`
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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. 8,309,122 to Kao et al.
`Issue Date: November 13, 2012
`Title: Oxymorphone Controlled Release Formulations
`
`_____________________
`
`Inter Partes Review No. Unassigned
`_____________________
`
`Petition for Inter Partes Review of U.S. Patent No. 8,309,122 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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`Petition for Inter Partes Review of USPN 8,309,122
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`TABLE OF CONTENTS
`
`2. 
`
`3. 
`
`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 ...................... 6 
`VIII.  IDENTIFICATION OF CHALLENGE (37 C.F.R. § 42.104(b)) .................. 7 
`1. 
`Ground 1: Claims 1-4, 16 and 18-20 Would Have
`Been Obvious Over Maloney ..................................................... 7 
`Ground 2: Claims 1-4, 16 and 18-20 Would Have
`Been Obvious Over The Penwest Statement and
`Baichwal ................................................................................... 22 
`Ground 3: Claims 1-4, 16, and 18-20 Would Have
`Been Obvious Over Maloney, the Penwest Statement
`and Baichwal ............................................................................ 29 
`Ground 4: Claims 1-4, 16 and 18-20 Would Have
`Been Obvious Over Maloney and Gordon .............................. 32 
`Ground 5: Claims 1-4, 16 and 18-20 Would Have
`Been Obvious Over Oshlack .................................................... 34 
`Ground 6: Claims 1-4, 16, and 18-20 Would Have
`Been Obvious Over Oshlack and the Handbook of
`Dissolution Testing .................................................................. 47 
`Ground 7: Claims 1-4, 16, 18 -20 Would Have Been
`Obvious Over Oshlack, the Penwest Statement and
`Baichwal ................................................................................... 49 
`Ground 8: Claims 1-4, 16 and 18-20 Would Have
`Been Obvious Over Oshlack and Gordon ................................ 52 
`IX.  OBJECTIVE INDICIA OF NONOBVIOUSNESS ..................................... 53 
`X. 
`CONCLUSION ............................................................................................. 57 
`CERTIFICATION OF SERVICE (37 C.F.R. §§ 42.6(e), 42.105(a)) .................... 58 
`
`
`4. 
`
`5. 
`
`6. 
`
`7. 
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`8. 
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`I.
`
`INTRODUCTION
`
`
`
`Petition for Inter Partes Review of USPN 8,309,122
`
`AMNEAL PHARMACEUTICALS, LLC and AMNEAL PHARMACEUTICALS OF NEW
`
`YORK petition for Inter Partes Review, seeking cancellation of claims 1-4, 16 and
`
`18-20 of U.S. Patent No 8,309,122 to Kao et al. ("the '122 patent") (AMN 1001),
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`which is owned by ENDO PHARMACEUTICALS INC.
`
`II. OVERVIEW
`The challenged claims of the '122 patent should never have been issued
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`because they are unpatentable over the art cited in this Petition. Because Petitioner
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`is, at a minimum, reasonably likely to prevail in showing unpatentability, this
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`Petition should be granted and trial instituted on all of the challenged claims.
`
`The claims of the '122 patent are drawn to controlled release oxymorphone
`
`compositions and methods that are readily found in the prior art. The claims recite
`
`simple controlled release compositions, or methods of using such compositions,
`
`comprising oxymorphone and at least one well-known controlled release excipient.
`
`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 the
`
`'122 patent. There will also be no dispute that controlled release opioid
`
`formulations were also well known in the art. The feature of the '122 patent claims
`
`that purportedly imparts them patentability is the broad in vitro dissolution profile
`
`recited in the claims. But oxymorphone formulations with this in vitro dissolution
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`profile are also present in the prior art. Nothing in the claims of the '122 patent was
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`Petition for Inter Partes Review of USPN 8,309,122
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`new as of the EPD.
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`The U.S. Patent & Trademark Office ("Office") recognized during
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`prosecution that the prior art disclosed the oxymorphone formulations claimed by
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`the '122 patent. After repeated rejections, applicants appealed to the Court of
`
`Appeals for the Federal Circuit ("CAFC"). See In re Kao, 639 F.3d 1057 (Fed. Cir.
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`2011). The court found that the Office had not provided sufficient evidence to
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`show that the claims were unpatentable, and it vacated and remanded the Office's
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`decision of unpatentability. Id. at 67. Without the ability to provide in vitro
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`dissolution testing evidence to demonstrate that the claimed formulations were not
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`new, the Office allowed the claims.
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`This Petition provides evidence of unpatentability that was not available to
`
`the Office during prosecution. This evidence shows that prior art oxymorphone
`
`controlled release compositions have the recited in vitro dissolution profiles. Had
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`such evidence had been available to the Office and the CAFC, the claims of the
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`'122 patent would never have been allowed.
`
`As shown herein, the claims of the '122 patent recite controlled release
`
`oxymorphone compositions that are readily found in the prior art. Even in view of
`
`any objective indicia of nonobviousness, the claims would have been obvious.
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`Thus, Petitioner is at least reasonably likely to prevail in showing obviousness over
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`the prior art. Inter partes review of the '122 patent should be instituted.
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`Petition for Inter Partes Review of USPN 8,309,122
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`III. STANDING (37 C.F.R. § 42.104(a)); PROCEDURAL STATEMENTS
`Petitioner certifies that (1) the '122 patent is available for IPR and (2)
`
`Petitioner is not barred or estopped from requesting IPR of any claim of the '122
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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
`
`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.
`
`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. 8,329,216, which is a
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`continuation of the '122 patent, over 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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`Petition for Inter Partes Review of USPN 8,309,122
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`Designation of Lead and Back-Up 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
`Washington, DC 20005
`202.772.8508 (telephone)
`202.371.2540 (facsimile)
`eellison-PTAB@skgf.com
`
`Back-Up Counsel
`Dennies Varughese (Reg. No. 61,868)
`STERNE, KESSLER, GOLDSTEIN & FOX
`P.L.L.C.
`1100 New York Avenue, NW
`Washington, DC 20005
`202.772.8805 (telephone)
`202.371.2540 (facsimile)
`dvarughe-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.
`
`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 1-4, 16 and 18-20 of the
`
`'122 patent. Petitioner's full statement of the reasons for the relief requested is set
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`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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`'122 patent.
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`The term "controlled release" is defined in the patent as encompassing "any
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`formulation which release no more than about 80% of their active pharmaceutical
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`Petition for Inter Partes Review of USPN 8,309,122
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`ingredients within 60 minutes" under the claimed dissolution conditions. (AMN
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`1001, 3:31-33.) Thus, the term "controlled release" encompasses any formulation
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`where no more than 80% of active agent is released in 60 minutes. (AMN 1003,
`
`¶22.)
`
`The term "about" as it is used in the context of the percent by weight of
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`oxymorphone released in dissolution testing should be construed to encompass at
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`least the standard statistical error for such dissolution testing values. The '122
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`patent states that "[r]eference to mean values reported herein for studies actually
`
`conducted are arrived at using standard statistical methods as would be employed
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`by one skilled in the art of pharmaceutical formulation and testing for regulatory
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`approval." (AMN 1001, 3:67 – 4:4.) As discussed in the attached Declaration of
`
`Ms. Vivian Gray, the United States Pharmacopeia ("USP") 24 states "the use of the
`
`word "about" indicates a quantity within 10% of the specified weight or volume."
`
`(AMN 1005, 8.) A POSA would have understood that the standard use of "about"
`
`for dissolution testing is a quantity within 10% of the value measured. Thus, a
`
`POSA would have understood the term "about," as it is used in the context of the
`
`percent by weight of oxymorphone released in dissolution testing, to encompass
`
`values of ± 10% of the value measured, e.g. about 72% to about 88% for a
`
`measured value of 80%. (AMN 1003, ¶23; AMN 1002, ¶20.)
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`Petition for Inter Partes Review of USPN 8,309,122
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`The remaining terms in challenged claims 1-4, 16 and 18-20 are plain on
`
`their face and 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 person of ordinary skill in the art ("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. A POSA in pharmaceutical testing as of
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`July 6, 2001, the earliest possible priority date ("EPD") of the '122 patent, would
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`typically have a Bachelors or Master's degree in Pharmacy, Chemistry or a related
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`field with at least 5 years of experience with pharmaceutical formulations
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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
`
`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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` As evidenced by knowledge in the art and the references described herein,
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`at least as of July 6, 2001, the subject matter claimed in claims 1-4, 16 and 18-20
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`was well known and readily available to a POSA.
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`Petition for Inter Partes Review of USPN 8,309,122
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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 '122
`
`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.
`
`Ground 35 U.S.C. (pre-
`March 16, 2013)
`§103
`§103
`
`1
`2
`
`3
`
`4
`5
`6
`
`7
`
`8
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`
`§103
`
`§103
`§103
`§103
`
`§103
`
`§103
`
`Index of References
`
`Maloney
`The Penwest Statement and
`Baichwal
`Maloney, the Penwest
`Statement and Baichwal
`Maloney and Gordon
`Oshlack
`Oshlack and the Handbook
`of Dissolution Testing
`Oshlack, the Penwest
`Statement and Baichwal
`Oshlack and Gordon
`
`'122 Patent
`Claims
`1-4, 16 and 18-20
`1-4, 16 and 18-20
`
`1-4, 16 and 18-20
`
`1-4, 16 and 18-20
`1-4, 16 and 18-20
`1-4, 16 and 18-20
`
`1-4, 16 and 18-20
`
`1-4, 16 and 18-20
`
`1. Ground 1: Claims 1-4, 16 and 18-20 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
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`Sustained-Release Formulation" published in English on February 8, 2001.
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`Petition for Inter Partes Review of USPN 8,309,122
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`Maloney qualifies as prior art to the '122 patent under 35 U.S.C. §102(a). Claims
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`1-4, 16 and 18-20 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
`
`Maloney, Petitioner's experts prepared an oxymorphone formulation following the
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`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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`Petition for Inter Partes Review of USPN 8,309,122
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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
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`Maloney for use in its controlled release formulations. (AMN 1006, 13:15-18;
`
`17:14-18.) The CAFC, in its decision on the appeal of the Office's rejection of the
`
`claims of the '122 patent over Maloney, "[a]ccept[ed] that it would be obvious to
`
`substitute oxymorphone in Maloney's Formula 6." In re Kao, 639 F.3d 1057, 1066
`
`(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, ¶68.) 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;
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`11:20; AMN 1003, ¶68.) "Where there is a range disclosed in the prior art, and the
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`Petition for Inter Partes Review of USPN 8,309,122
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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
`
`evidence that the prior art teaches away from the claimed subject matter of the '122
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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.
`
`The CAFC addressed the alleged nonobviousness of the claimed dissolution
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`profile in the appeal of the Office's rejection of the claims of the '122 patent. Kao,
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`639 F.3d at 1066. The 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
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`court explained "it matters not whether the hypothetical skilled artisan would have
`
`appreciated the 'correlation' at issue here, it matters greatly whether anything the
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`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
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`profiles recited therein. (AMN 1003, ¶70; AMN 1002, ¶ 67.)
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`Petition for Inter Partes Review of USPN 8,309,122
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`Further, a POSA would have had a reason to make controlled release
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`oxymorphone compositions as claimed from the teachings of Maloney. Maloney
`
`teaches that there are many therapeutic benefits to formulating opioids in
`
`controlled release form and provides oxymorphone as a preferred opioid. (AMN
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`1006, 1:23-2:7; 13:15-19; AMN 1003, ¶64.)
`
`The Maloney Test Formula shows oxymorphone release at 1, 4 and 10 hours
`
`as provided in Table 2. (AMN 1002, ¶¶ 57-59.) In vitro dissolution tests were
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`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 1-4, 16 and 18-
`
`20 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
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`obtained the oxymorphone controlled release compositions claimed from the
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`Petition for Inter Partes Review of USPN 8,309,122
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`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 '122 patent merely
`
`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.
`
`The '122 Patent
`1. An analgesically
`effective controlled
`release pharmaceutical
`composition with a twelve
`hour dosing interval in the
`form of a tablet,
`
`
`Maloney
`"A particularly useful formulation of oxycodone
`which has been found to effectively control pain1 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.
`"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.
`"Preferred opioid compounds useful in the present
`invention are selected, without limitation, from the
`group consisting of: …oxycodone hydrochloride,
`oxymorphone, …." AMN 1006, 13:15-19.
`
`comprising oxymorphone
`or a pharmaceutically
`acceptable salt thereof as
`the sole active ingredient
`in the tablet,
`and a controlled release
`
`1 Boldface type in the claim chart is added for emphasis throughout this petition.
`
`"The formulations of the present invention may
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`The '122 Patent
`delivery system
`comprising at least one
`pharmaceutical excipient,
`wherein upon placement
`of the composition 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.
`2. The pharmaceutical
`composition of claim 1
`wherein 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.
`3. The pharmaceutical
`composition of claim 1
`wherein at least about
`80%, by weight, of the
`oxymorphone or salt
`thereof is released from
`the tablet at about 10
`hours in the test.
`4. The pharmaceutical
`composition of claim 1
`wherein the controlled
`release delivery system
`
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`Petition for Inter Partes Review of USPN 8,309,122
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`Maloney
`include diluents, lubricants, glidants and
`additives…." AMN 1006, 10:28-29.
`
`See Maloney Test Formula in Table 1 above. AMN
`1006, 10:28 – 11:21; 13:3-19; 17, Table 3; AMN
`1003, ¶48.
`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, ¶66.
`
`See claim 1 above.
`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, ¶66.
`
`See claim 1 above.
`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, ¶66.
`
`See claim 1 above.
`Maloney: "Typical matrix-forming polymers useful in
`the present invention, include, without limitation,
`hydroxypropylmethyl cellulose …." AMN 1006,
`
`- 13 -
`
`

`

`
`
`
`
`The '122 Patent
`comprises a hydrophilic
`material that forms a gel
`upon exposure to
`gastrointestinal fluid.
`
`16. The pharmaceutical
`composition of claim 1
`wherein oxymorphone or
`pharmaceutically
`acceptable salt thereof is
`present in an amount of
`about 5 mg to about 80
`mg.
`
`18. A method of treating
`pain in a subject in need
`thereof, the method
`comprising administering
`to the subject the
`pharmaceutical
`composition of claim 1
`comprising about 5 mg to
`about 80 mg of
`oxymorphone or
`pharmaceutically
`acceptable salt thereof.
`
`19. An analgesically
`effective controlled
`release pharmaceutical
`composition with a twelve
`hour dosing interval in the
`
`
`
`Petition for Inter Partes Review of USPN 8,309,122
`
`Maloney
`
`9:17-19.
`The '122 Patent: "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: 6:49-59.
`See claim 1 above.
`Maloney: "It has been surprisingly found that
`formulations having from about 5 to about 100 mg
`oxycodone …" AMN 1006, 7:21-22
`Maloney: "there is disclosed a solid, oral, controlled
`release dosage form comprising a therapeutically
`effective amount of opioid compound…." AMN 1006,
`8:9-11.
`See claim 1 above.
`Maloney: "Yet another aspect of the present invention
`relates to methods for reducing the range in daily
`dosages required to control pain in a human using
`the formulations described." AMN 1006, 12:11-13
`Maloney: "A formulation of the present invention
`may comprise from about 0.1 - 500 mg opioid
`compound…." AMN 1006, 11:18-19
`Maloney: "there is disclosed a solid, oral, controlled
`release dosage form comprising a therapeutically
`effective amount of opioid compound…." AMN 1006,
`8:9-11.
`Maloney: "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
`
`- 14 -
`
`

`

`
`
`
`
`The '122 Patent
`form of a tablet,
`
`comprising oxymorphone
`or pharmaceutically
`acceptable salt thereof as
`the sole active ingredient
`in the tablet and
`a controlled release
`delivery system
`comprising a hydrophilic
`material that forms a gel
`upon exposure to
`gastrointestinal fluid,
`wherein upon placement
`of the composition 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 composition at about 1
`hour in the test, about
`45% to about 80%, by
`weight, of the
`oxymorphone or salt
`thereof is released from
`
`
`
`Petition for Inter Partes Review of USPN 8,309,122
`
`Maloney
`… 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.
`"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: "Preferred opioid compounds useful in the
`present invention are selected, without limitation,
`from the group consisting of:… oxycodone
`hydrochloride, oxymorphone, …." AMN 1006,
`13:15-19
`Maloney: "Typical matrix-forming polymers useful in
`the present invention, include, without limitation,
`hydroxypropylmethyl cellulose …." AMN 1006,
`9:17-19.
`
`See the Maloney Test Formula in Table 1 above.
`AMN 1006, 10:28 – 11:21; 13:3-19; 17, Table 3 AMN
`1003, ¶48.
`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, ¶66.
`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, ¶66.
`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, ¶66.
`
`- 15 -
`
`

`

`
`
`Petition for Inter Partes Review of USPN 8,309,122
`
`Maloney
`
`See claims 18 and 19 above.
`See discussion below.
`
`
`
`
`
`
`The '122 Patent
`the composition at about 4
`hours in the test, and at
`least about 80%, by
`weight, of the
`oxymorphone or salt
`thereof is released from
`the composition at about
`10 hours in the test.
`20. The method of claim
`18 wherein upon oral
`administration of the
`composition the
`oxymorphone AUC(o-inf) is
`no more than 20% higher
`when the composition is
`administered to the
`subject under fed as
`compared to fasted
`conditions.
`
`
`Claims 1-3: As shown in the claim chart above, Maloney discloses a
`
`controlled release oxymorphone composition having the in vitro dissolution
`
`profiles recited in claims 1-3. (AMN 1006, 10:28 – 11:21; 13:3-19; 17, Table 3;
`
`AMN 1003, ¶¶65, 70; AMN 1002, ¶68.) Maloney discloses controlled release
`
`opioid compositions comprising oxymorphone, controlled release gel-forming
`
`polymer (HPMC) and excipients such as diluents, lubricants, glidants and
`
`additives. (AMN 1006, 7:29 – 9:15; 10:28-29; 13:15-19.)
`
`As discussed above, Petitioner's experts prepared and tested the Maloney
`
`- 16 -
`
`

`

`
`
`
`Test Formula, using Formula 6 of Table 3 as a template. Formula 6 of Maloney
`
`
`
`Petition for Inter Partes Review of USPN 8,309,122
`
`contains oxycodone, while the Maloney Test Formula contains oxymorphone. Both
`
`oxymorphone and 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; 17:14-18.) As discussed above, all of the variations in the tested
`
`formulation as compared with Formula 6 are within the explicit parameters
`
`disclosed Maloney and would have been obvious to a POSA from the teachings of
`
`Maloney. (AMN 1003, ¶68.)
`
` The Maloney Test Formula has an in vitro dissolution profile within the
`
`scope of claims 1-3 of the '122 patent. Figure 1 in the Gray declaration compares
`
`the dissolution profile obtained from the Maloney Test Formula in different pH
`
`buffers against with the minimum and maximum release profiles recited in the
`
`claims. (AMN 1002, ¶67.) As shown in Table 2, the Maloney Test Formula has an
`
`average release of oxymorphone at 1 hour of 29% at pH 1.2, 31% at pH 4.5 and
`
`26% at pH 6.8. (AMN 1002, ¶69.)
`
`Claim 2 depends from claim 1 and recites that about 45% to about 80%
`
`oxymorphone is released at about 4 hours in the dissolution test. As shown in
`
`Table 2 above, the Maloney Test Formula released an average of 61% of
`
`oxymorphone at pH 1.2, 62% at pH 4.5 and 56% at pH 6.8 at four hours. (AMN
`
`1002, ¶69.) Claim 3 depends from claim 2 and recites that at least about 80%
`
`- 17 -
`
`

`

`
`
`
`oxymorphone is released at about ten hours in the dissolution test. As shown in
`
`
`
`Petition for Inter Partes Review of USPN 8,309,122
`
`Table 2 above, the Maloney Test Formula has an average release of oxymorphone
`
`at ten hours of 85% at pH 1.2, 82% at pH 4.5 and 79% at pH 6.8. (AMN 1002,
`
`¶69.)
`
`It is clear that the dissolution values obtained from the Maloney Test
`
`Formula at pH 1.2 and 4.5 fall within the ranges recited in claim 3. And as
`
`discussed above in Section VI, a POSA would have understood the term "about" as
`
`it is used in the context of the percent by weight of oxymorphone released in
`
`dissolution testing to encompass values of at least ± 10% of the value measured.
`
`Thus, a POSA would have understood that the term "at least about 80%"
`
`encompasses oxymorphone release of 78%, as occurred with two tablets under one
`
`set of test conditions. (AMN 1002, ¶70.) Because Maloney teaches the claimed
`
`oxymorphone compositions with the dissolution profiles recited in claims 1-3,
`
`these claims would have been obvious.
`
`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
`
`to a grade that provides a faster release. (AMN 1006, 2:22 – 3:7; AMN 1003, ¶72.)
`
`- 18 -
`
`

`

`
`
`
`
`
`
`Petition for Inter Partes Review of USPN 8,309,122
`
`Claim 4 depends from claim 1 and recites that the controlled release delivery
`
`system comprises a hydrophilic material that forms a gel upon exposure to
`
`gastrointestinal fluid. As shown in the claim chart above, one such hydrophilic
`
`material is HPMC, as the '122 patent itself recognizes. (AM