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. IPR2017-00594
`Patent No. 8,685,930
`__________________
`
`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 ’930 PATENT .................................................................... 3
`III.
`OVERVIEW OF THE ’930 PATENT .................................................................. ..3
`
`IV. FILE HISTORY OF THE ’930 PATENT ................................................................ 6
`IV.
`FILE HISTORY OF THE ’930 PATENT .............................................................. ..6
`
`V.
`
`LEGAL STANDARDS ....................................................................................... 9
`LEGAL STANDARDS ..................................................................................... ..9
`
`VI. LEVEL OF ORDINARY SKILL AND RELEVANT TIME ........................................ 12
`VI.
`LEVEL OF ORDINARY SKILL AND RELEVANT TIME ...................................... .. 12
`
`VII. CLAIM CONSTRUCTION ................................................................................ 13
`VII.
`CLAIM CONSTRUCTION .............................................................................. .. 13
`
`VIII. THE STATE OF THE ART................................................................................ 16
`VIII.
`THE STATE OF THE ART .............................................................................. .. 16
`
`IX. ASSERTED REFERENCES DISCLOSE OR SUGGEST EACH OF THE
`ASSERTED REFERENCES DISCLOSE OR SUGGEST EACH OF THE
`CLAIMED FEATURES OF THE ’930 PATENT .................................................... 24
`CLAIMED FEATURES OF THE ’930 PATENT .................................................. ..24
`
`
`
`
`
`
`
`GROUND 1. EACH OF CLAIMS 1-36 IS ANTICIPATED BY DING
`GROUND 1. EACH OF CLAIMS 1-36 IS ANTICIPATED BY DING
`’979 ............................................................................................................ 39
`’979 .......................................................................................................... ..39
`
`GROUND 2. THE TEACHINGS OF DING ’979 AND SALL MAKE
`GROUND 2. THE TEACHINGS OF DING ’97 9 AND SALL MAKE
`CLAIMS 1-10, 12-22, 24-34, AND 36 OBVIOUS. ............................................. 46
`CLAIMS 1-10, 12-22, 24-34, AND 36 OBVIOUS. ........................................... ..46
`
`GROUND 3. THE TEACHINGS OF DING ’979, SALL, AND
`GROUND 3. THE TEACHINGS OF DING ’979, SALL, AND
`ACHEAMPONG MAKE CLAIMS 11, 23, AND 35 OBVIOUS. ............................... 54
`ACHEAMPONG MAKE CLAIMS 11, 23, AND 35 OBVIOUS. ............................. ..54
`
`X. NO UNEXPECTED RESULTS ........................................................................... 57
`NO UNEXPECTED RESULTS ......................................................................... ..57
`
`XI. CONCLUDING STATEMENTS .......................................................................... 71
`XI.
`CONCLUDING STATEMENTS ........................................................................ ..71
`
`XII. APPENDIX – LIST OF EXHIBITS ..................................................................... 73
`XII.
`APPENDIX — LIST OF EXHIBITS ................................................................... ..7 3
`
`
`
`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
`
`-1-
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`

`
`characterization of ophthalmic formulations to undergraduate pharmacy and graduate
`
`students.
`
`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
`
`
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`

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`as an Honorary Member in the Phi Lambda Sigma Pharmacy Leadership Society, a
`
`fellowship as well as the Meritorious Manuscript Award 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. 8,685,930 (“the
`
`’930 patent,” Ex. 1001). I have been retained by the Petitioner as a technical expert to
`
`provide analysis and opinions regarding the ’930 patent. I have reviewed the ’930
`
`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 ’930 PATENT
`
`11.
`
`The ’930 patent issued April 1, 2014. The ’930 patent is entitled
`
`“Methods of Providing Therapeutic Effects using Cyclosporin Components.” The
`
`
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`-3-
`
`

`
`first page of the patent states that an application for the ’930 patent (U.S. Application
`
`No. 13/961,828, “the ’828 application”) was filed on August 7, 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 ’930 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 ’930 patent recites the following:
`1.
`human having keratoconjunctivitis sicca, wherein the topical ophthalmic
`
`A topical ophthalmic emulsion for treating an eye of a
`
`emulsion comprises cyclosporin A in an amount of about 0.05% by
`
`weight, polysorbate 80, acrylate/C10-30 alkyl acrylate cross-polymer,
`
`water, and castor oil in an amount of about 1.25% by weight; and
`
`wherein the topical ophthalmic emulsion is therapeutically
`
`effective in treating keratoconjunctivitis sicca.
`
`Ex. 1001, col. 14, ll. 41-48.
`
`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
`
`
`
`-4-
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`

`
`comprises glycerine in an amount of about 2.2% by weight, water, and a buffer,
`
`respectively. 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. Percent values refer to % by weight throughout this declaration
`
`unless otherwise indicated. 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 ’930 patent is an independent claim, which recites the
`
`same emulsion as in claim 1:
`
`13. A topical ophthalmic emulsion for treating an eye of a human,
`
`wherein the topical ophthalmic emulsion comprises cyclosporin A in an
`
`amount of 0.05% by weight, polysorbate 80, acrylate/C10-30 alkyl
`
`acrylate cross-polymer, water, and castor oil in an amount of about
`
`1.25% by weight; and
`
`wherein the first topical ophthalmic emulsion is therapeutically
`
`effective in treating dry eye disease.
`
`Id. at col. 15, ll. 14-21.
`
`15.
`
`Claims 14-24 depend directly or indirectly from independent claim 13,
`
`and recite the same limitations as in claims 2-12, discussed above.
`
`16.
`
`Claim 25 of the ’930 patent is also an independent claim, which recites
`
`the same emulsion as in independent claims 1 and 13:
`
`25. A topical ophthalmic emulsion for increasing tear
`
`production in the eye of a human having keratoconjunctivitis sicca,
`
`wherein the topical ophthalmic emulsion comprises cyclosporin A in an
`
`amount of 0.05% by weight, polysorbate 80, acrylate/C10-30 alkyl
`
`
`
`-5-
`
`

`
`acrylate cross-polymer, water, and castor oil in an amount of about
`
`1.25% by weight; and
`
`wherein the topical ophthalmic emulsion is therapeutically
`
`effective in increasing tear production in the eye of the human having
`
`keratoconjunctivitis sicca.
`
`Id. at col. 16, ll. 4-14.
`
`17.
`
`Finally, claims 26-36 depend directly or indirectly from independent
`
`claim 25, and recite the same limitations as in claims 2-12 and 14-24, discussed
`
`above.
`IV. FILE HISTORY OF THE ’930 PATENT
`
`18.
`
`As noted above, the instant patent that issued from the ’828 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 ’930
`
`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%
`
`
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`-6-
`
`

`
`(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 ’930 patent and find Composition II of the ’857 application to be
`
`indistinguishable from the emulsion claimed in the ’930 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 ’930 patent for convenient comparison.
`
`
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`-7-
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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 ’828 application resulted from a series of
`
`continuations from the abandoned ’857 application. Id. During prosecution of the
`
`’828 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.
`
`21.
`
`On December 4, 2013, the examiner conducted a telephone interview.
`
`Id. at 0190. According to the applicants’ interview summary, the applicants
`
`“proposed presenting data and evidence to support the patentability of the pending
`
`claims in the form of declarations.” 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 0185-89. The applicants
`
`stated without elaboration that “a prima facie case of obviousness cannot be properly
`
`established against the pending claims,” but based their argument on their assertion
`
`that “the unexpected results obtained from the claimed formulations successfully rebut
`
`any prima facie case of obviousness and support the patentability of the pending
`
`claims.” Id. at 0196. 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
`
`
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`-8-
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`

`
`(“Schiffman Declaration 1”) and the Attar Declaration that “there are new and
`
`unexpected results relative to the prior art.” Id. at 0192 (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.
`
`23.
`
`The examiner issued a Notice of Allowance on January 28, 2014. Id. at
`
`0268. 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 0276.
`
`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
`
`
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`-9-
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`

`
`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 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
`
`
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`
`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, 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.
`
`
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`-11-
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`
`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 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 ’930 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 ’930 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 ’930 patent prior to September 15, 2003. In my
`
`opinion, a person of ordinary skill in the relevant field as of September 15, 2003
`
`
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`
`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. 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 ’930 patent
`
`claims are to be given their broadest reasonable interpretation in view of the
`
`specification. I also understand that, absent some reason to the contrary, claim terms
`
`are typically given their ordinary and accustomed meaning as would be understood by
`
`one of ordinary skill in the art. I have followed these principles in my analysis
`
`throughout this declaration. The ’930 patent provides definitions for certain claim
`
`terms. In my opinion, these definitions are conventional. Certain claim terms are not
`
`
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`-13-
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`
`defined in the ’930 patent. I discuss a few terms below and what I understand as
`
`constructions of these terms.
`
`38.
`
`Claims 4-6, 9-10, 16-18, 21-22, 28-30 and 33-34 recite that the
`
`claimed emulsion comprises a “buffer,” while claims 5, 10, 17, 22, 29, and 34 recite
`
`that “the buffer is sodium hydroxide.” As discussed in the specification, “[t]he pH of
`
`the emulsions can be adjusted in a conventional manner using sodium hydroxide . . .
`
`to a physiological pH level.” Ex. 1001, col. 11, ll. 44-46. The specification also notes
`
`that “suitable buffer components, for example, and without limitation, phosphates,
`
`citrates, acetates, borates and the like and mixtures thereof, may be employed to
`
`maintain a suitable pH.” Id. at col. 11, ll. 51-54. Based on the specification of the ’930
`
`patent, a person of ordinary skill in the art would understand the term “buffer” to
`
`include “sodium hydroxide.”
`
`39.
`
`Claims 11, 23, and 35 recite that following administration of the
`
`claimed emulsion, “the blood of the human has substantially no detectable
`
`concentration of the cyclosporin A.” According to the specification: “Cyclosporin
`
`component concentration in blood preferably is determined using a liquid
`
`chromatography-mass spectroscopy-mass spectroscopy (LC-MS/MS), which test has
`
`a cyclosporin component detection limit of 0.1 ng/ml. Cyclosporin component
`
`concentrations below or less than 0.1 ng/ml are therefore considered substantially
`
`undetectable.” Ex. 1001, col. 5, ll. 27-33. Notably, neither the claims nor the
`
`specification discuss the time point at which the blood levels of CsA are measured.
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`40.
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`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
`
`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
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`CsA blood levels measured at a concentration below 0.1 ng/mL taken at either peak or
`
`trough levels.
`
`41.
`
`Claims 1, 13, and 25 recite that the claimed emulsion is “effective in
`
`treating keratoconjunctivitis sicca,” “effective in treating dry eye,” and “effective in
`
`increasing tear production,” respectively. The ’930 patent equates KCS with dry eye
`
`disease (Ex. 1001, col. 2, ll. 62-65, “The present invention is particularly effective in
`
`treating dry eye syndrome. Cyclosporin has been found as effective in treating
`
`immune mediated keratoconjunctivitis sicca (KCS or dry eye disease).”) and
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`characterizes KCS as “an absolute or partial deficiency in aqueous tear production.”
`
`Id. at col. 3, ll. 2-5; see also STEDMAN’S MEDICAL DICTIONARY 27TH
` EDITION (M.B.
`
`Pugh ed. 2000) (“Stedman’s,” Ex. 1022) at 0003 (KCS is an “inflammation of the
`
`conjunctive and of the cornea” that is “associated with decreased tears” and is a
`
`synonym of dry eye syndrome).
`
`42.
`
`During prosecution, the applicants relied on an increase in tearing as
`
`demonstrated by the Schirmer Tear Test to assert unexpected efficacy of the claimed
`
`emulsion for treating dry eye disease/KCS. See, e.g., Ex. 1004 at 0195 (arguing that
`
`
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`-15-
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`

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`the claimed emulsion was “therapeutically effective for the treatment of dry eye or
`
`[KCS] . . . according to corneal staining score, Schirmer score,” and other measures).
`
`In light of the discussion above and in the context of the specification of the ’930
`
`patent, I understand that an emulsion effective in increasing tear production is an
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`example of an emulsion effective in treating dry eye disease/KCS.
`
`43.
`
`Independent claims 1, 13, and 25 recite the phrase “therapeutically
`
`effective.” The word “therapeutic” means “[r]elating to . . . the treatment, remediating,
`
`or curing of a disorder or disease.” Ex. 1022 at 0007. This includes palliative
`
`treatments, which focus on remediation of a disease—i.e., they alleviate the symptoms
`
`of the disease. Id. at 0004-05.
`
`44.
`
`This comports with what the art recognized as a treatment for dry eye
`
`disease/KCS. See Medications for Dry Eye (1999) In PHYSICIANS’ DESK REFERENCE
`
`FOR OPHTHALMOLOGY (27th ed.) Montvale, NJ: PDR Network (“Ophthalmic PDR,”
`
`Ex. 1013) at 13 (“Dry eye is treated with artificial tear preparations and ophthalmic
`
`lubricants.”) A person of ordinary skill in the art would not understand the phrases
`
`“therapeutically effective” or “therapeutic effectiveness” to be limited to treatment of
`
`an immune-mediated response sometimes contributing to the condition.
`
`45.
`
`I have followed these definitions in my analysis throughout this
`
`declaration.
`
`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.
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`47.
`
`CsA, a well-known immunosuppressant, has been utilized for decades
`
`in the treatment of inflammatory diseases such as psoriasis and rheumatoid arthritis, as
`
`well as in the prevention of transplant rejection. K. Kunert et al., Analysis of Topical
`
`Cyclosporine Treatment of Patients with Dry Eye Syndrome 118 ARCH. OPHTHALMOL.
`
`1489 (2000) (“Kunert,” Ex. 1012). In the 1990’s, CsA was administered topically for
`
`the treatment of dry eye disease/KCS, “a deficiency in either the aqueous or mucin
`
`components of the precorneal tear film. The most commonly encountered aqueous-
`
`deficient dry eye in the United States is keratoconjunctivitis sicca [KCS].” Ex. 1013 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.
`
`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 OPHTHALMOL.
`
`
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`-17-
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`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 of selectivity for T lymphocytes. Available
`
`under the trade name Sandimmune, it has been used in a 2% t