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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. IPR2014-003601
`_____________________
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`DECLARATION OF ANTHONY PALMIERI III, PH.D.
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`
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`1 Case IPR2014-01365 has been joined with this proceeding.
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`Inter Partes Review of USPN 8,329,216
`Declaration of Anthony Palmieri (Exhibit 1104)
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`
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`TABLE OF CONTENTS
`
`
`Introduction ..................................................................................................... 3
`I.
`List of Documents I Considered in Formulating My Opinion ....................... 4
`II.
`Inherent properties of oxymorphone .............................................................. 4
`III.
`IV. Claims 85 and 86 are not supported by an adequate written description ....... 9
`V.
`Claims 85 and 86 are not enabled ................................................................. 11
`VI. Claims 85 and 86 are indefinite .................................................................... 12
`VII. Oshlack and the Handbook Render Amended Claims 83 and 84 Obvious .. 12
`VIII. Conclusion .................................................................................................... 13
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`2
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`I.
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`Inter Partes Review of USPN 8,329,216
`Declaration of Anthony Palmieri (Exhibit 1104)
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`I, Anthony Palmieri III, Ph.D., hereby declare as follows.
`
`Introduction
`I am the same Anthony Palmieri who submitted a declaration dated
`1.
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`January 16, 2014 (“First Declaration;”) in IPR2014-00360 and a declaration dated
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`January 26, 2015 in IPR2014-01365 ("Second Declaration"), both of which were
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`filed along with a Petition for inter partes review of U.S. Patent 8,329,216 (“the
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`’216 patent”). I hereby incorporate the contents of my First and Second
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`Declarations into this Third Declaration. I understand that the ’216 patent is owned
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`by Endo Pharmaceuticals, Inc. (“Endo.”) I also understand that inter partes review
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`was instituted for some of the claims of the ’216 patent and that cases IPR2014-
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`00360 and IPR2014-01365 were joined into one proceeding.
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`2.
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`I detailed my background and qualifications in the declaration that I
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`submitted in connection with the Petition in this Review. (See First Declaration, ¶¶
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`4-13). As provided in my First Declaration, I am an expert in the field of
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`pharmaceutical
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`formulation,
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`including controlled
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`release pharmaceutical
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`formulation, and have been since before 2001.
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`3.
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`In preparing this Declaration, I have reviewed Endo's Supplemental
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`Contingent Motion to Amend ("Supplemental Motion") and the Declaration of Dr.
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`Dianne Burgess (“Burgess Dec.”, Ex. 2090) and considered each of the documents
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`I have cited herein, in light of general knowledge in the art. In formulating my
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`3
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`opinions, I have also considered the viewpoint of a person of ordinary skill in the
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`Inter Partes Review of USPN 8,329,216
`Declaration of Anthony Palmieri (Exhibit 1104)
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`art (“POSA”) (i.e., a person of ordinary skill in the art) prior to July 6, 2001. I
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`defined a POSA at ¶15 of my First Declaration and submit that my previous
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`definition is correct and not countered by anything in the Burgess Dec.
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`4.
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`Nothing in the Burgess Dec. or other materials I have reviewed
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`changes my opinions provided in my First and Second Declarations.
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`II.
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`List of Documents I Considered in Formulating My Opinion
`In formulating my opinion, I have considered the documents cited in
`5.
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`my First and Second Declarations along with the following documents:
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`Exhibit
`#
`1105
`
`2090
`
`
`Description
`
`Transcript of testimony of Dr. David Lee, Endo Pharamceuticals Inc.
`and Grünenthal GMBH, ,v. Teva Pharmaceuticals USA, Inc. and Barr
`Laboratories, Inc., No. 12-cv-8060-TGD, (S.D.N.Y. 2012) March 25,
`2015
`Supplemental Declaration of Prof. Diane J. Burgess, Ph.D.
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`III.
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`Inherent properties of oxymorphone
`As discussed in my First declaration, the claims of the '216 patent
`6.
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`recite properties inherent to all oxymorphone formulations, such as food effects,
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`multiple peaks in blood plasma profiles and the ratio of 6-OH oxymorphone to
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`oxymorphone in blood plasma. First Declaration, ¶¶84, 85 and 94. Since
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`submitting my First and Second declarations, I have become aware of the trial
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`4
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`testimony of Dr. David Lee, an inventor on the '216 patent (AMN 1105.) Dr. Lee's
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`Inter Partes Review of USPN 8,329,216
`Declaration of Anthony Palmieri (Exhibit 1104)
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`testimony supports statements made in my First Declaration regarding the inherent
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`properties of oxymorphone.
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`7.
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`In my First Declaration at ¶94, I discussed that the food effect
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`properties of oxymorphone were inherent to the oxymorphone drug molecule itself
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`and not to a specific formulation. For example, claim 38 recites "wherein the
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`oxymorphone Cmax is at least 50% higher when the dosage form is administered to
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`the subject under fed versus fasted conditions." Dr. Lee's testimony supports my
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`conclusions that food effects are inherent to all oxymorphone formulations. Dr.
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`Lee stated during trial:
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`Q. My point is -- I'm trying to ask a different question
`and I didn't do a great job. The bioavailability of the drug
`depends mostly on that drug itself. So what I mean is,
`when you gave people the oxymorphone solution and
`measured the bioavailability, you were measuring the
`bioavailability of the oxymorphone itself, unencumbered
`by things that might interfere, right?
`
`A. That's correct, yes.
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`Q. Now, it was not a goal of your development project on
`Opana ER
`to
`increase
`the bioavailability of
`oxymorphone, correct?
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`5
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`Inter Partes Review of USPN 8,329,216
`Declaration of Anthony Palmieri (Exhibit 1104)
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`A. I think we would have liked to, but I don't think that
`was possible.
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`Q. … You didn't increase the bioavailability of the
`oxymorphone, correct?
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`A. That's correct.
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`…
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`Q. OK. So let me make it clear. So plain old immediate-
`release tablets of oxymorphone result in faster absorption
`if the patient has eaten a high-fat meal, as compared to
`taken on an empty stomach. Right?
`
`A. I'm not sure it's faster absorption, actually. So the
`classical concentration, the peak classical concentration
`may be higher in the presence of a high-fat meal, and the
`total amount absorbed over time may be a little higher.
`But I'm not sure that it gets in more rapidly. I may be
`wrong.
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`Q. OK. I may be wrong also. If so I stand corrected. So
`let me just ask. So what you found is that one of the
`characteristics of the drug oxymorphone is there was
`greater bioavailability on a high-fat meal as compared
`to an empty stomach. Right?
`
`A. That's correct, yes.
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`Q. And, again, that's not something that you invented.
`That was always a characteristic of oxymorphone. True?
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`6
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`Inter Partes Review of USPN 8,329,216
`Declaration of Anthony Palmieri (Exhibit 1104)
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`A. That is an inherent characteristic of oxymorphone.
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`(AMN 1105, p. 297, line 4 – p. 299, line 10, emphasis added.) Dr. Lee's statements
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`that the food effects claimed in the '216 patent are inherent to oxymorphone are
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`consistent with my statements in my First Declaration.
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`8.
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`In my First Declaration at ¶85, I discussed that the ratio of AUC(0 to inf)
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`for 6-OH oxymorphone compared to oxymorphone recited in the claims of the
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`'216 is an inherent property of all oxymorphone compositions. Dr. Lee's testimony
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`supports my conclusions that the ratio for 6-OH oxymorphone compared to
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`oxymorphone is inherent to all oxymorphone formulations. Dr. Lee stated during
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`trial:
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`Q. But oxymorphone is metabolized by the body into 6-
`hydroxy, which is an active metabolite, which itself
`contributes to the pain relief of the drug, right?
`
`A. That's correct.
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`Q. OK. And you did not design Opana ER to achieve
`any particular relationship between the parent
`compound and the metabolite, correct?
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`A. I don't think -- I'm not sure how that would have
`been possible, so, yes, that's correct.
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`(AMN 1105, p. 302, lines 10 – 18, emphasis added.) Dr. Lee's statements that the
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`ratio of AUC(0 to inf) for 6-OH oxymorphone compared to oxymorphone is inherent
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`to oxymorphone are consistent with my statements in my First Declaration.
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`7
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`Inter Partes Review of USPN 8,329,216
`Declaration of Anthony Palmieri (Exhibit 1104)
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`9.
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`In my First Declaration at ¶84, I discussed that presence of 2 or 3
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`blood plasma peaks after administration of any oxymorphone formulation is an
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`inherent property of all oxymorphone compositions. Dr. Lee's testimony supports
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`my conclusions that multiple oxymorphone peaks are inherent to all oxymorphone
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`formulations. Dr. Lee stated during trial:
`
`Q. Thank you. Now, you also observed, when you were
`doing the pharmacokinetic studies, that immediate-
`release oxymorphone, when measured in the plasma, had
`a second peak, right?
`
`A. Right.
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`Q. And that's not something that you invented. Right?
`
`A. That is not something we invented, no.
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`Q. And you didn't design for that in Opana ER, true?
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`A. That's true.
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`Q. That's also an inherent property of the way the
`body metabolizes oxymorphone. Correct?
`
`A. Most likely correct, yes.
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`(AMN 1105, p. 302, line 19 – p. 303, line 4, emphasis added.) Dr. Lee's statements
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`that the multiple peaks claimed in the '216 patent are inherent to oxymorphone are
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`consistent with my statements in my First Declaration.
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`8
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`IV. Claims 85 and 86 are not supported by an adequate written description
`I understand that Endo argues in its Supplemental Motion that there is
`10.
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`Inter Partes Review of USPN 8,329,216
`Declaration of Anthony Palmieri (Exhibit 1104)
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`written description in the specification of the '216 patent and its priority
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`documents for its proposed new claims 85 and 86, as shown on page 1 of the
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`Supplemental Motion. Both claims 85 and 86 depend from claim 43, which
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`depends from claim 38.
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`11. As discussed in ¶¶ 22-29 of my Second Declaration, there is no
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`written description support in the '216 patent for 12-hour dosage forms. As both
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`proposed claims 85 and 86 recite 12-hour dosage forms, there is no written
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`description support for claims 85 and 86 for the same reasons I discussed in my
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`Second Declaration. As discussed in ¶22 of my Second Declaration, the claims of
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`the '216 patent define a genus of formulations fitting in a particular dissolution
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`profile. The specification of the '216 patent contains a disclosure of three specific
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`embodiments, with no disclosure regarding the analgesic effectiveness of any
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`embodiment. And the '216 patent does not disclose sufficient species within this
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`genus to show a POSA that the inventors possessed the full scope of each claimed
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`genus. Further, the hydrophilic materials listed in proposed claim 86 are cellulose
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`derivatives. None of the embodiments in the '216 patent mentioned above are
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`formulations containing a cellulose derivative of any type, let alone the cellulose
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`derivatives recited in claim 86.
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`9
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`Inter Partes Review of USPN 8,329,216
`Declaration of Anthony Palmieri (Exhibit 1104)
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`12. As discussed in ¶ 13 of my Second Declaration, I understand that, in
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`evaluating the adequacy of the disclosure in describing the genus, courts look to
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`certain factors including the predictability of the aspect at issue. I now understand
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`that trial testimony of inventor Dr. David Lee supports my conclusion that the '216
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`patent does not disclose sufficient information about the analgesic effectiveness of
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`the oxymorphone compounds recited in the claims. Dr. Lee's testimony shows that
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`a POSA would not have been able to predict whether a formulation falling within
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`the scope of claims 85 and 86 would have analgesic efficacy for 12 hours. Dr. Lee
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`stated during trial:
`
`Q. And you testified earlier to the effect that you did not
`know if the formulations that you brought into the
`clinical trials would be effective for 12-hour pain relief
`until you got the results of the clinical trials. Right?
`
`A. That's correct.
`
`…
`
`Q. Let me ask again. The patent claim, Dr. Lee, has at the
`low end a product that dissolves only 15 percent at one
`hour. Right?
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`A. That's correct.
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`Q. And at the low end, that dissolves only 45 percent at
`four hours. Right?
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`A. That's correct.
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`10
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`Inter Partes Review of USPN 8,329,216
`Declaration of Anthony Palmieri (Exhibit 1104)
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`Q. And at the low end, that dissolves only 80 percent at
`ten hours, right?
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`A. That's correct.
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`Q. That's a slower dissolution than the product in your
`clinical trials. Right?
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`A. That is indeed a slower dissolution, yes.
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`Q. And you had no idea if that product would give
`effective pain relief for 12 hours, true?
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`A. Or any pain relief for that matter.
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`(AMN 1105, p. 305, line 21 – p. 306, line 20, emphasis added.) Thus, Dr. Lee's
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`trial testimony confirms that the embodiments provided in the specification of the
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`'216 patent would not have allowed a POSA to predict whether the oxymorphone
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`compositions having dissolution profiles within the ranges recited in claim 38
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`would be analgesically effective for 12 hours.
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`V.
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`Claims 85 and 86 are not enabled
`13. As discussed in ¶¶ 30-35 of my Second Declaration, the claims of the
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`'216 patent are not enabled as to the requirement of providing sustained pain
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`relief, i.e., analgesic effectiveness, for approximately 12 hours. As both proposed
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`claims 85 and 86 recite 12-hour dosage forms, the specification of the ’216 patent
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`does not provide a sufficient number of species to enable a POSA to practice the
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`11
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`Inter Partes Review of USPN 8,329,216
`Declaration of Anthony Palmieri (Exhibit 1104)
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`full scope of proposed claims 85 and 86 without undue experimentation for the
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`same reasons I discussed in my Second Declaration.
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`VI. Claims 85 and 86 are indefinite
`14. Endo construes a 12-hour dosage form as providing pain relief for
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`“approximately 12 hours.” (Supplemental Motion, 3-4.) As discussed in ¶¶ 36-37
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`of my Second Declaration, a POSA would not know from the disclosures of the
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`'216 patent specification what period of time is encompassed by the term
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`“approximately 12 hours.” As both proposed claims 85 and 86 recite 12-hour
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`dosage forms, a POSA could not determine with reasonable certainty the scope of
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`claims 85 and 86 in order to avoid infringement for the same reasons I discussed
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`in my Second Declaration.
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`VII. Oshlack and the Handbook Render Amended Claims 83 and 84 Obvious
`15. As discussed in ¶¶ 38-46 of my Second Declaration, Oshlack (U.S.
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`Patent No. 5,958,452; AMN 1007) teaches 12-hour dosage forms, and claims
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`reciting a 12-hour dosage form would have been obvious to a POSA over the
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`combination of Oshlack and the Handbook of Dissolution ("the Handbook"; AMN
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`1008). There is nothing additional in proposed claims 85 and 86 that a POSA
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`would not have found obvious over the combination of Oshlack and the
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`Handbook. The controlled release excipients recited in claims 85 and 86 are
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`12
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`Inter Partes Review of USPN 8,329,216
`Declaration of Anthony Palmieri (Exhibit 1104)
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`disclosed as controlled release excipients in Oshlack, for example, the cellulose
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`derivative hydroxypropylmethyl cellulose. AMN 1007, 5:27-31; 7:35-39; 8:62-65.
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`VIII. Conclusion
`In summary, proposed amended claims 85 and 86 are unpatentable in
`16.
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`view of the prior art for the reasons provided in my Second Declaration and the
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`additional reasons provided above.
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`17.
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`I hereby declare that all statements made herein of my own
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`knowledge are true and that all statements made on information and belief are
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`believed to be true, and further that these statements were made with the
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`knowledge that willful false statements and the like so made are punishable by fine
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`or imprisonment, or both, under Section 1001 of Title 18 of the United States
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`Code.
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`Respectfully submitted,
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`
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`Anthony Palmieri III, Ph.D.
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`Date: April 1, 2015
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`13
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