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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 VIVIAN A. GRAY
`
`
`
`
`
`
`
`
`Inter Partes Review of USPN 8,309,122
`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 ................................................................. 8
`V.
`The '122 Patent Specification ......................................................................... 9
`VI. The Claims of the '122 Patent ....................................................................... 10
`VII. State of the Art of Dissolution Testing as of July 6, 2001 ........................... 12
`VIII. In vitro Dissolution Testing of the Maloney Test Formulation ................... 18
`IX. The Dissolution Profile of the Maloney Test Formulation Falls Within the
`Ranges of the Dissolution Profiles in Claims 1-3 and 19 of the '122 Patent 28
`The Dissolution Profiles Disclosed in Oshlack Overlap With the Dissolution
`Profiles in Claims 1-3 and 19 of the '122 Patent .......................................... 33
`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 ............. 38
`XII. Conclusion .................................................................................................... 41
`
`
`X.
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`
`2
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`
`I.
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`Inter Partes Review of USPN 8,309,122
`Declaration of Vivian A. Gray (Exhibit 1002)
`
`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.
`
`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 $450 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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`("EPD"). The '122 patent names Huai-Hung Kao, Anand R. Baichwal, Troy
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`McCall and David Lee as inventors. The '122 patent issued on November 13, 2012,
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`from the '432 application. I further understand that, according to the USPTO
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`records, the '122 patent is currently assigned to Endo Pharmaceuticals, Inc.
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`("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. 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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`
`
`3
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`
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`
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`the viewpoint of a person of ordinary skill in the art ("POSA") (i.e., a person of
`
`Inter Partes Review of USPN 8,309,122
`Declaration of Vivian A. Gray (Exhibit 1002)
`
`ordinary skill in the field of in vitro dissolution testing, defined further below in
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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 '122 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 Fredricksburg, 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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`
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`4
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`
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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 8,309,122
`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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`troubleshooting problems with dissolution methods. I provide advice on
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`
`
`5
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`
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`regulations from USP, other pharmacopoeias, and regulatory agencies, including
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`Inter Partes Review of USPN 8,309,122
`Declaration of Vivian A. Gray (Exhibit 1002)
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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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`invited speaker for conferences more than 50 times, including 13 international
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`invitations, where I lectured in the areas of calibration, dissolution equipment,
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`
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`6
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`
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`sources of error in dissolution testing, method development and validation, new
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`Inter Partes Review of USPN 8,309,122
`Declaration of Vivian A. Gray (Exhibit 1002)
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`technology, and regulatory topics.
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`10.
`
`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
`1004
`1005
`
`
`
`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)
`
`7
`
`
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`
`
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`Amneal
`Exhibit
`#
`1006
`
`1007
`
`1008
`
`1014
`
`1015
`1019
`
`1020
`
`1021
`
`1022
`
`1023
`
`1024
`
`Inter Partes Review of USPN 8,309,122
`Declaration of Vivian A. Gray (Exhibit 1002)
`
`Description
`
`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
`
`
`
`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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`
`
`8
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`
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`conventional wisdom in the art, and is a person of ordinary creativity. A POSA in
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`Inter Partes Review of USPN 8,309,122
`Declaration of Vivian A. Gray (Exhibit 1002)
`
`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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`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 '122 Patent Specification
`14. This declaration is being submitted together with a petition for inter
`
`partes review of claims 1-4, 16 and 18-20 of the '122 patent.
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`15.
`
`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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`16. The '122 patent specification is directed to compositions and methods
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`of relieving pain by administering a controlled release pharmaceutical tablet
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`
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`9
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`
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`containing oxymorphone which produces a mean minimum blood plasma level 12
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`Inter Partes Review of USPN 8,309,122
`Declaration of Vivian A. Gray (Exhibit 1002)
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`to 24 hours after dosing, as well as tablets producing this sustained pain relief.
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`(AMN 1001, Abstract.)
`
`VI. The Claims of the '122 Patent
`17. Claim 1 of the '122 patent, from which claims 2-4, 16, 18 and 20
`
`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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`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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`18. 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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`19.
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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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`
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`10
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`
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`
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`in the form of a tablet, comprising oxymorphone or pharmaceutically acceptable
`
`Inter Partes Review of USPN 8,309,122
`Declaration of Vivian A. Gray (Exhibit 1002)
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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
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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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`20. 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 '122
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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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`("USP") 24 states "the use of the word "about" indicates a quantity within 10% of
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`
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`11
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`
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`the specified weight or volume." (AMN 1005, 8.) As a POSA would understand
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`Inter Partes Review of USPN 8,309,122
`Declaration of Vivian A. Gray (Exhibit 1002)
`
`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%.
`
`VII. State of the Art of Dissolution Testing as of July 6, 2001
`21.
`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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`22.
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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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`and rotating the basket at a set speed in dissolution media with set properties. In
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`
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`12
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`
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`
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`1990, the USP designated the wire basket method as USP Apparatus 1. (AMN
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`Inter Partes Review of USPN 8,309,122
`Declaration of Vivian A. Gray (Exhibit 1002)
`
`1008, p. 29, Figure 3-1.)
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`23. The dissolution method designated USP Apparatus 2 is the paddle
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`method. The specifications for the paddle method are the same as the basket
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`
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`13
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`
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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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`Inter Partes Review of USPN 8,309,122
`Declaration of Vivian A. Gray (Exhibit 1002)
`
`tested is placed directly in the dissolution media. (AMN 1008, p. 32, Figure 3-3.)
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`
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`24. 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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`the apparatus and the media used. (AMN 1008, pp. 35-39.) The specific parameters
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`of a dissolution test are usually specified in the drug monograph. These parameters
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`
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`14
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`
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`include the Apparatus to be used, the media characteristics, including volume, pH
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`Inter Partes Review of USPN 8,309,122
`Declaration of Vivian A. Gray (Exhibit 1002)
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`and temperature, and the stirring rate.
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`25. 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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`26.
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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
`
`1008, p. 35.)
`
`27. The parameters of dissolution testing discussed above have been well
`
`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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`rpm in 900 mL of media at 37 °C and adjusts parameters if necessary to obtain
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`suitable dissolution profiles.
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`28. Exemplary relevant art includes the references described below.
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`
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`15
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`Inter Partes Review of USPN 8,309,122
`Declaration of Vivian A. Gray (Exhibit 1002)
`
`29. 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
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`'122 patent because it published before July 6, 2001, the EPD of the '122 patent.
`
`Maloney is entitled "Opioid Sustained-Release Formulation."
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`30. 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 pH 7.5 for hours 2 through 12) at 37 °
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`C. (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
`
`dissolution profile in the claims of the '122 patent.
`
`31. Oshlack. Oshlack is U.S. Patent No. 5,958,452 (AMN 1007), filed
`
`April 10, 1997 and issued September 28, 1999. I understand that Oshlack is
`
`considered to be prior art to the '122 patent because it issued more than one year
`
`before July 6, 2001, the EPD of the '122 patent. Oshlack is entitled "Extruded
`
`Orally Administrable Opioid Formulations."
`
`
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`16
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`Inter Partes Review of USPN 8,309,122
`Declaration of Vivian A. Gray (Exhibit 1002)
`
`32. 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 of both the paddle and basket method
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`at 100 rpm in 900 mL aqueous buffer at 37 °C and a pH between 1.6 and 7.2.
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`(AMN 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 after 4 hours, from about 20 to about 90% opioid
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`released after 6 hours, 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 from about 55 to
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`about 100% opioid released after 24 hours, by weight. (AMN 1007, 26:39-49.)
`
`33. The Handbook of Dissolution Testing. "The Handbook of
`
`Dissolution Testing," 2nd ed. ("the Handbook"), by William A. Hanson. The
`
`Handbook was published in 1991. I understand that the Handbook is considered to
`
`be prior art to the '122 patent because it published more than one year before July
`
`6, 2001, the EPD of the '122 patent.
`
`34. 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
`
`
`
`17
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`
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`results. (AMN 1008, e.g., Chapter 3.) The Handbook compares the basket and
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`Inter Partes Review of USPN 8,309,122
`Declaration of Vivian A. Gray (Exhibit 1002)
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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.)
`
`VIII. In vitro Dissolution Testing of the Maloney Test Formulation
`35.
` As part of my analysis of the '122 patent, I designed a protocol for
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`and 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.)
`
`These formulations and the results of the dissolution testing are discussed below.
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`36. The formulations that I understand were tested are shown in Table 1
`
`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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`Table 1 – Formula 1
`
`INGREDIENT
`Oxymorphone hydrochloride
`Lactose, NF (Fast Flo)
`Amberlite IRP 69M Fine
`Particle Size
`Methocel K100M (Premium)
`
`AMOUNT
`30 mg (20% w/w)
`39.5% w/w
`5.0% w/w
`
`30.0% w/w
`
`
`
`18
`
`
`
`
`
`
`Inter Partes Review of USPN 8,309,122
`Declaration of Vivian A. Gray (Exhibit 1002)
`
`CR
`(hydroxypropylmethylcellulose,
`USP)
`Cab-O-Sil (M-5)
`Stearic Acid, NF (Powder)
`Theoretical Tablet Weight
`
`
`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
`
`37.
`
`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.
`
`38.
`
`I personally supervised the dissolution equipment and setup and
`
`personally supervised the dissolution testing of the Maloney formulation in
`
`dissolution media at pH 1.2 and 6.8. Dissolution testing at pH 4.5 was performed
`
`
`
`19
`
`
`
`
`
`the following day using the protocol I designed. (AMN 1024.) Dissolution testing
`
`Inter Partes Review of USPN 8,309,122
`Declaration of Vivian A. Gray (Exhibit 1002)
`
`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
`
`Method at 50 rpm in 500 mL media at 37º C. (AMN 1021, 8.) The specification of
`
`the "USP Paddle Method," can be found in § 711 of the USP 24 (2000) (AMN
`
`1005, 24.)
`
`39. 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
`
`the ranges of the dissolution tests recited in the claims of the '122 patent.
`
`40. Dissolution media was prepared as follows:
`
`41. pH 1.2 (0.1 N hydrochloric acid) media: 5 mL of concentrated
`
`hydrochloric acid was added to 6 L of DS water. The pH of the media was
`
`recorded as pH 1.2 using a pH meter that is calibrated daily. The media was
`
`heated, filtered and degassed through a 0.45 μm nylon membrane filter. Reagents
`
`used are shown in the attached notebook pages. (AMN 1021, 5.)
`
`42. pH 6.8 (phosphate buffer) media: 40.805 g of potassium phosphate
`
`monobasic and 6.012 g of sodium hydroxide was dissolved in 6 L of DS water.
`
`The media was mixed well and recorded as having a pH of 6.8 using a pH meter
`
`
`
`20
`
`
`
`
`
`that is calibrated daily. The media was heated, filtered and degassed. Reagents
`
`Inter Partes Review of USPN 8,309,122
`Declaration of Vivian A. Gray (Exhibit 1002)
`
`used are shown in the attached notebook pages. (AMN 1021, 5)
`
`43. pH 4.5 (acetate buffer) media: 17.95 g sodium acetate trihydrate and
`
`60 mL of 2 N acetic acid were dissolved in 6 L of DS water, mixed well and pH
`
`adjusted to pH 4.52 with further addition of 2N acetic acid. pH was measured on a
`
`pH meter calibrated daily. The media was heated, filtered and degassed through a
`
`0.45 μm nylon membrane filter. Reagents used are shown in the attached notebook
`
`pages. (AMN 1021, 11.)
`
`44. Dissolution testing: The dissolution testing was performed as
`
`follows:
`
`1. The dissolution apparatus with the paddle centered at 25± 2 mm
`
`above the bottom of each dissolution vessel was assembled.
`
`2. The assembly was checked for proper alignment and freedom from
`
`wobbling.
`
`3. 500 mL of dissolution medium was placed into each of the dissolution
`
`vessels and the temperature was maintained at 37.0 °C ± 0.5 °C.
`
`4. Each of the tablets was weighed individually and their weight was
`
`recorded.
`o Tablet weights are shown at AMN 1021, 7.
`
`
`
`21
`
`
`
`
`
`
`Inter Partes Review of USPN 8,309,122
`Declaration of Vivian A. Gray (Exhibit 1002)
`
`5. Tablets were placed sequentially
`
`into respective vessels and
`
`dissolution was run as per the parameters above.
`
`6. The vessels were covered with lids during the entire test.
`
`7. At the specified time intervals above, 5 mL of solution was withdrawn
`
`using an autosample.
`
`8. Each sample was filtered through a 0.45 μm nylon membrane syringe
`
`filter. The initial 2-3 mL of filtrate was discarded and the remainder
`
`collected into clean HPLC vials.
`
`9. Dissolution medium was used as a diluent for the samples.
`
`(AMN 1021, 6.)
`
`45. Preparation of Standards: Standard stock solution: 44.36 mg
`
`oxymorphone USPS was dissolved in a 100 mL volumetric flask containing about
`
`50 mL of DS water. The solution was sonicated for about 30 to 45 minutes with
`
`intermittent shaking and diluted with DS water and diluted to volume with DS
`
`water. Working standard solution: 5 mL of standard stock solution was pipeted into
`
`a 50 mL volumetric flask. The solution was diluted to volume with dissolution
`
`medium and mixed well. Reagents used are shown in the attached notebook pages.
`
`(AMN 1021, 8.)
`
`46. Mobile phase preparation
`
`for high performance
`
`liquid
`
`chromatograph (HPLC): Buffer preparation: 31.05 g of potassium phosphate
`
`
`
`22
`
`
`
`
`
`monobasic was dissolved in 8 L of DS water, mixed well and pH adjusted to 10.02
`
`Inter Partes Review of USPN 8,309,122
`Declaration of Vivian A. Gray (Exhibit 1002)
`
`with ammonium hydroxide solution. The buffer was degassed and filtered through
`
`a 0.45 μm nylon membrane filter. The mobile phase was prepared from the buffer
`
`and acetonitrile at a ratio of 80:20 (v/v) (AMN 1021, 8.)
`
`47. A strong wash solution for HPLC was prepared from DS water and
`
`acetonitrile at a ratio of 20:80 (v/v) and mixed well. A weak wash solution was
`
`prepared from DS water and acetonitrile at a ratio of 50:50 (v/v) and mixed well.
`
`(AMN 1021, 9.)
`
`48. Chromatographic conditions: The HPLC parameters are shown at
`
`AMN 1021, 10. One injection of diluent was done as a blank, followed by five
`
`replicate injections of working standard solution, and one injection of each sample
`
`solution. Two injections of standard solution were used as mid and end standards.
`
`(AMN 1021, 10.)
`
`49. Results were calculated comparing to standard injections using Waters
`
`HPLC "Empower" software and Microsoft Excel Spreadsheets. The results of the
`
`testing are provided as AMN 1022 and 1023.
`
`50. For each tablet and pH tested, the release of oxymorphone
`
`hydrochloride (in milligrams) was collected using an autosampler, measured and
`
`recorded at the following timepoints: 1, 2, 3, 4, 5, 6, 8, 10, and 12 hours. I
`
`observed and supervised sample collection up through the 8 hour time point. The
`
`
`
`23
`
`
`
`
`
`automatic sampler collected the remaining timepoints without observation as is
`
`Inter Partes Review of USPN 8,309,122
`Declaration of Vivian A. Gray (Exhibit 1002)
`
`often done during dissolution testing.
`
`51. For each test, I reviewed the lab notebooks of the laboratory scientists
`
`performing the tests, papers created during formulation and tableting and the raw
`
`dissolution data, including area counts. These documents are attached to this
`
`declaration as AMN 1021.
`
`52. The results of the tests for Formula 1 (30% HPMC) at each pH are
`
`shown in Tables 2-7 below. (See AMN 1022.)
`
`53. Table 3 – Testing at pH 1.2 – Formula 1 Numbers shown are
`
`percent release of oxymorphone.
`
`Sample
`1
`2
`3
`4
`5
`6
`mean
`Min
`Max
`RSD1
`
`
`
`1 hr
`30
`30
`28
`30
`28
`30
`29
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