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`UNITED STATES PATENT AND TRADEMARK OFFICE
`_____________________
`
`BEFORE THE PATENT TRIAL AND APPEAL BOARD
`_____________________
`
`
`AMNEAL PHARMACEUTICIALS, LLC
`Petitioner
`
`v.
`
`ENDO PHARMACEUTICALS, INC.
`Patent Owner
`
`U.S. Patent No. 8,329,216
`_____________________
`
`Case IPR2014-00360
`_____________________
`
`Declaration of Michael L. Weinberger, M.D.
`
`

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`
`Inter Partes Review of USPN 8,329,216
`Declaration of Michael L. Weinberger, M.D. (
`)
`TABLE OF CONTENTS
`Overview .......................................................................................................... 1
`I.
`Summary of opinions ....................................................................................... 2
`II.
`III. My background and qualifications .................................................................. 4
`IV. List of documents I considered in formulating my opinions........................... 6
`V.
`Person of ordinary skill in the art ..................................................................10
`VI. Basis of my analysis with respect to obviousness, long-felt need, and
`commercial success .......................................................................................11
`VII. Controlled-release opioids indicated for at least 12-hour dosing were known
`before July 6, 2001 ........................................................................................13
`A. Controlled-release morphine sulfate provided a controlled-release
`opioid indicated for long-term pain relief.........................................13
`B. Controlled-release oxycodone provided a controlled-release opioid
`indicated for long-term pain relief ....................................................15
`C. Controlled-release hydromorphone provided a controlled-release
`opioid indicated for long-term pain relief.........................................16
`D. Controlled-release fentanyl provided a controlled-release opioid
`indicated for long-term pain relief ....................................................16
`E. Methadone provided a long-acting opioid indicated for long-term
`pain relief ..........................................................................................17
`VIII. Inherent properties of oxymorphone determine Opana® ER's metabolic
`pathway ..........................................................................................................19
`IX. The claimed inventions of the '216 patent do not satisfy a long-felt unmet
`need for an extended-release opioid ..............................................................21
`A. There was no long-felt need for an additional controlled-release
`opioid ................................................................................................21
`B. Even if there once was a need for an extended-release opioid, any
`such need would have been satisfied by the prior art .......................24
`C. Dr. Burgess overstates the purported "therapeutic advantages" of
`Opana® ER .......................................................................................28
`X. Dr. Burgess does not show that Opana® ER is a commercial success or
`consider other aspects attributing to commercial sales of Opana® ER ........31
`
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`Inter Partes Review of USPN 8,329,216
`Declaration of Michael L. Weinberger, M.D. (
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`A. "Effective analgesia" is not a property unique to the claimed
`invention of the '216 patent ..............................................................32
`B. The "food effect" feature is not driving Opana® ER prescriptions
`and sales ............................................................................................33
`C. Endo's promotional efforts contribute to prescriptions and sales .....34
`XI. Conclusion .....................................................................................................38
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`I.
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`Inter Partes Review of USPN 8,329,216
`Declaration of Michael L. Weinberger, M.D. (
`)
`I, Michael L. Weinberger, hereby declare as follows.
`
`Overview
`I am over the age of eighteen (18) and otherwise competent to make
`1.
`
`this declaration.
`
`2.
`
`I have been retained as an expert witness on behalf of AMNEAL
`
`PHARMACEUTICALS, L.L.C and AMNEAL PHARMACEUTICALS COMPANY PVT. LTD.
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`(together "AMNEAL") for the above-captioned inter partes review (IPR). I am being
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`compensated for my time in connection with this IPR at my standard consulting
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`rate, which is $400 per hour. I understand that the petition for inter partes review
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`involves U.S. Patent No. 8,329,216 ("the '216 patent"), Exhibit 1001, which
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`resulted from U.S. Application No. 11/427,438 ("the '438 application"), filed on
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`June 29, 2006, naming Haui-Hung Kao, Anand R. Baichwal, Troy McCall, and
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`David Lee as inventors. The '216 patent issued on December 11, 2012, from the
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`'438 application. I further understand that, according to the USPTO records, the
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`'216 patent is currently assigned to Endo Pharmaceuticals, Inc. ("the patentee"). I
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`understand that the earliest possible priority date for the '216 patent is July 6, 2001.
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`3.
`
`I understand that certain claims of the '216 patent are directed to oral
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`controlled release formulations of oxymorphone. [Exhibit 1001, 26-27.] I
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`understand that certain claims of the '216 patent are directed to methods of
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`preparing pharmaceutical tablets comprising oxymorphone. [Exhibit 1001, 27-28.]
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`I understand that certain claims of the '216 patent are directed to methods of
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`Inter Partes Review of USPN 8,329,216
`Declaration of Michael L. Weinberger, M.D. (
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`treating pain by administering an oral solid dosage form of the controlled release
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`formulation of oxymorphone recited in other claims of the '216 patent. [Exhibit
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`1001, 28-30.] I understand that the '216 patent also claims an "analgesically
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`effective controlled release pharmaceutical composition for oral delivery"
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`comprising oxymorphone. [Exhibit 1001, 30-34.] I understand that certain claims
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`of the '216 patent are directed to a difference in drug absorption under fed and
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`fasted test conditions (a "food effect"). [Exhibit 1001, 28-34.]
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`4.
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`I understand that Endo has submitted a Contingent Motion to Amend
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`claims 21 and 31 of the '216 patent, should those claims be determined to be
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`unpatentable in this proceeding. [Paper 29.]
`
`II. Summary of opinions
`I provide this declaration in response to the testimony of Endo's
`5.
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`declarants, Dr. Diane Burgess and Mr. Marvin Kelly, concerning objective indicia
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`of non-obviousness1, specifically with respect to whether there existed a long-felt,
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`unmet need for an additional controlled-release oxymorphone formulation as
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`claimed in the '216 patent. Dr. Burgess states in her declaration that the '216 patent
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`1 I understand that objective indicia of non-obviousness are sometimes
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`called secondary considerations of non-obviousness.
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`purportedly "addressed" a long-felt need for an extended-release opioid. [Exhibit
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`Inter Partes Review of USPN 8,329,216
`Declaration of Michael L. Weinberger, M.D. (
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`2070, ¶ 199.] I disagree that there was any such long-felt, unmet need for an
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`extended-release opioid because several different controlled-release and long-
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`acting opioids were already known in the prior art. Moreover, Dr. Burgess does not
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`provide any evidence of a long-felt, unmet need for an extended-release opioid that
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`was recognized in the art.
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`6.
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`Even if there were a "long-felt, unmet need" for an extended-release
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`opioid, I disagree with Dr. Burgess's opinion that the formulations and methods
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`claimed in the '216 patent addressed any such need. [Exhibit 2070, ¶¶ 199-200.]
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`Any such need would have already been satisfied by treatment options that existed
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`in the prior art, such as Oxycontin®, MS Contin®, Kadian®, Oramorph® SR, or
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`Duragesic®.
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`7.
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`Dr. Burgess also states in her declaration that the commercial sales of
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`Opana® ER are directly attributed to the claimed inventions of the '216 patent.
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`[Exhibit 2070, ¶¶ 191-198.] I disagree with Dr. Burgess because there is no direct
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`link between the commercial sales of Opana® ER and any allegedly novel features
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`in the claims of the '216 patent or the amended claims. Dr. Burgess also fails to
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`consider other factors that contribute to sales, such as marketing and promotional
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`tactics. And, to the extent that Dr. Burgess bases her opinions on the declaration of
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`Mr. Kelley (Exhibit 2053), I further disagree with them on the ground that Mr.
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`Kelley's assertions are without merit for the reasons articulated by Dr. Meyer in her
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`Inter Partes Review of USPN 8,329,216
`Declaration of Michael L. Weinberger, M.D. (
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`declaration (Exhibit 1030). I have relied on Dr. Meyer's declaration for her analysis
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`of Opana® ER sales, prescription volume, market share, market dynamics, and
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`promotional efforts.
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`III. My background and qualifications
`I am an expert in pain medicine and have been an expert in this field
`8.
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`since before 2001.
`
`9.
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`I am presently Associate Clinical Professor of Anesthesiology,
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`Division Chief for the Division of Pain Medicine, and Medical Director of the Pain
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`Management Center at Columbia University Medical Center (New York
`
`Presbyterian Hospital). I am Board Certified in Internal Medicine, Anesthesiology
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`(including Pain Management), and Hospice and Palliative Medicine. I practice all
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`aspects of pain medicine. I have been practicing in the field of pain medicine for
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`more than 20 years. I have given numerous lectures and other medical
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`presentations in the field anesthesiology and pain management. My curriculum
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`vitae is provided as Exhibit 1061.
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`10.
`
`I earned a Bachelor of Arts degree in Biology from Clark University
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`in 1979. I earned an M.D. from Columbia University in 1983. I completed my
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`internship and residency in internal medicine at St. Vincent's Hospital and Medical
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`Center in New York, NY, in 1984 and 1986, respectively. I completed my
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`residency in anesthesiology at Columbia-Presbyterian Medical Center in New
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`Inter Partes Review of USPN 8,329,216
`Declaration of Michael L. Weinberger, M.D. (
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`York, NY in 1989. I completed a fellowship in Pain Management at Memorial
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`Sloan Kettering Cancer Center, New York, NY, in 1990. I am a licensed physician
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`in the state of New York.
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`11. During my career I served as a visiting professor at several
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`institutions, including the University of Vermont College of Medicine ("Palliative
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`Medicine and the Anesthesiologist," February 2012) and the University of
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`Colorado Health Sciences ("Current Concepts in Low Back Pain," March, 2001). I
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`have been awarded grants from institutions such as the Oak Foundation (Palliative
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`Medicine), Samuels Foundation (Palliative Care Program), and Boston Scientific
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`(Principle Investigator, Pain Fellowship).
`
`12.
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`I have served and currently serve on numerous committees related to
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`the practice of pain medicine. For example, I was the President of the Eastern Pain
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`Association, and I am currently Chairperson of the Palliative Medicine Special
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`Interest Group of the American Pain Society. A full list of my service activities and
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`committees is provided in my CV. [Exhibit 1061.]
`
`13.
`
`I have been an invited lecturer in the field of pain medicine on over 80
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`occasions. A full list of my lectures is included in my CV. [Exhibit 1061.] I have
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`also published medical articles and book chapters in the field.
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`14.
`
`I am a member of or affiliated with a number of organizations
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`dedicated to pain medicine, including the American Pain Society, Eastern Pain
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`Inter Partes Review of USPN 8,329,216
`Declaration of Michael L. Weinberger, M.D.
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`Association, International Association for the Study of Pain, American Society of
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`Anesthesiologists, New York State Society of Anesthesiologists, International
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`Anesthesia Research Society, and International Spinal Injection Society.
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`15.
`
`In view of my education, experience, and expertise described above, I
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`am an expert in the field of pain medicine and in the treatment of patients suffering
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`from acute or chronic pain. I have been an expert in this field since before 2001.
`
`IV. List of documents I considered in formulating my opinions
`In formulating my opinions, I considered all of the references cited
`16.
`
`herein, including the documents listed below.
`
`Description
`
`Exhibit or
`Paper No.
`Paper 1 Amneal's petition for inter partes review of U.S. Patent No.
`8,329,216
`Paper 16 Patent Trial & Appeal Board, Decision to Institute, Case IPR2014-
`00360
`Paper 29 Endo's Contingent Motion to Amend, Case IPR2014-00360
`Paper 31 Endo's Patent Owner Response, Case IPR2014-00360
`U.S. Patent No. 8,329,216 to Kao et al.
`1001
`1003
`Declaration of Dr. Anthony Palmieri
`1004
`File History of U.S. Patent No. 8,329,216
`1005
`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
`
`1006
`
`1007
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`Inter Partes Review of USPN 8,329,216
`Declaration of Michael L. Weinberger, M.D. (
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`Exhibit or
`Paper No.
`
`Description
`
`1008
`
`1009
`
`1010
`
`1011
`
`1012
`
`1013
`
`1014
`
`1017
`
`1018
`
`1019
`
`1020
`
`1021
`
`1022
`
`1023
`
`1024
`
`September 28, 1999)
`The Handbook of Dissolution Testing, 2nd ed., Revised, Hanson,
`W.A., ed., pp. v-xii, 1-13, 26-53, 69-91, 111-123 (1991)
`Penwest Pharmaceuticals Co.'s Form S-1 Registration Statement
`Under the Securities Act of 1953 (1997)
`Baichwal et al., U.S. Patent 5,128,143, "SUSTAINED RELEASE
`EXCIPIENT AND TABLET FORMULATION" (filed March 9,
`1990; issued July 7, 1992)
`Gordon et al., "Opioid Equianalgesic Calculations," Journal of
`Palliative Medicine 2(2):209-218 (1999)
`Poulain et al., "Relative Bioavailability Of Controlled Release
`Morphine Tablets (MST Continus) In Cancer Patients," Br. J.
`Anaesth. 61:569-574 (1988)
`Cone et al., "Oxymorphone Metabolism And Urinary Excretion In
`Human, Rat, Guinea, Pig, Rabbit, And Dog," Drug Metabolism and
`Disposition 11(5):446-450 (1983)
`Physicians' Desk Reference, 54th ed., NUMORPHAN®, pp. 1036
`and 1037 (2000)
`"TIMERx Oral Controlled-Release Drug Delivery System," by
`McCall et al., in Modified-Release Drug Delivery Technology,
`Chapter 2, Rathbone et al., eds., pp. 11-19 (2007)
`Lewenstein et al., U.S. Patent No. 2,806,033, "Morphine
`Derivative" (filed August 3, 1955; issued September 10, 1957)
`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-
`
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`Inter Partes Review of USPN 8,329,216
`Declaration of Michael L. Weinberger, M.D. (
`
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`Exhibit or
`Paper No.
`
`Description
`
`1026
`
`1030
`1042
`
`1049
`
`1051
`
`1052
`
`1053
`
`1054
`
`1055
`
`1056
`
`8115 (S.D.N.Y.) Formulation and Testing Protocol of Controlled-
`Release Oxymorphone Tablets, dated November 11, 2013, 3 pages
`Physicians' Desk Reference, 54th ed., Oxycontin®, pp. 2537-2541
`(2000)
`Declaration of Christine S. Meyer, Ph.D.
`Transcript of Deposition of Diane Burgess, Ph.D., December 11,
`2014
`Opana® ER Pharmacokinetics, available from
`http://www.opana.com/prescriber/product-
`information/pharmacokinetic-profile.aspx, last accessed December
`18, 2014
`Fugh-Berman, A. et al., "Following the Script: How Drug Reps
`Make Friends and Influence Doctors," PLOS Med. 4(4):621-625
`(2007)
`Oldani, M.J., "Thick Prescriptions: Toward an Interpretation of
`Pharmaceutical Sales Practices," Med. Anthropology Quarterly
`18(3):325-356 (2004)
`Physicians' Desk Reference, 54th ed., MS Contin®, pp. 2524-2527
`(2000)
`Physicians' Desk Reference, 54th ed., Oramorph® SR, pp. 2713-
`2716 (2000)
`Physicians' Desk Reference, 54th ed., Kadian®, pp. 1050-1053
`(2000)
`Physicians' Desk Reference, 54th ed., Duragesic®, pp. 1445-1448
`(2000)
`1065 Warfield, C.A., "Controlled-Release Morphine Tablets in Patients
`with Chronic Cancer Pain," Cancer, 82(12):2299-2306 (1998)
`Broomhead, A. et al., "Comparison of a Once-a-Day Sustained
`Release Morphine Formulation with Standard Oral Morphine
`Treatment for Cancer Pain," J. Pain & Symptom Management,
`14(2):63-73 (1997)
`Bloomfield, S.S. et al., "Analgesic efficacy and potency of two oral
`controlled-release morphine preparations," Clin. Pharm. &
`Therapeutics, 53(4):469-478 (1993)
`Hagen, N.A. et al., "Controlled-Release Oxycodone Formulation
`and Controlled-Release Hydromorphone in the Treatment of Cancer
`Pain," Cancer, 79(7):1428-1437 (1997)
`
`1066
`
`1067
`
`1068
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`Exhibit or
`Paper No.
`1069
`
`1070
`
`1071
`
`1072
`
`1073
`
`1074
`
`1076
`
`1079
`
`2011
`2053
`2054
`2055
`
`2056
`
`2057
`
`2058
`
`2059
`
`
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`
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`Inter Partes Review of USPN 8,329,216
`Declaration of Michael L. Weinberger, M.D.
`)
`
`Description
`
`Payne, R. et al., "Quality of Life and Cancer Pain: Satisfaction and
`Side Effects With Transdermal Fentanyl Versus Oral Morphine," J.
`Clin. Oncology, 16(4):1588-1593 (1998)
`Ripamonti, C. et al., "Switching From Morphine to Oral Methadone
`in Treating Cancer Pain: What is the Equianalgesic Dose Ratio?" J.
`Clin. Oncology, 16(10):3216-3221 (1998)
`Mercadante, S., "Opioid Rotation for Cancer Pain," Cancer,
`86(9):1856-1866 (1999)
`FDA Approved Drug Label "Dolophine® Hydrochloride
`(Methadone Hydrochloride Tablets, USP)" (2006)
`Prescribing information, "Opana® ER" (oxymorphone
`hydrochloride extended-release tablets, CII) (2010)
`Prescribing information highlights, "Opana®" (oxymorphone
`hydrochloride tablets, CII) (2013)
`Van Zee, A., "The Promotion and Marketing of OxyContin:
`Commercial Triumph, Public Health Tragedy," Am. J. Public Health
`99(2):221-227 (2009)
`Smith, H.S., "Opioid Metabolism," Mayo Clin. Proc. 84(7):613-624
`(2009)
`Curriculum vitae of Professor Diane J. Burgess, Ph.D.
`Declaration of Marv Kelly
`FDA's Orange Book listing for Palladone®
`Interaction,
`FDA Alert
`[7/2005]: Alcohol PALLADONE
`"Information
`for Healthcare Professionals: Hydromorphone
`Hydrochloride Extended–Release Capsules
`(marketed
`as
`Palladone)"
`Endo's "List of Extended-Release and Long-Acting Opioid
`Products"
`D.S. Craig, "Oxymorphone Extended-Release Tablets (Opana
`ER) For the Management of Chronic Pain," Pharm. & Ther. 35:324-
`57 (2010)
`T. Berner, et al., "A Comparison of Daily Average Consumption Of
`Oxycodone Controlled Release (OxyContin CR) and Oxymorphone
`Extended Release (Opana ER) In Patients with Low Back Pain,"
`Pharm. & Ther., 36:139-44 (2011)
`M. Rubino et al., "A Comparison of Daily Average
`Consumption (DACON) of Oxycodone and Oxymorphone
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`Inter Partes Review of USPN 8,329,216
`Declaration of Michael L. Weinberger, M.D.
`)
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`Exhibit or
`Paper No.
`
`Description
`
`2070
`2071
`2072
`2073
`
`2074
`2075
`2076
`2077
`2078
`2079
`
`2080
`2081
`
`2082
`
`Long-Acting Oral Tablets," J. Managed Care Pharm. 17:367-76
`(2011)
`Declaration of Prof. Diane J. Burgess, Ph.D.
`Curriculum vitae of Marv Kelly
`OPANA® ER sales from 2006 to September 30, 2014
`OPANA® ER sales by dosage strength from 2007 to September 30,
`2014
`IMS Health 12-month prescription audit presented April 2011
`Opana Situation Analysis
`Document entitled, "OPANA® ER Metrics"
`OPANA® ER Marketing Update
`Oxymorphone Situation Analysis
`OPANA® ER total prescriptions from 2006 to September 30,
`2014
`Long-acting opioid prescription trends
`Long-acting opioid total prescriptions by brand from March
`2009 to March 2010
`Number of commercially insured lives for which OPANA® ER
`is available
`
`V. Person of ordinary skill in the art
`I understand that a person of ordinary skill in the art ("POSA") is a
`17.
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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 of the
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`'216 patent, would typically have a Bachelor's or Master's degree in Pharmacy,
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`Chemistry or a related field with at least 5 years of experience with pharmaceutical
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`formulations including pharmaceutical testing. A POSA could have a Ph.D. in
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`Pharmaceutics, Chemistry or a related field with 2-3 years of experience with
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`pharmaceutical formulations including pharmaceutical testing. A POSA would
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`Inter Partes Review of USPN 8,329,216
`Declaration of Michael L. Weinberger, M.D.
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`typically have experience in the analytical characterization of drug formulations,
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`including in vitro dissolution testing of drug formulations. A POSA may work as
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`part of a multi-disciplinary team and draw upon not only his or her own skills, but
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`also take advantage of certain specialized skills of others in the team, to solve a
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`given problem. For example, a formulator, dissolution expert and/or a clinician
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`may be part of the team.
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`VI. Basis of my analysis with respect to obviousness, long-felt need, and
`commercial success
`I understand that an obviousness analysis involves comparing a patent
`18.
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`claim to the prior art to determine whether the claimed invention would have been
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`obvious to a person of ordinary skill in the art in view of the prior art, and in light
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`of the general knowledge in the art. I also understand when a person of ordinary
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`skill in the art would have reached the claimed invention through routine
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`experimentation, the invention may be deemed obvious. I also understand that
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`obviousness can be established by combining or modifying the teachings of the
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`prior art to achieve the claimed invention.
`
`19.
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`I understand that, in considering the obviousness of an invention, one
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`must also consider whether there are any objective indicia that support the non-
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`obviousness of the invention. I understand that two such objective indicia of non-
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`obviousness include long-felt, but unmet, need and commercial success.
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`Inter Partes Review of USPN 8,329,216
`Declaration of Michael L. Weinberger, M.D.
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`20.
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`I understand that a long-felt, but unmet, need may be evidence of non-
`
`obviousness when objective evidence shows (i) the need was a persistent need in
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`the prior art that was recognized by those of ordinary skill in the art; (ii) the need
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`was not satisfied by another before the invention claimed in the patent; and (iii) the
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`invention claimed in the patent satisfies the long-felt need. I also understand that
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`actual evidence of a long-felt need (e.g., evidence of the need recognized in the
`
`prior art) must be provided to prove the existence of the need, as opposed to mere
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`argument.
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`21.
`
`I understand that "commercial success" can be evidence of non-
`
`obviousness if there is proof that the commercial sales were a direct result of the
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`patented technology. I understand that commercial success arising from an
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`unclaimed feature of the invention is irrelevant for the purposes of a commercial
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`success analysis; and that commercial success arising from a feature of the
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`invention known in the prior art is not pertinent. I understand that if a product is
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`shown to be a commercial success, factors other than the patented technology must
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`be considered as possible causes for the commercial success, such as being the first
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`to enter the market and strong marketing/advertising efforts.
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`
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`- 12 -
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`

`

`
`Inter Partes Review of USPN 8,329,216
`Declaration of Michael L. Weinberger, M.D.
`
`
`
`
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`VII. Controlled-release opioids indicated for at least 12-hour dosing were
`known before July 6, 2001
`22. Before July 6, 2001, a POSA would have known of several opioid
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`formulations that provided (1) a controlled-release of the drug; (2) at least a 12-
`
`hour dosing regimen; and (3) long-term pain relief.
`
`23.
`
`I agree with Dr. Burgess that opioids are a class of analgesic
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`compounds, and that oxycodone, fentanyl, hydromorphone, hydrocodone, and
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`oxymorphone are types of opioid compounds. [Exhibit 2070, ¶ 20.] I also agree
`
`with Dr. Burgess that opioids can be prepared for oral administration as immediate
`
`release formulations or controlled-release (also known as extended-release)
`
`formulations. [Exhibit 2070, ¶¶ 21-22.] In addition to oral administration,
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`controlled-release opioid formulations can also be administered by transdermal
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`routes. [Exhibit 1071, at 5-6.] As of July 6, 2001, several different controlled-
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`release or "long-acting" opioid formulations were known in the art. Examples are
`
`discussed below.
`
`A. Controlled-release morphine sulfate provided a controlled-
`release opioid indicated for long-term pain relief
`
`24. Before July 6, 2001, controlled-release morphine sulfate formulations
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`were known in the art. For example, an oral, extended-release morphine sulfate
`
`formulation was first approved by the FDA in 1987 (MS Contin®, 30 mg; Purdue
`
`Pharma LP). [Exhibit 2056, at 28.] Additional oral dosage forms of MS Contin®
`
`
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`- 13 -
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`

`

`
`
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`were approved by the FDA in 1988 (60 mg), 1989 (15 mg), 1990 (100 mg), and
`
`
`Inter Partes Review of USPN 8,329,216
`Declaration of Michael L. Weinberger, M.D.
`
`
`1993 (200 mg). [Exhibit 2056, at 28-29.] MS Contin® is indicated for the
`
`treatment of pain by dosing every 12 hours. [Exhibit 1053, at 3-4.] A 1998 article
`
`by Warfield stated that controlled-release morphine tablets were considered routine
`
`therapy in pain management: "[c]ontrolled–release (CR) morphine tablets have
`
`become routine therapy in the management of cancer pain. Compared with short–
`
`acting, immediate–release (IR) morphine, CR morphine tablets provide the
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`advantage of dosing every 12 hours…." [Exhibit 1065, at 1 (emphasis added;
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`citations omitted).] Thus, before July 6, 2001, a POSA would have understood that
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`MS Contin® (1) provides a controlled-release opioid product; (2) is indicated for
`
`12-hour dosing; and (3) provides long-term pain relief.
`
`25. Other companies also developed oral controlled-release formulations
`
`of morphine sulfate before 2001. For example, a sustained-release morphine
`
`sulfate formulation known as Kadian® was approved by the FDA in 1996. [Exhibit
`
`2056, at 23.] Kadian® is indicated for the treatment of pain by dosing either every
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`12 hours or every 24 hours. [Exhibit 1055, at 3-5.] Thus, before July 6, 2001, a
`
`POSA would have understood that Kadian® (1) provides a controlled-release
`
`opioid product; (2) is indicated for at least 12-hour dosing; and (3) provides long-
`
`term pain relief.
`
`
`
`- 14 -
`
`

`

`
`
`
`
`
`Inter Partes Review of USPN 8,329,216
`Declaration of Michael L. Weinberger, M.D.
`
`
`26. Another oral, controlled-release morphine sulfate formulation known
`
`in the art before July 6, 2001 is Oramorph® SR tablets. Oramorph® SR is
`
`indicated for the treatment of pain by dosing every 12 hours. [Exhibit 1054, at 3-5.]
`
`Thus, before July 6, 2001, a POSA would have understood that Oramorph® SR (1)
`
`provides a controlled-release opioid product; (2) is indicated for 12-hour dosing;
`
`and (3) provides long-term pain relief.
`
`B. Controlled-release oxycodone provided a controlled-release
`opioid indicated for long-term pain relief
`
`27. An oral, controlled-release oxycodone formulation (Oxycontin®) was
`
`available and known in the art before July 6, 2001. [Exhibit 2070, ¶ 199.]
`
`Oxycontin® is a controlled-release opioid (oxycodone hydrochloride) tablet
`
`indicated for the treatment of pain by dosing every 12 hours. [Exhibit 1026, at 6.]
`
`28.
`
`In 1997, Hagen and Babul published a study comparing the clinical
`
`efficacy and safety of Oxycontin® with a controlled-release hydromorphone
`
`formulation. [Exhibit 1068.] At the conclusion of the publication, the authors
`
`stated, "the recently available controlled-release oxycodone formulation, with its
`
`biphasic absorption profile, is highly effective in the management of chronic
`
`severe cancer pain when administered every 12 hours." [Exhibit 1068, at 8
`
`(emphasis added).] Thus, before July 6, 2001, POSA would have understood that
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`
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`- 15 -
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`

`

`
`
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`Oxycontin® (1) provides a controlled-release opioid product; (2) is indicated for
`
`
`Inter Partes Review of USPN 8,329,216
`Declaration of Michael L. Weinberger, M.D. (
`)
`
`12-hour dosing; and (3) provides long-term pain relief.
`
`C. Controlled-release hydromorphone provided a controlled-
`release opioid indicated for long-term pain relief
`
`29. The Hagen and Babul article (Exhibit 1068) also shows that oral,
`
`controlled-release hydromorphone formulations were known in the art before July
`
`6, 2001. Here, the authors stated, "[t]he recent availability of controlled-release
`
`formulations of other opioids, such as hydromorphone, provides clinicians with
`
`therapeutic options for cancer pain management." [Exhibit 1068, at 2 (citations
`
`omitted; emphasis added).] The authors also stated, "the results of our study
`
`demonstrate that chronic severe cancer pain can be well controlled with a regular
`
`regimen of controlled-release oxycodone given every 12 hours and that the
`
`efficacy of this regimen is at least equal to that of controlled-release
`
`hydromorphone." [Exhibit 1068, at 7 (citations omitted; emphasis added).] Thus,
`
`before July 6, 2001, a POSA would have understood that a controlled-release
`
`hydromorphone formulations (1) provides a controlled-release opioid product; (2)
`
`is indicated for 12-hour dosing; and (3) provides long-term pain relief.
`
`D. Controlled-release fentanyl provided a controlled-release
`opioid indicated for long-term pain relief
`
`30. Before July 6, 2001, a transdermal, controlled-release formulation of
`
`
`
`- 16 -
`
`

`

`
`
`
`fentanyl was known in the art. Fentanyl is a "potent opioid analgesic." [Exhibit
`
`
`Inter Partes Review of USPN 8,329,216
`Declaration of Michael L. Weinberger, M.D.
`
`
`1056, at 2.] A transdermal fentanyl patch (Duragesic®; Janssen Pharms) was
`
`approved by the FDA in 1990. [Exhibit 2056, at 14.] Duragesic® patches are
`
`indicated for 72-hour dosing. [Exhibit 1056, at 2.] Thus, before July 6, 2001, a
`
`POSA would have understood that Duragesic® (1) provides a controlled-release
`
`opioid product; (2) is indicated for at least 12-hour dosing; and (3) provides long-
`
`term pain relief.
`
`31.
`
`In 1998, Payne et al. published a study comparing patient satisfaction
`
`and side effects during administration of Duragesic® or one of two oral sustained-
`
`release morphine sulfate formulations (MS Contin® or Oramorph SR®). [Exhibit
`
`1069, Abstract.] The authors reported that "there was greater satisfaction among
`
`transdermal fentanyl patients, as measured by significantly more willingness to
`
`continue the medication and a greater likelihood that the medication met their
`
`expectations." [Exhibit 1069, at 4.] Thus, before July 6, 2001, a POSA would have
`
`understood that transdermal fentanyl patches were another controlled-release
`
`opioid option for physicians in the field of pain medicine.
`
`E. Methadone provided a long-acting opioid indicated for long-
`term pain relief
`
`32. Before July 6, 2001, oral methadone formulations were known in the
`
`art. An oral formulation of methadone hydrochloride (Dolophine HCl®, 5 mg and
`
`
`
`- 17 -
`
`

`

`
`
`
`10 mg; Roxane) was approved by the FDA in 1982. [Exhibit 2056, at 12.] Similar
`
`
`Inter Partes Review of USPN 8,329,216
`Declaration of Michael L. Weinberger, M.D.
`
`
`to controlled-release opioids, methadone is administered in longer administration
`
`intervals – e.g., it is indicated for dosing every 8 to 12 hours. For example, the
`
`product label for Dolophine HCl® tablets states, "the usual oral methadone starting
`
`dose is 2.5 mg to 10 mg every 8 to 12 hours" in patients who are not already being
`
`treated with, and tolerant to, opioids. [Exhibit 1072, at