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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
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`
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`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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`Petition for Inter Partes Review of USPN 8,329,216
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`TABLE OF CONTENTS
`
`2. 
`
`3. 
`
`4. 
`
`INTRODUCTION .......................................................................................... 1 
`I. 
`OVERVIEW ................................................................................................... 1 
`II. 
`STANDING (37 C.F.R. § 42.104(a)); PROCEDURAL STATEMENTS ..... 3 
`III. 
`IV.  MANDATORY NOTICES (37 C.F.R. § 42.8(a)(1)) ..................................... 3 
`V. 
`STATEMENT OF THE PRECISE RELIEF REQUESTED AND THE
`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)) .................. 6 
`1. 
`Ground 1: Claims 1, 2, 6, 12-14, 17, 21-43, 45-51,
`and 54-82 Would Have Been Obvious Over Maloney .............. 7 
`Ground 2: Claims 1, 2, 6, 12-14, 17, 21-43, 45-51,
`and 54-82 Would Have Been Obvious Over Oshlack ............. 26 
`Ground 3: Claims 1, 2, 6, 12-14, 17, 21-43, 45-51,
`and 54-82 Would Have Been Obvious Over Oshlack
`and the Handbook of Dissolution Testing ............................... 39 
`Ground 4: Claims 1, 2, 6, 12-14, 17, 21-43, 45-51,
`and 54-82 Would Have Been Obvious Over The
`Penwest Statement and Baichwal ............................................ 42 
`Ground 5: Claims 1, 2, 6, 12-14, 17, 21-43, 45-51,
`and 54-82 Would Have Been Obvious Over Maloney,
`the Penwest Statement and Baichwal ...................................... 48 
`Ground 7: Claims 1, 31-34, 38, 49, 55 and 66 Would
`Have Been Obvious Over Maloney and Gordon ..................... 50 
`Ground 9: Claims 1, 66, 67, 69, 70, 75, 76 and 78
`Would Have Been Obvious Over Maloney and
`Poulain ..................................................................................... 53 
`IX.  OBJECTIVE INDICIA OF NONOBVIOUSNESS ..................................... 55 
`X. 
`CONCLUSION ............................................................................................. 59 
`CERTIFICATION OF SERVICE (37 C.F.R. §§ 42.6(e), 42.105(a)) .................... 60 
`
`
`5. 
`
`6. 
`
`7. 
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`I.
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`
`
`Petition for Inter Partes Review of USPN 8,329,216
`
`INTRODUCTION
`AMNEAL PHARMACEUTICALS, LLC and AMNEAL PHARMACEUTICALS OF NEW
`
`YORK petition for Inter Partes Review, seeking cancellation of claims 1, 2, 6, 12-
`
`14, 17, 21-43, 45-51, and 54-82 of U.S. Patent No 8,329,216 to Kao et al. ("the
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`'216 patent") (AMN 1001), which is owned by ENDO PHARMACEUTICALS INC.
`
`II. OVERVIEW
`The challenged claims of the '216 patent should never have been issued.
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`They are drawn to simple controlled release compositions of oxymorphone and
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`recite broad in vitro release and/or broad pharmacokinetic limitations. Neither the
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`compositions nor these performance characteristics are novel or nonobvious.
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`Because Petitioner is, at a minimum, reasonably likely to prevail in showing
`
`unpatentability, this Petition should be granted and trial instituted on all of the
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`challenged claims.
`
`There are a number of claims at issue in this Petition, but the various
`
`differences among those claims are inconsequential to patentability. There will be
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`no dispute that oxymorphone is an opioid drug that was known in the art more than
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`thirty years before the earliest possible priority date ("EPD") of the '216 patent.
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`There will also be no dispute that controlled release opioid formulations were also
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`known in the art, including controlled release oxymorphone. Rather, the crux of
`
`patentee's alleged invention is its selection of an in vitro dissolution profile that
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`encompasses an expansive range of potential formulations, including those taught
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`Petition for Inter Partes Review of USPN 8,329,216
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`in the prior art. None of the other recited limitations, alone or together, impart
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`patentability to the challenged claims because they too are found in the prior art
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`controlled release oxymorphone compositions.
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`In support of this Petition, Petitioner prepared a formulation that is an
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`embodiment of Maloney, a noteworthy prior art reference. Dissolution testing of
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`that
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`formulation demonstrates
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`that Maloney
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`teaches controlled-release
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`oxymorphone formulations that meet the dissolution profiles specified by '216
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`patent claims. And, as shown in the '216 patent, oxymorphone controlled release
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`compositions having the claimed in vitro dissolution profiles also necessarily
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`exhibit the in vivo blood profiles recited in the claims. Determining those
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`pharmacokinetic characteristics is a matter of simple and routine testing that is well
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`within the skill of a person of ordinary skill in the art ("POSA").
`
`But even if some differences are found between the challenged claims and
`
`the prior art, the claims would have been obvious. Given the prior art, a POSA
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`would have had a reasonable expectation of success in producing the claims. Even
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`in view of any objective indicia of nonobviousness, the claims would have been
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`obvious. Thus, Petitioner is at least reasonably likely to prevail in showing
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`obviousness over the prior art. Inter partes review of the '216 patent should be
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`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)
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`
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`Petition for Inter Partes Review of USPN 8,329,216
`
`Petitioner is not barred or estopped from requesting IPR of any claim of the '216
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`patent. This Petition is filed in accordance with 37 CFR § 42.106(a). Concurrently
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`filed herewith is a Power of Attorney and an Exhibit List per § 42.10(b) 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
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`PHARMACEUTICALS, LLC AND AMNEAL PHARMACEUTICALS CO. (I) PVT. LTD.
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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) In a Petition filed
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`concurrently herewith, Petitioner seeks IPR of U.S. Pat. No. 8,309,122, which is
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`the parent of the '299 patent, over certain references cited herein. (2) Petitioner also
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`filed IPR 2014-00160, which is pending, against U.S. Patent No. 7,851,482 on
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`November 18, 2013, against the same Patent Owner.
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`Designation of Counsel (37 C.F.R. § 42.8(b)(3)):
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`Petition for Inter Partes Review of USPN 8,329,216
`
`Back-Up Counsel
`Lead Counsel
`Dennies Varughese (Reg. No. 61,868)
`Eldora L. Ellison (Reg. No. 39,967)
`STERNE, KESSLER, GOLDSTEIN & FOX
`STERNE, KESSLER, GOLDSTEIN & FOX
`P.L.L.C.
`P.L.L.C.
`1100 New York Avenue, NW
`1100 New York Avenue, NW
`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 1, 2, 6, 12-14, 17, 21-43,
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`45-51, and 54-82 of the '216 patent. Petitioner's full statement of the reasons for the
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`relief 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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`
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`Petition for Inter Partes Review of USPN 8,329,216
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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
`
`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 value measured, 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. about 72% to about 88% for a
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`measured value of 80%. (AMN 1003, ¶23; AMN 1002, ¶ 21.)
`
`The remaining terms in the challenged claims are plain on their face and
`
`should be construed to have their ordinary and customary meanings.
`
`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,
`
`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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`Petition for Inter Partes Review of USPN 8,329,216
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`would typically have a Bachelors or Master's degree in Pharmacy, Chemistry or a
`
`related field with at least 5 years of experience with pharmaceutical formulations
`
`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/or a clinician may be
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`part of the team.
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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
`
`patent on the grounds for unpatentability listed in the index below. Per 37 C.F.R. §
`
`42.6(d), copies of the references are filed herewith. In support of the proposed
`
`grounds for unpatentability, this Petition is accompanied by declarations of
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`technical experts Dr. Anthony Palmieri (AMN 1003) and Ms. Vivian Gray (AMN
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`1002), which explain what the art would have conveyed to a POSA.
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`Petition for Inter Partes Review of USPN 8,329,216
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`Index of References
`
`'216 patent Claims
`
`Maloney
`
`Oshlack
`
`Oshlack and the Handbook of
`Dissolution Testing
`The Penwest Statement and
`Baichwal
`Maloney, the Penwest
`Statement and Baichwal
`Oshlack, the Penwest Statement
`and Baichwal
`Maloney and Gordon
`
`Oshlack and Gordon
`
`Maloney and Poulain
`
`Oshlack and Poulain
`
`
`
`
`
`Ground 35
`U.S.C.
`§103
`
`1
`
`2
`
`3
`
`4
`
`5
`
`6
`
`7
`
`8
`
`9
`
`10
`
`§103
`
`§103
`
`§103
`
`§103
`
`§103
`
`§103
`
`§103
`
`§103
`
`§103
`
`1, 2, 6, 12-14, 17, 21-43,
`49-51, and 54-82
`1, 2, 6, 12-14, 17, 21-43,
`49-51, and 54-82
`1, 2, 6, 12-14, 17, 21-43,
`49-51, and 54-82
`1, 2, 6, 12-14, 17, 21-43,
`49-51, and 54-82
`1, 2, 6, 12-14, 17, 21-43,
`49-51, and 54-82
`1, 2, 6, 12-14, 17, 21-43,
`49-51, and 54-82
`1, 31-34, 38, 49, 55 and
`66
`1, 31-34, 38, 49, 55 and
`66
`1, 66, 67, 69, 70, 75, 76,
`78
`1, 66, 67, 69, 70, 75, 76,
`78
`1. Ground 1: Claims 1, 2, 6, 12-14, 17, 21-43, 45-51, and 54-82
`Would Have Been Obvious Over Maloney
`International Publication No. WO01/08661 to Roxane Laboratories, Inc. lists
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`Ann M. Maloney as an inventor ("Maloney"; AMN 1006), titled "Opioid
`
`Sustained-Release Formulation" published in English on February 8, 2001.
`
`Maloney qualifies as prior art to the '216 patent under 35 U.S.C. §102(a). Claims 1,
`
`2, 6, 12-14, 17, 21-43, 45-51, and 54-82 would have been obvious over Maloney.
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`Maloney teaches systems for the controlled release delivery of opioids;
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`oxymorphone is one opioid to which Maloney is expressly directed. (AMN 1006,
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`13:15-18.) To demonstrate the unpatentability of the challenged claims over
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`Petition for Inter Partes Review of USPN 8,329,216
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`Maloney, Petitioner's experts prepared an oxymorphone formulation following the
`
`Maloney specifications, using Formula 6 of Table 3 as a template (the "Maloney
`
`Test Formula").
`
`The Maloney Test Formula is shown in Table 1 below.
`
`INGREDIENT
`Oxymorphone hydrochloride
`
`Lactose, NF (Fast Flo)
`Amberlite IRP 69M Fine
`Particle Size
`Methocel K100M (Premium)
`CR (hydroxypropyl
`methylcellulose, USP)
`Cab-O-Sil (M-5)
`Stearic Acid, NF (Powder)
`Theoretical tablet weight
`Table 1
`
`AMOUNT
`30 mg
`(20% w/w)
`39.5% w/w
`5.0% w/w
`
`30.0% w/w
`
`0.5% w/w
`5.0% w/w
`150 mg
`
`Formula 6 of Maloney contains oxycodone, while the Maloney Test Formula
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`contains oxymorphone. Substituting oxymorphone for oxycodone in the Maloney
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`Formula 6 would have been obvious to a POSA as both oxymorphone and
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`oxycodone are listed as preferred opioids in Maloney and both are claimed by
`
`Maloney for use in its controlled release formulations. (AMN 1006, 13:15-18;
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`17:14-18.) The Federal Circuit, in its decision on the appeal of the Office's
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`rejection of the claims of U.S. Application No. 11/680,432 ("the '432 application"),
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`Petition for Inter Partes Review of USPN 8,329,216
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`the parent of '216 patent, over Maloney, "[a]ccept[ed] that it would be obvious to
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`substitute oxymorphone in Maloney's Formula 6." In re Kao, 639 F.3d 1057, 1066
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`(Fed. Cir. 2011).
`
`Petitioner's experts made two other modifications to Maloney Formula 6 in
`
`performing
`
`their experiments. Both modifications are within
`
`the express
`
`parameters disclosed by Maloney and would have been obvious to a POSA from
`
`the teachings of Maloney. (AMN 1003, ¶75.) In particular, the Maloney Test
`
`Formula has a concentration of 30% by weight of the matrix-forming polymer
`
`HPMC, a concentration falling within the preferred range for the delivery systems
`
`taught by Maloney. (AMN 1006, 13:4-6.) In addition, the Maloney Test Formula
`
`has a concentration of 39.5% by weight of lactose, a diluent, a concentration within
`
`the range of diluents taught by Maloney (Id., 11:1-3; 17-20.) As the HPMC
`
`concentration of 30% and lactose concentration of 39.5% in the Maloney Test
`
`Formula are within the ranges specified by Maloney, it would have been obvious
`
`to a POSA to have prepared such a formulation. (Id., 8:9-11; 9:16-19; 11:2-3;
`
`11:20; AMN 1003, ¶75.) "Where there is a range disclosed in the prior art, and the
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`claimed invention falls within that range, the burden of production falls upon
`
`patentee to come forward with evidence" of a teaching away, unexpected results or
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`other secondary considerations. Galderma Labs., L.P. v. Tolmar, Inc., Appeal No.
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`2013-1034, slip op. at 9 (Fed. Cir. Dec. 11, 2013),. As discussed herein, there is no
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`Petition for Inter Partes Review of USPN 8,329,216
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`evidence that the prior art teaches away from the claimed subject matter of the '216
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`patent and no evidence of objective indicia of nonobviousness sufficient find the
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`claims nonobvious over the teachings of Maloney.
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`The CAFC addressed the alleged nonobviousness of the claimed dissolution
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`profile in the context of the related '432 application. Kao, 639 F.3d at 1066. The
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`court found that the Office did not meet its burden of showing the profile to be
`
`obvious over Maloney because the Office's conclusion rested on a facially
`
`unsupported assumption regarding the correlation between results from a USP
`
`basket dissolution test and USP paddle dissolution test. Id. The court explained "it
`
`matters not whether the hypothetical skilled artisan would have appreciated the
`
`'correlation' at issue here, it matters greatly whether anything the skilled artisan
`
`would be prompted by the prior art to do is in fact within the scope of the pending
`
`claims." Id (emphasis in original). As the analytical testing provided herein bears
`
`out, the oxymorphone formulations prompted by the teachings of Maloney are in
`
`fact within the scope of the claims, including the broad dissolution profiles recited
`
`therein. (AMN 1003, ¶71; AMN 1002, ¶ 72.)
`
`Further, a POSA would have had a reason to make controlled release
`
`oxymorphone compositions as claimed from the teachings of Maloney. Maloney
`
`teaches that there are many therapeutic benefits to formulating opioids in
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`controlled release form and provides oxymorphone as a preferred opioid. (AMN
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`Petition for Inter Partes Review of USPN 8,329,216
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`1006, 1:23-2:7; 13:15-19; AMN 1003, ¶¶73,74.)
`
`The Maloney Test Formula shows oxymorphone release at 1, 4 and 10 hours
`
`as provided in Table 2. (AMN 1002, ¶¶ 58, 61, and 65.) In vitro dissolution tests
`
`were performed using the USP Paddle Method at 50 rpm in 500 ml media at 37° C
`
`having the pH values shown.
`
`Release at 10 hr.
`Release at 4 hr.
`Release at 1 hr.
`
`pH Avg. Min. Max. Avg. Min. Max. Avg. Min. Max.
`1.2
`29%
`28%
`30%
`61%
`59%
`63%
`85%
`83%
`87%
`4.5
`31%
`31%
`32%
`62%
`61%
`64%
`82%
`80%
`85%
`6.8
`26%
`26%
`28%
`56%
`55%
`58%
`79%
`78%
`80%
`Table 2
`As illustrated in the claim chart and discussion below, claims 1, 2, 6, 12-14,
`
`17, 21-43, 45-51, and 54-82 would have been obvious to a POSA over the
`
`teachings of Maloney. In particular, Maloney discloses controlled release
`
`oxymorphone compositions having the components claimed. And the controlled
`
`release oxymorphone compositions disclosed by Maloney have the in vitro
`
`dissolution profile recited in the claims. A POSA would have had a reasonable
`
`expectation of success
`
`in obtained
`
`the oxymorphone controlled release
`
`compositions claimed from the teachings of Maloney.
`
`The CAFC has found that claiming a property of an old formulation does not
`
`make the formulation patentable. Santarus, Inc. v. Par Pharm., Inc., 694 F.3d
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`1344, 1354 (Fed. Cir. 2012). As shown herein, the claims of the '216 patent merely
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`Petition for Inter Partes Review of USPN 8,329,216
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`recite an old formulation and purport to be patentable by reciting an intrinsic
`
`property of that formulation. It is reasonably likely that Petitioner will prevail with
`
`regard to at least one challenged claim on the basis of Ground 1.
`
`Claim(s)
`1, 13, 21,
`31, 38,
`49, 55,
`66, 72, 77
`
`1, 13, 21,
`38, 49,
`55, 66,
`72, 77
`
`1, 31, 38,
`49, 55,
`66,
`
`Limitation(s)1
`Comprising oxymorphone
`
`1, 13:
`"comprising a hydrophilic
`material";
`21: "controlled release
`excipients";
`38, 49, 55, 66:
`"controlled release delivery
`system";
`72, 77:
`"a controlled release matrix,
`comprising about 10% to
`about 75% (by total weight of
`the controlled release matrix)
`of a gelling agent."
`"about 5 to about 80 mg
`oxymorphone"
`
`Maloney (AMN 1006)
`"Preferred opioid compounds … are
`selected … from the group
`consisting of: … oxycodone
`hydrochloride, oxymorphone2…."
`AMN 1006, 13:15-18
`Maloney discloses a formulation
`comprising HPMC, see the Maloney
`Test Formula in Table 1 above.
`"Typical matrix-forming polymers
`useful in the present invention,
`include, without limitation,
`hydroxypropylmethyl cellulose
`…." AMN 1006, 9:17-19.
`"the formulation comprises between
`about 30 and 65% matrix forming
`polymer…" AMN 1006, 7:22-24
`
`"It has been surprisingly found that
`formulations having from about 5
`to about 100 mg oxycodone …"
`
`
`1 Any limitations not specifically recited here are disclosed in Maloney as
`
`discussed below.
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`2 Bold type is used for emphasis throughout this petition.
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`Claim(s)
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`Limitation(s)1
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`Petition for Inter Partes Review of USPN 8,329,216
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`Maloney (AMN 1006)
`AMN 1006, 7:21-22
`Formula 6 of Maloney contains 30
`mg oxycodone. AMN 1006, 17,
`Table 3.
`"A particularly useful formulation
`of oxycodone which has been found
`to effectively control pain in a
`wide variety of patients without
`significant pain breakthrough
`between doses comprises a solid,
`oral, controlled release dosage form
`… wherein the dissolution rate in
`vitro of the dosage form, …
`between about 60 and 80% (by
`weight) oxycodone released after
`twelve hours." AMN 1006, 14:4-
`15.
`
`In in vitro dissolution tests shown in
`Table 2 above, the Maloney Test
`Formula has an average release at 1
`hour of 29% at pH 1.2, 31% at pH
`4.5 and 26% at pH 6.8. AMN 1002,
`¶72.
`
`In in vitro dissolution tests shown in
`Table 2 above, the Maloney Test
`Formula has an average release at 4
`hours of 61% at pH 1.2, 62% at pH
`4.5 and 56% at pH 6.8. AMN 1002,
`
`1: " the duration of the
`analgesic effect is through at
`least about 12 hours after
`administration"
`31, 38, 49:
`"at least 12 hours to provide
`sustained pain relief over this
`same period";
`21: " alleviates pain for 12 to
`24 hours";
`55, 66: " over at least 12 hours
`to provide sustained pain relief
`over this same period";
`31, 38: "method for treating
`pain"; and
`49, 55, 66:"analgesically
`effective"
`"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 released from the
`tablet at about 1 hour in the
`test."
`"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
`
`- 13 -
`
`1, 21, 31,
`38, 49,
`55, 66
`
`13, 21,
`31, 38,
`49, 55,
`66, 72, 77
`
`38, 77
`
`

`

`
`
`
`
`Claim(s)
`
`
`
`Petition for Inter Partes Review of USPN 8,329,216
`
`Maloney (AMN 1006)
`
`Limitation(s)1
`at least about 80%, by weight,
`of the oxymorphone or salt
`thereof is released from the
`tablet at about 10 hours in the
`test
`
`¶72.
`In in vitro dissolution tests shown in
`Table 2 above, the Maloney Test
`Formula has an average release at
`10 hours of 85% at pH 1.2, 82% at
`pH 4.5 and 79% at pH 6.8. AMN
`1002, ¶72.
`"Coating and wet granulation may
`be used in conjunction with the
`present invention in order to obtain
`desired tablet configurations…."
`AMN 1006, 8:18-19.
`Maloney: "Typical matrix-forming
`polymers useful in the present
`invention, include, without
`limitation, hydroxypropylmethyl
`cellulose …." AMN 1006, 9:17-19.
`The '216 Patent explains: "In this
`embodiment, the oxymorphone or
`oxymorphone salt is dispersed in a
`controlled release delivery system
`that comprises a hydrophilic
`material (gelling agent) which
`upon exposure to gastrointestinal
`fluid forms a gel matrix that
`releases oxymorphone at a
`controlled rate. Such hydrophilic
`materials include … cellulose
`ethers…. Suitable cellulose ethers
`include … HPMC…." AMN 1001:
`6:48-58.
`Hydrophilic Material Limitations (claims 1, 2, 6, 14, 17, and 43):
`
`"granules"; "tablet"
`
`13, 21
`
`"gelling agent which forms a
`gel upon exposure to
`gastrointestinal fluid"
`
`72, 77
`
`Independent claims 1 and 13 and dependent claim 43 each require the presence of
`
`a hydrophilic material. Dependent claims 2 and 14 require that the hydrophilic
`
`material be a cellulose ether and dependent claims 6 and 17 further limit the
`
`- 14 -
`
`

`

`
`
`
`hydrophilic material to hydroxypropyl methylcellulose ("HPMC"). Maloney
`
`
`
`Petition for Inter Partes Review of USPN 8,329,216
`
`discloses HPMC, which the '216 patent admits is a hydrophilic material and a
`
`cellulose ether. (AMN 1006, 9:17-19; AMN 1003, ¶78.)
`
`Dosage Limitations (claims 1, 31, 32-34, 38, 49, 51, 55, 66, 81 and 82):
`
`Several independent and dependent claims recite compositions comprising certain
`
`amounts of oxymorphone: claims 1, 31, 38, 49, 55, 66, 81 and 82 (about 5 to about
`
`80 mg). The CAFC has already found that Maloney teaches dose amounts between
`
`5 mg and 100 mg. Kao, 639 F.3d at 1071. This is supported by the fact that
`
`Maloney teaches the use of opioids at therapeutically effective concentrations and
`
`teaches oxycodone concentrations of 5 – 100 mg. (AMN 1006, 7:21-22; 8:9-11.) A
`
`POSA would have found it obvious to substitute oxymorphone for oxycodone in
`
`the example formulations of Maloney and Maloney lists oxymorphone as an
`
`alternative to oxycodone. (AMN 1006, 13:15-19.) Consequently, the 5 – 80 mg
`
`range recited in these claims would have been obvious to a POSA in light of
`
`Maloney. (AMN 1003, ¶80.)
`
`Dependent claims 32-34, 51 and 81 further recite particular amounts of
`
`oxymorphone that are present in the claimed formulation: claims 32 and 51 (about
`
`40mg); claim 33 (about 20 mg); claim; claim 34 (about 20 to about 40 mg); claim
`
`81 (about 5 to about 80 mg). As shown the claim chart above, Maloney teaches
`
`controlled release compositions containing 30 mg opioid. (AMN 1006, 17, Table
`
`- 15 -
`
`

`

`
`
`
`3.) A POSA would have found it obvious to substitute oxymorphone for
`
`
`
`Petition for Inter Partes Review of USPN 8,329,216
`
`oxycodone in the example formulations of Maloney. (AMN 1003, ¶81.)
`
`Consequently, a POSA would have also had a reasonable expectation of success of
`
`formulating either a 20 or 40 mg dose of oxymorphone using the controlled-release
`
`systems in Maloney to achieve similar in vitro release profiles. (Id., ¶81.)
`
`6-OH Limitations (claims 1, 37, 42, 68, 76, 78): Independent claim 1 and
`
`dependent claims 37, 42, 68, 76, and 78 all further require that the controlled
`
`release oxymorphone compositions have certain pharmacokinetic characteristics
`
`relating to an oxymorphone metabolite that would necessarily be present in a
`
`controlled release oxymorphone composition as disclosed and taught by Maloney.
`
`These include: (1) detectable blood plasma levels of the metabolite 6-OH
`
`oxymorphone and oxymorphone; (2) peak plasma levels of 6-OH oxymorphone
`
`and oxymorphone within one to eight hours after administration; (3) an AUC(0 to inf)
`
`ratio of 6-OH oxymorphone to oxymorphone of about 0.5 to about 1.5; (4) a 12
`
`hour analgesic effect; and (5) two to three blood plasma peaks of oxymorphone
`
`within 12 hours of administration.
`
`6-OH oxymorphone was a known metabolite of oxymorphone, as
`
`demonstrated by Cone et al., Drug Metabolism and Deposition, 11(5):446-450
`
`(1983) ("Cone"; AMN 1013). Cone analyzed the metabolites of oxymorphone in
`
`mammals. Cone states that "6βOxymorphol [6-OH oxymorphone] was found in the
`
`- 16 -
`
`

`

`
`
`
`urine of all species" tested. (AMN 1013, p. 446, Abstract.) Thus, a POSA would
`
`
`
`Petition for Inter Partes Review of USPN 8,329,216
`
`necessarily find 6-OH oxymorphone as well as oxymorphone in blood plasma after
`
`administration of oxymorphone. (AMN 1003, ¶83.)
`
`Obtaining multiple peak plasma levels of oxymorphone and 6-OH
`
`oxymorphone after one to eight hours is likewise not a novel feature of the claimed
`
`compositions. This is demonstrated by the patentee's own data in the '216 patent,
`
`which shows that immediate release oxymorphone formulations will necessarily
`
`also show peaks at about 3 hours after administration. For example, Figure 6 shows
`
`peaks at about 3 hours and about 12 hours after administration of an immediate
`
`release oxymorphone composition, treatment 2C. (AMN 1001 Figure 6.)
`
`Moreover, immediate release formulations also achieve multiple blood plasma
`
`peaks within twelve hours of administration as required by these claims. (See, e.g.,
`
`AMN 1001, Figure 7.) Consequently, the presence of 2 or 3 peaks after
`
`administration of any oxymorphone formulation is an inherent property of all
`
`oxymorphone compositions. (AMN 1003, ¶95.) See also, Santarus, Inc. v. Par
`
`Pharm., Inc., 694 F.3d 1344, 1354 (Fed. Cir. 2012).
`
`The data provided in the '216 patent show that the ratio of AUC(0 - inf) for 6-
`
`OH oxymorphone compared to oxymorphone range from about 0.5 to about 1.5
`
`(clause (iii) of claim 1) is not specific to controlled release formulations. As can
`
`been seen by comparing the data in Tables 23 (oxymorphone) and 27 (6-OH
`
`- 17 -
`
`

`

`
`
`
`oxymorphone), the ratios of AUC(0 - inf) for 6-OH oxymorphone compared to
`
`
`
`Petition for Inter Partes Review of USPN 8,329,216
`
`oxymorphone are 0.82 for Treatment 5A and 0.80 for Treatment 5B, both
`
`controlled release formulations, and 0.96 for Treatment 5C and 0.68 for Treatment
`
`5D, both immediate release formulations. (AMN 1003, ¶85.) As the ratios for both
`
`controlled release and immediate release formulations fall within those recited in
`
`clause (iii) of claim 1, it is clear that the ratio of AUC(0 - inf) for 6-OH oxymorphone
`
`compared to oxymorphone recited in claim 1 is an inherent property of all
`
`oxymorphone compositions. (Id., ¶85.)
`
`But even
`
`if
`
`these pharmacokinetic characteristics were considered
`
`independent of the particular controlled release oxymorphone formulations recited
`
`by the '216 patent, they are characteristics that would certainly be achieved by the
`
`controlled release oxymorphone formulations disclosed by Maloney. As set forth
`
`in more detail below, Maloney
`
`teaches controlled release oxymorphone
`
`formulations that have the same in vitro dissolution profile as required by the '216
`
`patent claims. (AMN 1003, ¶¶87-92.) Consequently, such formulations must
`
`necessarily also have the pharmacokinetic behavior of the formulations claimed by
`
`the '216 patent because, as the '216 patent acknowledges, the "[in vitro r]elease rate
`
`is a critical variable in attempting to control the blood plasma levels of
`
`oxymorphone and 6-hyroxyoxymorphone in a patient." (AMN 1001, 10:44-46.)
`
`Thus, a POSA would recognize that controlled release oxymorphone compositions
`
`- 18 -
`
`

`

`
`
`
`having the dissolution rates claimed would also have the pharmacokinetic
`
`
`
`Petition for Inter Partes Review of USPN 8,329,216
`
`characteristics claimed. (AMN 1003, ¶86.)
`
`One Hour Dissolution Limitation (claims 13, 21, 22, 31, 38, 49, 54, 55,
`
`66, 72-74, 77 and 79-80): Claims 13, 21, 22, 31, 38, 49, 54, 55, 66, 72-74, 77 and
`
`79-80 all require that "about 15% to about 50%, by weight, of the oxymorphone is
`
`released from the tablet at about 1 hour" under specified testing conditions. As
`
`shown in the claim chart above, the Maloney Test Formula releases between 15%
`
`to about 50% of oxymorphone at 1 hour at all tested pH levels. Figure 1 of the
`
`Gray Declaration shows a plot of the dissolution profile obtained from the
`
`Maloney Test Formula in different pH buffers with the minimum and maximum
`
`release profiles recited in the claims. (AMN 1002, ¶ 73.)
`
`And even if the Maloney Test Formula were found to not inherently have the
`
`dissolution profiles claimed, a POSA would have had a reasonable expectation of
`
`success in obtaining these profiles from the teachings of Maloney. This is because
`
`a POSA would have understood that faster release could be obtained by lowering
`
`the concentration of HPMC taught by Maloney or by changing the grade of HPMC
`
`