UNITED STATES PATENT AND TRADEMARK OFFICE
`_____________________________
`
`BEFORE THE PATENT TRIAL AND APPEAL BOARD
`
`_____________________________
`
`
`
`MYLAN PHARMACEUTICALS INC.,
`Petitioner,
`
`v.
`
`ALLERGAN, INC.,
`Patent Owner.
`
`_____________________________
`
`Patent No. 9,248,191
`
`_____________________________
`
`
`
`DECLARATION OF MANSOOR AMIJI, PH.D.
`
`
`
`TEVA - EXHIBIT 1002
`
`
`_____________________________
`
`BEFORE THE PATENT TRIAL AND APPEAL BOARD
`
`_____________________________
`
`
`
`MYLAN PHARMACEUTICALS INC.,
`Petitioner,
`
`v.
`
`ALLERGAN, INC.,
`Patent Owner.
`
`_____________________________
`
`Patent No. 9,248,191
`
`_____________________________
`
`
`
`DECLARATION OF MANSOOR AMIJI, PH.D.
`
`
`
`TEVA - EXHIBIT 1002
`
`
`
`TABLE OF CONTENTS
`
`
`
`I.
`
`QUALIFICATIONS ........................................................................................... 1
`
`II.
`
`SCOPE OF WORK ............................................................................................ 3
`
`III. OVERVIEW OF THE ’191 PATENT .................................................................... 3
`
`IV. FILE HISTORY OF THE ’191 PATENT ................................................................ 9
`
`V.
`
`LEGAL STANDARDS ..................................................................................... 11
`
`VI. LEVEL OF ORDINARY SKILL AND RELEVANT TIME ........................................ 14
`
`VII. CLAIM CONSTRUCTION ................................................................................ 15
`
`VIII. THE STATE OF THE ART................................................................................ 19
`
`IX. ASSERTED REFERENCES DISCLOSE OR SUGGEST EACH OF THE
`CLAIMED FEATURES OF THE ’191 PATENT ..... Error! Bookmark not defined.
`
`
`
`
`
`A. Brief Overview of the Asserted ReferencesError! Bookmark not defined.
`
`B. DETAILED DESCRIPTION OF THE CLAIMS .................................................. 43
`
`
`
`
`
`
`
`GROUND 1. THE TEACHINGS OF DING ’979 AND SALL
`MAKE CLAIMS 1-16 AND 21-27 OBVIOUS. .......................................... 43
`
`GROUND 2. THE TEACHINGS OF DING ’979, SALL, AND
`ACHEAMPONG MAKE CLAIMS 1-16 AND 21-27 OBVIOUS. ................... 60
`
`GROUND 3. THE TEACHINGS OF DING ’979, SALL, AND
`GLONEK MAKE CLAIMS 17-20 OBVIOUS. ........................................... 62
`
`GROUND 4. THE TEACHINGS OF DING ’979, SALL,
`ACHEAMPONG, AND GLONEK MAKE CLAIM 20 OBVIOUS. ................... 66
`
`X. NO UNEXPECTED RESULTS ........................................................................... 68
`
`XI. CONCLUDING STATEMENTS .......................................................................... 83
`
`XII. APPENDIX – LIST OF EXHIBITS...................................................................... 84
`
`
`
`i
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`
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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
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`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
`
`
`
`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
`
`as an Honorary Member in the Phi Lambda Sigma Pharmacy Leadership Society, a
`
`
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`-2-
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`
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`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. 9,248,191 (“the
`
`’191 patent,” Ex. 1001). I have been retained by the Petitioner as a technical expert to
`
`provide analysis and opinions regarding the ’191 patent. I have reviewed the ’191
`
`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 ’191 PATENT
`
`11. The ’191 patent issued February 11, 2014. The ’191 patent is entitled
`
`“Methods of Providing Therapeutic Effects using Cyclosporin Components.” The
`
`first page of the patent states that an application for the ’191 patent (U.S. Application
`
`
`
`-3-
`
`
`
`No. 14/222,478, “the ’478 application”) was filed on March 21, 2014 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 ’191 patent is generally directed to methods of treatment of ocular
`
`disorders using pharmaceutical compositions of cyclosporin A (referred to herein as
`
`“CsA”). Claim 1 of the ’191 patent recites the following:1
`
`1.
`
`A method of treating dry eye disease, the method comprising topically
`
`administering to a human eye in need thereof a first topical ophthalmic
`
`emulsion at a frequency of twice a day, wherein the first topical ophthalmic
`
`emulsion comprises cyclosporin A in an amount of about [0.05] % by weight,
`
`polysorbate 80, acrylate/C10-30 alkyl acrylate cross-polymer, water, and castor
`
`oil in an amount of about 1.25% by weight;
`
`wherein the method is therapeutically effective in treating dry eye
`
`disease;
`
`wherein the method provides overall efficacy substantially equal to
`
`administration of a second topical ophthalmic emulsion to a human eye
`
`in need thereof at a frequency of twice a day, the second emulsion
`
`comprising cyclosporin A in an amount of about 0.1% by weight and
`
`castor oil in an amount of about 1.25% by weight; and
`
`
`
`1 Claim 1 of the patent as published recites “cyclosporin A in an amount of about
`
`005% by weight.” On February 16, 2016, a request was filed for a certificate of
`
`correction, including a request to replace “005%” with “0.05%.” Ex. 1004 at 0006. In
`
`my analysis, I assume that claim 1 is intended to recite “0.05%.”
`
`
`
`-4-
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`
`
`wherein the method results in substantially no detectable
`
`concentration of cyclosporin A in the blood of the human.
`
`Ex. 1001, col. 15, ll. 20-38.
`
`13. Claim 2 depends from claim 1 and recites that the emulsion further
`
`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 emulsion comprises acrylate/C10-30 alkyl
`
`acrylate cross-polymer in an amount of about 0.05% by weight, and that the emulsion
`
`further comprises glycerine in an amount of 2.2% by weight and a buffer,
`
`respectively. Claim 10 depends from claim 9, reciting that the buffer is sodium
`
`hydroxide. Claim 11 depends from claim 6 and recites that the emulsion has a pH in
`
`the range of about 7.2 to about 7.6. 2 Percent values refer to % by weight throughout
`
`this declaration unless otherwise indicated. Claim 12 depends from claim 1, reciting
`
`that the “substantially no detectable concentration” of CsA in the blood means that the
`
`concentration of CsA in the blood is “less than about 0.1 ng/ml.” Id. at col. 15, l. 67.
`
`
`
`2 The certificate of correction mentioned in footnote 1 includes a request to make
`
`claim 11 depend on claim 6 instead of claim 2. Ex. 1004 at 0006. Regardless of
`
`whether claim 11 depends from claim 2 or 6, my conclusions remain the same.
`
`
`
`-5-
`
`
`
`14. Claim 13 of the ’191 patent is an independent claim to a method of
`
`treatment and recites the following:
`
`13. A method of enhancing tearing in a human eye, the method
`
`comprising topically administering to a human eye in need thereof a first
`
`topical ophthalmic emulsion at a frequency of twice a day, wherein the
`
`first topical ophthalmic emulsion comprises cyclosporin A in an amount
`
`of about 0.05% by weight, polysorbate 80, acrylate/C10-30 alkyl acrylate
`
`cross-polymer, water, and castor oil in an amount of about 1.25% by
`
`weight;
`
`wherein the method is therapeutically effective in treating dry eye
`
`disease and wherein the method achieves at least as much therapeutic
`
`efficacy as administration of a second topical ophthalmic emulsion to a
`
`human eye in need thereof at a frequency of twice a day, the second
`
`emulsion comprising cyclosporin A in an amount of about 0.1% by
`
`weight and castor oil in an amount of about 1.25% by weight; and
`
`wherein the method results in a concentration of cyclosporin A in
`
`the blood of the human of less than about 0.1 ng/ml.
`
`Ex. 1001, col. 16, ll. 1-20.
`
`15. Claims 14 and 16 depend from claim 13, and further recite that the
`
`emulsion comprises acrylate/C10-30 alkyl acrylate cross-polymer in an amount of
`
`about 0.05% by weight, polysorbate 80 in an amount of about 1.0% by weight,
`
`glycerine in an amount of about 2.2% by weight and a buffer, and that the method is
`
`effective in enhancing lacrimal gland tearing. Claim 15 depends from claim 14 and
`
`further recites the emulsion has a pH range from about 7.2 to about 7.6.
`
`16. Claim 17 of the ’191 patent is an independent claim to a method of
`
`treatment and recites the following:
`
`
`
`-6-
`
`
`
`17. A method of treating dry eye disease, the method
`
`comprising topically administering to a human eye in need thereof a first
`
`topical ophthalmic emulsion at a frequency of twice a day wherein the
`
`first topical ophthalmic emulsion comprises cyclosporin A in an amount
`
`of about 0.05% by weight, polysorbate 80, acrylate/C10-30 alkyl acrylate
`
`cross-polymer, water, and castor oil in an amount of about 1.25% by
`
`weight; and
`
`Wherein the first topical ophthalmic emulsion breaks down more
`
`quickly in the human eye, once administered to the human eye, thereby
`
`reducing visual distortion in the human eye as compared to a second
`
`topical ophthalmic emulsion that contains only about 50% as much castor
`
`oil as the first topical ophthalmic emulsion.
`
`Ex. 1001, col. 16, ll. 33-46.
`
`17. Claim 18 depends from claim 17, and recites that the emulsion further
`
`comprises acrylate/C10-30 alkyl acrylate cross-polymer in an amount of about 0.05%
`
`by weight, polysorbate 80 in an amount of about 1.0% by weight, glycerine in an
`
`amount of about 2.2% by weight and a buffer. Claim 19 depends from claim 18 and
`
`further recites that the emulsion has a pH in the range of about 7.2 to about 7.6. Claim
`
`20 recites that the method of claim 19 results in a CsA blood concentration of less
`
`than about 0.1 ng/ml.
`
`18. Claim 21 of the ’191 patent is an independent claim to a method of
`
`treatment and recites the following:
`
`22. A method of restoring tearing, the method comprising
`
`topically administering to a human eye in need thereof a first topical
`
`ophthalmic emulsion at a frequency of twice a day, wherein the first
`
`topical ophthalmic emulsion comprises cyclosporin A in an amount of
`
`
`
`-7-
`
`
`
`about 0.05% by weight, polysorbate 80, acrylate/C10-30 alkyl acrylate
`
`cross-polymer, water, and castor oil in an amount of about 1.25% by
`
`weight;
`
`wherein the method demonstrates a reduction in adverse events in
`
`the human compared to administration of a second topical ophthalmic
`
`emulsion to a human in need thereof at a frequency of twice a day, the
`
`second topical ophthalmic emulsion comprising cyclosporin A in an
`
`amount of about 0.1% by weight and castor oil in an amount of about
`
`1.25% by weight; and
`
`wherein the method achieves at least as much therapeutic efficacy
`
`as administration of the second topical ophthalmic emulsion to a human
`
`in need thereof at a frequency of twice a day.
`
`Id. at col. 16, l. 60 – col. 17, l. 11.
`
`19. Claims 22-24 depends from claim 21, reciting that the method results in a
`
`blood CsA concentration of less than 0.1 ng/ml, that the adverse events are selected
`
`from the group consisting of visual distortion and eye irritation, and that the emulsion
`
`further comprises acrylate/C10-30 alkyl acrylate cross-polymer in an amount of about
`
`0.05% by weight, polysorbate 80 in an amount of about 1.0% by weight, glycerine in
`
`an amount of 2.2% by weight, and a buffer. Claim 25 depends from claim 24 and
`
`recites that the emulsion has a pH in the range of about 7.2 to about 7.6. Finally,
`
`claims 26 and 27 depend from claim 21 and recite that the method is effective in
`
`restoring lacrimal gland tearing and that the adverse events are selected from the
`
`group consisting of visual distortion and eye irritation and the CsA blood
`
`concentration is less than about 0.1 ng/ml following emulsion administration.
`
`
`
`
`-8-
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`
`
`IV.
`
`FILE HISTORY OF THE ’191 PATENT
`
`20. As noted above, the instant patent that issued from the ’478 application
`
`resulted from continuations of the ’857 application. During 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 method of treatment
`
`claims in the ’191 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.
`
`
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`-9-
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`
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`21.
`
`I have reviewed the content of the ’857 application concurrently with that
`
`of the ’191 patent and find Composition II of the ’857 application to be
`
`indistinguishable from the emulsion claimed in the ’191 patent. A table submitted by
`
`the applicant during prosecution of the ’857 application has been included below, and
`
`extended to include the emulsion of the ’191 patent for convenient comparison.
`
`Composition of the
`'191 Patent Claims
`
`
`
`Ex. 1005 at 0434 (right-most column added). The ’857 application was ultimately
`
`abandoned. Ex. 1004 at 0797.
`
`22. As mentioned above, the ’478 application resulted from a series of
`
`continuations from the abandoned ’857 application. Id. During prosecution of the
`
`’478 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 0803. The examiner thereafter rejected the
`
`
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`-10-
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`
`
`claims for non-statutory double patenting over U.S. Patent Nos. 8,648,048, 8,629,111,
`
`8,633,162, 8,642,556, and 8,685,930... Id. at 0153-54.
`
`23. The examiner issued a Notice of Allowance on December 18, 2015 (id. at
`
`0116), relying on declarations submitted during the prosecution of parent U.S. Patent
`
`Application No. 13/961,828, which issued as the 8,685,930 patent. During
`
`prosecution of the ’828 application, 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 0022; see also Ex. 1026 (’930 file history) 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 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
`
`
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`-11-
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`
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`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
`
`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
`
`
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`-12-
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`
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`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.
`
`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
`
`
`
`-13-
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`
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`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 ’191 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 ’191 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 ’191 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
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`organic chemistry, pharmaceutical chemistry, medicinal chemistry, pharmaceutics,
`
`
`
`-14-
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`
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`physical pharmacy, or a related field, or could have less education but considerable
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`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
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`relating to dry eye/KCS, its causes and known, useful treatments, whether palliative or
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`therapeutic.
`
`36.
`
`In particular, one of ordinary skill in the art would likely have some
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`combination of the following skills and experience: (i) experience formulating
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`pharmaceutical products; (ii) experience designing and preparing drug formulations
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`intended for topical ocular administration; (iii) the ability to understand results and
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`findings presented or published by others in the field, including the publications
`
`discussed in this declaration.
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`VII.
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`CLAIM CONSTRUCTION
`
`37.
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`I have been advised that, in the present proceeding, the ’191 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 ’191 patent provides definitions for certain claim
`
`terms. In my opinion, these definitions are conventional. Certain claim terms are not
`
`defined in the ’191 patent. I discuss a few terms below and what I understand as
`
`constructions of these terms.
`
`
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`-15-
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`
`
`38. Claims 4-6, 9, 10, 14, 18, and 24 recite that the emulsion of the claimed
`
`method comprises a “buffer,” while claims 5 and 10 recite that “the buffer is sodium
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`hydroxide.” As discussed in the specification, “[t]he pH of the emulsions can be
`
`adjusted in a conventional manner using sodium hydroxide . . . to a physiological pH
`
`level.” Ex. 1001, col. 12, ll. 25-27. The specification also notes that “suitable buffer
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`components, for example, and without limitation, phosphates, citrates, acetates,
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`borates and the like and mixtures thereof, may be employed to maintain a suitable
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`pH.” Id. at col. 12, ll. 32-35. Based on the specification of the ’191 patent, a person of
`
`ordinary skill in the art would understand the term “buffer” to include “sodium
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`hydroxide.”
`
`39. Claims 1 and 21 recite that following administration of the claimed
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`emulsion, “the blood of a human has substantially no detectable concentration of the
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`cyclosporin A.” Claims 12, 13, 20, 22, and 27 recite that the method results in a CsA
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`blood concentration of less than about 0.1 ng/mL. According to the specification:
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`“Cyclosporin component concentration in blood preferably is determined using a
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`liquid chromatography-mass spectroscopy-mass spectroscopy (LC-MS/MS), which
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`test 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, ll. 57-63. Notably, neither the claims nor the
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`specification discuss the time point at which the blood levels of CsA are measured. A
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`person of ordinary skill in the art could measure blood concentration at either peak or
`
`trough levels, e.g., taking blood samples at serial time points, and determining the
`
`
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`-16-
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`
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`maximal concentration, or by taking and testing a blood sample just prior to a second
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`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
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`phrase “substantially no detectable concentration” of CsA includes CsA blood levels
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`measured at a concentration below 0.1 ng/mL taken at either peak or trough levels.
`
`40.
`
`Independent claims 1 and 13 state that the method is “therapeutically
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`effective in treating dry eye disease.” Claim 16 depends from claim 13 and recites that
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`the method is effective in enhancing lacrimal gland tearing. The patent states that “it is
`
`believed that, in certain embodiments of the present invention, the cyclosporin
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`component acts to enhance or restore lacrimal gland tearing in providing the desired
`
`therapeutic effect.” Ex. 1001, col. 9, ll. 13-16. Consistent with this statement,
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`dependent claim 26 recites that the method is effective in restoring lacrimal gland
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`tearing. As lacrimal glands are tear glands, and tears are simply “the fluid secreted by
`
`the lacrimal glands,” the plain meaning of “lacrimal gland tearing” is “tearing.” Ex.
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`1022 at 0008-09.
`
`41. Additionally, as dry eye disease/KCS involves the drying of the eye,
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`“associated with decreased tears,” enhancing tearing in a patient suffering from dry
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`eye/KCS would constitute restoration of tearing in that patient. Id. at 0003. In light of
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`the discussion above and in the context of the specification of the ’191 patent, I
`
`understand that an emulsion effective in increasing tear production is an example of
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`an emulsion effective in enhancing and restoring lacrimal gland tearing and in treating
`
`dry eye disease.
`
`
`
`-17-
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`
`
`42. Claim 1 further recites that the method “provides overall efficacy
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`substantially equal to” a method involving the administration of a second emulsion
`
`containing 0.1% CsA and 1.25% castor oil. Claims 13 and 21 recite that the method
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`“achieves at least as much therapeutic efficacy as” the method of administering this
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`second emulsion. 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. This comports with what the art recognized
`
`as a treatment for dry eye disease/KCS. See Medications for Dry Eye (1999) In
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`PHYSICIANS’ DESK REFERENCE FOR OPHTHALMOLOGY (27th ed.) Montvale, NJ: PDR
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`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,” “therapeutic efficacy,” or
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`“overall efficacy” to be limited to treatment of an immune-mediated response
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`sometimes contributing to the condition.
`
`43. Claims 21 and 23 respectively recite that claimed method “demonstrates
`
`a reduction in adverse events” relative to a second emulsion, and that the “adverse
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`events” are “selected from the group consisting of visual distortion and eye irritation.”
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`The specification further refers to adverse events as “e.g. side effects, drug
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`interactions and the like.” Ex. 1001, col. 15, ll. 7-14. In the context of the claimed
`
`method, which involves the administration of Composition II described in the
`
`specification, however, the patent specifies that “both Composition I and composition
`
`
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`-18-
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`
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`II are found to be substantially non-irritating in use.” Ex. 1001, col. 14, ll. 53-55.
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`Thus, as the specification
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