`
`Paper No.
`Filed: January 6, 2017
`
`Filed on behalf of Teva Pharmaceuticals USA, Inc.
`By: Mark D. Schuman
`
`Gary J. Speier
`CARLSON, CASPERS, VANDENBURGH,
`
`
`LINDQUIST & SCHUMAN, P.A.
`
`225 South Sixth Street, Suite 4200
`
`Minneapolis, MN 55402
`
`
`
`UNITED STATES PATENT AND TRADEMARK OFFICE
`
`
`
`BEFORE THE PATENT TRIAL AND APPEAL BOARD
`
`
`
`TEVA PHARMACEUTICALS USA, INC.
`Petitioner,
`
`v.
`
`ALLERGAN, INC.,
`Patent Owner.
`
`
`
`Patent No. 8,648,048
`
`
`
`DECLARATION OF WALTER CHAMBLISS, PH.D.
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`TEVA - EXHIBIT 1025
`
`
`
`TABLE OF CONTENTS
`
`QUALIFICATIONS ....................................................................................... 1
`
`Brief Overview of the Asserted References ....................................... 31
`
`SCOPE OF WORK ......................................................................................... 3
`
`I.
`
`II.
`
`III. OVERVIEW OF THE ‘048 PATENT ........................................................... 4
`
`IV. FILE HISTORY OF THE ‘048 PATENT ....................................................... 8
`
`V. LEGAL STANDARDS ................................................................................ 12
`
`VI. LEVEL OF ORDINARY SKILL AND RELEVANT TIME ...................... 15
`
`VII. CLAIM CONSTRUCTION ......................................................................... 17
`
`VIII. THE STATE OF THE ART ......................................................................... 22
`
`IX. ASSERTED REFERENCES DISCLOSE OR SUGGEST EACH OF THE
`CLAIMED FEATURES OF THE ‘048 PATENT ....................................... 31
`
`A.
`
`B. Detailed Analysis of the Claims ......................................................... 48
`
`
`
`GROUND 1. THE TEACHINGS OF DING ’979 AND SALL MAKE
`CLAIMS 1-10, 12-14, 16-20, 22, AND 23 OBVIOUS. ............................... 49
`
`GROUND 2. THE TEACHINGS OF DING, SALL, AND
`ACHEAMPONG MAKE CLAIMS 11 AND 21 OBVIOUS. ..................... 66
`
`GROUND 3. THE TEACHINGS OF DING SALL, AND
`GLONEK MAKE CLAIMS 11 AND 21 OBVIOUS. ................................. 69
`
`
`X. NO UNEXPECTED RESULTS ................................................................... 72
`
`XI. CONCLUDING STATEMENTS ................................................................. 87
`
`XII. APPENDIX – LIST OF EXHIBITS ............................................................. 89
`
`i
`
`
`
`
`
`I, Walter G. Chambliss, declare as follows:
`
`I. QUALIFICATIONS
`
`
`
`1. My name is Walter Chambliss. I received a B.S. in Pharmacy in
`
`1977, an M.S. in Pharmaceutics in 1980, and a Ph.D. in Pharmaceutics in 1982
`
`from the University of Mississippi.
`
`
`
`2.
`
`I worked for seventeen years in research and development in the
`
`pharmaceutical industry at G.D. Searle, Bristol-Myers and Schering-Plough, where
`
`I was involved in formulation development and/or process development of over
`
`300 products. I was Vice President of Research and Development for the
`
`HealthCare Products Division of Schering-Plough for five years.
`
`
`
`3.
`
`For the past seventeen years, I have been a Professor of Pharmaceutics
`
`at the University of Mississippi, where I teach graduate courses in pharmaceutics.
`
`I am also a Research Professor in the Research Institute of Pharmaceutical
`
`Sciences where I am responsible for managing pharmaceutical development
`
`projects. In addition, I am the Director of Technology Management and oversee
`
`the technology transfer activities for the University.
`
`
`
`4.
`
`I provide broad research and development consulting to the
`
`pharmaceutical industry, and have been an invited speaker in the areas of
`
`formulation and product development.
`
`
`
`1
`
`
`
`
`
`5.
`
`I have authored or co-authored over twenty publications in the field of
`
`pharmaceutical development, including a book chapter concerning delivery of
`
`pharmaceutical products to the eye, and I am a co-inventor of a U.S. patent.
`
`
`
`6.
`
`I am a member of numerous technical societies, including the
`
`Academy of Pharmaceutical Research and Sciences of the American Pharmacists
`
`Association, and the American Association of Pharmaceutical Scientists. I am also
`
`a member of Rho Chi, a national professional honor society. I am a Past President
`
`of the Academy of Pharmaceutical Research and Sciences, and previously served
`
`as a member of the Board of Trustees of the American Pharmacists Association. I
`
`received the Distinguished Alumni Award from the University of Mississippi
`
`School of Pharmacy, and have served on several external scientific advisory boards
`
`of profit and non-profit organizations. I am also a Fellow of the Academy of
`
`Pharmaceutical Research and Science of the American Pharmacists Association
`
`and the American Association of Indian Pharmaceutical Scientists. I served on the
`
`International Steering Committee for the 2nd, 3rd and 4th Editions of the
`
`Handbook of Pharmaceutical Excipients and wrote monographs for excipients
`
`included in several editions.
`
`
`
`7.
`
`I was responsible for the formulation development of numerous oil-
`
`based and water-based formulations at Bristol-Myers and Schering-Plough
`
`including formulations designed to be administered to the eye. A majority of these
`
`
`
`2
`
`
`
`formulations were oil-in-water emulsions for topical administration consisting of
`
`the active pharmaceutical ingredient(s) dispersed or dissolved in oil. I have
`
`significant experience in the use of polymers, including acrylate/C10-30 alkyl
`
`acrylate cross-polymer, and surfactants, including polysorbate 80, as inactive
`
`ingredients in oil-in-water emulsion formulations. In addition, I have significant
`
`experience in the selection of other inactive ingredients commonly used in oil-in-
`
`water emulsion formulations including tonicity agents, demulcents, pH adjusting
`
`agents, and buffers.
`
`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. 1026.
`
`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. 8,648,048 (“the
`
`’048 patent,” Ex. 1001). I have been retained by the Petitioner as a technical
`
`expert to provide analysis and opinions regarding the ’162 patent. I have reviewed
`
`the ’048 patent and relevant sections of its prosecution history in the United States
`
`Patent and Trademark Office. Ex. 1004. I understand that the ’048 patent is
`
`currently subject to another IPR, Mylan Pharmaceuticals Inc., v. Allergan, Inc.,
`
`Case IPR2016-01130 (the “Mylan IPR”). I understand that Petitioner Teva seeks
`
`
`
`3
`
`
`
`to become a party to the Mylan IPR. I have reviewed the materials submitted with
`
`the petition filed in the Mylan IPR, including the petition itself (IPR2016-01131,
`
`Paper 3) and the Declaration of Dr. Mansoor Amiji (IPR2016-01131, Exhibit
`
`1002). I have also reviewed and considered other documents such as the relevant
`
`prior art, and cite them herein. For convenience, documents cited in this
`
`declaration are listed in the Appendix in Section XII. I note that I agree in all
`
`material respects with the analysis and opinions set forth by the petitioner Mylan’s
`
`expert, Dr. Amiji, in the declaration that was submitted in the Mylan IPR and share
`
`the same opinions below. Because my independent analysis of the claims and
`
`prior art led to the same conclusions as Dr. Amiji, coupled with the fact that the
`
`Petitioner Teva is seeking to become a party to the Mylan IPR, I have incorporated
`
`below Dr. Amiji’s opinions and characterizations as my own.
`
`10.
`
`I am compensated at the rate of $800 per hour for non-testifying time
`
`spent on this case and $1,000 per hour for time spent testifying at deposition or
`
`trial. I have no financial interest in the outcome of this matter.
`
`III. OVERVIEW OF THE ‘048 PATENT
`
`11. The ‘048 patent issued February 11, 2014. The ‘048 patent is entitled
`
`“Methods of Providing Therapeutic Effects using Cyclosporin Components.” The
`
`first page of the patent states that an application for the ‘048 patent (U.S.
`
`Application No. 13/967,168, “the ’168 application”) was filed on August 14, 2013
`
`
`
`4
`
`
`
`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 ‘048 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 ’048 patent recites the following:
`
`
`A method of increasing tear production in the eye of a human, the
`1.
`method comprising topically administering to the eye of the human in need
`thereof an emulsion at a frequency of twice a day, wherein the 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 effective in
`increasing tear production.
`
`
`
`Ex. 1001, col. 15, ll. 15-23.
`
`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
`
`
`
`5
`
`
`
`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. Percent values refer to % by
`
`weight throughout this declaration unless otherwise indicated.
`
`14. Claim 11 depends from claim 1, reciting, “when the emulsion is
`
`administered to an eye of a human in an effective amount in increasing tear
`
`production, the blood of the human has substantially no detectable concentration of
`
`cyclosporin A.” Id. at col. 15, ll. 44-47. Claim 12 depends from claim 6, reciting
`
`that the emulsion has a pH in the range of about 7.2 to about 7.6. Claims 13 and 14
`
`depend from claim 1, reciting respectively that the emulsion is “as substantially
`
`therapeutically effective as” and “achieves at least as much therapeutic
`
`effectiveness as,” a similar emulsion comprising CsA in an amount of 0.10% by
`
`weight and castor oil in an amount of 1.25% by weight. Id. at col. 15, l. 50 – col.
`
`16, l. 3. Similarly, claim 15 depends from claim 1, reciting that the emulsion
`
`breaks down more quickly in the eye of a human, “thereby reducing vision
`
`distortion” as compared to a second emulsion that contains only 50% as much
`
`castor oil. Id. at col. 16, ll. 4-8. Claim 16 depends from claim 1, reciting that the
`
`emulsion, when administered to the human eye, demonstrates “a reduction in
`
`adverse events” as compared to a second emulsion comprising 0.10% by weight
`
`
`
`6
`
`
`
`CsA and 1.25% castor oil. Id. at col. 16, ll. 9-14. Claim 17 further depends from
`
`claim 16, reciting that the adverse events are side effects.
`
`15. Claim 18 of the ’048 patent is an independent claim to a method of
`
`treatment, and recites the following:
`
`18. A method of treating keratoconjunctivitis sicca, the
`method comprising the step of topically administering to an eye of a
`human in need thereof an emulsion at a frequency of twice a day, the
`emulsion comprising:
`cyclosporin A in an amount of about 0.05% by weight;
`castor oil in an amount of 1.25% by weight;
`polysorbate 80 in an amount of about 1.0% by weight;
`acrylate/C10-30 alkyl acrylate cross-polymer in an amount of about
`0.05% by weight;
`a tonicity component or a demulcent component in an amount of
`about 2.2% by weight;
`a buffer; and
`water;
`wherein the emulsion is effective in treating
`keratoconjunctivitis sicca and wherein the topical ophthalmic
`emulsion has a pH in the range of about 7.2 to about 7.6.
`
`Id. at col. 16, ll. 17-32.
`
`16. Claims 19-21 depend from claim 18, and recite that the buffer is
`
`sodium hydroxide, the tonicity/demulcent component is glycerine, and that “when
`
`the emulsion is administered to the eye of a human in an effective amount in
`
`treating keratoconjunctivitis sicca, the blood of the human has substantially no
`
`detectable concentration of the cyclosporin A.” Id. at col. 16, ll. 37-41.
`
`17. Claim 22 of the ’048 patent is an independent claim to a method for
`
`the treatment of keratoconjunctivitis sicca, and recites the following:
`7
`
`
`
`
`
`22. A method comprising:
`administering an emulsion topically to the eye of a human having
`keratoconjunctivitis sicca at a frequency of twice a day, wherein the
`emulsion comprises:
`cyclosporin A in an amount of about 0.05% by weight;
`castor oil in an amount of about 1.25% by weight;
`polysorbate 80 in an amount of about 1.0% by weight;
`acrylate/C10-30 alkyl acrylate cross-polymer in an amount of about
`0.05% by weight;
`glycerine in an amount of about 2.2% by weight;
`sodium hydroxide; and
`water; and
`wherein the emulsion is effective in increasing tear production in the
`human having keratoconjunctivitis sicca.
`
`Id. at col. 16, ll. 42-55. Finally, claim 23 depends from claim 22, reciting that the
`
`emulsion has a pH in the range of about 7.2 to about 7.6.
`
`IV. FILE HISTORY OF THE ‘048 PATENT
`
`
`18. As noted above, the instant patent that issued from the ’168
`
`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 ‘048 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
`8
`
`
`
`
`
`of those examples. As the examiner correctly observes, one of ordinary
`skill in the art “would readily envisage” such a composition, especially in
`view of Example 1B: having selected 0.05% as the concentration of
`cyclosporin, Example 1B (wherein the ratio of cyclosporin to castor oil is
`0.04) teaches that the concentration of castor oil should be 1.250%
`(0.05% / 1.250% = 0.04). The applicants concede that in making this
`selection (0.05% cyclosporin and 1.250% castor oil) there would have
`been a reasonable expectation of success; the differences between
`Examples 1A-1E and Composition II are too small to believe otherwise.
`The formulation of Composition II is squarely within the teachings of the
`Ding [’979] reference, and the Office should disregard any statements by
`the applicants suggesting otherwise[.]
`
`Ex. 1005 at 0435.
`
`As discussed below, I agree with these statements.
`
`19.
`
`I have reviewed the content of the ’857 application concurrently with
`
`that of the ‘048 patent and find Composition II of the ’857 application to be
`
`indistinguishable from the emulsion claimed in the ‘048 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 ‘048 patent for convenient
`
`comparison.
`
`
`
`9
`
`
`
`
`
`Ex. 1005 at 0434 (right-most column added). The ’857 application was ultimately
`
`abandoned. Ex. 1004 at 0002.
`
`20. As mentioned above, the ’168 application resulted from a series of
`
`continuations from the abandoned ’857 application. Id. During prosecution of the
`
`’168 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 0178-92.
`
`21. On October 3, 2013, the examiner conducted a telephone interview
`
`with four representatives of applicants. Id. at 0246. According to the applicants’
`
`interview summary, the applicants presented “Data demonstrating unexpected
`
`results and commercial success of the claimed method” and “Data and information
`
`
`
`10
`
`
`
`regarding the claimed method’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 14, 2013, the applicants amended the claims to, among
`
`other things, substitute the generic term “acrylate/C10-30 alkyl acrylate
`
`crosspolymer” 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, commercial success, and
`
`satisfaction of long felt need obtained from the claimed methods and the failure of
`
`others overcome the prima facie obviousness rejection asserted in the Office
`
`Action.” Id. at 0247. 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 0248 (emphasis in original).
`
`The applicants relied on “unexpected results compared to the prior art” in Schirmer
`
`Tear Testing and decreased corneal staining, as well as reduction of blurred vision
`
`
`
`11
`
`
`
`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 2, 2013. Id.
`
`at 0461. The examiner concluded that applicants had failed to demonstrate
`
`commercial success or long-felt need. Id. at 0469-71. 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 0473.
`
`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
`
`
`
`12
`
`
`
`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.
`
`
`
`13
`
`
`
`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
`
`one field of endeavor prompted for use in either the same field or a different field
`
`
`
`14
`
`
`
`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
`
`
`
`15
`
`
`
`ordinary creativity. I understand that the relevant timeframe for assessing the
`
`validity of claims of the ‘048 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 ‘048 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 ‘048 patent prior to September 15, 2003. In
`
`my opinion, a person of ordinary skill in the relevant field as of September 15,
`
`2003would typically have an advanced degree, such as a medical degree, or a
`
`Ph.D. inorganic 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
`
`
`
`16
`
`
`
`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 ‘048 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 ‘048 patent provides definitions for
`
`certain claim terms. In my opinion, these definitions are conventional. Certain
`
`claim terms are not defined in the ‘048 patent. I discuss a few terms below and
`
`what I understand as constructions of these terms.
`
`38. Claims 4-6, 9, 10, 18, and 19 recite that the emulsion of the claimed
`
`method comprises a “buffer,” while claims 5, 10, and 19, 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. 12, ll. 15-17. The specification also notes
`
`that “suitable buffer components, for example, and without limitation, phosphates,
`
`citrates, acetates, borates and the like and mixtures thereof, may be employed to
`
`maintain a suitable pH.” Id. at col. 12, ll. 22-25. Based on the specification of the
`
`
`
`17
`
`
`
`‘048 patent, a person of ordinary skill in the art would understand the term “buffer”
`
`to include “sodium hydroxide.”
`
`39. Claims 11 and 21 recite that following administration of the claimed
`
`emulsion, “the blood of the human has substantially no detectable concentration of
`
`the cyclosporin A.” According to the specification: “Cyclosporin component
`
`concentration in blood preferably is determined using a liquid chromatography-
`
`mass spectroscopy-mass spectroscopy (LC-MS/MS), which test has a cyclosporin
`
`component detection limit of 0.1 ng/ml. Cyclosporin component concentrations
`
`below or less than 0.1 ng/ml are therefore considered substantially undetectable.”
`
`Ex. 1001, col. 5, l. 64 – col. 6, l. 3. Notably, neither the claims nor the
`
`specification discuss the time point at which the blood levels of CsA are measured.
`
`A person of ordinary skill in the art could measure blood concentration at either
`
`peak or trough levels, e.g., taking blood samples at serial time points, and
`
`determining the maximal concentration, or by taking and testing a blood sample
`
`just prior to a second administration of the drug to determine the trough level of the
`
`drug in the blood. Taking the broadest reasonable construction for the purposes of
`
`this proceeding, the phrase “substantially no detectable concentration” of CsA
`
`includes CsA blood levels measured at a concentration below 0.1 ng/mL taken at
`
`either peak or trough levels.
`
`
`
`18
`
`
`
`40.
`
`Independent claim 1 states that the claimed emulsion is “effective in
`
`increasing tear production” and independent claim 22 states that the emulsion is
`
`“effective in increasing tear production in the human having keratoconjunctivitis
`
`sicca [(KCS)].” Independent claim 18 states that the emulsion is “effective in
`
`treating keratoconjunctivitis sicca [(KCS)].” The ’048 patent characterizes KCS as
`
`“an absolute or partial deficiency in aqueous tear production.” Ex. 1001, 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). 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 0253 (arguing that the claimed method 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 ’048 patent, I understand that an emulsion effective in
`
`increasing tear production is an example of an emulsion effective in treating KCS.
`
`41. Dependent claims 13 and 14 respectively describe the emulsion as
`
`being “as substantially therapeutically effective as” and having “at least as much
`
`therapeutic effectiveness as” a second emulsion with 0.10% CsA and 1.25% castor
`
`
`
`19
`
`
`
`oil. 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 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
`
`immunemediated response sometimes contributing to the condition.
`
`42. Claims 13 and 14 each depend from claim 1, and therefore a person of
`
`ordinary skill in the art would understand the phrases “as substantially
`
`therapeutically effective as” and “at least as much therapeutic effectiveness as” to
`
`refer back to the efficacy recited in claim 1, “effective in increasing tear
`
`production.” Even if these phrases were understood somehow to import the term
`
`“keratoconjunctivitis sicca” found in independent claim 18, but not in claims 1 or
`
`13-14, a person of ordinary skill would still understand the phrases to include
`
`efficacy in increasing tear production because, as discussed above, an emulsion
`
`effective in increasing tear production is an example of an emulsion effective in
`
`
`
`20
`
`
`
`treating KCS. Accordingly, the plain meanings
Accessing this document will incur an additional charge of $.
After purchase, you can access this document again without charge.
Accept $ Charge
Still Working On It
This document is taking longer than usual to download. This can happen if we need to contact the court directly to obtain the document and their servers are running slowly.
Give it another minute or two to complete, and then try the refresh button.
A few More Minutes ... Still Working
It can take up to 5 minutes for us to download a document if the court servers are running slowly.
Thank you for your continued patience.
This document could not be displayed.
We could not find this document within its docket. Please go back to the docket page and check the link. If that does not work, go back to the docket and refresh it to pull the newest information.
Your account does not support viewing this document.
You need a Paid Account to view this document. Click here to change your account type.
Your account does not support viewing this document.
Set your membership
status to view this document.
With a Docket Alarm membership, you'll
get a whole lot more, including:
- Up-to-date information for this case.
- Email alerts whenever there is an update.
- Full text search for other cases.
- Get email alerts whenever a new case matches your search.
One Moment Please
The filing “” is large (MB) and is being downloaded.
Please refresh this page in a few minutes to see if the filing has been downloaded. The filing will also be emailed to you when the download completes.
Your document is on its way!
If you do not receive the document in five minutes, contact support at support@docketalarm.com.
Sealed Document
We are unable to display this document, it may be under a court ordered seal.
If you have proper credentials to access the file, you may proceed directly to the court's system using your government issued username and password.
Access Government Site
