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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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`
`AMNEAL PHARMACEUTICALS, LLC
`Petitioner
`v.
`
`ENDO PHARMACEUTICALS INC.
`Patent Owner
`
`U.S. Patent No. 8,329,216
`_____________________
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`Inter Partes Review Case No. Unassigned
`_____________________
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`DECLARATION OF ANTHONY PALMIERI III, PH.D.
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`Inter Partes Review of USPN 8,329,216
`Declaration of Anthony Palmieri (Exhibit 1003)
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`
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`TABLE OF CONTENTS
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`
`I. 
`II. 
`III. 
`IV. 
`V. 
`VI. 
`VII. 
`
`XI. 
`
`0B0BIntroduction ..................................................................................................... 4 
`1B1BMy Background and Qualifications ................................................................ 5 
`2B2BList of Documents I Considered in Formulating My Opinion ....................... 9 
`3B3BPerson of Ordinary Skill in the Art ............................................................... 10 
`4B4BThe '216 Patent Specification ....................................................................... 11 
`5B5BThe Claims of the '216 Patent ....................................................................... 11 
`6B6BState of the Art of Controlled Release Opioid Compositions as of July 6,
`2001 .............................................................................................................. 14 
`VIII.  7B7BSummary Chart of Analysis Over the Art .................................................... 22 
`IX. 
`8B8BThe Basis of My Analysis with Respect to Obviousness ............................. 22 
`X. 
`9B9BGround 1: Claims 5, 16, 44, 46 and 47 Would Have Been Obvious Over
`Oshlack and The Handbook of Dissolution Testing .................................... 24 
`14B14BHydrophilic Material Limitations (claims 1, 5, 13, 43, 44, 46
`A. 
`and 47) ................................................................................................. 28 
`15B15BDosage Limitations (claims 1 and 38) ................................................ 30 
`16B16B6-OH Limitations (claim 1) ................................................................. 31 
`17B17BOne Hour Dissolution Limitation (claim 13) and Four and
`Ten Hour Dissolution Limitations (claim 38) ..................................... 34 
`18B18BFood Effect Limitations (claim 38) ..................................................... 36 
`19B19BMethod of Treating Pain (claim 38) .................................................... 37 
`20B20BA POSA Would Have Had a Reasonable Expectation of
`Success in Modifying Oshlack and the Handbook to Obtain
`the Claimed Subject Matter ................................................................. 37 
`10B10BGround 2: Claims 72-82 Would Have Been Obvious Over Oshlack, the
`Handbook and Pharmaceutical Excipients ................................................... 40 
`A.  Gelling Agent Limitations (claims 72 and 77) .................................... 43 
`B. 
`22B22BDosage Limitations (claims 81 and 82) .............................................. 44 
`C. 
`23B23B6-OH Limitations (claims 75, 76, and 78) .......................................... 44 
`
`B. 
`C. 
`D. 
`
`E. 
`F. 
`G. 
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`XII. 
`
`D. 
`
`E. 
`F. 
`G. 
`
`E. 
`F. 
`G. 
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`Inter Partes Review of USPN 8,329,216
`Declaration of Anthony Palmieri (Exhibit 1003)
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`2. 
`
`3. 
`
`24B24BOne Hour Dissolution Limitation (claims 72 and 77) and
`Four and Ten Hour Dissolution Limitations (claims 74, 75,
`77, 78 and 79) ...................................................................................... 46 
`25B25BFood Effect Limitations (claims 77 and 81) ....................................... 46 
`26B26BMethod of Treating Pain (claims 81 and 82) ...................................... 47 
`27B27BA POSA Would Have Had a Reasonable Expectation of
`Success in Modifying Oshlack to Obtain the Claimed
`Subject Matter ..................................................................................... 47 
`11B11BGround 3: Claims 72-82 Would Have Been Obvious Over Baichwal '757,
`The Penwest Statement Baichwal '933 and Gordon ..................................... 50 
`A.  Gelling Agent Limitations (claims 72 and 77) .................................... 54 
`B. 
`29B29BDosage Limitations (claims 81 and 82) .............................................. 55 
`C. 
`30B30B6-OH Limitations (claims 75, 76, and 78) .......................................... 55 
`D. 
`31B31BOne Hour Dissolution Limitation (claims 72 and 77) and
`Four and Ten Hour Dissolution Limitations (claims 74, 75,
`77, 79 and 80) ...................................................................................... 56 
`35B35BBaichwal '757 and '933 disclose controlled release
`1. 
`formulations containing soluble agents ................................... 57 
`36B36BBaichwal
`'757 discloses comparable
`in vitro
`dissolution tests ........................................................................ 58 
`37B37BExamples of Baichwal '757 and '933 meet the claimed
`dissolution profiles ................................................................... 59 
`38B38BBaichwal '757 and '933 teach how to adjust release ................ 60 
`4. 
`32B32BFood Effect Limitations (claims 77 and 81) ....................................... 61 
`33B33BMethod of Treating Pain (claims 81 and 82) ...................................... 61 
`34B34BA POSA Would Have Had a Reasonable Expectation of
`Success in Modifying Baichwal '757 and the Penwest
`Statement to Obtain the Claimed Subject Matter ................................ 62 
`XIII.  12B12BObjective Indicia of Nonobviousness ........................................................... 63 
`XIV.  13B13BConclusion .................................................................................................... 65 
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`I.
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`Inter Partes Review of USPN 8,329,216
`Declaration of Anthony Palmieri (Exhibit 1003)
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`I, Anthony Palmieri III, Ph.D., hereby declare as follows.
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`0B0BIntroduction
`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 Amneal
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`Pharmaceuticals, LLC for the above-captioned inter partes review (IPR). I am
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`being compensated for my time in connection with this IPR at my standard legal
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`consulting rate, which is $400 per hour. I understand that the petition for inter
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`partes review involves U.S. Patent No. 8,329,216 ("the '216 patent"), AMN 1001,
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`which resulted from U.S. Application No. 11/427,438 ("the '438 application"),
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`filed on June 29, 2006, and alleging an earliest priority date of July 6, 2001. The
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`'216 patent names Huai-Hung Kao, Anand R. Baichwal, Troy McCall and David
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`Lee as inventors. The '216 patent issued on December 11, 2012, from the '432
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`application. I further understand that, according to the USPTO records, the '216
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`patent is currently assigned to Endo Pharmaceuticals, Inc. ("Endo.")
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`3.
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`I submitted a Declaration dated January 16, 2014 in IPR2014-00360,
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`which also involved review of the '216 patent. IPR as to some of the claims of the
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`'216 patent was instituted by the U.S. Patent and Trademark Office ("USPTO") on
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`July 25, 2014.
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`Inter Partes Review of USPN 8,329,216
`Declaration of Anthony Palmieri (Exhibit 1003)
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`4.
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`In preparing this Declaration, I have reviewed the '216 patent and
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`considered each of the documents cited herein, in light of general knowledge in the
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`art as of July 6, 2001. In formulating my opinions, I have relied upon my
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`experience, education and knowledge in the relevant art. In formulating my
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`opinions, I have considered the viewpoint of a person of ordinary skill in the art
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`("POSA") (i.e., a person of ordinary skill in the field of in vitro dissolution testing,
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`defined further below in Section IV) prior to July 6, 2001.
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`II.
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`1B1BMy Background and Qualifications
`5.
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`I am an expert in the field of pharmaceutical formulation and have
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`been since before 2001. I have almost 40 years of experience in the design of
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`pharmaceutical
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`formulations,
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`including controlled
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`release pharmaceutical
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`formulations.
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`6.
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`I received my B.S. and M.S. in Pharmacy from the University of
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`Rhode Island in Kingston, Rhode Island. I received my Ph.D. in Pharmaceutics
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`from the University of Georgia in Athens, Georgia. The title of my dissertation
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`was, “Microencapsulation of drugs suspended in an oil: preparation and dissolution
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`properties of microcapsules of prednisone and hydrocortisone”. Throughout my
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`career, my research interests have included drug form design, dissolution,
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`microencapsulation and other sustained release delivery systems and drug release
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`from suppositories.
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`5
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`Inter Partes Review of USPN 8,329,216
`Declaration of Anthony Palmieri (Exhibit 1003)
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`7.
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`From 1975 to 1980, I was Assistant Professor of Pharmaceutics and
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`from 1980 to 1984 I was a tenured Associate Professor of Pharmaceutics at the
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`University of Wyoming in Laramie, Wyoming. During my time at the University
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`of Wyoming I taught courses in dose form design, including sustained release of
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`pain relievers, physical pharmacy, problems in pharmacy and dissolution, among
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`others.
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`8.
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`From 1984 to 1988, I was Senior Patent Liaison Scientist in the
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`Research and Development Division of the Upjohn Company in Kalamazoo,
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`Michigan. From 1988 to 1992 I was a Manager of Intellectual Property at Upjohn.
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`From 1992 to 1994, I was a Manager of Intellectual Property and Research
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`Contracts at Upjohn. From 1994 to 1996 I was a Manager of Technology
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`Protection and Tracking at Upjohn. In these positions my responsibilities included
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`patent decisions, manuscript review, negotiation of scientific and monetary terms
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`for research and scientific collaborations between Upjohn, other companies,
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`academia and government agencies.
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`9.
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`From 1996 to 2000, I was Manager of Technology Protection at
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`Pharmacia & Upjohn. In this position I had daily interactions with dose form
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`scientists assisting in evaluation of various dosage forms. Among other patent
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`duties, I also evaluated commercial potential of inventions, educated the scientific
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`community on intellectual property issues and assisted in determining patentability
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`6
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`of inventions from a scientific standpoint. During all of my time at Upjohn I had
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`Inter Partes Review of USPN 8,329,216
`Declaration of Anthony Palmieri (Exhibit 1003)
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`daily interactions with other scientists concerning dose form design and evaluation
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`of these formulations including extended release formulations.
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`10. From 2000 to the present I have worked at the University of Florida in
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`Gainesville, Florida. From 2000 to 2006 I was an Adjunct Professor of
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`Pharmaceutics and Assistant Director of the Office of Technology Licensing. In
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`this position I interacted with faculty in the College of Pharmacy, College of
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`Medicine, Engineering, and the chemistry department and others on a daily basis to
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`discuss experiments, experimental design and evaluation of results. I also
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`evaluated the University’s intellectual property portfolio in the life sciences and
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`providing assistance in the protection and commercializing of this intellectual
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`property.
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`11. From 2006 to 2011 I was a Clinical Assistant Professor of
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`Pharmaceutics and from 2011 to 2013 I was Assistant Scholar of Pharmaceutics at
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`the University of Florida. In 2014 I was promoted to Associate Scholar. In these
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`position my responsibilities include instructing graduate and undergraduate
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`students in clinical biochemistry, dose form design, sustained release and
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`dissolution. I am Graduate Student Coordinator for Pharmaceutics and member of
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`Graduate Studies Committee. I am also a member of numerous research
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`committees for graduate students.
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`7
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`Inter Partes Review of USPN 8,329,216
`Declaration of Anthony Palmieri (Exhibit 1003)
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`12.
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`I am the author of over 80 publications and presentations on
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`pharmaceutics,
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`intellectual property, dosage forms, dissolutions, pharmacy
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`education and the history of pharmacy. By 2001 I was the author of more than 16
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`peer-reviewed publications on pharmaceutical dosage forms. I am the author of 6
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`book chapters on pharmaceutical formulations and the author of numerous
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`monographs for the Handbook of Pharmaceutical Excipients. I have given more
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`than 40 presentations on pharmacy, intellectual property and related topics. Many
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`of my research presentations and publications concerned the area of drug release
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`from dose forms, including sustained release, and dissolution. I have also written
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`chapters on dissolution and was the editor of a well-recognized textbook on
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`dissolution theory, methodology and practice.
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`13.
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`I am on the Editorial Advisory Board of the Journal of Chemical and
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`Pharmaceutical Sciences and the Research Journal of Pharmaceutical Biological
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`and Chemical Sciences. I was the Steering Committee chairman for the American
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`Pharmacists Association’s Handbook of Pharmaceutical Excipients, 2nd edition. I
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`was the laboratory chair for the 3rd edition and have reviewed as well as written
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`monographs for each edition of the Handbook of Pharmaceutical Excipients which
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`is the preeminent reference on excipients and the use of excipients in
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`pharmaceutical dosage form. I am a Fellow of the Academy of Pharmaceutical
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`Research and Sciences and the past president of that organization.
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`Inter Partes Review of USPN 8,329,216
`Declaration of Anthony Palmieri (Exhibit 1003)
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`14. Accordingly, I am an expert in
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`the field of pharmaceutical
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`formulation, including controlled release pharmaceutical formulation, and I have
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`been an expert in this field since prior to July 6, 2001. My full professional
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`background is detailed in my curriculum vitae. (AMN 1016).
`
`III.
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`2B2BList of Documents I Considered in Formulating My Opinion
`15.
`
`In formulating my opinion, I have considered
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`the following
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`documents:
`
`Description
`
`1004
`1005
`
`Amneal
`Exhibit
`#
`1001 Kao et al., U.S. Patent No. 8,329,216 B2, "Oxymorphone Controlled
`Release Formulations" (filed June 29, 2006; issued December 11,
`2012)
`File history of U.S. Patent No. 8,329,216
`The United States Pharmacopeia 24: The National Formulary 19, pp. 8,
`1941-1943 (1999)
`1006 Maloney, International Pub. No. WO 01/08661 A2, "Opioid Sustained-
`Released Formulation" (filed July 27, 2000; published February 8,
`2001)
`1007 Oshlack et al., U.S. Patent No. 5,958,452, "Extruded Orally
`Administrable Opioid Formulations" (filed April 10, 1997; issued
`September 28, 1999)
`The Handbook of Dissolution Testing, 2nd ed., Revised, Hanson, W.A.,
`ed., pp. v-xii, 1-13, 26-53, 69-91, 111-123 (1991)
`Penwest Pharmaceuticals Co.'s Form S-1 Registration Statement
`Under the Securities Act of 1953 (1997)
`1011 Gordon et al., "Opioid Equianalgesic Calculations," Journal of
`Palliative Medicine 2(2):209-218 (1999)
`Cone et al., "Oxymorphone Metabolism and Urinary Excretion in
`Human Rat, Guinea Pig, Rabbit and Dog," Drug Metabolism and
`Disposition 11(5):446-450 (1983)
`
`1008
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`1009
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`1013
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`Amneal
`Exhibit
`#
`1014
`
`Inter Partes Review of USPN 8,329,216
`Declaration of Anthony Palmieri (Exhibit 1003)
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`Description
`
`Physicians' Desk Reference, 54th ed., NUMORPHAN®, pp. 1036 and
`1037 (2000)
`Curriculum Vitae of Dr. Anthony Palmieri
`"TIMERx Oral Controlled-Release Drug Delivery System," by McCall
`et al., in Modified-Release Drug Delivery Technology, Chapter 2,
`Rathbone et al., eds., pp. 11-19 (2007)
`Lewenstein et al., U.S. Patent No. 2,806,033, "MORPHINE
`DERIVATIVE" (filed August 3, 1955; issued September 10, 1957)
`1019 Handbook of Pharmaceutical Excipients, 3rd ed., Kibbe, A., ed., pp.
`252-255 and 599-601 (2000)
`Baichwal et al., U.S. Patent No. 5,135,757, "Compressible Sustained
`Release Solid Dosage Forms" (filed January 16, 1991; issued August 4,
`1992)
`Baichwal et al., U.S. Patent No. 5,662,933, "Controlled Release
`Formulation (Albuterol)," (filed November 3, 1993; issued September
`2, 1997)
`
`1016
`1017
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`1018
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`1031
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`1032
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`
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`IV.
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`3B3BPerson of Ordinary Skill in the Art
`16.
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`I understand that a person of ordinary skill in the art ("POSA") is a
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`hypothetical person presumed to be aware of all pertinent art, thinks along
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`conventional wisdom in the art, and is a person of ordinary creativity. A POSA in
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`pharmaceutical testing as of July 6, 2001, the earliest possible priority date
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`("EPD") of the '216 patent, would typically have a Bachelors or Master's degree in
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`Pharmacy, Chemistry or a related field with at least 5 years of experience with
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`pharmaceutical formulations including pharmaceutical testing. A POSA could have
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`a Ph.D. in Pharmaceutics, Chemistry or a related field with 2-3 years of experience
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`with pharmaceutical formulations including pharmaceutical testing. A POSA
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`Inter Partes Review of USPN 8,329,216
`Declaration of Anthony Palmieri (Exhibit 1003)
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`would typically have experience in the analytical characterization of drug
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`formulations, including in vitro dissolution testing of drug formulations. A POSA
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`may work as part of a multi-disciplinary team and draw upon not only his or her
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`own skills, but also take advantage of certain specialized skills of others on the
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`team, to solve a given problem. For example, a formulator, dissolution expert and a
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`clinician may be part of the team.
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`V.
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`4B4BThe '216 Patent Specification
`17. This declaration is being submitted together with a petition for inter
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`partes review of claims 5, 16, 44, 46, 47 and 72-82 of the '216 patent.
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`18.
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`I have considered the disclosure and file history of the '216 patent in
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`light of general knowledge in the art as of the EPD of the '216 patent, July 6, 2001.
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`19. The '216 patent specification is directed to methods of relieving pain
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`by administering a controlled
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`release pharmaceutical
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`tablet containing
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`oxymorphone which produces a mean minimum blood plasma level 12 to 24 hours
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`after dosing, as well as tablets producing this sustained pain relief. (AMN 1001,
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`Abstract.)
`
`VI.
`
`5B5BThe Claims of the '216 Patent
`20.
`
`Independent claim 1 of the '216 patent is directed to an oral controlled
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`release oxymorphone formulation comprising about 5 mg to about 80 mg of
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`Inter Partes Review of USPN 8,329,216
`Declaration of Anthony Palmieri (Exhibit 1003)
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`oxymorphone and a hydrophilic material, wherein upon administration of the
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`formulation to a subject, (i) the formulation provides detectable blood plasma
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`levels of 6-OH oxymorphone and oxymorphone; (ii) the blood plasma levels of 6-
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`OH oxymorphone and oxymorphone peak within about 1 hour to about 8 hours
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`after administration; (iii) the blood plasma levels of 6-OH oxymorphone and
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`oxymorphone exhibit a ratio of area under the curve (AUC(0 to inf)) of blood plasma
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`level versus time for 6-OH oxymorphone compared to oxymorphone in a range of
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`about 0.5 to about 1.5; (iv) the duration of the analgesic effect is through at least
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`about 12 hours after administration; and (v) the blood plasma levels of
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`oxymorphone exhibit
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`two or
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`three peaks within about 12 hours after
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`administration.
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`21.
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`Independent claims 13 and 72 of the '216 patent, are generally
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`directed
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`to a controlled release pharmaceutical composition comprising
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`oxymorphone or a pharmaceutically acceptable salt thereof and a controlled
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`release delivery system, wherein upon placement of the composition in an in vitro
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`dissolution test comprising USP Paddle Method at 50 rpm in 500 ml media having
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`a pH of 1.2 to 6.8 at 37 °C, about 15% to about 50%, by weight, of the
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`oxymorphone or salt thereof is released from the tablet at about 1 hour in the test.
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`22.
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`Independent claims 38 and 77 are generally directed to controlled
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`release
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`pharmaceutical
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`compositions
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`comprising
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`oxymorphone
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`or
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`pharmaceutically acceptable salt thereof and a controlled release delivery system,
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`Inter Partes Review of USPN 8,329,216
`Declaration of Anthony Palmieri (Exhibit 1003)
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`wherein upon placement of the composition in an in vitro dissolution test
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`comprising USP Paddle Method at 50 rpm in 500 ml media having a pH of 1.2 to
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`6.8 at 37 °C, about 15% to about 50%, by weight, of the oxymorphone or salt
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`thereof is released from the composition at about 1 hour in the test, about 45% to
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`about 80%, by weight, of the oxymorphone or salt thereof is released from the
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`composition at about 4 hours in the test, and at least about 80%, by weight, of the
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`oxymorphone or salt thereof is released from the composition at about 10 hours in
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`the test. 
`
`23. A POSA would recognize that the term "controlled release" is defined
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`in the patent as encompassing "any formulation which release no more than about
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`80% of their active pharmaceutical ingredients within 60 minutes" under the
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`claimed dissolution conditions. (AMN 1001, 3:30-33.) Thus, a POSA would
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`understand that the term claimed release encompasses any formulation where no
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`more than 80% of active agent is released in 60 minutes. One such system
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`described by the '216 patent is a "system that comprises a hydrophilic material
`
`which, upon exposure to gastrointestinal fluid, forms a gel matrix that releases
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`oxymorphone at a controlled rate." (AMN 1001, 4:7-10.)
`
`24. A POSA would understand the term "about" as it relates to the percent
`
`by weight of oxymorphone released in dissolution testing to mean at least the
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`typical variability for such dissolution testing values. The '216 patent states that
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`Inter Partes Review of USPN 8,329,216
`Declaration of Anthony Palmieri (Exhibit 1003)
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`"[r]eference to mean values reported herein for studies actually conducted are
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`arrived at using standard statistical methods as would be employed by one skilled
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`in the art of pharmaceutical formulation and testing for regulatory approval."
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`(AMN 1001, 3:67 – 4:4.) The term "about" has a plain and ordinary meaning in the
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`field of pharmaceutical testing. The United States Pharmacopeia ("USP") 24 states
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`"the use of the word "about" indicates a quantity within 10% of the specified
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`weight or volume." (AMN, 1005, 8.) As a POSA would understand that the
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`standard use of about for dissolution testing is a quantity within 10% of an
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`indicated value, a POSA would understand the term "about" as it is used in the
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`context of the percent by weight of oxymorphone released in dissolution testing to
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`encompass values of ± 10% of the value measured.
`
`25.
`
` A POSA would have understood that the remaining terms in claims 5,
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`16, 44, 46, 47 and 72-82 are plain on their face. Thus, I have given the terms their
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`plain and ordinary meaning under a broadest reasonable interpretation in light of
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`the specification.  
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`VII.
`
`6B6BState of the Art of Controlled Release Opioid Compositions as of July 6,
`2001
`26. Oxymorphone is a well-known opioid analgesic that was developed in
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`the early 1900s and was patented in the U.S. in 1957 (See U.S. Patent 2,806,033;
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`AMN 1018.) By 2001, various opioids, such as oxymorphone, oxycodone,
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`morphine and hydromorphone were used to provide pain relief in patients and their
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`Inter Partes Review of USPN 8,329,216
`Declaration of Anthony Palmieri (Exhibit 1003)
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`strengths relative to one another had been well-characterized. (AMN 1011.) It was
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`recognized well before 2001 that it could be useful to switch one opioid for another
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`in the treatment of pain in a patient. For example, Gordon states "[c]linicians may
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`need to switch opioids to improve pain control, reduce opioid toxicity or side
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`effects, provide a more convenient treatment regimen for the patient, or to reduce
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`the invasiveness of therapy." (AMN 1011, p. 211, col. 1, ¶1.) Thus, it was known
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`well before 2001 that one opioid may be substituted for another, and the art
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`provided extensive guidance for making such substitutions.
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`27. Benefits to formulating opioids into controlled release compositions
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`were well-known by 2001. For example, Maloney states:
`
`Among the many possible therapeutic benefits provided
`by sustained-release dosage forms are: (1) the allowance
`of more constant blood levels over time (thus avoiding
`large spike and trough levels not infrequently seen with
`rapidly dissolving dosage forms) leading to a more
`consistent therapeutic effect; (2) delay of the release of
`drug such that significant absorption of the drug may
`occur at more desirable sites (e.g., causing the bulk of the
`absorption to occur in a more desirable pH milieu and
`thus reducing decomposition of the drug); (3) reduction
`in concentration dependent gastrointestinal irritation
`(owing to reduction in the concentration of drug in
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`Inter Partes Review of USPN 8,329,216
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`contact with a particular surface of the gastrointestinal
`tract); and (4) improvement of drug safety with respect to
`acute toxicity owing to lower concentrations of drug
`being released at a particular time as compared to readily
`available dosage forms of similar dose.
`
`(AMN 1006, 1:23 – 2:7.)
`
`28. Oshlack also recognized the benefits of formulating opioids for
`
`controlled release:
`
`In the present invention, the oral opioid analgesics have
`been formulated to provide for an increase [sic] duration
`of analgesic. Surprisingly,
`these
`formulations, at
`comparable daily dosages of conventional immediate-
`release drug, are associated with a lower incidence in
`severity of adverse drug reactions and can also be
`administered at a lower daily dose than conventional oral
`medication while maintaining pain control.
`
`(AMN 1007, 8:1-8.)
`
`29. Various pharmaceutical systems for obtaining controlled release were
`
`known as of 2001. For example, Maloney discusses a number of known controlled
`
`release systems, including matrix-based, microencapsulation, multilayering and
`
`ion-exchange systems. (AMN 1006, 2-5.) Matrix-based systems are formulated
`
`with a polymer that forms a gel upon exposure to aqueous liquid. Drug slowly
`
`
`
`16
`
`

`

`
`
`
`diffuses through the gel to the surface of the tablet where it is released. The gel
`
`Inter Partes Review of USPN 8,329,216
`Declaration of Anthony Palmieri (Exhibit 1003)
`
`also slowly erodes allowing more dry polymer to come into contact with the
`
`surrounding liquid, further gel formation and further gel release. (AMN 1006, 2:
`
`23-27.) The use of such matrix systems was well understood as of 2001.
`
`30. Exemplary relevant art includes the references described below.
`
`31. Oshlack. Oshlack is U.S. Patent No. 5,958,452 (AMN 1007), filed
`
`April 10, 1997, and issued September 28, 1999. I understand that Oshlack is
`
`considered to be prior art to the '216 patent because it issued more than one year
`
`before July 6, 2001, the EPD of the '216 patent. Oshlack is entitled "Extruded
`
`Orally Administrable Opioid Formulations."
`
`32. Oshlack teaches sustained release matrix pharmaceutical formulations
`
`with opioid active agents. (AMN 1007, 1:10-14; 3:58-65.) Oshlack teaches that
`
`oxymorphone is a preferred opioid for use in these sustained release formulations.
`
`(AMN 1007, 7:35-39.) Oshlack teaches using both the paddle and basket method at
`
`100 rpm in 900 mL aqueous buffer at 37 °C and a pH between 1.6 and 7.2. (AMN
`
`1007, 11:60 – 12:12.) Oshlack discloses sustained release pharmaceutical
`
`formulations containing oxymorphone that have a dissolution profile using the
`
`basket method at 100 rpm of:
`
` from about 1 to about 42.5% opioid release after one hour,
`
` from about 5 to about 65% opioid released after 2 hours,
`
`
`
`17
`
`

`

`
`
`
`
`Inter Partes Review of USPN 8,329,216
`Declaration of Anthony Palmieri (Exhibit 1003)
`
` from about 15 to about 85% opioid released after 4 hours,
`
` from about 20 to about 90% opioid released after 6 hours,
`
` from about 35 to about 95% opioid released after 12 hours,
`
` from about 45 to about 100% opioid released after 18 hours, and
`
` from about 55 to about 100% opioid released after 24 hours, by weight.
`
`(AMN 1007, 26:39-49.)
`
`33. The Handbook of Dissolution Testing. "The Handbook of
`
`Dissolution Testing," 2nd ed. ("the Handbook"), by William A. Hanson. The
`
`Handbook was published in 1991. I understand that the Handbook is considered to
`
`be prior art to the '216 patent because it published more than one year before July
`
`6, 2001, the EPD of the '216 patent.
`
`34. The Handbook is a guide to dissolution testing and discusses the
`
`various apparatuses used for testing and different parameters that affect dissolution
`
`results. (AMN 1008, e.g., Chapter 3.) The Handbook compares the basket and
`
`paddle methods and discusses their similarities and differences. (AMN 1008, pp.
`
`28-42.) The Handbook notes that "rates of 50 rpm for the paddle and 100 rpm for
`
`the basket are recommended and have proved to be roughly equivalent to one
`
`another in producing dissolution." (AMN 1008, p. 35, ¶5.)
`
`35. Pharmaceutical Excipients. Pharmaceutical Excipients is "The
`
`Handbook of Pharmaceutical Excipients," 3rd ed, edited by Arthur H. Kibbe.
`
`
`
`18
`
`

`

`
`
`
`Pharmaceutical Excipients was published in January of 2000. I understand that
`
`Inter Partes Review of USPN 8,329,216
`Declaration of Anthony Palmieri (Exhibit 1003)
`
`Pharmaceutical Excipients is considered to be prior art to the '216 patent because it
`
`published before July 6, 2001, the EPD of the '216 patent. As mentioned in ¶13
`
`above, I was the laboratory chair for the 3rd edition of this handbook and I have
`
`reviewed as well as written monographs for each edition of the Handbook of
`
`Pharmaceutical Excipients.
`
`36. Pharmaceutical Excipients is a well-respected, readily available
`
`handbook used in industry and academics that provides information about
`
`excipients used in pharmaceutical formulations. The entry for hydroxypropyl
`
`methylcellulose ("HPMC") is provided as part of AMN 1019. Pharmaceutical
`
`excipients states that high viscosity grade HPMC is used in controlled release
`
`matrix formulations at concentrations of 10% to 80% by weight. (AMN 1019, 252:
`
`col. 2.)
`
`37. Baichwal '757. Baichwal '757 is U.S. Patent No. 5,135,757 (AMN
`
`1031), filed January 16, 1991 and issued August 4, 1992. I understand that
`
`Baichwal '757 is considered to be prior art to the '216 patent because it issued more
`
`than one year before July 6, 2001, the EPD of the '216 patent. Baichwal '757 is
`
`entitled "Compressible Sustained Release Solid Dosage Forms."
`
`38. Baichwal
`
`'757 teaches sustained release matrix pharmaceutical
`
`formulations with opioid active agents. (AMN 1031, 4:10-25, 10:1-3.) Baichwal
`
`
`
`19
`
`

`

`
`
`
`'757 teaches use of mixtures of gelling agent gums, particularly xanthan and locust
`
`Inter Partes Review of USPN 8,329,216
`Declaration of Anthony Palmieri (Exhibit 1003)
`
`bean gum, in controlled release formulations. (AMN 1031, 5:56 – 6:48.) Baichwal
`
`'757 teaches that the release rates of these controlled release systems may be
`
`adjusted by varying the ratio of xanthan gum to locust bean gum and by varying
`
`the total concentration of gelling agent in the matrix. (AMN 1031, 9:9:6-20, 11:25-
`
`29.)
`
`39. The Penwest Statement. The Penwest Statement
`
`is Penwest
`
`Pharmaceuticals Co.'s Form S-1 Registration Statement Under the Securities Act of
`
`1953 (AMN 1009). The Penwest Statement published in 1997. I understand that
`
`the Penwest Statement is considered to be prior art to the '216 patent because it
`
`published more than one year before July 6, 2001, the EPD of the '216 patent.
`
`40. The Penwest Statement states that Penwest and Endo were developing
`
`a controlled release formulation of Numorphan (the commercial name for
`
`oxymorphone) using Penwest's TIMERx controlled release technology. (AMN
`
`1009, pp. 34 and 36.)
`
`41. Baichwal '933. Baichwal '933 is U.S. Patent No. 5,662,933 (AMN
`
`1032), filed November 3, 1995 and issued September 2, 1997. I understand that
`
`Baichwal '933 is considered to be prior art to the '216 patent because it issued more
`
`than one year before July 6, 2001, the EPD of the '216 patent. Baichwal '933 is
`
`entitled "Controlled Release Formulation (Albuterol)."
`
`
`
`20
`
`

`

`
`
`
`
`Inter Partes Review of USPN 8,329,216
`Declaration of Anthony Palmieri (Exhibit 1003)
`
`42. Baichwal '933 discloses sustained release formulations containing
`
`xanthan gum and locust bean gum. (AMN 1032, 5:21-28.) Baichwal '933 discloses
`
`in vitro dissolution testing of such formulations using the USP Paddle Method