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`UNITED STATES PATENT AND TRADEMARK OFFICE
`_____________________
`
`BEFORE THE PATENT TRIAL AND APPEAL BOARD
`_____________________
`
`
`AMNEAL PHARMACEUTICALS, LLC
`Petitioner
`v.
`
`ENDO PHARMACEUTICALS INC.
`Patent Owner
`
`U.S. Patent No. 8,309,122
`_____________________
`
`Inter Partes Review Case No. Unassigned
`_____________________
`
`DECLARATION OF ANTHONY PALMIERI III, PH.D.
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`
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`

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`Inter Partes Review of USPN 8,309,122
`Declaration of Anthony Palmieri (Exhibit 1003)
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`
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`TABLE OF CONTENTS
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`
`Introduction ..................................................................................................... 4 
`I. 
`II.  My Background and Qualifications ................................................................ 5 
`III.  List of Documents I Considered in Formulating My Opinion ....................... 9 
`IV.  Person of Ordinary Skill in the Art ............................................................... 10 
`V. 
`The '122 Patent Specification ....................................................................... 11 
`VI.  The Claims of the '122 Patent ....................................................................... 11 
`VII.  State of the Art of Controlled Release Opioid Compositions as of July 6,
`2001 .............................................................................................................. 15 
`VIII.  Summary Chart of Analysis Over the Art .................................................... 21 
`IX.  The Basis of My Analysis with Respect to Obviousness ............................. 22 
`X.  Maloney Test Formula .................................................................................. 24 
`XI.  Ground 1: Claims 1-4, 16 and 18-20 Would Have Been Obvious Over
`Maloney ........................................................................................................ 32 
`XII.  Ground 2: Claims 1-4, 16 and 18-20 Would Have Been Obvious Over The
`Penwest Statement and Baichwal ................................................................. 44 
`XIII.  Ground 3: Claims 1-4, 16, 18 and 20 Would Have Been Obvious Over
`Maloney, the Penwest Statement and Baichwal ........................................... 51 
`XIV.  Ground 4: Claims 1-4, 16 and 18-20Would Have Been Obvious Over
`Maloney and Gordon .................................................................................... 55 
`XV.  Ground 5: Claims 1-4, 16 and 18-20 Would Have Been Obvious to a POSA
`in View of Oshlack ....................................................................................... 57 
`XVI.  Ground 6: Claims 1-4, 16, 18 and 20 Would Have Been Obvious Over
`Oshlack and the Handbook of Dissolution Testing ...................................... 70 
`XVII. Ground 7: Claims 1-4, 16, 18- 20 Would Have Been Obvious Over Oshlack,
`and the Penwest Statement and Baichwal .................................................... 73 
`XVIII.Ground 8: Claims 1-4, 16, and 18-20 Would Have Been Obvious Over
`Oshlack and Gordon ..................................................................................... 76 
`XIX.  Objective Indicia of Nonobviousness ........................................................... 78 
`
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`XX.  Conclusion .................................................................................................... 81 
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`Inter Partes Review of USPN 8,309,122
`Declaration of Anthony Palmieri (Exhibit 1003)
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`I.
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`Inter Partes Review of USPN 8,309,122
`Declaration of Anthony Palmieri (Exhibit 1003)
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`I, Anthony Palmieri III, Ph.D., hereby declare as follows.
`
`Introduction
`1.
`
`I am over the age of eighteen (18) and otherwise competent to make
`
`this declaration.
`
`2.
`
`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. 8,309,122 ("the '122 patent"), AMN 1001,
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`which resulted from U.S. Application No. 11/680,432 ("the '432 application"),
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`filed on February 28, 2007, and alleging an earliest priority date of July 6, 2001.
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`The '122 patent names Huai-Hung Kao, Anand R. Baichwal, Troy McCall and
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`David Lee as inventors. The '122 patent issued on November 13, 2012, from the
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`'432 application. I further understand that, according to the USPTO records, the
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`'122 patent is currently assigned to Endo Pharmaceuticals, Inc. ("Endo.")
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`3.
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`In preparing this Declaration, I have reviewed the '122 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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`4
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`("POSA") (i.e., a person of ordinary skill in the field of in vitro dissolution testing,
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`Inter Partes Review of USPN 8,309,122
`Declaration of Anthony Palmieri (Exhibit 1003)
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`defined further below in Section IV) prior to July 6, 2001.
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`II. My Background and Qualifications
`4.
`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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`5.
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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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`6.
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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, physical pharmacy, problems in
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`pharmacy and dissolution, among others.
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`
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`5
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`Inter Partes Review of USPN 8,309,122
`Declaration of Anthony Palmieri (Exhibit 1003)
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`7.
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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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`8.
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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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`of inventions from a scientific standpoint. During all of my time at Upjohn I had
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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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`9.
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`From 2000 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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`
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`6
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`this position I interacted with faculty in the College of Pharmacy, College of
`
`Inter Partes Review of USPN 8,309,122
`Declaration of Anthony Palmieri (Exhibit 1003)
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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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`10. 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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`11.
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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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`7
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`
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`than 40 presentations on pharmacy, intellectual property and related topics. Many
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`Inter Partes Review of USPN 8,309,122
`Declaration of Anthony Palmieri (Exhibit 1003)
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`of my research presentations and publications concerned the area of drug release
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`from dose forms and dissolution. I have also written chapters on dissolution and
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`was the editor of a well-recognized textbook on dissolution theory, methodology
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`and practice.
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`12.
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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
`
`and Chemical Sciences. I was the Steering Committee chairman for the American
`
`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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`13. Accordingly, I am an expert in
`
`the field of pharmaceutical
`
`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).
`
`
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`8
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`
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`III. List of Documents I Considered in Formulating My Opinion
`14.
`In formulating my opinion, I have considered
`the following
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`Inter Partes Review of USPN 8,309,122
`Declaration of Anthony Palmieri (Exhibit 1003)
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`documents:
`
`Amneal
`Exhibit
`#
`1001
`
`1002
`1004
`1005
`
`1006
`
`1007
`
`1008
`
`1009
`
`1010
`
`1011
`
`1014
`
`1015
`1017
`
`
`
`Description
`
`Kao et al., U.S. Patent No. 8,309,122 B2, "OXYMORPHONE
`CONTROLLED RELEASE FORMULATIONS" (filed February 28,
`2007; issued November 13, 2012)
`Declaration of Ms. Vivian A. Gray
`File history of U.S. Patent No. 8,309,122 B2
`The United States Pharmacopeia 24: The National Formulary 19, pp. 8,
`1941-1943 (1999)
`Maloney, International Pub. No. WO 01/08661 A2, "OPIOID
`SUSTAINED-RELEASED FORMULATION" (filed July 27, 2000;
`published February 8, 2001)
`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)
`Baichwal et al., U.S. Patent 5,128,143, "SUSTAINED RELEASE
`EXCIPIENT AND TABLET FORMULATION" (filed March 9, 1990;
`issued July 7, 1992)
`Gordon et al., "Opioid Equianalgesic Calculations," Journal of
`Palliative Medicine 2(2):209-218 (1999)
`Physicians' Desk Reference, 54th ed., NUMORPHAN®, pp. 1036 and
`1037 (2000)
`Curriculum Vitae of Ms. Vivian A. Gray
`"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)
`
`9
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`Amneal
`Exhibit
`#
`1018
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`1019
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`1020
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`1021
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`1022
`
`1023
`
`1024
`
`Inter Partes Review of USPN 8,309,122
`Declaration of Anthony Palmieri (Exhibit 1003)
`
`Description
`
`Lewenstein et al., U.S. Patent No. 2,806,033, "MORPHINE
`DERIVATIVE" (filed August 3, 1955; issued September 10, 1957)
`Handbook of Pharmaceutical Excipients, 3rd ed., Kibbe, A., ed., pp.
`252-255 and 599-601 (2000)
`Laboratory Notebook, Project PD161-02, pp. 1-3, dated November 13-
`14, 2013
`Laboratory Notebook, Notebook No. PD162, Amneal Pharmaceuticals,
`assigned to Dilip Makwana, pp. 1-39, dated November 14-21, 2013,
`Product Lot #PD161-01, R&D Analytical Laboratory, Amneal
`Pharmaceutical of NY, LLC, Calculation Sheet for Dissolution of
`Tablets/Capsules by HPLC/UPLC, Oxymorphone HCL ER Tablet
`Product Lot #PD161-02, R&D Analytical Laboratory, Amneal
`Pharmaceutical of NY, LLC, Calculation Sheet for Dissolution of
`Tablets/Capsules by HPLC/UPLC, Oxymorphone HCL ER Tablet
`Re: Endo Pharms., Inc. v. Amneal Pharms., LLC, Case No. 1:12-cv-
`8115 (S.D.N.Y.) Formulation and Testing Protocol of Controlled-
`Release Oxymorphone Tablets, dated November 11, 2013, 3 pages
`
`
`IV. Person of Ordinary Skill in the Art
`15.
`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 '122 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 8,309,122
`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 in the
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`team, to solve a given problem. For example, a formulator, dissolution expert
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`and/or a clinician may be part of the team.
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`V.
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`The '122 Patent Specification
`16. This declaration is being submitted together with a petition for inter
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`partes review of claims 1-4, 16 and 18-20 of the '122 patent.
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`17.
`
`I have considered the disclosure and file history of the '122 patent in
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`light of general knowledge in the art as of the EPD of the '122 patent, July 6, 2001.
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`18. The '122 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.)
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`VI. The Claims of the '122 Patent
`19. Claim 1 of the '122 patent, from which claims 2-4, 16, 18 and 20
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`depend, is directed to an analgesically effective controlled release pharmaceutical
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`composition with a twelve hour dosing interval in the form of a tablet, comprising
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`Inter Partes Review of USPN 8,309,122
`Declaration of Anthony Palmieri (Exhibit 1003)
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`oxymorphone or a pharmaceutically acceptable salt thereof as the sole active
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`ingredient in the tablet, and a controlled release delivery system comprising at least
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`one pharmaceutical excipient, wherein upon placement of the composition in an in
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`vitro dissolution test comprising USP Paddle Method at 50 rpm in 500 ml media
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`having 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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`20. Claim 2 is directed to the formulation of claim 1 where 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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`tablet at about 4 hours in the test. Claim 3 is directed to the formulation of claim 1
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`where at least about 80%, by weight, of the oxymorphone or salt thereof is released
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`from the tablet at about 10 hours in the test.
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`21.
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`Independent claim 19 is directed to an analgesically effective
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`controlled release pharmaceutical composition with a twelve hour dosing interval
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`in the form of a tablet, comprising oxymorphone or pharmaceutically acceptable
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`salt thereof as the sole active ingredient in the tablet and a controlled release
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`delivery system comprising a hydrophilic material that forms a gel upon exposure
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`to gastrointestinal fluid, 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 composition at about 1 hour in
`
`Inter Partes Review of USPN 8,309,122
`Declaration of Anthony Palmieri (Exhibit 1003)
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`the test, about 45% to about 80%, by weight, of the oxymorphone or salt thereof is
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`released from the composition at about 4 hours in the test, and at least about 80%,
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`by weight, of the oxymorphone or salt thereof is released from the composition at
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`about 10 hours in the test.
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`22. 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
`
`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 '122 patent is a "system that comprises a hydrophilic material
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`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.)
`
`23. A POSA would understand the term "about" as it relates to the percent
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`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 '122 patent states that
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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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`Inter Partes Review of USPN 8,309,122
`Declaration of Anthony Palmieri (Exhibit 1003)
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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 USP, 8.) As a POSA would understand that the standard
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`use of about for dissolution testing is a quantity within 10% of an indicated value,
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`a POSA would understand the term "about" as it is used in the context of the
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`percent by weight of oxymorphone released in dissolution testing to encompass
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`values of ± 10% of the value measured.
`
`24. A POSA would recognize that the term "controlled release delivery
`
`system" is defined the '122 patent as a "system that comprises a hydrophilic
`
`material which, upon exposure to gastrointestinal fluid, forms a gel matrix that
`
`releases oxymorphone at a controlled rate." Thus, a POSA would understand that
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`the term "controlled release delivery system" in the claims encompasses any
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`formulation comprising a hydrophilic material that forms a gel matrix.
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`25. A POSA would have understood that the remaining terms in claims 1-
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`4, 16 and 18-20 are plain on their face. Thus, I have given the terms their plain and
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`ordinary meaning under a broadest reasonable interpretation in light of the
`
`specification.  
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`VII. State 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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`Inter Partes Review of USPN 8,309,122
`Declaration of Anthony Palmieri (Exhibit 1003)
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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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`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
`
`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 of to reduce
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`the invasiveness of therapy." (AMN 1011, p. 211, col. 1, ¶1.) Thus, it was known
`
`well before 2001 that one opioid may be substituted for another, and the art
`
`provided extensive guidance for making such substitutions.
`
`27. Benefits to formulating opioids into controlled release compositions
`
`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
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`Inter Partes Review of USPN 8,309,122
`Declaration of Anthony Palmieri (Exhibit 1003)
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`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
`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.)
`
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`Inter Partes Review of USPN 8,309,122
`Declaration of Anthony Palmieri (Exhibit 1003)
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`29. Various pharmaceutical systems for obtaining controlled release were
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`known as of 2001. For example, Maloney discusses a number of known controlled
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`release systems, including matrix-based, microencapsulation, multilayering and
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`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
`
`diffuses through the gel to the surface of the tablet where it is released. The gel
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`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. Maloney. Maloney
`
`is
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`International
`
`Publication
`
`No.
`
`WO01/08661(AMN 1006), which was filed on July 27, 2000 and published on
`
`February 8, 2001. I understand that Maloney is considered to be prior art to the
`
`'122 patent because it published before July 6, 2001, the EPD of the '122 patent.
`
`Maloney is entitled "Opioid Sustained-Release Formulation."
`
`32. Maloney teaches controlled release opioid matrix formulations. (AMN
`
`1006, 8:9-14.) Maloney teaches that oxymorphone is a preferred opioid for use in
`
`these formulations. (AMN 1006, 13:15-19.) The examples of Maloney provide
`
`sustained release profiles measured by the basket method at 100 rpm in 900 mL
`
`aqueous buffer (pH 1.2 for the first hour and 7.5 for hours 2 through 12) at 37 ° C.
`
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`17
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`(AMN 1006, 14:9-15.) And as provided in the testimony of Ms. Vivian Gray, an
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`Inter Partes Review of USPN 8,309,122
`Declaration of Anthony Palmieri (Exhibit 1003)
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`expert on in vitro dissolution testing, a controlled release oxymorphone
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`composition formulation embodied in Maloney has the in vitro dissolution profile
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`in the claims of the '122 patent. (AMN 1002, ¶.)
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`33. Oshlack. Oshlack is U.S. Patent No. 5,958,452 (AMN 1007), filed
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`April 10, 1997 and issued September 28, 1999. I understand that Oshlack is
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`considered to be prior art to the '122 patent because it issued more than one year
`
`before July 6, 2001, the EPD of the '122 patent. Oshlack is entitled "Extruded
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`Orally Administrable Opioid Formulations."
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` Oshlack teaches sustained release matrix pharmaceutical formulations
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`with opioid active agents. (AMN 1007, 1:10-14; 3:58-65.) Oshlack
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`teaches that oxymorphone is a preferred opioid for use in these sustained
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`release formulations. (AMN 1007, 7:35-39.) Oshlack teaches using both
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`the paddle and basket method at 100 rpm in 900 mL aqueous buffer at
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`37 °C and a pH between 1.6 and 7.2. (AMN 1007, 11:60 – 12:12.)
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`Oshlack discloses sustained
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`release pharmaceutical
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`formulations
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`containing oxymorphone that have a dissolution profile using the basket
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`method at 100 rpm of: from about 1 to about 42.5% opioid release after
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`one hour,
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` from about 5 to about 65% opioid released after 2 hours,
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`18
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`Inter Partes Review of USPN 8,309,122
`Declaration of Anthony Palmieri (Exhibit 1003)
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` from about 15 to about 85% opioid released after 4 hours,
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` from about 20 to about 90% opioid released after 6 hours,
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` from about 35 to about 95% opioid released after 12 hours,
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` from about 45 to about 100% opioid released after 18 hours, and
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` from about 55 to about 100% opioid released after 24 hours, by weight.
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`(AMN 1007, 26:39-49.)
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`34. The Penwest Statement. The Penwest Statement
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`is Penwest
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`Pharmaceuticals Co.'s Form S-1 Registration Statement Under the Securities Act of
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`1953 (AMN 1009). The Penwest Statement published in 1997. I understand that
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`the Penwest Statement is considered to be prior art to the '122 patent because it
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`published more than one year before July 6, 2001, the EPD of the '122 patent.
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`35. The Penwest Statement states that Penwest and Endo were developing
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`a controlled release formulation of Numorphan (the commercial name for
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`oxymorphone) using Penwest's TIMERx controlled release technology. (AMN
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`1009, pp. 34 and 36.)
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`36. Gordon. Gordon, et al., "Opioid Equianalgesic Calculations," Journal
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`of Palliative Medicine, 2(2):209-218 was published in1999. I understand that
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`Gordon is considered to be prior art to the '122 patent because it published more
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`than one year before July 6, 2001, the EPD of the '122 patent.
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`
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`19
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`Inter Partes Review of USPN 8,309,122
`Declaration of Anthony Palmieri (Exhibit 1003)
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`37. Gordon discusses equianalgesic dosing – the doses of analgesic that
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`are considered to be "approximately equal in analgesic effect." (AMN 1011, p.
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`211, col. 2, ¶2.) Gordon provides an equianalgesic table, which provides equivalent
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`doses for different opioids. (AMN 1011, p. 212, Table 1.)
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`38. Baichwal. Baichwal is U.S. Patent 5,128,143, filed March 9, 1990,
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`and issued July 7, 1992. I understand that Baichwal is considered to be prior art to
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`the '122 patent because it issued more than one year before July 6, 2001, the EPD
`
`of the '122 patent. Baichwal is entitled "Sustained Release Excipient and Tablet
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`Formulation."
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`39. Baichwal is listed as a patent covering Penwest Pharmaceutical's
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`TIMERx system in a chapter on TIMERx co-authored by inventor Anand
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`Baichwal in the book "Modified-Release Drug Delivery Technology." (AMN
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`1017, Chapter 2, p. 19, fn. 3; "the TIMERx Chapter.") Baichwal teaches a slow
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`release pharmaceutical excipient comprising a hydrophilic material comprising a
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`heteropolysaccharide and a polysaccharide material capable of cross-linking the
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`heteropolysaccharide in the presence of aqueous solutions. (AMN 1010, 4:16-21.)
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`As shown in the TIMERx Chapter, the TIMERx system is made up of the same
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`excipients disclosed in Baichwal: "a pregranulated blend composed of synergistic
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`heterodisperse polysaccharides (usually xanthan gum and locust bean gum)
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`together with a saccharide component (generally dextrose)." (AMN 1017, Chapter
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`
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`20
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`
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`2., p. 11.) Baichwal states that its controlled release system can be used with
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`Inter Partes Review of USPN 8,309,122
`Declaration of Anthony Palmieri (Exhibit 1003)
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`analgesics. (AMN 1010, 10:42-45.) Baichwal provides examples of multiple active
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`agents formulated for controlled release with its heteropolysaccharide and
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`polysaccharide system. (AMN 1010, Examples.)
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`40. The Handbook of Dissolution Testing. "The Handbook of
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`Dissolution Testing," 2nd ed. ("the Handbook"), by William A. Hanson. The
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`Handbook was published in 1991. I understand that the Handbook is considered to
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`be prior art to the '122 patent because it published more than one year before July
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`6, 2001, the EPD of the '122 patent.
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`41. The Handbook is a guide to dissolution testing and discusses the
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`various apparatuses used for testing and different parameters that affect dissolution
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`results. (AMN 1008, e.g., Chapter 3.) The Handbook compares the basket and
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`paddle methods and discusses their similarities and differences. (AMN 1008, pp.
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`28-42.) The Handbook notes that "rates of 50 rpm for the paddle and 100 rpm for
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`the basket are recommended and have proved to be roughly equivalent to one
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`another in producing dissolution." (AMN 1008, p. 35.)
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`VIII. Summary Chart of Analysis Over the Art
`42. Below is a summary of my analysis of the '122 patent.
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`Ground 
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`References 
`
`Claims 
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`1. Obviousness
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`Maloney
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`1-4, 16 and 18-20
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`
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`21
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`

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`
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`Ground 
`
`2. Obviousness
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`3. Obviousness
`
`4. Obviousness
`5. Obviousness
`6. Obviousness
`7. Obviousness
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`8. Obviousness
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`
`Inter Partes Review of USPN 8,309,122
`Declaration of Anthony Palmieri (Exhibit 1003)
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`References 
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`Claims 
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`The Penwest Statement and
`Baichwal
`Maloney, the Penwest Statement
`and Baichwal
`Maloney and Gordon
`Oshlack
`Oshlack and the Handbook
`Oshlack, the Penwest Statement
`and Baichwal
`Oshlack and Gordon
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`1-4, 16 and 18-20
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`1-4, 16 and 18-20
`1-4, 16 and 18-20
`1-4, 16 and 18-20
`1-4, 16 and 18-20
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`1-4, 16 and 18-20
`1-4, 16 and 18-20
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`IX. The Basis of My Analysis with Respect to Obviousness
`43.
`I understand that an obviousness analysis involves comparing a claim
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`to the prior art to determine whether the claimed invention would have been
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`obvious to a POSA in view of the prior art, and in light of the general knowledge
`
`in the art. I also understand when a POSA would have reached the claimed
`
`invention through routine experimentation, the invention may be deemed obvious.
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`44.
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`I also understand that obviousness can be established by combining or
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`modifying the teachings of the prior art to achieve the claimed invention. It is also
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`my understanding that where this is a reason to modify or combine the