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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. 8,329,216
`_____________________
`
`Inter Partes Review Case No. Unassigned
`_____________________
`
`DECLARATION OF VIVIAN A. GRAY
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`Inter Partes Review of USPN 8,329,216
`Declaration of Vivian A. Gray (Exhibit 1002)
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`
`
`TABLE OF CONTENTS
`
`
`Introduction ..................................................................................................... 3
`I.
`II. My Background and Qualifications ................................................................ 4
`III. List of Documents I Considered in Formulating My Opinion ....................... 7
`IV. Person of Ordinary Skill in the Art ................................................................. 9
`V.
`The '216 patent Specification ......................................................................... 9
`VI. The Claims of the '216 patent ....................................................................... 10
`VII. State of the Art of Dissolution Testing as of July 6, 2001 ........................... 13
`VIII. In vitro Dissolution Testing of the Maloney Test Formula .......................... 19
`IX. The Dissolution Profile of the Maloney Test Formula Falls Within the
`Ranges of the Dissolution Profiles in the Claims of the '216 patent ............ 31
`The Dissolution Profiles Disclosed in Oshlack Overlap With the Dissolution
`Profiles in the Claims of the '216 patent ....................................................... 42
`XI. A POSA Would Have Known From The Handbook of Dissolution Testing
`A Stirring Rate of 50 RPM for the Paddle Method and 100 RPM for the
`Basket Method are Roughly Equivalent In Producing Dissolution ............. 53
`XII. Conclusion .................................................................................................... 56
`
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`X.
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`2
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`I.
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`Inter Partes Review of USPN 8,329,216
`Declaration of Vivian A. Gray (Exhibit 1002)
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`I, Vivian A. Gray, hereby declare as follows.
`
`Introduction
`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 $450 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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`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. In formulating my opinions, I have relied upon my experience, education and
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`knowledge in the relevant art. In formulating my opinions, I have also considered
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`the viewpoint of a person of ordinary skill in the art ("POSA") (i.e., a person of
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`3
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`ordinary skill in the field of in vitro dissolution testing, defined further below in
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`Inter Partes Review of USPN 8,329,216
`Declaration of Vivian A. Gray (Exhibit 1002)
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`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 testing of pharmaceutical delivery
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`systems and have been since before 2001. I have almost 40 years experience in
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`designing and performing dissolution testing of pharmaceutical compositions. The
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`results of such dissolution tests are recited in the claims of the '216 patent.
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`5.
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`I received my B.Sc. in Chemistry from Mary Washington College of
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`the University of Virginia in Fredericksburg, VA. From 1974 to 1982, I was a
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`Chemist at the United States Pharmacopeia ("USP") in Rockville, Maryland,
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`where, as part of my duties, I performed dissolution testing and experimented with
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`dissolution testing parameters. From 1982 to 1990, I was Supervisor in the
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`Methods group at the USP, where I was responsible for the development of new
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`dissolution tests and evaluation of existing dissolution tests. From 1990 to 1997, I
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`was a Scientist and Liaison to the USP Subcommittee on Dissolution and
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`Bioavailability, General Chapters Subcommittee and Chemistry 4 Subcommittee.
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`In my role as a Scientist and committee Liaison, I was involved in revising current
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`and proposing new USP dissolution tests in cooperation with other subcommittee
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`experts. I also interacted with industry, FDA and other parties to improve standards
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`4
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`for dissolution tests and reviewed and evaluated validation data for improved or
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`Inter Partes Review of USPN 8,329,216
`Declaration of Vivian A. Gray (Exhibit 1002)
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`new dissolution tests.
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`6.
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`From 1997 to 2001, I was a Senior Research Scientist and Group
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`Leader of Dissolution Testing in the Analytical Research and Development section
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`of Dupont Pharmaceuticals Company, which became Bristol-Myers Squibb
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`Pharmaceutical Company in 2001. In this position I was responsible for managing
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`the group that performed dissolution testing of candidate formulations, including
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`method development and selection of dissolution conditions, stability/clinical
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`release testing, technology transfer and cleaning certifications. In this role I
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`supervised three supervisors and a team of 11 chemists. I was responsible for the
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`dissolution portion of the Chemistry, Manufacturing and Controls section of New
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`Drug Applications and Marketing Authorization Application submissions to the
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`FDA. I interacted frequently with formulators and principal investigators to
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`interpret dissolution data, support formulation development and ensure project
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`timelines were met.
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`7.
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`From 2002 to the present, I have been the President of V.A. Gray
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`Consulting, Inc. My company provides consulting services in developing and
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`validating dissolution methods, writing regulatory documents and justifications for
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`methodology and specifications, assessing current dissolution methods and
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`5
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`
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`troubleshooting problems with dissolution methods. I provide advice on
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`Inter Partes Review of USPN 8,329,216
`Declaration of Vivian A. Gray (Exhibit 1002)
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`regulations from USP, other pharmacopoeias, and regulatory agencies, including
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`the FDA and others. I consult on developing methods and evaluating new
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`technology for conventional and novel dosage forms. I also prepare laboratory
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`staff for audits and inspections, supervise and direct in vitro dissolution testing,
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`and provide training for method development, validation, recognizing sources of
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`error and importance of observations during the test.
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`8.
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`From 2003 to the present, I have been Managing Director and
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`Research Editor of Dissolution Technologies, a quarterly peer-reviewed indexed
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`journal consisting of technical articles on the subject of dissolution testing. A
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`Question and Answer section is also included in the journal along with meeting
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`reports. In my role as Research Editor, I collect and review articles for the journal,
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`coordinate peer-review and proofreading of articles and organize themed issues.
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`9.
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`I am co-author of the "Handbook of Dissolution Testing," 3rd Edition,
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`which published in 2004. I am an author on more than 50 publications and 6 book
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`chapters on dissolution testing. I have also been involved in writing and revising
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`USP Chapters, initiating change in USP methods, organizing workshops, serving
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`on
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`the USP Biopharmaceutics Expert Committee and
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`the International
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`Pharmaceutical Formulation (FIP) Dissolution Working Group. I have also been an
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`6
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`invited speaker for conferences more than 50 times, including 13 international
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`Inter Partes Review of USPN 8,329,216
`Declaration of Vivian A. Gray (Exhibit 1002)
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`invitations, where I lectured in the areas of calibration, dissolution equipment,
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`sources of error in dissolution testing, method development and validation, new
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`technology, and regulatory topics.
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`10.
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`I have received various awards throughout my career. I received a
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`Research Reward from the American Society of Hospital Pharmacists Research
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`and Education Foundation in 1982. In 1998, I received the FDA Commissioner's
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`Special Citation award. In 2012, I received the Service Award of the Analysis and
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`Pharmaceutical Quality Section of the American Association of Pharmaceutical
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`Scientists.
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`11.
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` Accordingly, I am an expert in the field of testing of pharmaceutical
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`delivery systems, and I have been an expert in this field since prior to July 6, 2001.
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`My full professional background is detailed in my curriculum vitae. (AMN 1015).
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`III. List of Documents I Considered in Formulating My Opinion
`12.
`In formulating my opinion, I have considered
`the following
`
`documents:
`
`Amneal
`Exhibit
`#
`1001
`
`1002
`
`
`
`Description
`
`Kao et al., U.S. Patent No. 8,329,216 B2, "OXYMORPHONE
`CONTROLLED RELEASE FORMULATIONS" (filed June 29, 2006;
`issued December 11, 2012)
`Declaration of Ms. Vivian A. Gray
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`7
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`Inter Partes Review of USPN 8,329,216
`Declaration of Vivian A. Gray (Exhibit 1002)
`
`Description
`
`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 (1991)
`Physicians' Desk Reference, 54th ed., NUMORPHAN®, pp. 1036 and
`1037 (2000)
`Curriculum Vitae of Ms. Vivian A. Gray
`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
`
`8
`
`
`
`
`Amneal
`Exhibit
`#
`1004
`1005
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`1006
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`1007
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`1008
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`1014
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`1015
`1019
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`1020
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`1021
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`1022
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`1023
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`1024
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`Inter Partes Review of USPN 8,329,216
`Declaration of Vivian A. Gray (Exhibit 1002)
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`
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`IV. Person of Ordinary Skill in the Art
`13.
`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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`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.
`
`The '216 patent Specification
`14. This declaration is being submitted together with a petition for inter
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`partes review of claims 1, 2, 6, 12-14, 17, 21-43, 45-51, and 54-82 of the '216
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`patent.
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`
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`9
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`Inter Partes Review of USPN 8,329,216
`Declaration of Vivian A. Gray (Exhibit 1002)
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`15.
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`I have considered the disclosure and file history of the '216 patent in
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`
`
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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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`16. The '216 patent is directed to compositions and methods of relieving
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`pain by administering a controlled release pharmaceutical 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. The Claims of the '216 patent
`17. Claims 13, 21, 31, 49, 55, 66 and 72 of the '216 patent, are generally
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`directed
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`to a controlled
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`release pharmaceutical composition comprising
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`oxymorphone or a pharmaceutically acceptable salt thereof and a controlled release
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`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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`18. Claims 22, 38, 54, 71 and 73 are directed to a formulation where
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`about 45% to about 80%, by weight, of the oxymorphone or salt thereof is released
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`from the tablet at about 4 hours in the test. Claims 22, 38, 54, 71, and 74 are
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`directed to a formulation where at least about 80%, by weight, of the oxymorphone
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`or salt thereof is released from the tablet at about 10 hours in the test. Claim 79 is
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`
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`10
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`
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`directed to a formulation where about 58% to about 66%, by weight, of the
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`
`Inter Partes Review of USPN 8,329,216
`Declaration of Vivian A. Gray (Exhibit 1002)
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`oxymorphone or salt thereof is released from the tablet at about 4 hours in the test.
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`Claim 80 is directed to a formulation where about 85% to about 96%, by weight, of
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`the oxymorphone or salt thereof is released from the tablet at about 4 hours in the
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`test.
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`19.
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`Independent claims 38 and 77 are generally directed to controlled
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`release pharmaceutical composition comprising oxymorphone or pharmaceutically
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`acceptable salt thereof and a controlled release delivery system, wherein upon
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`placement of the composition in an in vitro dissolution test comprising USP Paddle
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`Method at 50 rpm in 500 ml media having a pH of 1.2 to 6.8 at 37 °C, about 15%
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`to about 50%, by weight, of the oxymorphone or salt thereof is released from the
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`composition at about 1 hour in the test, about 45% to about 80%, by weight, of the
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`oxymorphone or salt thereof is released from the composition at about 4 hours in
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`the test, and at least about 80%, by weight, of the oxymorphone or salt thereof is
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`released from the composition at about 10 hours in the test.
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`20. Claims 23 and 57 of the '216 patent are directed to the compositions
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`of claims 21 and 55, respectively, wherein at least 27%, 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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`at least 40%, by weight, of the oxymorphone or salt thereof is released from the
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`
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`11
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`tablet at about 2 hours in the test, at least 50%, by weight, of the oxymorphone or
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`Inter Partes Review of USPN 8,329,216
`Declaration of Vivian A. Gray (Exhibit 1002)
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`salt thereof is released from the tablet at about 3 hours in the test, at least 64%, by
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`weight, of the oxymorphone or salt thereof is released from the tablet at about 5
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`hours in the test, at least 70%, by weight, of the oxymorphone or salt thereof is
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`released from the tablet at about 6 hours in the test, at least 79%, by weight, of the
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`oxymorphone or salt thereof is released from the tablet at about 8 hours in the test,
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`at least 85%, by weight, of the oxymorphone or salt thereof is released from the
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`tablet at about 10 hours in the test, and at least 89%, by weight, of the
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`oxymorphone or salt thereof is released from the tablet at about 12 hours in the
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`test. Claims 24-30 and 58-65 recite specific timepoints within those recited in
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`claims 23 and 57 with the same release profiles.
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`21. 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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`mean at least the typical variability for such dissolution testing values. The '216
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`patent states that "[r]eference to mean values reported herein for studies actually
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`conducted are arrived at using standard statistical methods as would be employed
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`by one skilled in the art of pharmaceutical formulation and testing for regulatory
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`approval." (AMN 1001, 3:67 – 4:4.) The term "about" has a plain and ordinary
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`meaning in the field of pharmaceutical testing. The United States Pharmacopeia
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`
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`12
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`
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`("USP") 24 states "the use of the word "about" indicates a quantity within 10% of
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`Inter Partes Review of USPN 8,329,216
`Declaration of Vivian A. Gray (Exhibit 1002)
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`the specified weight or volume." (AMN 1005, 8.) As a POSA would understand
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`that the 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, e.g. if the value measured is
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`80%, a POSA would understand the term about to encompass about 72% to about
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`88%.
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`VII. State of the Art of Dissolution Testing as of July 6, 2001
`22.
`In vitro dissolution testing of solid dose pharmaceutical formulations
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`has been performed since the 1960s, and the first official method was adopted in
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`the USP XVIII in 1970. (AMN 1008, p. 9.) Dissolution testing is a routine part of
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`the drug development process and is also a routine part of product quality
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`assurance for solid dose formulation. It is used to evaluate and compare new
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`formulations and to provide feedback for the optimization of formulations. It is
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`also commonly used to satisfy FDA drug approval requirements. Two of the more
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`common methods used in dissolution testing are the rotating basket method and the
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`paddle method, both of which are the subject of compendial standards.
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`23.
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` The first official dissolution testing method adopted was the rotating
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`basket method, which involves placing the tablet to be tested in a wire mesh basket
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`13
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`and rotating the basket at a set speed in dissolution media with set properties. In
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`Inter Partes Review of USPN 8,329,216
`Declaration of Vivian A. Gray (Exhibit 1002)
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`1990, the USP designated the wire basket method as USP Apparatus 1. (AMN
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`1008, p. 29, Figure 3-1.)
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`14
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`Inter Partes Review of USPN 8,329,216
`Declaration of Vivian A. Gray (Exhibit 1002)
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`24. The dissolution method designated USP Apparatus 2 is the paddle
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`
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`method. The specifications for the paddle method are the same as the basket
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`method, except that a paddle is used in place of the basket and the tablet to be
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`tested is placed directly in the dissolution media. (AMN 1008, p. 32, Figure 3-3.)
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`25. The basket and paddle methods have many constraints that are
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`common to both methods, including the geometry and alignment of the rotating
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`shaft, the vertical position of the paddle or basket, the dissolution flask used with
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`15
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`
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`the apparatus and the media used. (AMN 1008, pp. 35-39.) The specific parameters
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`Inter Partes Review of USPN 8,329,216
`Declaration of Vivian A. Gray (Exhibit 1002)
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`of a dissolution test are usually specified in the drug monograph. These parameters
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`include the Apparatus to be used, the media characteristics, including volume, pH
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`and temperature, and the stirring rate.
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`26. Typical media volumes are between 500 and 1000 mL. (AMN 1008,
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`p. 39.) Within the range of 500 to 1000 mL dissolution media, the volume used
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`typically only affects the dissolution profile if the drug has a low solubility. (AMN
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`1008, p. 116.) For drugs that are readily soluble in water, the volume of dissolution
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`media has almost no effect on the dissolution profile.
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`27.
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`If the stirring rate is not specified in the monograph, standard rates are
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`50 rpm for the paddle method and 100 rpm for the basket method. As noted in the
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`Handbook of Dissolution, these stirring rates for paddle and basket methods "have
`
`proved to be roughly equivalent to one another in producing dissolution." (AMN
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`1008, p. 35.)
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`28. The parameters of dissolution testing discussed above have been well
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`studied and a POSA as of the EPD would have understood how adjustments to
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`these parameters affect the dissolution profile obtained. In developing a standard
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`dissolution test for a new drug formulation, a person performing dissolution testing
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`usually starts with either the basket method at 100 rpm or the paddle method at 50
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`
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`16
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`
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`rpm in 900 mL of media at 37 °C and adjusts parameters if necessary to obtain
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`Inter Partes Review of USPN 8,329,216
`Declaration of Vivian A. Gray (Exhibit 1002)
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`suitable dissolution profiles.
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`29. Exemplary relevant art includes the references described below.
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`30. Maloney. Maloney
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`is
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`International
`
`Publication
`
`No.
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`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
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`'216 patent because it published before July 6, 2001, the EPD of the '216 patent.
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`Maloney is entitled "Opioid Sustained-Release Formulation."
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`31. Maloney teaches controlled release opioid matrix formulations. (AMN
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`1006, 8:9-14.) Maloney teaches that oxymorphone is a preferred opioid for use in
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`these formulations. (AMN 1006, 13:15-19.) The examples of Maloney provide
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`sustained release profiles measured by the basket method at 100 rpm in 900 mL
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`aqueous buffer (pH 1.2 for the first hour and 7.5 for hours 2 through 12) at 37 ° C.
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`(AMN 1006, 14:9-15.) The dissolution testing method disclosed in Maloney is
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`frequently used in testing controlled release formulations. As discussed further
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`below, an oxymorphone formulation disclosed in Maloney has the in vitro
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`dissolution profile in the claims of the '216 patent.
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`32. 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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`
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`17
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`
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`considered to be prior art to the '216 patent because it published more than one
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`Inter Partes Review of USPN 8,329,216
`Declaration of Vivian A. Gray (Exhibit 1002)
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`year before July 6, 2001, the EPD of the '216 patent. Oshlack is entitled "Extruded
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`Orally Administrable Opioid Formulations."
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`33. Oshlack teaches sustained release matrix pharmaceutical formulations
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`with opioid active agents. (AMN 1007, 1:10-14; 3:58-65.) Oshlack teaches that
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`oxymorphone is a preferred opioid for use in these sustained release formulations.
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`(AMN 1007, 7:35-39.) Oshlack teaches use both the paddle and basket method at
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`100 rpm in 900 mL aqueous buffer at 37 °C and a pH between 1.6 and 7.2. (AMN
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`1007, 11:60 – 12:12.) Oshlack discloses sustained release pharmaceutical
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`formulations containing oxymorphone that have a dissolution profile using the
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`basket method at 100 rpm of: from about 1 to about 42.5% opioid release after one
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`hour, from about 5 to about 65% opioid released after 2 hours, from about 15 to
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`about 85% opioid released at 4 hours, from about 20 to about 90% opioid released
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`after 6 hours, from about 35 to about 95% opioid released after 12 hours, from
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`about 45 to about 100% opioid released after 18 hours, and from about 55 to about
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`100% opioid released after 24 hours, by weight. (AMN 1007, 26:39-49.)
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`34. 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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`18
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`be prior art to the '216 patent because it published more than one year before July
`
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`Inter Partes Review of USPN 8,329,216
`Declaration of Vivian A. Gray (Exhibit 1002)
`
`6, 2001, the EPD of the '216 patent.
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`35. 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. In vitro Dissolution Testing of the Maloney Test Formula
`36. As part of my analysis of the '216 patent, I designed a protocol for and
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`supervised in vitro dissolution tests of two formulations that I understand from
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`discussions with Dr. Anthony Palmieri to be disclosed in Maloney. (AMN 1024.)
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`These formulations and the results of the dissolution testing are discussed below.
`
`37. The formulations that I understand were tested are shown in Table 1
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`and Table 2 below. The formulation in Table 1-Formula 1 was Batch # PD161-01
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`and the formulation in Table 2-Formula-2 was Batch PD161.02. I understand from
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`discussions with Dr. Palmieri that the formulations were manufactured according
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`to steps outlined in Maloney.
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`19
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`
`Inter Partes Review of USPN 8,329,216
`Declaration of Vivian A. Gray (Exhibit 1002)
`
`Table 1 – Formula 1
`
`INGREDIENT
`Oxymorphone hydrochloride
`Lactose, NF (Fast Flo)
`Amberlite IRP 69M Fine
`Particle Size
`Methocel K100M (Premium)
`CR
`(hydroxypropylmethylcellulose,
`USP)
`Cab-O-Sil (M-5)
`Stearic Acid, NF (Powder)
`Theoretical Tablet Weight
`
`
`AMOUNT
`30 mg (20% w/w)
`39.5% w/w
`5.0% w/w
`
`30.0% w/w
`
`0.5% w/w
`5.0% w/w
`150 mg
`
`Table 2 – Formula 2
`
`INGREDIENT
`Oxymorphone hydrochloride
`Lactose, NF (Fast Flo)
`Amberlite IRP 69M Fine
`Particle Size
`Methocel K100M (Premium)
`CR
`(hydroxypropylmethylcellulose,
`USP)
`Cab-O-Sil (M-5)
`Stearic Acid, NF (Powder)
`Theoretical Tablet Weight
`
`
`
`AMOUNT
`30 mg (20% w/w)
`24.5% w/w
`5.0% w/w
`
`45.0% w/w
`
`0.5% w/w
`5.0% w/w
`150 mg
`
`20
`
`
`
`
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`
`Inter Partes Review of USPN 8,329,216
`Declaration of Vivian A. Gray (Exhibit 1002)
`
`38.
`
`I personally observed the tableting of the above formulations. The
`
`
`
`
`tablets were tested in dissolution media at pH 1.2 and pH 6.8 on the day they were
`
`made. The tablets were tested in dissolution media at pH 4.5 the following day.
`
`39.
`
`I personally supervised the dissolution equipment and setup and
`
`personally supervised the dissolution testing of the Maloney formulation in
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`dissolution media at pH 1.2 and 6.8. Dissolution testing at pH 4.5 was performed
`
`the following day using the protocol I designed. (AMN 1024.) Dissolution testing
`
`was performed by a laboratory scientist experienced in dissolution testing. As is
`
`standard protocol, six samples of the Maloney formulation were tested at each of
`
`three different pH values. Dissolution testing was performed using the USP Paddle
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`Method at 50 rpm in 500 mL media at 37º C. (AMN 1021, 8.) The specification of
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`the "USP Paddle Method," can be found in § 711 of the USP 24 (2000) (AMN
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`1005, 24.)
`
`40. As mentioned above, testing was performed using dissolution media
`
`at three different pH values: 1.2, 4.5, and 6.8. These testing conditions fall within
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`the ranges of the dissolution tests recited in the claims of the '216 patent.
`
`41. Dissolution media was prepared as follows:
`
`42. pH 1.2 (0.1 N hydrochloric acid) media: 5 mL of concentrated
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`hydrochloric acid was added to 6 L of DS water. The pH of the media was
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`21
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`
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`recorded as pH 1.2 using a pH meter that is calibrated daily. The media was
`
`
`Inter Partes Review of USPN 8,329,216
`Declaration of Vivian A. Gray (Exhibit 1002)
`
`heated, filtered and degassed through a 0.45 μm nylon membrane filter. Reagents
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`used are shown in the attached notebook pages. (AMN 1021, 5.)
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`43. pH 6.8 (phosphate buffer) media: 40.805 g of potassium phosphate
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`monobasic and 6.012 g of sodium hydroxide was dissolved in 6 L of DS water.
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`The media was mixed well and recorded as having a pH of 6.8 using a pH meter
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`that is calibrated daily. The media was heated, filtered and degassed. Reagents
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`used are shown in the attached notebook pages. (AMN 1021, 5.)
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`44. pH 4.5 (acetate buffer) media: 17.95 g sodium acetate trihydrate and
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`60 mL of 2 N acetic acid were dissolved in 6 L of DS water, mixed well and pH
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`adjusted to pH 4.52 with further addition of 2N acetic acid. pH was measured on a
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`pH meter calibrated daily. The media was heated, filtered and degassed through a
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`0.45 μm nylon membrane filter. Reagents used are shown in the attached notebook
`
`pages. (AMN 1021, 11.)
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`45. Dissolution testing: The dissolution testing was performed as
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`follows:
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`1. The dissolution apparatus with the paddle centered at 25± 2 mm
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`above the bottom of each dissolution vessel was assembled.
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`22
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`Inter Partes Review of USPN 8,329,216
`Declaration of Vivian A. Gray (Exhibit 1002)
`
`2. The assembly was checked for proper alignment and freedom from
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`wobbling.
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`3. 500 mL of dissolution medium was placed into each of the dissolution
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`vessels and the temperature was maintained at 37.0 °C ± 0.5 °C.
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`4. Each of the tablets was weighed individually and their weight was
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`recorded.
`o Tablet weights are shown at AMN 1021, 7.
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`5. Tablets were placed sequentially
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`into respective vessels and
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`dissolution was run as per the parameters above.
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`6. The vessels were covered with lids during the entire test.
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`7. At the specified time intervals above, 5 mL of solution was withdrawn
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`using an autosample.
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`8. Each sample was filtered through a 0.45 μm nylon membrane syringe
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`filter. The initial 2-3 mL of filtrate was discarded and the remainder
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`collected into clean HPLC vials.
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`9. Dissolution medium was used as a diluent for the samples.
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`(AMN 1021, 6.)
`
`46. Preparation of Standards: Standard stock solution: 44.36 mg
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`oxymorphone USPS was dissolved in a 100 mL volumetric flask containing about
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`23
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`50 mL of DS water. The solution was sonicated for about 30 to 45 minutes with
`
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`Inter Partes Review of USPN 8,329,216
`Declaration of Vivian A. Gray (Exhibit 1002)
`
`intermittent shaking and diluted with DS water and diluted to volume with DS
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`water. Working standard solution: 5 mL of standard stock solution was pipeted into
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`a 50 mL volumetric flask. The solution was diluted to volume with dissolution
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`medium and mixed well. Reagents used are shown in the attached notebook pages.
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`(AMN 1021, 8.)
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`47. Mobile phase preparation
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`for high performance
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`liquid
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`chromatograph (HPLC): Buffer preparation: 31.05 g of potassium phosphate
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`monobasic was dissolved in 8 L of DS water, mixed well and pH adjusted to 10.02
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`with ammonium hydroxide solution. The buffer was degassed and filtered through
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`a 0.45 μm nylon membrane filter. The mobile phase was prepared from the buffer
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`and acetonitrile at a ratio of 80:20 (v/v) (AMN 1021, 9.)
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`48. A strong wash solution for HPLC was prepared from DS water and
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`acetonitrile at a ratio of 20:80 (v/v) and mixed well. A weak wash solution was
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`prepared from DS water and acetonitrile at a ratio of 50:50 (v/v) and mixed well.
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`(AMN 1021, 9.)
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`49. Chromatographic conditions: The HPLC parameters are shown at
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`AMN 1021, 10. One injection of diluent was done as a blank, followed by five
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`replicate injections of working standard solution, and one injection of each sample
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`24
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`solution. Two injections of standard
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