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`UNITED STATES PATENT AND TRADEMARK OFFICE
`_____________________
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`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. 8,633,162
`_____________________
`
`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 8,633,162
`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 ............................................................... 14 
`VI.  The '162 Patent Specification ....................................................................... 15 
`VII.  Claim Construction ....................................................................................... 16 
`VIII.  State of the Art Before September 15, 2003 ................................................. 21 
`IX.  Summary Chart of Analysis Over the Art .................................................... 41 
`X. 
`The Basis of my Analysis with Respect to Obviousness ............................. 42 
`A.  Ground 1: The '607 Patent, as it Incorporates the '979 Patent,
`and Sall Provide a Reason to Arrive at the Invention of
`Claims 1-10, 12-14, 16-20, and 22-24 with a Reasonable
`Expectation of Success ........................................................................ 44 
`B.  Ground 2: The '607 Patent, as it Incorporates the '979 Patent,
`Sall, and Acheampong Provide a Reason to Arrive at the
`Invention of Claims 11 and 21 with a Reasonable
`Expectation of Success ......................................................................115 
`C.  Ground 3: The '607 Patent, as it Incorporates the '979 Patent,
`Sall, and the '586 Patent Provide a Reason to Arrive at the
`Invention of Claim 15 with a Reasonable Expectation of
`Success ..............................................................................................125 
`Secondary Considerations of Non-obviousness ................................133 
`1. 
`No Unexpectedly Superior Results ........................................ 134 
`2. 
`No Long-Felt, Unmet Need ................................................... 146 
`3. 
`No Failure of Others .............................................................. 149 
`4. 
`No Industry Praise .................................................................. 149 
`5. 
`Commercial Success .............................................................. 151 
`Other Objective Evidence ...................................................... 153 
` 
`6.
`153 
`XI.  Conclusion .................................................................................................. 154 
`
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`D. 
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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 8,633,162
`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.
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`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.
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`I understand that the petition for inter partes review involves U.S.
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`Patent No. 8,633,162 ("the '162 patent"), APO1001, which resulted from U.S.
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`Patent Application No. 13/967,179 ("the '179 application"), which is a continuation
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`of U.S. Patent Application No. 13/961,818 ("the '818 application"), filed August 7,
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`2013, which is a continuation of U.S. Patent Application No. 11/897,177 ("the '177
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`application"), filed August 28, 2007, now U.S. Patent No. 8,618,064, which is a
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`continuation of U.S. Patent Application No. 10/927,857 ("the '857 application"),
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`filed August 27, 2004. I also understand that the '162 patent claims priority to U.S.
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`Provisional Patent Application No. 60/503,137, filed on September 15, 2003. The
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`'162 patent names Andrew Acheampong, Diane D. Tang-Liu, James N. Chang, and
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`David F. Power as the inventors. The '162 patent issued on January 21, 2014, from
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`the '179 application. I understand that, according to the United States Patent and
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`Trademark Office ("USPTO") records, the '162 patent is currently assigned to
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`Inter Partes Review of USPN 8,633,162
`Declaration of Erning Xia, Ph.D (APO1005)
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`Allergan, Inc. ("the patentee"). The patentee is referred to herein as "Allergan."
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`4.
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`I understand that the '162 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; APO1002, 11,
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`6:25-27; APO1003, 4, 5:10-12. I also understand that the compositions recited in
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`the methods of the '162 patent contain several components, including 0.05%
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`cyclosporine1 A ("CsA") and 1.25% castor oil. APO1001, 11, 15:22-30.
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`5.
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`In preparing this Declaration, I have reviewed the '162 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 8,633,162
`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 8,633,162
`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 8,633,162
`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 and
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`methods of the '162 patent in relation to the state of the art before September 15,
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`2003. The prior art references that I considered when comparing the claims of the
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`'162 patent to the state of the art include, but are not limited to, U.S. Patent Nos.
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`5,981,607 ("the
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`'607 patent") (APO1002), 5,474,979 ("the
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`'979 patent")
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`(APO1003), and 5,578,586 ("the '586 patent") (APO1031), a Phase Three study
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`published by Sall, et al. ("Sall") (APO1004), and a systemic blood distribution
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`study published by Acheampong, et al ("Acheampong") (APO1017). I also
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`considered the file history of the '162 patent (APO1019), as well as Declarations of
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`Drs. Rhett M. Schiffman (APO1019, 2130-2154 and 2185-2298) and Mayassa
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`Attar (APO1019, 2156-2173), 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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`Inter Partes Review of USPN 8,633,162
`Declaration of Erning Xia, Ph.D (APO1005)
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`of the '162 patent claims. A summary of my opinions follows.
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`15. Claims 1-24 of the '162 patent are directed to methods of treating dry
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`eye disease and reducing side effects in a human by administering an emulsion to
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`the human twice a day, where the emulsion comprises several components known
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`in the art, including 0.05%2 cyclosporine A ("CsA") and 1.25% castor oil.
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`APO1001, 11, 15:22 to 16:62.
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`16. Claims 1-24 would have been obvious in view of the prior art. A
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`POSA would have had a reason to modify the emulsions taught in the '607 patent,
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`as it incorporates the '979 patent, based on the teachings in Sall to arrive at the
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`methods of claims 1-10, 12-14, 16-20, and 22-24 because the '607 and '979 patents
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`disclose safe, stable, and comfortable topical ophthalmic emulsions that are
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`effective in treating dry eye disease, and Sall teaches the advantages of twice a day
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`administration of castor oil emulsions containing 0.05% CsA. APO1003, 3, 4:33-
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`43 and 4, 5:10-12; APO1004, 1, Abstract. Also, a POSA seeking to maximize
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`safety would want to utilize the lowest efficacious dose of a drug, and Sall
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`indicates that CsA is at the top of its dose-response curve at a concentration of
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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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`0.05%. See APO1004, 1, Abstract. Furthermore, the working examples in the '607
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`Inter Partes Review of USPN 8,633,162
`Declaration of Erning Xia, Ph.D (APO1005)
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`and '979 patents contain the same components and concentrations as the emulsions
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`of the '162 patent. APO1003, 3, 4:33-43.
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`17. A POSA would have understood that both CsA and castor oil were
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`useful agents to treat dry eye disease and reduce side effects. APO1002, 11, 6:25-
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`28; APO1003, 4, 5:10-12; APO1004, 1 and 5-6. Sall reported that castor oil in
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`water emulsions containing 0.05% CsA were safe and efficacious when
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`administered twice a day. APO1004, 1. Both the '607 patent and Sall teach the
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`importance of castor oil and how increasing its concentration can increase the
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`emulsion's residence time on the eye surface. APO1002, 8, Fig. 7; APO1004, 8.
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`The '607 and '979 patents taught several working examples, including emulsions
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`containing 1.25% castor oil and CsA, that were for the treatment of dry eye
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`disease. APO1002, 11, 6:1-11 and 6:25-28; APO1003, 3, 4:33-43 and 4, 5:10-12.
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`Also, Sall reported that topical 0.05% and 0.1% CsA emulsions exhibited
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`statistically equivalent therapeutic effectiveness and that 0.05% CsA emulsions
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`resulted in fewer adverse events and side effects as compared to an emulsion
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`containing 0.1% CsA. APO1004, 5-6.
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`18. 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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`Inter Partes Review of USPN 8,633,162
`Declaration of Erning Xia, Ph.D (APO1005)
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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 treating
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`dry eye disease and contain every component and concentration of the emulsions
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`recited in the claimed methods. APO1019, 951; APO1003, 3, 4:33-43. There
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`would have also been a reasonable expectation of success because Sall discloses
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`that 0.05% and 0.1% CsA emulsions have statistically equivalent efficacies and
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`that 0.05% CsA emulsions result in fewer adverse events and side effects than
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`emulsions containing 0.1% CsA. APO1004, 5-6.
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`19. Also, a POSA seeking to maximize the safety of the topical
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`ophthalmic emulsions would have had a reason to 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 methods of claims
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`11 and 21, because both Sall and Acheampong taught that 0.05% CsA emulsions
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`resulted in substantially no detectable concentration of CsA in the blood at any
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`Inter Partes Review of USPN 8,633,162
`Declaration of Erning Xia, Ph.D (APO1005)
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`time following treatment.
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`20. Furthermore, a POSA would have understood that quicker emulsion
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`break down time following administration to the eye results in reduced vision
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`distortion. See APO1031, 4, 6:35-42. A POSA seeking to reduce emulsion break
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`down time after application to the eye would have had a reason to combine the
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`teachings of the '586 patent with the emulsions taught in the '607 patent, the '979
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`patent, and Sall because the '586 patent recognized the importance of emulsion
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`break down time and provided methods to optimize it. APO1031, 4, 6:33-55, 11,
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`20:24-30. The '586 patent teaches the advantages of a meta-stable ophthalmic
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`emulsion that is "sufficiently stable to provide a uniform dose to the eye but is
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`relatively unstable and rapidly differentiates upon contact with the eye[.]"
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`APO1031, 4, 6:53-55. According to the '586 patent, a meta-stable emulsion can be
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`optimized by decreasing the surfactant to oil ratio – for example, by increasing the
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`oil concentration while maintaining a constant surfactant concentration – to a level
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`that retains the storage stability, but results in a quicker emulsion break down time
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`after application to the eye. APO1031, 4, 6:53-55 and 11, 20:24-30. Therefore, a
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`POSA would have had a reasonable expectation of success in arriving at the
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`method of claim 15, because the '586 patent teaches how increasing the oil
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`concentration while keeping the surfactant concentration constant will reduce the
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`Inter Partes Review of USPN 8,633,162
`Declaration of Erning Xia, Ph.D (APO1005)
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`emulsion break down time, thereby reducing vision distortion.
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`21.
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`In addition, I disagree with the arguments Allergan presented in the
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`file history of the '162 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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`22. First, the data presented in the Schiffman and Attar Declarations do
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`not support the declarants' conclusions that the claimed methods provided
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`unexpectedly superior results over the closest prior art. Instead, a closer look at
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`Allergan's data in the Schiffman and Attar declarations shows that, at best, the
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`formulations recited in the methods claimed in the '162 patent exhibited properties
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`that were comparable to – not superior to – the closest prior art, and were not
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`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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`23. Second, I disagree with Dr. Schiffman's assertion that there was a
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`long-felt, unmet need for the methods claimed in the '162 patent before September
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`15, 2003. Dr. Schiffman does not provide any evidence of a long-felt, unmet need
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`before this date. Moreover, even if a long-felt, unmet need did exist, the need
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`would have been satisfied by disclosures in the prior art before September 15,
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`Inter Partes Review of USPN 8,633,162
`Declaration of Erning Xia, Ph.D (APO1005)
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`2003.
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`24. Third, I disagree with Dr. Schiffman's opinions that other companies
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`have tried and "failed" to produce formulations as recited in the claimed methods.
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`Dr. 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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`25. 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
`26.
`In formulating my opinions, I have considered all the references and
`
`documents cited herein, including those listed below.
`
`Apotex
`Exhibit #
`1001 Acheampong, A., et al., "Methods of Providing Therapeutic Effects
`
`Description
`
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`Inter Partes Review of USPN 8,633,162
`Declaration of Erning Xia, Ph.D (APO1005)
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`Apotex
`Exhibit #
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`Description
`
`1002
`
`1003
`
`1004
`
`1013
`
`1015
`
`1016
`
`1017
`
`Using Cyclosporin Components," U.S. Patent No. 8,633,162 (filed
`on August 14, 2013; issued on January 21, 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)
`
`1018
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`Apotex
`Exhibit #
`1019 USPN 8,633,162 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
`1024
`http://www.personalcarecouncil.org/ (last accessed Jan. 29, 2015)
`1027 Chidambaram, N. and Burgess, D.J., "Effect of Nonionic Surfactant
`on Transport of Surface-Active and Non-Surface-Active Model
`Drugs and Emulsion Stability in Triphasic Systems," AAP Pharmsci
`2: 1-11 (2000)
`Pflugfelder, S.C., et al., "The Diagnosis and Management of Dry
`Eye-A Twenty-five-Year Review," Cornea 19: 644-679 (2000)
`Glonek, T., et al., "Dry Eye Treatment Process And Solution," U.S.
`Patent No. 5,578,586 (filed on February 4, 1994; issued on
`November 26, 1996)
`Rowe, E.L., "Effect of Emulsifer Concentration and Type on the
`Particle Size Distribution of Emulsions," Journal of Pharmaceutical
`Science 54: 262-264 (1965)
`Goto, E. et al., "Low-concentration Homogenized Castor Oil Eye
`Drops for Noninflamed Obstructive Meibomian Gland Dysfunction,"
`Ophthalmology 109: 2030-2035 (2002)
`Chanana, G., and Sheth, B., "Particle Size Reduction of Emulsions
`by Formulation Design-II: Effect of Oil and Surfactant
`Concentration," PDA J. Pharm. Sci. & Tech., 49: 71-76 (1995)
`Food and Drug Administration, Orange Book: Approved Drug
`Products with Therapeutic Equivalence Evaluations, patent and
`exclusivity data for RESTASIS® (last accessed Jan. 12, 2015)
`
`1020
`
`1021
`
`1022
`
`1023
`
`1028
`
`1031
`
`1032
`
`1033
`
`1041
`
`1058
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`Inter Partes Review of USPN 8,633,162
`Declaration of Erning Xia, Ph.D (APO1005)
`
`Description
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`- 13 -
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`APOTEX 1005
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`Apotex
`Exhibit #
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`1059
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`Inter Partes Review of USPN 8,633,162
`Declaration of Erning Xia, Ph.D (APO1005)
`
`Description
`
`Maïssa, C., et al., " Effect of Castor Oil Emulsion Eyedrops on Tear
`Film Composition and Stability," Contact Lens & Anterior Eye 33:
`76-82 (2010)
`
`V.
`
`Person of Ordinary Skill in the Art
`27.
`
`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 '162 patent, a POSA would typically have had (i) an
`
`M.D. or a Ph.D. in chemistry, biochemistry, pharmaceutics, or in a related field in
`
`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.
`
`28. 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
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`September 2003 earliest possible priority date of the '162 patent, the state of the art
`
`included the teachings provided by the references discussed in each of the
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`APOTEX 1005
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`unpatentability grounds set forth below. Additionally, a POSA would have been
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`Inter Partes Review of USPN 8,633,162
`Declaration of Erning Xia, Ph.D (APO1005)
`
`aware of other important information and references relating to dry eye, its causes,
`
`and useful treatments.
`
`VI. The '162 Patent Specification
`29.
`I understand that this declaration is being submitted together with a
`
`petition for inter partes review of claims 1-24 of the '162 patent.
`
`30.
`
`I have considered the disclosure of the '162 patent in light of general
`
`knowledge in the art and the teachings of the scientific literature before the earliest
`
`possible priority date of the '162 patent, which I understand to be September 15,
`
`2003. I have also reviewed the file history of the '162 patent. APO1019.
`
`31. The '162 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 '162 patent is
`
`also directed to methods of providing desired therapeutic effects to humans or
`
`animals using compositions containing cyclosporine. APO1001, 4, 1:18-20.
`
`32. The '162 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 '162 patent specification further acknowledges that CsA
`
`oil-in-water emulsions had previously been clinically tested, including emulsions
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`with castor oil. APO1001, 4, 1:53-57.
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`Inter Partes Review of USPN 8,633,162
`Declaration of Erning Xia, Ph.D (APO1005)
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`VII. Claim Construction
`33.
`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 '162 patent.
`
`34. "Buffer." Claims 4, 6, 9, and 18 recite that the emulsion of the
`
`claimed method 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, 12:25-27. Also, the '162 specification states that "[a]lthough buffer
`
`components are not required, . . . 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[.]" APO1001, 9, 12:31-35
`
`(emphasis added). Thus, a POSA would understand that the suitable buffers are not
`
`limited to phosphates, citrates, acetates, and borates.
`
`35. The '162 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, 12:25-27. Also, claims 5, 10, and 19 of the
`
`'162 patent explicitly require that "the buffer is sodium hydroxide." APO1001, 11,
`
`15:37-38, 15:49-50, and 16:37-38. Therefore, a POSA would understand that the
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`patentee intended the term "buffer" to encompass sodium hydroxide.
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`Inter Partes Review of USPN 8,633,162
`Declaration of Erning Xia, Ph.D (APO1005)
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`36. "Substantially No Detectable Concentration of Cyclosporine A."
`
`Claims 11 and 21 of the '162 patent recite a method wherein when the topical
`
`ophthalmic emulsion is administered to an eye of a human, "the blood of the
`
`human has substantially no detectable concentration of the cyclosporin A."
`
`APO1001, 11, 15:51-53 and 16:41-44. The
`
`'162 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 below or less than 0.1 ng/ml are therefore considered
`
`substantially undetectable." APO1001, 6, 5:64-6:3.
`
`37. Therefore, based on the express language of the specification of the
`
`'162 patent, a POSA would consider the blood of a human to have substantially no
`
`detectable concentration of the CsA if the treatment method resulted in a blood
`
`concentration of less than 0.1 ng/ml. See also APO1004, 7.
`
`38. Neither claim 11 nor 21 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
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`peak/maximal concentration; or 2) after many days of administration of a drug, by
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`Inter Partes Review of USPN 8,633,162
`Declaration of Erning Xia, Ph.D (APO1005)
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`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.
`
`39. Accordingly, a POSA would understand that blood samples for CsA
`
`measurement could be taken at time points reflecting trough or peak levels.
`
`40. "Effective," "Substantially Therapeutically Effective as a Second
`
`Emulsion," "At Least As Much Therapeutic Effectiveness as a Second
`
`Emulsion." Claims 1, 13, 14, 22, and 23 recite that the emulsion of the claimed
`
`method is "effective", "substantially therapeutically effective as a second
`
`emulsion", or achieves "at least as much therapeutic effectiveness as a second
`
`emulsion". APO1001, 11, col. 15-16. The '162 patent does not specifically define
`
`these terms. However, the '162 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 therape