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`UNITED STATES PATENT AND TRADEMARK OFFICE
`_____________________
`
`BEFORE THE PATENT TRIAL AND APPEAL BOARD
`_____________________
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`
`APOTEX CORP.
`APOTEX, INC.
`Petitioner
`
`v.
`
`ALLERGAN, INC.
`Patent Owner
`
`U.S. Patent No. 8,629,111
`_____________________
`
`Inter Partes Review Case No. Unassigned
`_____________________
`
`DECLARATION OF ERNING XIA, PH.D
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`APOTEX 1005
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`Inter Partes Review of USPN 8,629,111
`Declaration of Erning Xia, Ph.D (APO1005)
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`TABLE OF CONTENTS
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`Introduction ..................................................................................................... 1 
`I. 
`II.  My Background and Qualifications ................................................................ 3 
`III.  Summary of Opinions ..................................................................................... 5 
`IV.  List of Documents I Considered in Formulating My Opinions ................... 11 
`V. 
`Person of Ordinary Skill in the Art ............................................................... 13 
`VI.  The '111 Patent Specification ....................................................................... 14 
`VII.  Claim Construction ....................................................................................... 15 
`VIII.  State of the Art Before September 15, 2003 ................................................. 18 
`IX.  Summary Chart of Analysis Over the Art .................................................... 37 
`X. 
`The Basis of my Analysis with Respect to Anticipation .............................. 37 
`A.  Ground 1: The '979 Patent Discloses Every Limitation of
`Claims 1-27 ......................................................................................... 38 
`XI.  The Basis of my Analysis with Respect to Obviousness ............................. 84 
`A.  Ground 2: The '607 Patent, as it Incorporates the '979 Patent,
`and Sall Provide a Reason to Arrive at the Invention of
`Claims 1-10, 12-15, and 17-27 with a Reasonable
`Expectation of Success ........................................................................ 85 
`B.  Ground 3: The '607 Patent, as it Incorporates the '979 Patent,
`Sall, and Acheampong Provide a Reason to Arrive at the
`Invention of Claims 11 and 16 with a Reasonable
`Expectation of Success ......................................................................141 
`Secondary Considerations of Non-obviousness ................................146 
`1. 
`No Unexpectedly Superior Results ........................................ 148 
`2. 
`No Long-Felt, Unmet Need ................................................... 159 
`3. 
`No Failure of Others .............................................................. 162 
`4. 
`No Industry Praise .................................................................. 162 
`5. 
`Commercial Success .............................................................. 164 
`6. 
`Other Objective Evidence ...................................................... 166 
`XII.  Conclusion .................................................................................................. 167 
`
`
`C. 
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`APOTEX 1005
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`I, Erning Xia, Ph.D, hereby declare as follows.
`I.
`
`Introduction
`
`Inter Partes Review of USPN 8,629,111
`Declaration of Erning Xia, Ph.D (APO1005)
`
`1.
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`I am over the age of eighteen (18) and otherwise competent to make
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`this declaration.
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`2.
`
`I have been retained as an expert witness on behalf of APOTEX, CORP.,
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`and APOTEX, INC. ("APOTEX") for the above-captioned inter partes review (IPR). I
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`am being compensated for my time in connection with this IPR at my standard
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`consulting rate, which is $400 per hour.
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`3.
`
`I understand that the petition for inter partes review involves U.S.
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`Patent No. 8,629,111 ("the '111 patent"), APO1001, which resulted from U.S.
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`Patent Application No. 13/967,163 ("the '163 application"), which is a continuation
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`of U.S. Patent Application No. 13/961,828 ("the '828 application"), filed August 7,
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`2013, now U.S. Patent No. 8,685,930, which is a continuation of U.S. Patent
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`Application No. 11/897,177 ("the '177 application"), filed August 28, 2007, now
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`U.S. Patent No. 8,618,064, and a continuation of U.S. Patent Application No.
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`10/927,857 ("the '857 application"), filed August 27, 2004. I also understand that
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`the '111 patent claims priority to U.S. Provisional Patent Application No.
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`60/503,137, filed on September 15, 2003. The '111 patent names Andrew
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`Acheampong, Diane D. Tang-Liu, James N. Chang, and David F. Power as the
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`inventors. The '111 patent issued on January 14, 2014, from the '163 application. I
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`understand that, according to the United States Patent and Trademark Office
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`Inter Partes Review of USPN 8,629,111
`Declaration of Erning Xia, Ph.D (APO1005)
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`("USPTO") records, the '111 patent is currently assigned to Allergan, Inc. ("the
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`patentee"). The patentee is referred to herein as "Allergan."
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`4.
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`I understand that the '111 patent is directed generally to the field of
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`ophthalmic drug delivery and formulation, and more specifically to methods and
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`compositions for treating an eye of a human or animal having dry eye disease (also
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`referred to as keratoconjunctivitis sicca). APO1001, 1, Abstract, and 4, 2:65-67;
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`APO1002, 11, 6:25-27; APO1003, 4, 5:10-12. I also understand that the
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`compositions of the '111 patent contain several components, including 0.05%
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`cyclosporine1 A ("CsA") and 1.25% castor oil. APO1001, 11, 15:14-20.
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`5.
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`In preparing this Declaration, I have reviewed the '111 patent and each
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`of the documents cited herein, in light of general knowledge in the art. In
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`formulating my opinions, I have relied upon my experience, education, and
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`knowledge in the relevant art. In formulating my opinions, I have also considered
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`the viewpoint of a person of ordinary skill in the art ("POSA") (i.e., a person of
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`1 This declaration uses the term "cyclosporine." However, several prior art
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`references that are quoted in this declaration use the term "cyclosporin." It was
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`known in the art that both terms are used interchangeably and encompass the same
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`class of compounds. See APO1003, 2, 1:11-13.
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`ordinary skill in the field of drug delivery and formulation, defined further below
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`Inter Partes Review of USPN 8,629,111
`Declaration of Erning Xia, Ph.D (APO1005)
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`in Section V) prior to September 15, 2003.
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`II. My Background and Qualifications
`6.
`I am an expert in the field of topical ophthalmic drug formulation, and
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`I have been an expert in this field since prior to 2003. I am presently employed by
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`Fulcrum International Technologies, Inc. I obtained a Bachelor of Science degree
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`in Pharmacy from Nanjing College of Pharmacy in 1982, a Master of Science
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`degree in Biopharmaceuticals from China Pharmaceutical University in 1985, and
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`a Ph.D. in Pharmaceutics from the University of Iowa in 1995.
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`7.
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`I was an Assistant Professor and Research Associate for the College
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`of Pharmacy at the China Pharmaceutical University from August 1985 to
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`December 1987, a Research Associate at Illinois State University from January
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`1988 to December 1989, and a Research and Teaching Assistant for the University
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`of Iowa College of Pharmacy from 1990 to 1995. After receiving my Ph.D. in
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`Pharmaceutics, I held the positions of Senior Formulation Process Scientist and
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`Principal Formulation Process Scientist with Bausch & Lomb in Rochester, NY
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`from 1995-1999 and 1999-2001, respectively. I subsequently held the positions of
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`Senior Principal Formulation Process Scientist from 2001-2004, Research Fellow
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`from 2004-2005, and Site Leader/Research Fellow from 2006-2008 at Bausch &
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`Lomb.
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`Inter Partes Review of USPN 8,629,111
`Declaration of Erning Xia, Ph.D (APO1005)
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`8.
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`I served as Program Director and Research Fellow at Valeant
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`Pharmaceuticals in Rochester, NY from 2009-2013. I currently hold the position of
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`Distinguished Research Fellow and Chief Technology Officer ("CTO") at Fulcrum
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`International Technologies, Inc. ("Fulcrum") and have served in this position since
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`September of 2013.
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`9. My curriculum vitae is provided as APO1006.
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`10.
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`I have experience formulating topical ophthalmic products for treating
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`dry eye, including products that decrease the evaporation of natural tears and
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`products that increase tear production. While serving as CTO at Fulcrum, I helped
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`develop a water-soluble based nutritional product for eye fatigue called 7-Hours™.
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`Previously, I led Vision Care research initiatives as Program Director at Valeant
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`Pharmaceuticals and dry eye initiatives and dry eye portfolio management as a
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`Research Fellow at Bausch & Lomb in Rochester, NY. Also, while at Bausch &
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`Lomb, my colleagues and I often consulted with physicians to determine the
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`current ophthalmic needs in the market, and then made efforts to meet those needs.
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`11.
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`I have received several honors in my career, including the Bausch &
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`Lomb In Focus Recognition in 2010, the Bausch & Lomb CSO Innovation Award
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`in 2007, the National Award for Science Spectrum Trailblazer in 2005, and the
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`National Emerald Award for Career Achievement in Industry in 2004.
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`Inter Partes Review of USPN 8,629,111
`Declaration of Erning Xia, Ph.D (APO1005)
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`12. During my nearly 30 years of experience in topical ophthalmic drug
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`formulation, I have authored or co-authored 36 scientific articles. I am also a
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`named inventor on 106 U.S. patents and patent applications. Each publication,
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`patent, and patent application is listed in my curriculum vitae, APO1006.
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`13. Accordingly, I am an expert in the field of topical ophthalmic drug
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`formulation. My full background is detailed in my curriculum vitae. APO1006.
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`III. Summary of Opinions
`14.
`In this declaration, I consider the topical ophthalmic emulsions of the
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`'111 patent in relation to the state of the art before September 15, 2003. The prior
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`art references that I considered when comparing the claims of the '111 patent to the
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`state of the art include, but are not limited to, U.S. Patent Nos. 5,981,607 ("the '607
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`patent") (APO1002) and 5,474,979 ("the '979 patent") (APO1003), a Phase Three
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`study published by Sall, et al. ("Sall") (APO1004), and a systemic blood
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`distribution study published by Acheampong, et al ("Acheampong") (APO1017). I
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`also considered the file history of the '111 patent (APO1019), as well as
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`Declarations of Drs. Rhett M. Schiffman (APO1019, 246-270 and 301-414) and
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`Mayassa Attar (APO1019, 272-289), and the data and references cited therein. I
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`understand that Allergan submitted the Schiffman and Attar Declarations to the
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`United States Patent and Trademark Office to support the purported patentability
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`of the '111 patent claims. A summary of my opinions follows.
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`Inter Partes Review of USPN 8,629,111
`Declaration of Erning Xia, Ph.D (APO1005)
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`15. Claims 1-27 of the '111 patent are directed to topical ophthalmic
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`emulsions for treating the eye of a human, including treating dry eye disease,
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`treating keratoconjunctivitis sicca, and increasing tear production, where the
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`emulsion comprises several components known in the art, including 0.05%2
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`cyclosporine A ("CsA") and 1.25% castor oil. APO1001, 11, 15:14 to 16:59.
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`16. Claims 1-27 are anticipated by the prior art. The emulsions claimed in
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`the '111 patent contain 0.05% CsA, 1.25% castor oil, and the same excipients at
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`identical concentrations as those taught in the art. See, e.g., APO1001, 11, 16:20-
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`32; APO1003, 3, 4:33-43. The '979 patent discloses working examples of topical
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`ophthalmic castor oil in water emulsions containing CsA, including one containing
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`0.05% CsA with 0.625% castor oil, and one containing 0.1% CsA with 1.25%
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`castor oil, with the remaining ingredients being identical to those in the claimed
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`emulsions. APO1003, 3, 4:33-43. Also, the emulsions disclosed in the '979 patent
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`were developed to treat dry eye disease or keratoconjunctivitis sicca, and
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`cyclosporine A was known to increase tear production. APO1003, 2, 1:37-39 and
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`4, 5:10-14.
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`2 Percent values refer to % by weight throughout this declaration unless
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`otherwise indicated.
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`Inter Partes Review of USPN 8,629,111
`Declaration of Erning Xia, Ph.D (APO1005)
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`17. A POSA would have understood that the '979 patent discloses a small
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`group of four CsA concentrations and four castor oil concentrations. APO1003, 3,
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`4:33-43. Based on the disclosures in the '979 patent, I agree with Allergan's
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`statement that "one of ordinary skill in the art 'would readily envisage'" emulsions
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`containing 0.05% CsA and 1.25% castor oil. APO1019, 951. Also, it is an inherent
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`property of the prior art emulsions containing 0.05% CsA that substantially no
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`detectable blood concentration of CsA results from treatment. See APO1004, 7;
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`APO1017, 6. Therefore, the '979 patent discloses each and every limitation of
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`claims 1-27 of the '111 patent, either expressly or inherently, arranged as claimed.
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`18. Furthermore, the
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`'979 patent explicitly discloses five working
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`examples that include each component and concentration of the claimed emulsions,
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`and a preferred weight ratio of CsA to castor oil, between which the claimed
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`formulation falls. See APO1003, 3, 3:16-20 and 4:33-43. Thus, the disclosure of
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`the '979 patent would have allowed a POSA to make and use the claimed topical
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`ophthalmic emulsions without the need for undue experimentation.
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`19. Claims 1-27 of the '111 patent would have also been obvious in view
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`of the prior art. A POSA would have had a reason to modify the emulsions taught
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`in the '607 patent, as it incorporates the '979 patent, based on the teachings in Sall
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`to arrive at the emulsions of claims 1-10, 12-15, and 17-27 because the '607 and
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`'979 patents disclose safe, stable, and comfortable topical ophthalmic emulsions
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`that are effective in treating dry eye disease, treating keratoconjunctivitis sicca, and
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`Inter Partes Review of USPN 8,629,111
`Declaration of Erning Xia, Ph.D (APO1005)
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`increasing tear production, and Sall teaches the advantages of administering castor
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`oil emulsions containing 0.05% CsA. APO1003, 3, 4:33-43 and 4, 5:10-12;
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`APO1004, 1, Abstract. Also, a POSA seeking to maximize safety would want to
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`utilize the lowest efficacious dose of a drug, and Sall indicates that CsA is at the
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`top of its dose-response curve at a concentration of 0.05%. See APO1004, 1,
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`Abstract. Furthermore, the working examples in the '607 and '979 patents contain
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`the same components and concentrations as the emulsions of the '111 patent.
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`APO1003, 3, 4:33-43.
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`20. A POSA would have understood that both CsA and castor oil were
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`useful agents to treat dry eye disease or keratoconjunctivitis sicca, and that
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`compositions containing CsA increased tear production in the eye. APO1002, 11,
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`6:25-28; APO1003, 2, 1:37-39, and 4, 5:10-12; APO1004, 1. Sall reported that
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`castor oil in water emulsions containing 0.05% CsA were safe and efficacious.
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`APO1004, 1. Both the '607 patent and Sall teach the importance of castor oil and
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`how increasing its concentration can increase the emulsion's residence time on the
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`eye surface. APO1002, 8, Fig. 7; APO1004, 8. Also, both the '607 and '979 patents
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`taught several working examples, including emulsions containing 1.25% castor oil
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`and CsA, that were for the treatment of dry eye or keratoconjunctivitis sicca.
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`APO1002, 11, 6:1-11 and 6:25-28; APO1003, 3, 4:33-43 and 4, 5:10-12. Finally,
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`the '979 patent taught that compositions containing CsA increased tear production
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`Inter Partes Review of USPN 8,629,111
`Declaration of Erning Xia, Ph.D (APO1005)
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`in the eye. APO1003, 2, 1:37-39.
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`21. Therefore, based on the disclosures in the prior art, I agree with
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`Allergan's statement that emulsions containing 0.05% CsA and 1.25% castor oil
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`"would have been obvious[.]" APO1019, 951. I also agree with Allergan's
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`statement that "in making this selection (0.05% cyclosporin and 1.250% castor oil)
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`there would have been a reasonable expectation of success" because the '979 and
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`'607 patents provide working examples of emulsions that are effective in increasing
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`tear production and treating keratoconjunctivitis sicca and dry eye that contain
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`every component and concentration of the claimed emulsions. APO1019, 951;
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`APO1003, 3, 4:33-43.
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`22. Also, a POSA seeking to maximize the safety of the topical
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`ophthalmic emulsions would have had a reason to further combine the teachings of
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`Acheampong with the '607 patent, the '979 patent, and Sall because Acheampong
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`tested blood levels of CsA at numerous time points following administration to the
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`eye. See APO1017, 6. Acheampong and Sall indicated that topical ophthalmic
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`emulsions containing 0.05% CsA resulted in no detectable concentration of CsA in
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`the blood at any time point following administration to the eye, including at both
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`trough and peak time points. APO1004, 7; APO1017, 6. Therefore, a POSA would
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`have had a reasonable expectation of success in arriving at the emulsions of claims
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`11 and 16, because both Sall and Acheampong taught that 0.05% CsA emulsions
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`Inter Partes Review of USPN 8,629,111
`Declaration of Erning Xia, Ph.D (APO1005)
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`resulted in substantially no detectable concentration of CsA in the blood at any
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`time following treatment.
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`23.
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`In addition, I disagree with the arguments Allergan presented in the
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`file history of the '111 patent and the conclusions Drs. Schiffman and Attar drew
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`regarding secondary considerations of non-obviousness, which allegedly included
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`unexpectedly superior results, long-felt need, failure of others, and industry praise.
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`24. First, the data presented in the Schiffman and Attar Declarations do
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`not support the declarants' conclusions that the ophthalmic emulsions claimed in
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`the '111 patent provided unexpectedly superior results over the closest prior art.
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`Instead, a closer look at Allergan's data in the Schiffman and Attar declarations
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`shows that, at best, the formulations as claimed in the '111 patent exhibited
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`properties that were comparable to – not superior to – the closest prior art, and
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`were not unexpected. Furthermore, the data presented in the Schiffman and Attar
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`declarations are missing key information. The omissions and uncertainties
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`surrounding these data render them unreliable, and no reasonable scientific
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`conclusions can be drawn from the data.
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`25. Second, I disagree with Dr. Schiffman's assertion that there was a
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`long-felt, unmet need for the ophthalmic emulsions claimed in the '111 patent
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`before September 15, 2003. Dr. Schiffman does not provide any evidence of a
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`long-felt, unmet need before this date. Moreover, even if a long-felt, unmet need
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`Inter Partes Review of USPN 8,629,111
`Declaration of Erning Xia, Ph.D (APO1005)
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`did exist, the need would have been satisfied by disclosures in the prior art before
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`September 15, 2003.
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`26. Third, I disagree with Dr. Schiffman's opinions that other companies
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`have tried and "failed" to produce formulations as claimed in the '111 patent. Dr.
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`Schiffman does not provide any evidence that other companies tried to develop
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`ophthalmic emulsions but "failed" due to technical reasons and not due to
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`commercial or business reasons.
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`27. Finally, I have reviewed the documents cited in Dr. Schiffman’s
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`second declaration, and I disagree that the documents show industry praise unique
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`to Restasis. Instead, the documents provide quotations from certain individual
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`physicians who describe their general approval of treating patients with topical
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`cyclosporine A and other anti-inflammatory medications. Dr. Schiffman's
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`documents further show that the same physicians' preferred treatment for dry eye
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`patients is a combination of topical cyclosporine A and other dry eye treatments,
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`such as topical steroids or other anti-inflammatory therapies.
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`IV. List of Documents I Considered in Formulating My Opinions
`28.
`In formulating my opinions, I have considered all the references and
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`documents cited herein, including those listed below.
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`Inter Partes Review of USPN 8,629,111
`Declaration of Erning Xia, Ph.D (APO1005)
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`Apotex
`Exhibit #
`
`Description
`
`1001
`
`1002
`
`1003
`
`1004
`
`Acheampong, A., et al., "Methods of Providing Therapeutic Effects
`Using Cyclosporin Components," U.S. Patent No. 8,629,111 (filed
`on August 14, 2013; issued on January 14, 2014)
`Ding, S., et al., "Emulsion Eye Drop For Alleviation of Dry Eye
`Related Symptoms in Dry Eye Patients and/or Contact Lens
`Wearers," U.S. Patent No. 5,981,607 (filed on January 20, 1998;
`issued on November 9, 1999)
`Ding, S., et al. "Nonirritating Emulsions For Sensitive Tissue," U.S.
`Patent No. 5,474,979 (filed on May 17, 1994; issued December 12,
`1995)
`Sall, K., et al., "Two Multicenter, Randomized Studies of the
`Efficacy and Safety of Cyclosporine Ophthalmic Emulsion in
`Moderate to Severe Dry Eye Disease," Ophthalmology 107: 631-639
`(2000)
`1006 Curriculum Vitae of Erning Xia, Ph.D.
`1009 Coles, W.H. and Jaros, P.A., "Dynamics of ocular surface pH," Brit.
`J. Ophthalmol. 68: 549-552 (1984)
`1010 Declaration of Harry C. Boghigian
`"CTFA Becomes the Personal Care Products Council," available at
`http://www.personalcarecouncil.org/ctfa-becomes-personal-care-
`products-council (last accessed Jan. 29, 2015)
`Kunert, K., et al., "Analysis of topical Cyclosporine Treatment of
`Patients With Dry Eye Syndrome," Arch Ophthalmol 118: 1489-
`1496 (2000)
`Turner, K., et al., "Interleukin-6 Levels in the Conjunctival
`Epithelium of Patients with Dry Eye Disease Treated with
`Cyclosporine Opthalmic Emulsion," Cornea 19: 492-496 (2000)
`Acheampong, A., et al., "Cyclosporine Distribution Into The
`Conjunctiva, Cornea, Lacrimal Gland, And Systemic Blood
`Following Topical Dosing Of Cyclosporine To Rabbit, Dog, And
`Human Eyes," in Lacrimal Gland, Tear Film, And Dry Eye
`Syndromes 2 - Basic Science and Clinical Relevance,Plenum Press,
`New York New York, Chapter 144, pp. 1001-1004 (1998)
`Small, D., et al., "Blood Concentrations of Cyclosporin A During
`Long-Term Treatment With Cyclosporin A Ophthalmic Emulsions in
`Patients With Moderate to Severe Dry Eye Disease," Journal of
`Ocular Pharmacology and Therapeutics 18: 411-418 (2002)
`
`1013
`
`1015
`
`1016
`
`1017
`
`1018
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`Inter Partes Review of USPN 8,629,111
`Declaration of Erning Xia, Ph.D (APO1005)
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`Description
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`Apotex
`Exhibit #
`1019 USPN 8,629,111 File History
`Murphy, R., "The Once and Future Treatment Of Dry Eye," Review
`of Optometry January 2000 Cover Focus, available at
`http://legacy.revoptom.com/archive/FEATURES/ro0200f6.htm
`6 (last accessed January 5, 2015)
`Inatomi, T., et al., "Expression of Secretory Mucin Genes by Human
`Conjunctival Epithelia," Invest Ophthalmol 37: 1684-1692 (1996)
`Solomon, A., et al., "Doxycycline Inhibition of Interleukin-1 in the
`Corneal Epithelium," Invest Ophthalmol Vis Sci 41: 2544-2557
`(2000)
`Stevenson, D., et al., "Efficacy and Safety of Cyclosporin A
`Ophthalmic Emulsion in the Treatment of Moderate-to-Severe Dry
`Eye Disease," Ophthalmology 107: 967-974 (2000)
`"Personal Care Production Council," available at
`http://www.personalcarecouncil.org/ (last accessed Jan. 29, 2015)
`Pflugfelder, S.C., et al., "The Diagnosis and Management of Dry
`Eye-A Twenty-five-Year Review," Cornea 19: 644-679 (2000)
`Goto, E. et al., "Low-concentration Homogenized Castor Oil Eye
`Drops for Noninflamed Obstructive Meibomian Gland Dysfunction,"
`Ophthalmology 109: 2030-2035 (2002)
`Food and Drug Administration, Orange Book: Approved Drug
`Products with Therapeutic Equivalence Evaluations, patent and
`exclusivity data for RESTASIS® (last accessed Jan. 12, 2015)
`Maïssa, C., et al., " Effect of Castor Oil Emulsion Eyedrops on Tear
`Film Composition and Stability," Contact Lens & Anterior Eye 33:
`76-82 (2010)
`
`1020
`
`1021
`
`1022
`
`1023
`
`1024
`
`1028
`
`1033
`
`1058
`
`1059
`
`V.
`
`Person of Ordinary Skill in the Art
`29.
`
`I understand that a person of ordinary skill in the art ("POSA") is a
`
`hypothetical person who is presumed to be aware of all pertinent art, thinks along
`
`conventional wisdom in the art, and is a person of ordinary creativity. With respect
`
`to the subject matter of the '111 patent, a POSA would typically have had (i) an
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`M.D. or a Ph.D. in chemistry, biochemistry, pharmaceutics, or in a related field in
`
`Inter Partes Review of USPN 8,629,111
`Declaration of Erning Xia, Ph.D (APO1005)
`
`the biological or chemical sciences, and have at least about two years of experience
`
`in the formulation of topical ophthalmics or (ii) a Master's degree in chemistry,
`
`biochemistry, pharmaceutics, or in a related field in the biological or chemical
`
`sciences, and have at least about five years of experience in formulation of topical
`
`ophthalmics.
`
`30. A POSA typically would work as part of a multidisciplinary team and
`
`draw upon not only his or her own skills, but also take advantage of certain
`
`specialized skills of others in the team to solve a given problem. For example, a
`
`clinician having experience in treating dry eye may be part of the team. As of the
`
`September 2003 earliest possible priority date of the '111 patent, the state of the art
`
`included the teachings provided by the references discussed in each of the
`
`unpatentability grounds set forth below. Additionally, a POSA would have been
`
`aware of other important information and references relating to dry eye, its causes,
`
`and useful treatments.
`
`VI. The '111 Patent Specification
`31.
`I understand that this declaration is being submitted together with a
`
`petition for inter partes review of claims 1-27 of the '111 patent.
`
`32.
`
`I have considered the disclosure of the '111 patent in light of general
`
`knowledge in the art and the teachings of the scientific literature before the earliest
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`possible priority date of the '111 patent, which I understand to be September 15,
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`Inter Partes Review of USPN 8,629,111
`Declaration of Erning Xia, Ph.D (APO1005)
`
`2003. I have also reviewed the file history of the '111 patent. APO1019.
`
`33. The '111 patent is directed generally to the field of ophthalmic drug
`
`delivery and formulation, and more specifically to methods and compositions for
`
`treating an eye of a human or animal. APO1001, 1, Abstract. The '111 patent is
`
`also directed to methods of providing desired therapeutic effects to humans or
`
`animals using compositions containing cyclosporine. APO1001, 4, 1:18-20.
`
`34. The '111 patent specification acknowledges that the use of CsA and
`
`CsA derivatives to treat ophthalmic conditions was previously known in the art.
`
`APO1001, 4, 1:26-57. The '111 patent specification further acknowledges that CsA
`
`oil-in-water emulsions had previously been clinically tested, including emulsions
`
`with castor oil. APO1001, 4, 1:53-57.
`
`VII. Claim Construction
`35.
`I understand that terms of the claims are to be given their broadest
`
`reasonable interpretation in light of the language of the claims and specification of
`
`the '111 patent.
`
`36. "Buffer." Claims 4-6, 9, 10, 13, and 14 recite that the topical
`
`ophthalmic emulsion comprises a "buffer." A POSA would understand that a
`
`buffer is commonly used to control and adjust the pH of a solution or formulation.
`
`See APO1001, 9, 12:17-19. Also, the '111 specification states that "[a]lthough
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`buffer components are not required, . . . suitable buffer components, for example,
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`Inter Partes Review of USPN 8,629,111
`Declaration of Erning Xia, Ph.D (APO1005)
`
`and without limitation, phosphates, citrates, acetates, borates and the like and
`
`mixtures thereof, may be employed to maintain a suitable pH[.]" APO1001, 9,
`
`12:23-27 (emphasis added). Thus, a POSA would understand that the suitable
`
`buffers are not limited to phosphates, citrates, acetates, and borates.
`
`37. The '111 specification further states that "[t]he pH of the emulsions
`
`can be adjusted in a conventional manner using sodium hydroxide . . . to a
`
`physiological pH level." APO1001, 9, 12:17-19. Also, claims 5, 10, and 14 of the
`
`'111 patent explicitly require that "the buffer is sodium hydroxide." APO1001, 11,
`
`15:28-29, 15:44, and 16:8. Therefore, a POSA would understand that the patentee
`
`intended the term "buffer" to encompass sodium hydroxide.
`
`38. "Substantially No Detectable Concentration of Cyclosporine A."
`
`Claims 11 and 16 of the '111 patent recite that the topical ophthalmic emulsion
`
`"wherein, when . . . administered to an eye of a human, the blood of the human has
`
`substantially no detectable concentration of cyclosporin A." APO1001, 11, 15:45-
`
`48 and 16:12-15. The '111 patent states that the "[c]yclosporin 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
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`below or less than 0.1 ng/ml are therefore considered substantially undetectable."
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`Inter Partes Review of USPN 8,629,111
`Declaration of Erning Xia, Ph.D (APO1005)
`
`APO1001, 6, 5:65-6:4.
`
`39. Therefore, based on the express language of the specification of the
`
`'111 patent, a POSA would consider the blood of a human to have substantially no
`
`detectable concentration of the CsA if the topical ophthalmic emulsion resulted in
`
`a blood concentration of less than 0.1 ng/ml. See also APO1004, 7.
`
`40. Neither claim 11 nor 16 recites any particular time after treatment for
`
`measuring the blood levels of CsA. However, a POSA administering ophthalmic
`
`CsA would be cognizant of potential systemic effects if CsA levels in the blood
`
`became elevated. See APO1003, 2, 1:64 to 2:4. Thus, POSAs typically measure
`
`blood concentration in two possible ways: 1) in a time course by administering an
`
`ophthalmic preparation, taking serial blood sample time points, and determining
`
`peak/maximal concentration; or 2) after many days of administration of a drug, by
`
`taking a trough level blood sample just before a next dose is administered.
`
`APO1018, 3-4; APO1017, 4. For example, the trough level blood sample would be
`
`taken at about 12 hours after dosing with a twice-a-day dosing regimen. See
`
`APO1004, 7. Trough
`
`levels are often measured
`
`to monitor steady-state
`
`accumulation of CsA in the blood over the treatment period that could lead to
`
`systemic toxicity. See APO1017, 6.
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`Inter Partes Review of USPN 8,629,111
`Declaration of Erning Xia, Ph.D (APO1005)
`
`41. Accordingly, a POSA would understand that blood samples for CsA
`
`measurement could be taken at time points reflecting trough or peak levels.
`
`42. "Therapeutically Effective." Claims 20-27 state that the emulsion is
`
`"therapeutically effective." The
`
`'111 patent does not specifically define
`
`"therapeutically effective." However, the '111 patent states that the invention
`
`relates to "administering to an eye of a human or animal a therapeutically effective
`
`amount of a cyclosporin component to provide a desired therapeutic effect,
`
`preferably a desired ophthalmic or ocular therapeutic effect." APO1001, 4, 1:21-
`
`25. Accordingly, a POSA would understand "therapeutically effective" to mean
`
`capable of achieving a desired result.
`
`43. Any term I have not expressly interpreted above, I have given its plain
`
`and ordinary meaning to a POSA consistent with the specification of the '111
`
`patent.
`
`VIII. State of the Art Before September 15, 2003
`44. Before September 15, 2003, it was known that dry eye disease was an
`
`ophthalmic condition that resulted in many troublesome symptoms, such as
`
`burning, irritation, discomfort, photophobia, blurred vision, lack of natural tear
`
`production, contact lens intolerance, and an increased risk of ocular surface
`
`damage and infection. APO1004, 1. A POSA would have known that dry eye was
`
`characterized by an elevated inflam