectively, are “therapeutically effective in treating
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`keratoconjunctivitis sicca.” Dependent claim 17 recites that the emulsion of
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`independent claim 13 is also “effective in treating keratoconjunctivitis sicca.”
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`Dependent claims 22, 24, and 27 recite that the emulsion of independent claims 1,
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`13, and 18, respectively are “therapeutically effective in increasing tear
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`production.”
`
`41.
`
`The ’111 patent equates KCS with dry eye disease (Ex. 1001, col.
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`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
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`keratoconjunctivitis sicca (KCS or dry eye disease)”) and characterizes KCS as “an
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`absolute or partial deficiency in aqueous tear production.” Id. at col. 3, ll. 3-5; see
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`also STEDMAN’S MEDICAL DICTIONARY 27TH
` EDITION (M.B. Pugh ed. 2000)
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`(“Stedman’s,” Ex. 1022) at 0003 (KCS is an “inflammation of the conjunctive and
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`of the cornea” that is “associated with decreased tears” and is a synonym of dry
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`eye syndrome).
`
`42.
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`During prosecution, the applicants relied on an increase in tearing
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`as demonstrated by the Schirmer Tear Test to assert unexpected efficacy of the
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`claimed emulsion for treating dry eye disease/KCS. See, e.g., Ex. 1004 at 0240
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`
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`-16-
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`(arguing that the claimed emulsion was “therapeutically effective for the treatment
`
`of dry eye or keratoconjunctivitis sicca . . . according to corneal staining score,
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`Schirmer score,” and other measures). In light of the discussion above and in the
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`context of the specification of the ’111 patent, I understand that an emulsion
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`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,
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`remediating, or curing of a disorder or disease.” Ex. 1022 at 0007. This includes
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`palliative treatments, which focus on remediation of a disease—i.e., they alleviate
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`the symptoms of the disease. Id. at 0004-05.
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`44.
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`This comports with what the art recognized as a treatment for dry
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`eye disease/KCS. See Medications for Dry Eye (1999) In PHYSICIANS’ DESK
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`REFERENCE FOR OPHTHALMOLOGY (27th ed.) Montvale, NJ: PDR Network
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`(“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
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`sometimes contributing to the condition.
`
`45.
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`declaration.
`
`I have followed these definitions in my analysis throughout this
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`
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`-17-
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`VIII. THE STATE OF THE ART
`
`46.
`
`Below I describe some of the relevant aspects of what was
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`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.,
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`Analysis of Topical Cyclosporine Treatment of Patients with Dry Eye Syndrome
`
`118 ARCH. OPHTHALMOL. 1489 (2000) (“Kunert,” Ex. 1012). In the 1990’s, CsA
`
`was administered topically for the treatment of dry eye disease/KCS, “a deficiency
`
`in either the aqueous or mucin components of the precorneal tear film. The most
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`commonly encountered aqueous-deficient dry eye in the United States is
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`keratoconjunctivitis sicca [KCS].” Ex. 1013 at 13.