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`IN THE 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 to Kao et al.
`Issue Date: December 11, 2012
`Title: Oxymorphone Controlled Release Formulations
`
`_____________________
`
`Inter Partes Review No. Unassigned
`_____________________
`
`Petition for Inter Partes Review of U.S. Patent No. 8,329,216 Under 35 U.S.C.
`§§ 311-319 and 37 C.F.R. §§ 42.1-.80, 42.100-.123
`
`
`
`
`
`Mail Stop "PATENT BOARD"
`Patent Trial and Appeal Board
`U.S. Patent and Trademark Office
`P.O. Box 1450
`Alexandria, VA 22313-1450
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`

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`Petition for Inter Partes Review of USPN 8,329,216
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`
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`TABLE OF CONTENTS
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`INTRODUCTION .......................................................................................... 1 
`I. 
`II.  OVERVIEW ................................................................................................... 1 
`III.  STANDING (37 C.F.R. § 42.104(a)); PROCEDURAL STATEMENTS ..... 2 
`IV.  MANDATORY NOTICES (37 C.F.R. § 42.8(a)(1)) ..................................... 3 
`STATEMENT OF THE PRECISE RELIEF REQUESTED AND THE
`V. 
`REASONS THEREFOR (37 C.F.R. § 42.22(a)) ...................................................... 4 
`VI.  CLAIM CONSTRUCTION ........................................................................... 4 
`VII.  PERSON OF SKILL IN THE ART & STATE OF THE ART ...................... 5 
`VIII.  IDENTIFICATION OF CHALLENGE (37 C.F.R. § 42.104(b)) .................. 7 
`Ground 1: Claims 5, 16, 44, 46 and 47 Would Have
`1. 
`Been Obvious Over Oshlack and The Handbook of
`Dissolution Testing .................................................................... 7 
`Ground 2: Claims 72-82 Would Have Been Obvious
`Over Oshlack, the Handbook and Pharmaceutical
`Excipients ................................................................................. 24 
`Ground 3: Claims 72-82 Would Have Been Obvious
`Over Baichwal '757, The Penwest Statement,
`Baichwal '933 and Gordon ....................................................... 37 
`IX.  OBJECTIVE INDICIA OF NONOBVIOUSNESS ..................................... 51 
`X. 
`CONCLUSION ............................................................................................. 54 
`CERTIFICATION OF SERVICE (37 C.F.R. §§ 42.6(e), 42.105(a)) .................... 56 
`
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`2. 
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`3. 
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`I.
`
`
`Petition for Inter Partes Review of USPN 8,329,216
`
`
`
`INTRODUCTION
`AMNEAL PHARMACEUTICALS, LLC and AMNEAL PHARMACEUTICALS OF NEW
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`YORK petition for Inter Partes Review, seeking cancellation of claims 5, 16, 44,
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`46, 47 and 72-82 of U.S. Patent No 8,329,216 to Kao et al. ("the '216 patent")
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`(AMN 1001), which is owned by ENDO PHARMACEUTICALS INC.
`
`II. OVERVIEW
`The challenged claims of the '216 patent are not patentable. They are drawn
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`to simple controlled release compositions of oxymorphone (or methods of using
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`such compositions) and recite broad in vitro release and/or broad pharmacokinetic
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`limitations. Neither the compositions nor these performance characteristics are
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`novel or would have been nonobvious. Because Petitioner is, at a minimum,
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`reasonably likely to prevail in showing unpatentability, this Petition should be
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`granted and trial instituted on all of the challenged claims.
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`There will be no dispute that oxymorphone is an opioid drug that was known
`
`in the art more than thirty years before the earliest possible priority date ("EPD") of
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`the '216 patent and that controlled release opioid formulations were also known in
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`the art, including controlled release oxymorphone formulations. Endo alleges its
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`invention lies in the recited in vitro dissolution profiles. But the claims encompass
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`an expansive range of potential formulations and dissolution profiles that are
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`taught in the prior art. None of the other recited limitations, alone or together,
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`impart patentability to the challenged claims because they too are found in the
`
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`Petition for Inter Partes Review of USPN 8,329,216
`
`
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`prior art.
`
`As shown here, the cited art teaches or suggests the in vitro dissolution
`
`profiles recited in the claims of the '216 patent. In addition, oxymorphone
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`controlled release compositions having the claimed in vitro dissolution profiles
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`also necessarily exhibit the in vivo blood profiles recited in the claims –the '216
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`patent itself acknowledges that relationship.
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`This petition is submitted with a Motion for Joinder within one month of the
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`institution of trial to join the proposed Grounds with those instituted in IPR2014-
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`00360. The current petition challenges claims 44 and 47, which were asserted after
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`petitioner filed the petition in IPR2014-00360, along with additional similar
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`claims. The current petition also provides
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`information showing
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`that
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`the
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`concentration of about 10% to about 75% gelling agent recited in claims 72-82 was
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`well known in the art and does not impart patentability to these claims.
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`Petitioner is at least reasonably likely to prevail in showing obviousness over
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`the prior art. Inter partes review of the '216 patent should be instituted.
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`III. STANDING (37 C.F.R. § 42.104(a)); PROCEDURAL STATEMENTS
`Petitioner certifies that (1) the '216 patent is available for IPR and (2) if the
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`PTAB grants the accompanying motion for joinder, Petitioner is not barred or
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`estopped from requesting IPR of any claim of the '216 patent. This Petition is filed
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`in accordance with 37 CFR § 42.106(a). Concurrently filed herewith is a Power of
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`Petition for Inter Partes Review of USPN 8,329,216
`
`
`
`Attorney
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`and
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`an
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`Exhibit
`
`List
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`per
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`§
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`42.10(b)
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`and
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`§ 42.63(e), respectively. The required fee is paid via online credit card payment.
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`The Office is authorized to charge fee deficiencies and credit overpayments to
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`Deposit Acct. No. 19-0036 (Customer ID No. 45324).
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`IV. MANDATORY NOTICES (37 C.F.R. § 42.8(a)(1))
`Real Party-In-Interest
`(37 C.F.R. § 42.8(b)(1))
`
`is: AMNEAL
`
`PHARMACEUTICALS, LLC AND AMNEAL PHARMACEUTICALS OF NEW YORK.
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`Notice of Related Matters (37 C.F.R. § 42.8(b)(2)):
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`Judicial matters: (1) Endo Pharmaceuticals Inc. and Grunenthal GMBH v.
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`Amneal Pharmaceuticals, LLC and Amneal Pharmaceuticals of New York, C.A.
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`No. 12-CIV-8115 (S.D.N.Y.). Administrative matters: (1) A Petition for IPR of the
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`'216 patent was granted in part for claims 1, 2, 6, 12-14, 17, 21-43, 43-51, and 54-
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`71 in IPR2014-00360. (2) Petitioner also filed IPR 2014-00160, which is pending,
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`against U.S. Patent No. 7,851,482 on November 18, 2013, against the same Patent
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`Owner.
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`Designation of Counsel (37 C.F.R. § 42.8(b)(3)):
`
`Lead Counsel
`Eldora L. Ellison (Reg. No. 39,967)
`STERNE, KESSLER, GOLDSTEIN & FOX
`P.L.L.C.
`1100 New York Avenue, NW
`
`Back-Up Counsel
`Dennies Varughese (Reg. No. 61,868)
`STERNE, KESSLER, GOLDSTEIN & FOX
`P.L.L.C.
`1100 New York Avenue, NW
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`Petition for Inter Partes Review of USPN 8,329,216
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`
`
`Back-Up Counsel
`Lead Counsel
`Washington, DC 20005
`Washington, DC 20005
`202.772.8805 (telephone)
`202.772.8508 (telephone)
`202.371.2540 (facsimile)
`202.371.2540 (facsimile)
`dvarughe-PTAB@skgf.com
`eellison-PTAB@skgf.com
`Notice of Service Information (37 C.F.R. § 42.8(b)(4)): Please direct all
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`correspondence regarding this Petition to lead counsel at the above address.
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`Petitioner consents to service by email at: eellison-PTAB@skgf.com and
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`dvarughe-PTAB@skgf.com.
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`V.
`
`STATEMENT OF THE PRECISE RELIEF REQUESTED AND THE
`REASONS THEREFOR (37 C.F.R. § 42.22(a))
`Petitioner requests IPR and cancellation of claims 5, 16, 44, 46, 47 and 72-
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`82 of the '216 patent. Petitioner's full statement of the reasons for the relief
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`requested is set forth in detail in § VIII.
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`VI. CLAIM CONSTRUCTION
`In accordance with 37 C.F.R. § 42.100(b), the challenged claims must be
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`given their broadest reasonable interpretations in light of the specification of the
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`'216 patent.
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`The term "controlled release" is defined in the patent as encompassing "any
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`formulations which release no more than about 80% of their active pharmaceutical
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`ingredients within 60 minutes" under the claimed dissolution conditions. (AMN
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`1001, 3:31-33.)
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`The term "about" as it relates to the percent by weight of oxymorphone
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`released in dissolution testing should be construed to encompass at least the
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`Petition for Inter Partes Review of USPN 8,329,216
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`
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`standard statistical error for such dissolution testing values. The '216 patent states
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`that "[r]eference to mean values reported herein for studies actually conducted are
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`arrived at using standard statistical methods as would be employed by one skilled
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`in the art of pharmaceutical formulation and testing for regulatory approval."
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`(AMN 1001, 3:67 – 4:4.) The United States Pharmacopeia ("USP") 24 states "the
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`use of the word "about" indicates a quantity within 10% of the specified weight or
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`volume." (AMN 1005, 8.) As a POSA would have understood that the standard use
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`of "about" for dissolution testing is a quantity within 10% of the measured value, a
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`POSA would have understood the term "about" as it is used in the context of the
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`percent by weight of oxymorphone released in dissolution testing to encompass
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`values of ± 10% of the value measured, e.g. approximately 72% to approximately
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`88% for a measured value of 80%. (AMN 1003, ¶24.)
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`The remaining terms in the challenged claims are plain on their face and
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`should be construed to have their ordinary and customary meanings.
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`VII. PERSON OF SKILL IN THE ART & STATE OF THE ART
`A POSA is a hypothetical person presumed to be aware of all pertinent art,
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`thinks along conventional wisdom in the art, and is a person of ordinary creativity.
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`A POSA in pharmaceutical testing as of July 6, 2001, the EPD of the '216 patent,
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`would typically have a Bachelors or Master's degree in Pharmacy, Chemistry or a
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`related field with at least 5 years of experience with pharmaceutical formulations
`
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`Petition for Inter Partes Review of USPN 8,329,216
`
`
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`including pharmaceutical testing. A POSA could have a Ph.D. in Pharmaceutics,
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`Chemistry or a related field with 2-3 years of experience with pharmaceutical
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`formulations including pharmaceutical testing. A POSA would typically have
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`experience in the analytical characterization of drug formulations, including in
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`vitro dissolution testing of drug formulations. A POSA may work as part of a
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`multi-disciplinary team and draw upon not only his or her own skills, but also take
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`advantage of certain specialized skills of others in the team, to solve a given
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`problem. For example, a formulator, dissolution expert and a clinician may be part
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`of the team.
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`Oxymorphone is a well-known opioid analgesic that was developed in the
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`early 1900s and was patented in the U.S. in 1957 (See U.S. Patent 2,806,033;
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`AMN 1018.) By 2001, various opioids, such as oxymorphone, oxycodone,
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`morphine and hydromorphone, were used to provide pain relief in patients and
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`their strengths relative to one another had been well-characterized. (AMN 1011.) It
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`was recognized well before 2001 that it could be useful to switch one opioid for
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`another in the treatment of pain in a patient. For example, Gordon et al., ("Opioid
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`Equianalgesic Calculations," Journal of Palliative Medicine, 2(2):209-218) states
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`"[c]linicians may need to switch opioids to improve pain control, reduce opioid
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`toxicity or side effects, provide a more convenient treatment regimen for the
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`patient, or to reduce the invasiveness of therapy." (AMN 1011, p. 211, col. 1, ¶1.)
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`Petition for Inter Partes Review of USPN 8,329,216
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`Thus, it was known well before 2001 that one opioid may be substituted for
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`another, and the art provided extensive guidance for making such substitutions.
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`(AMN 1003, ¶26.) And, as shown in the grounds below, formulation of opioids,
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`including oxymorphone, for controlled release was also known well before 2001.
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`(AMN 1003, ¶¶27-30.)
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`VIII. IDENTIFICATION OF CHALLENGE (37 C.F.R. § 42.104(b))
`Amneal requests inter partes review of the challenged claims of the '216
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`patent on the grounds for unpatentability listed in the index below. Per 37 C.F.R. §
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`42.6(d), copies of the references are filed herewith. In support of the proposed
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`grounds for unpatentability, this Petition is accompanied by a declaration from
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`technical expert Dr. Anthony Palmieri (AMN 1003), which explains what the art
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`would have conveyed to a POSA.
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`Index of References
`Oshlack and The Handbook of Dissolution
`Testing
`Oshlack, The Handbook of Dissolution
`Testing and The Handbook of
`Pharmaceutical Excipients
`Baichwal '757, The Penwest Statement,
`Baichwal '933 and Gordon
`1. Ground 1: Claims 5, 16, 44, 46 and 47 Would Have Been
`Obvious Over Oshlack and The Handbook of Dissolution
`Testing
`U.S. Patent No. 5,958,452 to Oshlack et al. (AMN 1007) was issued on
`
`'122 Patent Claims
`5, 16, 44, 46 and 47
`
`72-82
`
`72-82
`
`Ground
`1
`
`2
`
`3
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`September 28, 1999. "The Handbook of Dissolution Testing," 2nd ed. ("the
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`Petition for Inter Partes Review of USPN 8,329,216
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`
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`Handbook"; AMN 1008), was published in 1991. Both Oshlack and the
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`Handbook are § 102(b) prior art to the '216 patent.
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`A POSA would have had a reason to combine the teachings of Oshlack
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`and the Handbook. As discussed below, Oshlack discloses controlled release
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`oxymorphone formulations and discloses testing those formulations using in vitro
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`dissolution methods. (AMN 1007, 6:23-25, 7:35-39, 26:39-43.) The Handbook is a
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`well-known general reference consulted when performing dissolution testing.
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`(AMN 1003, ¶53.) A POSA would have looked to the teachings of the Handbook,
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`a main general reference in the field of dissolution testing, for further specifics on
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`the dissolution tests provided in Oshlack. (AMN 1003, ¶53.)
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`Independent claims 1, 13 and 38 are not challenged in this Petition, but
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`intervening claim 43 and challenged claims 5, 16, 44, 46 and 47 each depend from
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`one of these claims. As the dependent claims include the limitations of the claims
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`from which they depend, an analysis of these base claims is provided to show how
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`the challenged dependent claims would have been obvious over Oshlack and the
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`Handbook. The Board has already instituted trial for claims 1, 13, 38 and 43 as
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`obvious over Oshlack and the Handbook in related proceeding IPR2014-00360.
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`(Institution Decision in IPR2014-00360 at 14-20.)
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`As illustrated in the claim chart and discussion below, claims 5, 16, 44, 46
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`and 47 would have been obvious over the teachings of Oshlack and the Handbook.
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`Petition for Inter Partes Review of USPN 8,329,216
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`Oshlack discloses a controlled release oxymorphone composition comprising the
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`excipient HPMC. (AMN 1007, 5:27-31; 7:35-39; 8:62-65.) It also discloses in vitro
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`dissolution profiles that overlap with the profiles recited by the claims of the '216
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`patent. As discussed below, a POSA would have had a reason to produce the
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`subject matter of claims 5, 16, 44, 46 and 47 from the teachings of Oshlack and the
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`Handbook and would have had a reasonable expectation of success in doing so.
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`Independent claims 1, 13 and 38:
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`Claims and Limitation(s)1
`1, 13, 38: Comprising
`oxymorphone
`
`1, 13: "comprising a
`hydrophilic material";
`38: "controlled release delivery
`system";
`
`
`Oshlack and the Handbook
`Oshlack: "10. The formulation of claim 7
`wherein said therapeutically active agent is an
`opioid analgesic selected from the group
`consisting of … oxycodone, oxymorphone,
`….." AMN 1007, 26:34-38.
`
`Oshlack: "Specifically, the hydrophobic fusible
`carrier may comprise … hydrophobic and
`hydrophilic polymers having hydrocarbon
`backbones." AMN 1007, 9:16-23.
`"The present invention relates to the use of melt
`extrusion technology in the production of
`bioavailable sustained-release matrix
`pharmaceutical formulations." AMN 1007,
`1:10-12.
`
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`1 Any limitations not specifically addressed here are disclosed in Oshlack or the
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`Handbook as discussed below.
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`Claims and Limitation(s)1
`
`1, 38: "about 5 to about 80 mg
`oxymorphone"
`
`
`1: " the duration of the
`analgesic effect is through at
`least about 12 hours after
`administration"
`38: "at least 12 hours to provide
`sustained pain relief over this
`same period"
`38: "method for treating pain"
`
`13, 38: "wherein upon
`placement of the tablet in an in
`vitro dissolution test
`comprising USP Paddle
`Method at 50 rpm in 500 ml
`media having a pH of 1.2 to 6.8
`at 37o C, about 15% to about
`50%, by weight, of the
`oxymorphone or salt thereof is
`
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`Petition for Inter Partes Review of USPN 8,329,216
`
`
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`Oshlack and the Handbook
` "The pharmaceutical extrudates of the present
`invention may be prepared by blending the
`drug together with all matrix ingredients
`(hydrophobic material, binder and any additional
`(optional) excipients)…." AMN 1007, 4:39-43.
`"In addition to the above ingredients, a
`sustained-release matrix incorporating melt-
`extruded multiparticulates may also contain
`suitable quantities of other materials, … in
`amounts up to about 50% by weight of the
`particulate if desired." AMN 1007, 9:46-52.
`Oshlack: "In one preferred embodiment the
`sustained-release opioid oral dosage form of the
`present invention includes … in an amount from
`about 4 to about 64 mg hydromorophone
`hydrochloride…. include from about 5 mg to
`about 400 mg oxycodone." AMN 1007, 7:40-56.
`Oshlack: "The terms 'sustained release',
`'extended duration,' and 'controlled release' are
`defined for purposes of the present invention as
`the release of the drug (e.g., opioid analgesic) at
`such a rate the blood (e.g., plasma) levels are
`maintained within the therapeutic range but
`below toxic levels over a period of time greater
`than 8 hours, more preferably for about 12 to
`about 24 hours, or longer." AMN 1007, 5:25-
`32.
`Oshlack: "11. The formulation of claim 10,
`which provides an in-vitro release when assessed
`by the USP Paddle or Basket Method at 100
`prm [sic] at 900 ml aqueous buffer (pH between
`1.6 and 7.2) at 37° C from about 1 to about
`42.5% opioid release after one hour…." AMN
`1007, 26:39-43.
`The Handbook: "Stirring rate (rpm). As
`specified in individual monographs – but for
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`Claims and Limitation(s)1
`released from the tablet at about
`1 hour in the test."
`
`38: "about 45% to about 80%,
`by weight, of the oxymorphone
`or salt thereof is released from
`the tablet at about 4 hours in the
`test, and
`at least about 80%, by weight,
`of the oxymorphone or salt
`thereof is released from the
`tablet at about 10 hours in the
`test
`
`13: "granules"; "tablet"
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`Petition for Inter Partes Review of USPN 8,329,216
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`Oshlack and the Handbook
`general purposes when not otherwise specified –
`rates of 50 rpm for the paddle and 100 rpm for
`the basket are recommended and have proved to
`be roughly equivalent to one another in
`producing dissolution." AMN 1008, p. 35, ¶5.
`Oshlack: "11. The formulation of claim 10,
`which provides an in-vitro release when assessed
`by the USP Paddle or Basket Method at 100
`prm [sic] at 900 ml aqueous buffer (pH between
`1.6 and 7.2) at 37° C …. from about 15 to about
`85% opioid released after 4 hours, …. from
`about 20 to about 90% opioid released after 6
`hours, from about 35 to about 95% opioid
`released after 12 hours…." AMN 1007, 26:39-
`47.
`The Handbook: "[F]or general purposes when
`not otherwise specified – rates of 50 rpm for the
`paddle and 100 rpm for the basket are
`recommended and have proved to be roughly
`equivalent to one another in producing
`dissolution." AMN 1008, p. 35, ¶5.
`Oshlack: "The melt extruded multiparticulate
`system can be, for example, in the form of
`granules…." AMN 1007, 10:28-29.
`"The unit dose of multiparticulates may then be
`incorporated into tablets." AMN 1007 4:34-36.
`
`Intervening claim 43 and challenged claims 5, 13, 44, 46 and 47:
`
`Claim
`43. The method of claim 38 wherein
`the system further comprises a
`hydrophilic material.
`44. The method of claim 43 wherein
`the hydrophilic material is selected
`from the group consisting of a gum,
`
`Oshlack and The Handbook
`(See discussion of claim 38)
`Oshlack: "Specifically, the hydrophobic
`fusible carrier may comprise …
`hydrophobic and hydrophilic polymers
`having hydrocarbon backbones." AMN
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`a cellulose ether, an acrylic resin, a
`protein-derived
`material,
`and
`mixtures thereof.
`47. The method of claim 43 wherein
`the hydrophilic material is selected
`from the group consisting of …
`hydroxypropyl
`methylcellulose,
`carboxymethylcellulose,
`and
`mixtures thereof.
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`Petition for Inter Partes Review of USPN 8,329,216
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`
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`1007, 9:16-23.
`Oshlack: "In other embodiments, the
`hydrophobic material is selected from
`materials such as hydroxyalkylcelluloses
`such as hydroxypropylmethylcellulose
`[HPMC]…." AMN 1007, 8:62-65.
`
`
`
`
`Claim limitations
`5, 16, 46: wherein
`the
`a
`hydrophilic material
`is
`cellulose ether selected from
`the group consisting of a
`hydroxyalkyl
`cellulose,
`a
`carboxyalkyl cellulose, and
`mixtures thereof.
`
`
`Oshlack and The Handbook
`(See discussion of claims 1, 13 and 43)
`Oshlack: "In other embodiments, the
`hydrophobic material is selected from materials
`such as hydroxyalkylcelluloses such as
`hydroxypropylmethylcellulose [HPMC]…."
`AMN 1007, 8:62-65.
`
`
`As shown herein, a POSA would have had a reason to combine the
`
`disclosures of Oshlack and the Handbook and would have had a reasonable
`
`expectation of success in arriving at the subject matter of each of claims 5, 16, 44,
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`46 and 47 in making this combination. (AMN 1003, ¶53.) As the Board recognized
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`when it instituted trial on claims 1, 13, 38, and 43, Oshlack and the Handbook
`
`disclose the following limitations found in claims 5, 16, 44, 46, and 74: hydrophilic
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`material, dosage, 6-OH, one-hour, four and ten dissolution, food effect, and
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`method of treating pain. IPR2014-00360. (Institution Decision in IPR2014-00360
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`at 14-20.)
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`Petition for Inter Partes Review of USPN 8,329,216
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`Hydrophilic Material Limitations (claims 1, 5, 13, 43, 44, 46 and 47):
`
`Independent claims 1 and 13 each require the presence of a hydrophilic material.
`
`Claim 43 depends from claim 38 and requires a hydrophilic material. Claim 44
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`depends from claim 43 and recites that the hydrophilic material is selected from a
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`group including a cellulose ether. Claims 5, 16 and 46 depend from claims 1, 13
`
`and 43, respectively, and recite that the hydrophilic material is selected from a
`
`group including a hydroxyalkyl cellulose. Claim 47 depends from claim 43 and
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`recites that the hydrophilic material is selected from a group including
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`hydroxypropyl methylcellulose (HPMC). As the Board has previously recognized
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`by instituting trial on claims 1 and 43 on this ground, Oshlack discloses controlled
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`release opioid formulations containing HPMC. (AMN 1007, 8:62-65.) IPR2014-
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`00360. (Institution Decision in IPR2014-00360 at 14-20.) HPMC meets the
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`hydrophilic material limitation of each of claims 1, 5, 13, 43, 44, 46 and 47. (AMN
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`1003, ¶59.) And the Board has already recognized that Oshlack discloses the
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`hydroxylakylcellulose HPMC. In IPR2014-00360, the Board instituted trial for
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`claims 6 and 17 – which recite HPMC – in the obviousness ground over Oshlack
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`and the Handbook. (Institution Decision at 18.)
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`As shown in the claim chart above, Oshlack teaches controlled release
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`matrix formulations comprising hydrophilic materials. AMN 1007, 9:16-23.
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`Petition for Inter Partes Review of USPN 8,329,216
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`Oshlack also teaches a controlled release oxymorphone composition comprising
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`HPMC. (AMN 1007, 9:16-23; 26:34-38.) The '216 patent defines HPMC as a
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`hydrophilic material that forms a gel upon exposure to gastrointestinal fluid (AMN
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`1001, 6:49-59), notwithstanding that Oshlack refers to HPMC as a hydrophobic
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`agent. (AMN 1007, 8:52-65.) Both Oshlack and the '216 patent disclose matrix
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`based controlled release formulations that release active agent through erosion of
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`the matrix, and a POSA would have understood that the HPMC disclosed in
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`Oshlack and the '216 patent would have functioned in such matrix systems. (AMN
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`1003, ¶XX; AMN 1001: 6:53-54; AMN 1007, 1:10-14.) A POSA would have
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`understood that Oshlack teaches HPMC as a gelling agent for use in a controlled
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`release formulation A POSA would have also understood that HPMC is a gel
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`forming polymer. (AMN 1003, ¶XX.) Further, Oshlack teaches that HPMC is a
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`hydroxyalkyl cellulose, a type of cellulose ether. (AMN 1007, 8:62-65; AMN 1003
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`¶XX.) Thus, Oshlack teaches the hydrophilic material recited in each of claims 1,
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`5, 13, 43, 44, 46 and 47.
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`Dosage Limitations (claims 1 and 38): Claims 1 and 38 recite
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`oxymorphone concentrations of about 5 to about 80 mg. It was well known that
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`oxymorphone could be provided at a therapeutically effective oral dosage of 10
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`mg. (See Gordon, AMN 1011, 212, Table 1; AMN 1003, ¶62.) As shown in the
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`claim chart, Oshlack discloses controlled release compositions with about 4 to
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`Petition for Inter Partes Review of USPN 8,329,216
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`about 64 mg hydromorphone and about 5 to about 400 mg oxycodone. (AMN
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`1007, 7:40-56.) A POSA would have found oxymorphone to be substitutable for
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`oxycodone or hydromorphone because Oshlack discloses that oxymorphone is an
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`alternative preferred opioid to oxycodone or hydromorphone (AMN 1007, 7:35-39;
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`AMN 1003, ¶¶26, 63.) As the opioid concentration ranges in Oshlack overlap and
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`are similar to the claimed oxymorphone concentration range of about 5 to about 80
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`mg, a POSA would have found the claimed range obvious. See In re Peterson, 315
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`F.3d 1325, 1330 (Fed. Cir. 2003); see also, Galderma Labs. v. Tolmar, Appeal No.
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`2013-1034, slip op. 9.
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`6-OH Limitations (claim 1): Independent claim 1 requires that the
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`controlled release oxymorphone compositions have certain pharmacokinetic
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`characteristics relating to an oxymorphone metabolite that would necessarily be
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`present in a controlled release oxymorphone composition as disclosed and taught
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`by Oshlack. (AMN 1003, ¶64.) These characteristics include: (1) detectable blood
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`plasma levels of 6-OH oxymorphone and oxymorphone; (2) peak plasma levels of
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`6-OH oxymorphone and oxymorphone within one
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`to eight hours after
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`administration; (3) an AUC(0 to inf) ratio of 6-OH oxymorphone to oxymorphone of
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`about 0.5 to about 1.5; (4) a 12 hour analgesic effect; and (5) two to three blood
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`plasma peaks of oxymorphone within 12 hours of administration.
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`Petition for Inter Partes Review of USPN 8,329,216
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`6-OH oxymorphone was a known metabolite of oxymorphone, as
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`demonstrated by Cone et al., Drug Metabolism and Deposition, 11(5):446-450
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`(1983) ("Cone"; AMN 1013). Cone analyzed the metabolites of oxymorphone in
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`mammals. Cone states that "6βOxymorphol [6-OH oxymorphone] was found in the
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`urine of all species" tested. (AMN 1013, p. 446, Abstract.) Thus, a POSA would
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`necessarily find 6-OH oxymorphone as well as oxymorphone in blood plasma after
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`administration of oxymorphone. (AMN 1003, ¶65.)
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`Obtaining multiple peak plasma levels of oxymorphone and 6-OH
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`oxymorphone after one to eight hours is likewise not a novel feature of the claimed
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`compositions. This is demonstrated by the Endo's own data in the '216 patent,
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`which shows that immediate release oxymorphone formulations will necessarily
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`also show peaks at about 3 hours after administration. For example, Figure 6 shows
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`peaks at about 3 hours and about 12 hours after administration of an immediate
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`release oxymorphone composition, treatment 2C. (AMN 1001 Figure 6.)
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`Moreover, immediate release formulations also achieve multiple blood plasma
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`peaks within twelve hours of administration as required by these claims. (See, e.g.,
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`AMN 1001, Figure 7.) Consequently, the presence of 2 or 3 peaks after
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`administration of any oxymorphone formulation is an inherent property of all
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`oxymorphone compositions. (AMN 1003, ¶66.) Such inherent characteristics do
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`not impart patentability to the challenged claims over the prior art. See Santarus,
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`Inc. v. Par Pharm., Inc., 694 F.3d 1344, 1354 (Fed. Cir. 2012).
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`Petition for Inter Partes Review of USPN 8,329,216
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`The data provided in the '216 patent also show that the ratio of AUC(0 to inf)
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`for 6-OH oxymorphone compared to oxymorphone range from about 0.5 to about
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`1.5 (clause (iii) of claim 1) is not specific to controlled release formulations. As
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`can been seen by comparing the data in Tables 23 (oxymorphone) and 27 (6-OH
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`oxymorphone), the ratios of AUC(0 to inf) for 6-OH oxymorphone compared to
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`oxymorphone are 0.82 for Treatment 5A and 0.80 for Treatment 5B, both
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`controlled release formulations, and 0.96 for Treatment 5C and 0.68 for Treatment
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`5D, both immediate release formulations. (AMN 1003, ¶67.) As the ratios for both
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`controlled release and immediate release formulations fall within those recited in
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`clause (iii) of claim 1, it is clear that the ratio of AUC(0
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`inf) for 6-OH
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`to
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`oxymorphone compared to oxymorphone recited in claim 1 is an inherent property
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`of all oxymorphone compositions. (Id., ¶67.)
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`But even
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`if
`
`these pharmacokinetic characteristics were considered
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`independent of the particular controlled release oxymorphone formulations recited
`
`by the '216 patent, they are characteristics that would certainly be achieved by the
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`controlled release oxymorphone formulations disclosed by Oshlack. (AMN 1003,
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`¶68.) As discussed in detail below, Oshlack and the Handbook teach controlled
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`release oxymorphone compositions with the in vitro dissolution profile recited in
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`the claims of the '216 patent.
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`Petition for Inter Partes Review of USPN 8,329,216
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`A POSA would recognize that the '216 patent acknowledges that in vitro
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`dissolution rate is related to the blood plasma levels of 6-OH oxymorphone and
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`oxymorphone claimed. (AMN 1003, ¶68.) The '216 patent states that "[in vitro
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`r]elease rate is a critical variable in attempting to control the blood plasma levels of
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`oxymorphone and 6-hyroxyoxymorphone in a patient." (AMN 1001, 10:44-46.)
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`Thus, a POSA would have had a reasonable expectation of success that a
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`controlled release oxymorphone composition having a dissolution profile as
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`disclosed in Oshlack and the Handbook has the blood plasma characteristics
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`recited in claim 1. (AMN 1003, ¶68.) Therefore, Oshlack must necessarily disclose
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`the blood plasma profiles recited in claim 1.
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`One Hour Dissolution Limitation (claim 13) and Four and Ten Hour
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`Dissolution Limitations (claim 38): Claims 13 and 38 require that "about 15% to
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`about 50%, by weight, of the oxymorphone is released from the tablet at about 1
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`hour" under specified testing conditions. Claim 38 also recites that about 45% to
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`about 80% oxymorphone is released at about four hours and that at least about
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`80% oxymorphone is released at about ten hours.
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`Oshlack discloses in vitro testing of controlled release opioid compositions
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`using the USP Paddle or Basket method at 100 rpm, pH 1.6 to 7.2 and 37° C.
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`(AMN 1007, 26:39-43.) Oshlack discloses in vitro dissolution release of about 1%
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`to about 42.5% at 1 hour, and about 20% to about 90% at 4 hours. (AMN 1007, 26:
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`39-45.) The ranges at the 1 and 4 hour time points overlap the ranges claimed in
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`Petition for Inter Partes Review of USPN 8,329,216
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`the '216 patent at these time points, which are about 15% to about 50% at 1 hour
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`and about 45% to about 80% at 4 hours. (AMN 1003, ¶ 70.) Oshlack discloses that
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`20% to 90% oxymorphone is released at 6 hours and that 35% to 95% is released
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`at 12 hours. While it does not provide a range at the 10 hour timepoint, the Board
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`agreed that Oshlack profile squarely encompasses release of at least 80% at 10
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`hours. (Institution Decision at 17; AMN 1003, ¶70.)
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`Oshlack teaches a controlled release oxymorphone composition comprising
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`excipients as recited in the claims that has an in vitro dissolution profile
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`overlapping the claimed profile. (AMN 1003, ¶ 71.) Although the profile in the
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`claims of the '216 p