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. IPR2017-00598
`Patent No. 8,642,556
`__________________
`
`DECLARATION OF MANSOOR AMIJI, PH.D.
`
`
`
`
`
`EXHIBIT 1002
`
`

`
`TABLE OF CONTENTS
`
`
`
`I.
`
`QUALIFICATIONS ........................................................................................... 1
`
`II.
`
`SCOPE OF WORK ............................................................................................ 3
`
`III. OVERVIEW OF THE ’556 PATENT .................................................................... 3
`
`IV. FILE HISTORY OF THE ’556 PATENT ................................................................ 7
`
`V.
`
`LEGAL STANDARDS ..................................................................................... 11
`
`VI. LEVEL OF ORDINARY SKILL AND RELEVANT TIME ........................................ 13
`
`VII. CLAIM CONSTRUCTION ................................................................................ 14
`
`VIII. THE STATE OF THE ART................................................................................ 19
`
`IX. ASSERTED REFERENCES DISCLOSE OR SUGGEST EACH OF THE
`CLAIMED FEATURES OF THE ’556 PATENT .................................................... 27
`
`
`
`
`
`
`
`
`
`
`
`GROUND 1. EACH OF CLAIMS 1-20 IS ANTICIPATED BY DING
`’979 ............................................................................................................ 42
`
`GROUND 2. THE TEACHINGS OF DING ’979 AND SALL MAKE
`CLAIMS 1-20 OBVIOUS. ................................................................................ 54
`
`GROUND 3. THE TEACHINGS OF DING ’979, SALL, AND
`GLONEK MAKE CLAIMS 14 AND 19 OBVIOUS. .............................................. 65
`
`GROUND 4. THE TEACHINGS OF DING ’979, SALL, AND
`ACHEAMPONG MAKE CLAIMS 11, 18, AND 20 OBVIOUS. ............................... 68
`
`GROUND 5. THE TEACHINGS OF DING ’979, SALL,
`ACHEAMPONG, AND GLONEK MAKE CLAIM 19 OBVIOUS. ............................. 71
`
`X. NO UNEXPECTED RESULTS ........................................................................... 73
`
`XI. CONCLUDING STATEMENTS .......................................................................... 88
`
`XII. APPENDIX – LIST OF EXHIBITS ..................................................................... 89
`
`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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`-1-
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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. 8,642,556 (“the
`
`’556 patent,” Ex. 1001). I have been retained by the Petitioner as a technical
`
`expert to provide analysis and opinions regarding the ’556 patent. I have reviewed
`
`the ’556 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 ’556 PATENT
`
`11. The ’556 patent issued February 4, 2014. The ’556 patent is entitled
`
`“Methods of Providing Therapeutic Effects using Cyclosporin Components.” The
`
`first page of the patent states that an application for the ’556 patent (U.S.
`
`Application No. 13/967,189, “the ’189 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 ’556 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 ’556 patent recites the following:
`1.
`a human, wherein the first topical ophthalmic emulsion comprises
`
`A first topical ophthalmic emulsion for treating an eye of
`
`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 first topical ophthalmic emulsion is therapeutically
`
`effective in treating dry eye disease; and
`
`wherein the first topical ophthalmic emulsion provides overall
`
`efficacy substantially equal to a second topical ophthalmic emulsion
`
`comprising cyclosporin A in an amount of about 0.1% by weight and
`
`castor oil in an amount of 1.25% by weight.
`
`Ex. 1001, col. 15, l. 65 – col. 16, l. 10.
`
`13. Claim 2 depends from claim 1 and recites that the emulsion further
`
`comprises a tonicity agent or a demulcent component. Claim 3 further depends
`
`from claim 2, and recites that the tonicity agent or demulcent component is
`
`glycerine. Claim 4 depends from claim 1, reciting that the emulsion further
`
`comprises a buffer; claim 5 further depends from claim 4, and recites that the
`
`buffer is sodium hydroxide. Claims 6-9 also depend from claim 1, reciting that the
`
`topical ophthalmic emulsion further comprises glycerine and a buffer, that the
`
`emulsion comprises polysorbate 80 in an amount of 1.0% by weight, that the
`
`
`
`-4-
`
`

`
`emulsion comprises acrylate/C10-30 alkyl acrylate cross-polymer in an amount of
`
`about 0.05% by weight, and that the emulsion further comprises glycerine in an
`
`amount of 2.2% by weight and a buffer, respectively. Claim 10 depends from
`
`claim 9, reciting that the buffer is sodium hydroxide. Claim 11 depends from
`
`claim 1, reciting, that “when the first topical ophthalmic emulsion is administered
`
`to an eye of a human in an effective amount in amount in treating dry eye disease,
`
`the blood of the human has substantially no detectable concentration of cyclosporin
`
`A.” Id. at col. 16, ll. 39-42. Claim 12 depends from claim 6, reciting that the
`
`emulsion has a pH in the range of about 7.2 to about 7.6. Percent values refer to %
`
`by weight throughout this declaration unless otherwise indicated.
`
`14. Claim 13 of the ’556 patent is an independent claim to a
`
`pharmaceutical formulation, and recites the following:
`
`13. A first topical ophthalmic emulsion for treating an eye of
`
`a human, wherein the first 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 and wherein the first topical
`
`ophthalmic emulsion achieves at least as much therapeutic
`
`effectiveness as a second topical ophthalmic emulsion comprising
`
`cyclosporin A in an amount of about 0.1% by weight and castor oil in
`
`an amount of about 1.25% by weight.
`
`15. Claim 14 of the ’556 patent is an independent claim to a
`
`pharmaceutical formulation, and recites the following:
`
`
`
`-5-
`
`

`
`14. A first topical ophthalmic emulsion for treating an eye of
`
`a human, wherein the first 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 breaks down
`
`more quickly in the eye of a human, once administered to the eye of
`
`the human, thereby reducing vision distortion in the eye of the human
`
`as compared to a second topical ophthalmic emulsion that contains
`
`only about 50% as much castor oil as the first topical emulsion.
`
`Id. at col. 16, l. 59 – col. 17, l. 4.
`
`16. Claim 15 of the ’556 patent is also an independent claim to a
`
`pharmaceutical formulation, and recites the following:
`
`15. A first topical ophthalmic emulsion for treating an eye of
`
`a human, wherein the first 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, when
`
`administered to the eye of a human, demonstrates a reduction in
`
`adverse events in the human, relative to a second topical ophthalmic
`
`emulsion comprising cyclosporin A in an amount of about 0.1% by
`
`weight and castor oil in an amount of about 1.25% by weight.
`
`Id. at col. 17, ll. 5-15.
`
`17. Claim 16 depends from claim 15, and recites that the adverse events
`
`are side effects. Claim 17 further depends from claim 16, and recites that the side
`
`effects are selected from a group consisting of visual distortion and eye irritation.
`
`Claims 18-20 depend from independent claims 13-15, respectively, and recite that
`
`
`
`-6-
`
`

`
`following administration of the claimed emulsion to the eye of a human, “the blood
`
`of the human has substantially no detectable concentration of cyclosporin A.” Id. at
`
`col. 17, ll. 4-16.
`IV. FILE HISTORY OF THE ’556 PATENT
`
`18. As noted above, the instant patent that issued from the ’189
`
`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 ’556 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.
`
`
`
`-7-
`
`

`
`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 ’556 patent and find Composition II of the ’857 application to be
`
`indistinguishable from the emulsion claimed in the ’556 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 ’556 patent for convenient
`
`comparison.
`
`Ex. 1005 at 0434 (right-most column added). The ’857 application was ultimately
`
`abandoned. Ex. 1004 at 0002.
`
`
`
`
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`-8-
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`

`
`20. As mentioned above, the ’189 application resulted from a series of
`
`continuations from the abandoned ’857 application. Id. During prosecution of the
`
`’189 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 0134-52.
`
`21. On October 3, 2013, the examiner conducted an interview with four
`
`representatives of applicants. Id. at 0199. According to the applicants’ interview
`
`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 0195-98. 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 0200.
`
`
`
`-9-
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`

`
`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 0201 (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 December 27, 2013.
`
`Id. at 0408. The examiner concluded that applicants had failed to demonstrate
`
`commercial success or long-felt need. Id. at 0417-19. 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 0421.
`
`24. As set forth in detail throughout this declaration, I disagree with the
`
`opinions of Dr. Schiffman and Dr. Attar that the results in the submitted
`
`declarations were unexpected or surprising.
`
`
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`

`
`V. LEGAL STANDARDS
`
`25.
`
`I understand that a claim is not patentable under 35 U.S.C. § 102, for
`
`lack of novelty, if each and every element of the claim is described, either
`
`expressly or inherently, in a single prior art reference.
`
`26.
`
`I have been informed that a claimed invention is not patentable under
`
`35 U.S.C. § 103, for obviousness, if the differences between the invention and the
`
`prior art are such that the subject matter as a whole would have been obvious at the
`
`time the invention was made to “a person having ordinary skill in the art” to which
`
`the subject matter of the invention pertains. I understand that “a person of ordinary
`
`skill in the art” is a hypothetical person who is presumed to have known the
`
`relevant art at the time of the invention. As discussed above, I understand that 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.
`
`
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`-11-
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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
`
`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,
`
`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
`
`
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`-12-
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`

`
`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
`
`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 ’556 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 ’556 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 ’556 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.
`
`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 ’556 patent
`
`claims are to be given their broadest reasonable interpretation in view of the
`
`
`
`-14-
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`

`
`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 ’556 patent provides definitions for
`
`certain claim terms. In my opinion, these definitions are conventional. Certain
`
`claim terms are not defined in the ’556 patent. I discuss a few terms below and
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`what I understand as constructions of these terms.
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`38. Claims 4-6 and 9-10 recite that the claimed emulsion comprises a
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`“buffer,” while claims 5 and 10 recite that “the buffer is sodium hydroxide.” As
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`discussed in the specification, “[t]he pH of the emulsions can be adjusted in a
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`conventional manner using sodium hydroxide . . . to a physiological pH level.” Ex.
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`1001, col. 13, ll. 4-6. The specification also notes that “suitable buffer components,
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`for example, and without limitation, phosphates, citrates, acetates, borates and the
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`like and mixtures thereof, may be employed to maintain a suitable pH.” Id. at col.
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`13, ll. 11-14. Based on the specification of the ’556 patent, a person of ordinary
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`skill in the art would understand the term “buffer” to include “sodium hydroxide.”
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`39. Claims 11 and 18-20 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. 36 – 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.
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`Independent claims 1 and 13 state that the emulsion is “effective in
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`treating dry eye disease.” The ’556 patent identifies that in treating dry eye disease,
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`cyclosporin “acts to enhance or restore lacrimal gland tearing in providing the
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`desired therapeutic effect.” Ex. 1001, col. 9, ll. 36-40. During prosecution, the
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`applicants relied on an increase in tearing as demonstrated by the Schirmer Tear
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`Test to assert unexpected efficacy of the claimed emulsion for treating dry eye
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`disease/KCS. See, e.g., Ex. 1004 at 0205 (arguing that the claimed emulsion was
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`“therapeutically effective for the treatment of dry eye or keratoconjunctivitis sicca .
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`. . according to corneal staining score, Schirmer score,” and other measures). In
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`light of the discussion above and in the context of the specification of the ’556
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`patent, I understand that an emulsion effective in increasing tear production is an
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`example of an emulsion effective in treating dry eye disease.
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`41.
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`Independent claims 1 and 13 respectively also describe the emulsion
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`as having “overall efficacy substantially equal to” and “at least as much therapeutic
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`effectiveness as” a second emulsion with 0.10% CsA and 1.25% castor oil. The
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`word “therapeutic” means “[r]elating to . . . the treatment, remediating, or curing of
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`a disorder or disease.” Ex. 1022 at 0007. This includes palliative treatments, which
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`focus on remediation of a disease—i.e., they alleviate the symptoms of the disease.
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`Id. at 0004-05.
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`42. This comports with what the art recognized as a treatment for dry eye
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`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
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`preparations and ophthalmic lubricants.”) A person of ordinary skill in the art
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`would not understand the phrases “therapeutically effective” or “therapeutic
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`effectiveness” to be limited to treatment of an immune-mediated response
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`sometimes contributing to the condition.
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`43.
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`Independent claim 15 and dependent claim 16 respectively recite that
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`the claimed emulsion has fewer “adverse events” relative to a second emulsion,
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`and that the “adverse events” are “side effects.” Dependent claim 17 further recites
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`that the side effects are “selected from the group consisting of visual distortion and
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`eye irritation.” The specification further refers to adverse events as “e.g. side
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`effects, drug interactions and the like.” Ex. 1001, col. 15, ll. 51-58. The plain
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`meaning of the phrase “side effects” is “A result of a drug or other therapy in
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`addition to or in extension of the desired therapeutic effect; usually but not
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`necessarily, denoting an undesired effect.” Ex. 1022 at 0006. Accordingly, I
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`understand “adverse events” to include undesirable side effects as well as other
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`negative reactions to the drug. In the context of an agent topically administered to
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`the eye, undesirable side effects commonly include burning, stinging, and general
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`eye pain. See Ex. 1007 at 636, Table 3. The specification also gives an example of
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`side effects “which may result from the presence of the cyclosporin component in
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`the blood of the human or animal being treated.” Id. at col. 4, ll. 58-60. The ’556
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`patent also teaches “[o]ne of the important advantages of the present invention is
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`the reduced concentration of the cyclosporin component in the blood of the human
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`or animal,” and that “[o]ne very useful embodiment of the present administering
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`step provides no substantial detectable concentration of cyclosporin component in
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`the blood.” Id. at col. 5, ll.28-36. A person of ordinary skill in the art would
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`understand that the subset of side effects in the context of the ’556 patent “which
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`may result in the presence of the cyclosporin component in the blood” do not occur
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`when there is no substantial detectable concentration of cyclosporin component in
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`the blood.
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`44. Claim 14 recites that the first emulsion “breaks down” more quickly
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`in the eye of a human as compared to a second emulsion containing only 50% as
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`much castor oil. The ’556 patent states that “a relatively high concentration of
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`hydrophobic compon