`LLC
`
`
`
`Jeffrey D. Blake, Esq.
`MERCHANT & GOULD P.C.
`191 Peachtree Street N.E., Suite 4300
`Atlanta, GA 30303
`jblake@merchantgould.com
`Main Telephone: (404) 954-5100
`Main Facsimile: (404) 954-5099
`
`
`UNITED STATES PATENT AND TRADEMARK OFFICE
`_____________________
`
`BEFORE THE PATENT TRIAL AND APPEAL BOARD
`_____________________
`
`
`COALITION FOR AFFORDABLE DRUGS II LLC
`Petitioner
`
`
`By:
`
`
`
`
`
`
`
`
`v.
`
`
`NPS PHARMACEUTICALS, INC.
`Patent Owner
`
`_____________________
`
`Case No. To Be Assigned
`Patent No. 7,056,886
`_____________________
`
`
`PETITION FOR INTER PARTES REVIEW OF U.S. PATENT NO. 7,056,886
`(CLAIMS 1-45) UNDER 35 U.S.C. §§ 311-319 and 37 C.F.R. § 42.100 et seq.
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`
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`i
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`TABLE OF CONTENTS
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`INTRODUCTION .......................................................................................... 1
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`
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`I.
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`II. MANDATORY NOTICES PURSUANT TO 37 C.F.R. § 42.8 ..................... 3
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`III. PAYMENT OF FEES ..................................................................................... 6
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`IV. REQUIREMENTS UNDER 37 C.F.R. § 42.104 ............................................ 6
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`V.
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`VI. PETITIONER HAS A REASONABLE LIKELIHOOD OF
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` PREVAILING ............................................................................................ 17
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`A.
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`B.
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`C.
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`Real Party-In-Interest ............................................................................ 3
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`Related Matters ...................................................................................... 4
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`Lead and Backup Counsel ..................................................................... 5
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`D.
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`Service Information ............................................................................... 5
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`A. Grounds for Standing ............................................................................ 6
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`B.
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`Identification of Challenge and Precise Relief Requested .................... 7
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`1.
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`2.
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`3.
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`4.
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`Claims for Which Inter Partes Review is Requested ................. 7
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`Statutory Ground on Which the Challenge is Based .................. 7
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`Evidence Relief Upon to Support the Challenge ........................ 8
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`How the Challenge Claims Are to be Construed ........................ 8
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`SUMMARY OF THE '886 PATENT............................................................ 11
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`A.
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`B.
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`Lineage of the '886 patent ................................................................... 11
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`Examination of the '886 patent ............................................................ 11
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`C. Overview of the Cited Prior Art and the State of the Art ................... 15
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`
`
`ii
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`A.
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`Each Reference Relied on for Grounds 1-4 Is Prior Art ..................... 19
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`1.
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`2.
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`3.
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`4.
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`Ground 1: Claims 1-27, 33-35, 38 and 45 are obvious over
`Drucker '379 (Ex. 1029) and further in view of
`Kornfelt (Ex. 1027), and Osterberg (Ex. 1030) ........................ 19
`
`Ground 2: Claims 31-32 and 44 are obvious over Drucker '379
`and further in view of
`Kornfelt, Osterberg , and Munroe(Ex. 1022)............................ 19
`
`Ground 3: Claims 28-30, and 39-43, are obvious over Drucker
`'379 and further in view of Kornfelt, Osterberg,
`and Holthuis (Ex.1005) ............................................................. 20
`
`Ground 4: Claims 36-37 are obvious over Drucker ‘379, and
`further in view of Kornfelt, Osterberg, and Drucker
`‘574 (Ex.1028)………………………………………………..20
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`B. A Person of Ordinary Skill in the Art ................................................. 21
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`C.
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`Claims 1-45 are Obvious ..................................................................... 21
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`D.
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`E.
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`F.
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`1.
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`2.
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`3.
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`Grounds 1 and 2: All of the limitations of Claims 1-27, 31-35,
`38,and 44-45 directed to a GLP-2 formulation are disclosed in
`the combination of the cited references .................................... 22
`
`Ground 3: The limitations of Claims 28-30, and 39-43 directed
`further to a lyophilized formulation are disclosed in the
`combination of the prior art references ..................................... 42
`
`Ground 4: The limitations of Claims 36-37 directed further to a
`formulation of a GLP-2 analog are disclosed in the combination
`of the prior art references .......................................................... 46
`
`There was a Reason to Combine the Cited References ...................... 48
`
`There was a Reasonable Expectation of Success ................................ 52
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`There is no Evidence of Secondary Considerations ............................ 55
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`iii
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`VII. CONCLUSION .............................................................................................. 57
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`CERTIFICATE OF SERVICE…………………………………………………..59
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`iv
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`TABLE OF AUTHORITIES
`
`
`Page(s)
`
`
`Cases
`
`Galderma Labs., L.P. v. Tolmar, Inc.,
` 737 F.3d 731 (Fed. Cir. 2013) .................................................................... 54
`
`Graham v. John Deere Co.,
` 383 U.S. 1, 17-18 (1966) ...................................................................... 18, 19
`
`KSR Int’l Co. v. Teleflex, Inc.,
` 550 U.S. 398 (2007) ............................................................................. 19, 46
`
`Merck & Co. v. Teva Pharms. USA, Inc.,
` 395 F.3d 1364, (Fed. Cir. 2005) .................................................................. 17
`
`Par Pharm., Inc. v. TWI Pharms., Inc.,
` 773 F.3d. 1186 (Fed. Cir. 2014) ................................................................. 52
`
`Pfizer, Inc. v. Apotex, Inc.,
` 480 F.3d 1348 (Fed. Cir. 2007) ...................................................... 46, 52, 54
`
`Statutes
`
`35 U.S.C. § 102 (b) .............................................................................. 8, 19, 20
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`35 U.S.C. § 103(a) ........................................................................... 7, 8, 17, 18
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`35 U.S.C. § 112 ........................................................................................ 12, 13
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`35 U.S.C. §§ 311-319 ...................................................................................... 1
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`35 U.S.C. § 318(a) ........................................................................................... 6
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`Other Authorities
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`37 C.F.R. § 42.100 ................................................................................... 1,8,57
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`v
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`37 C.F.R. § 42.6(c) ........................................................................................ 18
`37 CPR. §42.6(c) ........................................................................................ 18
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`37 C.F.R. § 42.6(e) ........................................................................................ 57
`37 CPR. § 42.6(e) ........................................................................................ 57
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`37 C.F.R. § 42.8(b)(1) ..................................................................................... 3
`37 CPR. § 42.8(b)(1) ..................................................................................... 3
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`37 C.F.R. § 42.8(b)(2) ..................................................................................... 4
`37 CPR. § 42.8(b)(2) ..................................................................................... 4
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`37 C.F.R. § 42.10(b) ........................................................................................ 5
`37 CPR. § 42.10(b) ........................................................................................ 5
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`37 C.F.R. § 42.15(a)(1-4) ................................................................................ 6
`37 CPR. §42.15(a)(1-4) ................................................................................ 6
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`37 C.F.R. § 42.15(a)(3)) .................................................................................. 6
`37 CPR. §42.15(a)(3)) .................................................................................. 6
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`37 C.F.R. § 42.15(a)(4)) .................................................................................. 6
`37 CPR. § 42.15(a)(4)) .................................................................................. 6
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`37 C.F.R. § 42.102(a)(2) .................................................................................. 6
`37 CPR. § 42.102(a)(2) .................................................................................. 6
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`37 C.F.R. § 42.104(a) ...................................................................................... 6
`37 CPR. § 42.104(a) ...................................................................................... 6
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`37 C.F.R. § 42.104(b) ...................................................................................... 7
`37 CPR. § 42.104(b) ...................................................................................... 7
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`
`vi
`Vi
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`I.
`
`INTRODUCTION
`
`
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`Coalition for Affordable Drugs II LLC (“Petitioner” or “CFAD”)
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`respectfully requests an Inter Partes (“IPR”) review for Claims 1-45 of U.S.
`
`Patent No. 7,056,886, issued on June 6, 2006, to Isaacs (“the ’886 patent”) (Ex.
`
`1003) in accordance with 35 U.S.C. §§ 311-319 and 37 C.F.R. § 42.100 et seq.
`
`Independent claim 1 is directed to a formulation containing a peptide
`
`known as “glucagon-like peptide-2” (“GLP-2”) or an analog thereof. There is a
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`reasonable likelihood that this independent claim and those claims depending
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`therefrom are unpatentable because they would have been obvious to a person
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`of ordinary skill in the art.
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`Formulations of GLP-2 and analogs thereof, and the therapeutic use of
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`such formulations for treatment of gastrointestinal disorders were well known
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`before the earliest effective filing date of the ’886 patent. Storage stable
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`lyophilized formulations of a related peptide, glucagon, were also disclosed in
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`the prior art. As shown herein, the combination of the cited prior art references
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`discloses all of the limitations of the claimed GLP-2 formulations.
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`A person of ordinary skill in the art would have been motivated to
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`combine these prior art references in order to form a stable GLP-2 formulation
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`for therapeutic use because there was a known design need for storage stable
`
`formulations. It was known that formulations of peptides, including peptides
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`
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`1
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`
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`such as glucagon, lack storage stability. A solution to this problem, provided by
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`the prior art, was to lyophilize the formulation in the presence of L-histidine and
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`sucrose or mannitol to increase storage stability. Furthermore, GLP-2 and
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`glucagon disclosed in the prior art are structurally similar leading one of
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`ordinary skill in the art to combine disclosures in the prior art references with a
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`view to forming a stable GLP-2 formulation.
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`The combination of the prior art also provides a reasonable expectation of
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`success in formulating GLP-2 in combination with L-histidine and sucrose or
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`mannitol to create a storage stable lyophilized formulation. Through routine
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`experimentation, a person of ordinary skill in the art would have easily substituted
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`active ingredients having a similar physical and chemical profile to glucagon into
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`stable formulations disclosed in the cited art. At the very least, storage stable
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`lyophilized formulations taught in the prior art for glucagon would have been
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`obvious to try with GLP-2.
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`The claimed subject matter represents nothing more than the predictable use
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`of known components having known functions, and represents a strong case for
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`obviousness that overcomes any evidence of secondary considerations. The
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`Patentee has not argued and cannot argue that the claimed subject matter provides
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`unexpected results because similar results are shown for storage stable
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`formulations of glucagon in the cited prior art. To the extent Patentee alleges
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`
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`2
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`commercial success to rebut the obviousness of claims 1-45, no nexus between
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`these claims and any alleged commercial success exists.
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`Thus, the claimed formulations of GLP-2 are obvious given the state of the
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`art before the filing date of the ’886 patent. As a result, claims 1-45 are
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`unpatentable and an IPR should be instituted on this basis.
`
`II. MANDATORY NOTICES PURSUANT TO 37 C.F.R. § 42.8
`
`A. Real Party-In-Interest
`
`Pursuant to 37 C.F.R. § 42.8(b)(1), Petitioner certifies that Coalition For
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`Affordable Drugs II LLC (“CFAD”), Hayman Credes Master Fund, L.P.
`
`(“Credes”), Hayman Orange Fund SPC – Portfolio A (“HOF”), Hayman Capital
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`Master Fund, L.P. (“HCMF”), Hayman Capital Management, L.P. (“HCM”),
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`Hayman Offshore Management, Inc. (“HOM”), Hayman Investments, L.L.C.
`
`(“HI”), nXn Partners, LLC (“nXnP”), IP Navigation Group, LLC (“IPNav”), J
`
`Kyle Bass, and Erich Spangenberg are the real parties in interest (collectively,
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`“RPI”). The RPI hereby certify the following information: CFAD is a wholly
`
`owned subsidiary of Credes. Credes is a limited partnership. HOF is a
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`segregated portfolio company. HCMF is a limited partnership. HCM is the
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`general partner and investment manager of Credes and HCMF. HCM is the
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`investment manager of HOF. HOM is the administrative general partner of
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`Credes and HCMF. HI is the general partner of HCM. J Kyle Bass is the sole
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`3
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`member of HI and sole shareholder of HOM. CFAD, Credes, HOF and HCMF
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`act, directly or indirectly, through HCM as the general partner and/or
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`investment manager of Credes, HOF and HCMF. nXnP is a paid consultant to
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`HCM. Erich Spangenberg is 98.5% member of nXnP. IPNav is a paid
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`consultant to nXnP. Erich Spangenberg is the 98.5% member of IPNav. Other
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`than HCM and J Kyle Bass in his capacity as the Chief Investment Officer of
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`HCM and nXnP and Erich Spangenberg in his capacity as the Manager/CEO of
`
`nXnP, no other person (including any investor, limited partner, or member or
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`any other person in any of CFAD, Credes, HOF, HCMF, HCM, HOM, HI,
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`nXnP or IPNav) has authority to direct or control (i) the timing of, filing of,
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`content of, or any decisions or other activities relating to this Petition or (ii) any
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`timing, future filings, content of, or any decisions or other activities relating to
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`the future proceedings related to this Petition. All of the costs associated with
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`this Petition will be borne by HCM, CFAD, Credes, HOF and/or HCMF.
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`B.
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`Related Matters
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`
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`Pursuant to 37 C.F.R. § 42.8(b)(2), Petitioner states that the ‘886 is the
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`subject of Pending Petition IPR2015-00990 also filed by Petitioner on April 1,
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`2015 that could affect, or be affected by, a decision in this proceeding.
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`4
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`C.
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`Lead and Backup Counsel
`
`Lead Counsel:
`Jeffrey D. Blake, Esq.
`Registration No. 58,884
`MERCHANT & GOULD P.C.
`191 Peachtree Street N.E.
`Suite 4300
`Atlanta, GA 30303
`Main Telephone: (404) 954-5100
`Main Facsimile: (404) 954-5099
`jblake@merchantgould.com
`
`
`
`Backup Counsel:
`Matthew L. Fedowitz, Esq.
`Registration No. 61,386
`MERCHANT & GOULD P.C.
`1701 Duke Street, Suite 310
`Alexandria, VA 22314
`Main Telephone: (703) 684-2500
`Main Facsimile: (703) 684-2501
`mfedowitz@merchantgould.com
`
`Katherine M. Kowalchyk, Esq.
`Registration No. 36,848
`Brent E. Routman
`(Pro Hac Vice)
`MERCHANT & GOULD P.C.
`3200 IDS Center
`80 South Eighth Street
`Minneapolis, MN 55402
`Main Telephone: (612) 332-5300
`Main Facsimile: (612) 322-9081
`kkowalchyk@merchantgould.com
`broutman@merchantgould.com
`
`A Power of Attorney is being filed concurrently herewith in accordance with
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`37 C.F.R. § 42.10(b).
`
`D.
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`Service Information
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`Papers concerning this matter should be served by EXPRESS MAIL, hand-
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`delivery, or electronic mail at the following addresses:
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`
`
`
`
`
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`Mailing Address: Jeffrey D. Blake, Esq.
`
`
`
`MERCHANT & GOULD P.C.
`
`
`
`191 Peachtree Street N.E., Suite 4300
`
`
`
`Atlanta, GA 30303
`Electronic Mail:
`jblake@merchantgould.com
`
`
`
`5
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`Main Telephone: 404-954-5100
`Main Facsimile: 404-954-5099
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`III. PAYMENT OF FEES
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`Payment of $ 40,000 for the fees set forth in 37 C.F.R. § 42.15(a)(1-4) for
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`this Petition for Inter Partes Review accompanies this request by way of credit
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`card payment. Forty-five claims are challenged and excess claim fees in the
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`amount of $5000 (under 37 C.F.R. § 42.15(a)(3)) and $12,000 (under 37 C.F.R. §
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`42.15(a)(4)) are included. The undersigned further authorizes payment for any
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`additional fees that might be due in connection with this Petition to be charged to
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`Deposit Account No. 13-2725.
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`IV. REQUIREMENTS UNDER 37 C.F.R. § 42.104
`
`A. Grounds for Standing
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`Pursuant to 37 C.F.R. § 42.104(a), Petitioner hereby certifies that the ’886
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`patent is available for Inter Partes review in accordance with 37 C.F.R. §
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`42.102(a)(2), and that the Petitioner is not barred or estopped from requesting Inter
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`Partes review challenging the claims of the ’886 patent on the grounds identified
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`in this Petition. Neither Petitioner nor any privy of Petitioner has received a final
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`written decision under 35 U.S.C. § 318(a) with respect to any claim of the ’886
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`patent on any ground that was raised or could have been raised by Petitioner or its
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`privies in any Inter Partes review, post grant review, or covered business method
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`patent review.
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`6
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`B.
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`Identification of Challenge and Precise Relief Requested
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`Pursuant to 37 C.F.R. § 42.104(b), Petitioner challenges Claims 1-45 of the
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`’886 patent and requests that these claims be found unpatentable over the prior art
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`for the reasons given herein.
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`1.
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`Claims for Which Inter Partes Review is Requested
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`
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`Petitioner requests Inter Partes review of Claims 1-45 of the ’886 patent.
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`The claims of the ’886 patent at issue are directed to GLP-2 peptide formulations
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`(claims 1-45). Claim 1 is an independent claim and claims 2-45 all depend directly
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`or indirectly from Claim 1.
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`2. Statutory Ground on Which the Challenge is Based
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`
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`Claims 1-27, 33-35, 38 and 45 are unpatentable because they are obvious
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`under 35 U.S.C. § 103(a) in view of the combined teachings of U.S. Patent No.
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`5,789,379 to Drucker et al. (“Drucker ’379”) (Ex. 1029), U.S. Patent No.
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`5,652,216 to Kornfelt et al. (“Kornfelt”) (Ex. 1027), and Osterberg et al., “Physical
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`State of L-histidine after Freeze Drying and Long Term Storage,” European
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`Journal of Pharmaceutical Sciences 8(1999)301-308 (“Osterberg”) (Ex.1030).
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`Claims 31, 32, and 44 are unpatentable because they are obvious over Drucker
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`‘379, Kornfelt, Osterberg and Munroe et al., Prototypic G-protein coupled receptor
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`for the intestinotrophic factor glucagon –like peptide 2, Proc. Nat’l Acad. Sci.
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`96:1569 (1999)(“Munroe”)(Ex. 1022). Claims 28-30 and 39-43 are obvious over
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`7
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`
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`Drucker ‘379, Kornfelt, Osterberg, and U. S. Patent No. 5,496,801 to Holthuis et
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`al, (“Holthuis”)(Ex. 1005). Claims 36-37 are obvious over Drucker ‘379,
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`(“Drucker ’547) (Ex. 1028), Kornfelt, and Osterberg.
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`3.
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`Evidence Relied Upon to Support the Challenge
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`Petitioner relies upon each of the publications cited herein. Each publication
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`has a publication date more than one year prior to the ’886 patent’s effective filing
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`date of December 30, 2000. On this basis, they are available as prior art under 35
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`U.S.C. § 102 (b). Petitioner also relies upon the Declaration of Dr. Anthony
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`Palmieri III, Ph.D., R.Ph., an Associate Scholar of Pharmaceutics at the University
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`of Florida College of Pharmacy (Ex. 1001), and the documents cited therein (Exs.
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`1002-1031), including Dr. Palmieri’s curriculum vitae (Ex. 1002).
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`4. How the Challenged Claims Are to be Construed
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`The terms of the claims of the ’886 patent are to be given their broadest
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`reasonable interpretation in light of the specification, as understood by a person of
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`ordinary skill in the art. See 37 C.F.R. § 42.100(b).
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`An “analog” of GLP-2 is construed to mean a peptide that incorporates one
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`or more amino acid substitutions, deletions, additions, or modifications into a
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`natural GLP-2 peptide and retains biological activity (Ex. 1003 at 4:33-36, 1:30-
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`37; Ex. 1001 at ¶ 26). During prosecution, the Applicant overcame an
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`indefiniteness rejection by confirming that term “analog” conformed to this
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`8
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`definition (Ex. 1008 at 3; Ex. 1001 at ¶ 26). Similarly, Applicant stated that
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`“biological activity” means that “GLP-2 and analogs thereof act as trophic agents
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`to enhance and maintain the functioning of the gastrointestinal tract and to promote
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`the growth of intestinal tissue” to overcome a similar indefiniteness rejection (Ex.
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`1008 at 4; Ex. 1001 at ¶ 26).
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`“Medically useful amount” is defined in the specification to mean an amount
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`of GLP-2 or analog thereof that ranges from a few micrograms to milligrams. This
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`amount includes the ranges specified in the specification of about 0.1 to about 50
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`mg/ml of GLP-2, preferably about 5 to about 40 mg/ml, more preferably about 7 to
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`about 30 mg/ml, even more preferably about 10 to about 20 mg/ml, and most
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`preferably about 20 mg/ml (Ex. 1003 at 2:14-19,5:59-61, 6:12-19; Ex. 1001 at ¶
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`27).
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`“Medically useful amount” or “medically effective amount is construed to
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`mean an amount which is useful either therapeutically or diagnostically (Ex. 1003
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`at 5:59-61; Ex. 1001 at ¶ 27).
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`“Therapeutically effective amount” is defined in the specification to mean an
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`amount of GLP-2 or analog thereof including unit dosage amounts useful to treat a
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`subject including multidose amounts (Ex. 1003 at 5:64-67, 6:5-7; Ex. 1001 at ¶
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`28).
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`9
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`“An amount sufficient to adjust the pH of the formulation to a physiological
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`tolerable level” is defined in the ’886 specification, to mean an amount that
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`buffers the formulation to a pH that elicits reactions, in a recipient, that are not so
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`extreme to preclude further administration of the formulation (Ex. 1003 at 5:45-51;
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`Ex. 1001 at ¶ 29). The specification states that this includes a pH of greater than
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`about 5.5, more preferably greater than about 6, even more preferably of about 6.9
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`to about 7.9, and most preferably about 7.3 to about 7.4 (Ex. 1003 at 5:52-56; Ex.
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`1001 at ¶ 29).
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`“An amount sufficient to adjust the pH of the formulation to a
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`pharmaceutically tolerable level” refers to an exemplary pH of “above about 6.0”
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`as set forth in the specification (Ex. 1003 at 2:9-11; Ex. 1001 at ¶ 30).
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`“An amount sufficient to stabilize the formulation” is defined in the
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`specification, as an amount of histidine that increases “the length of time that the
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`GLP-2 peptide remains intact prior to degradation” (Ex. 1003 at 5:30-32; Ex. 1001
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`at ¶ 31). This amount includes 0.5 to 1% histidine (Ex. 1003 at 6:25-26; Ex. 1001
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`at ¶ 31). The specification specifies that the formulation when reconstituted from a
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`lyophilized form is stable at least about 12 hours and preferably up to 24 hours at
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`4°C (Ex. 1003 at 7:1-3; Ex. 1001 at ¶ 31). Stability or degradation of GLP-2 or
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`analogs thereof is measured by determining the purity and quantity of the peak of
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`10
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`GLP-2 using reverse phase high pressure liquid chromatography. (Ex. 1003 at 9:65
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`to10:8; Ex. 1001 at ¶ 31).
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`V.
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`SUMMARY OF THE ’886 PATENT
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`A. Lineage of the ’886 patent
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`The ’886 patent is entitled “GLP-2 Formulations.” (Ex. 1003, Cover page.)
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`The ’886 patent issued on June 6, 2006, from U.S. Patent Application Serial No.
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`09/750,022, filed on December 29, 2000 (“the ’022 application”) (Ex. 1003. Cover
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`page). The ’022 application claims priority to Great Britain Patent Application No.
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`9930882 (Ex. 1003, Cover Page), filed on December 30, 1999.
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`B.
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`Examination of the ’886 patent
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`Relevant portions of the file history of ’886 patent are presented herein. The
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`’886 patent issued from the ’022 application, filed on December 29, 2000. Before
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`allowance, the Examiner issued three Non Final Actions, a Final Action that was
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`withdrawn, followed by another Non Final Action. The claim rejections asserted
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`by the Examiner were based on indefiniteness and obviousness. The obviousness
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`rejections were overcome by the Applicant arguing that there was no motivation to
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`combine the uncontested prior art.
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`A first Non-Final Office Action issued on March 8, 2002 (Ex. 1007). The
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`Examiner rejected claims 1-54 under 35 U.S.C. § 112, second paragraph finding
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`many claim terms indefinite (Ex. 1007 at 3-4). The indefinite terms included:
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`“GLP-2;” “an analog;” “one or more amino acid substitutions, addition, deletions
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`or modifications;” “biological activity;” claiming pH ranges with the term “about;”
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`“less than about;” “for up to at least;” “up to about 24 hours;” and “a disorder,
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`disease or condition” (Id.). The Office Action did not include any rejections based
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`on prior art. Applicant filed an Amendment and Reply on June 10, 2002,
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`addressing the indefiniteness rejections (Ex. 1008).
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`A second Non-Final Office Action issued on February 5, 2003 (Ex. 1009).
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`There, the Examiner rejected the claims as being obvious over a combination of
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`Knudsen (WO 99/043361) (Ex. 1025) and Makino (U.S. Patent No. 4,985,244)
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`(Ex.1026) (Ex. 1009 at 3). The Examiner supplemented the obviousness rejection
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`by citing to Hora et al., (US Patent No.5,997,856) Drucker et al. (WO 97/39031)
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`Thim et al. (U.S. Patent No. 5,912,229) and Drucker (U.S. Patent No. 5,952,301)
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`to reject claims 1-22, 31, 43-46, and 49-54 (Id. at 4-7).
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`Applicant filed an Amendment and Reply on July 9, 2003, where it was
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`argued that the Examiner had not demonstrated a motivation to combine or a
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`reasonable expectation of success in view of the combination of Knudsen and
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`Makino (Ex. 1010 at 4-5). Notably, Applicant did not challenge the contention that
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`the combination of the references disclosed all of the limitations of the claims (Id.
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`at 4-5.).
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`A third Non-Final Office Action issued on September 16, 2003 (Ex. 1011).
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`The Examiner once again rejected numerous claims as indefinite (Ex. 1011 at 3-
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`5.). The Examiner rejected claims 1-22, 31-33,43-46, and 49-55 as obvious in view
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`of Knudsen (Ex. 1025) in combination with Yamazaki et al. (U.S. Patent No.
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`6,120,761) (Ex. 1006) (Ex. 1011 at 5-6) and the same supplementary references as
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`the previous obviousness rejection.
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`In response, Applicant filed an Amendment and Reply on March 16, 2004
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`(Ex. 1012). Applicant once again argued that the Examiner had not demonstrated a
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`motivation to combine the prior art references and was using an improper “obvious
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`to try” standard (Id. at 15-1.). Applicant argued that one of skill in the art would
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`not have been motivated to design a formulation for GLP-2 peptides because of
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`differences between the erythropoietin protein of Yamazaki and GLP-2 (Id.).
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`A Final Office Action issued on June 8, 2004 with the Examiner allowing
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`numerous claims and rejecting a number of others as indefinite under 35 U.S.C.
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`§112, second paragraph (Ex. 1013). Applicant filed an Amendment and Reply on
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`September 7, 2004 arguing the claims were not indefinite (Ex. 1014).
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`The Final Office Action was surprisingly withdrawn, and a fourth Non-Final
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`Office Action issued on October 4, 2004, with the Examiner rejecting a number of
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`claims as indefinite and as being obvious (Ex. 1015). The Examiner rejected
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`claims 1-22, 43-46, and 73-78 using Knudsen (Ex. 1025) in combination with
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`Kornfelt (U.S. Patent No. 5,652,216) (Ex. 1027) and the same supplementary
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`references as previously discussed (Id. at 4-5).
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`Applicant filed an Amendment and Reply on January 4, 2005, arguing that
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`the Examiner had failed to demonstrate a motivation to combine the prior art cited
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`and that the claims would not be indefinite to one of skill in the art (Ex. 1016).
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`Applicant argued that there would be no reason to combine Knudsen and Kornfelt,
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`despite the fact that Kornfelt expressly disclosed histidine stabilized glucagon
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`formulations, and that glucagon and GLP-2 were known to be related peptides (Id.
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`at 15-16). Applicant argued that GLP-2 differs from glucagon in sequence and in
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`solubility in water at a pH of 2-4(Id. at 16). Applicant further argued that one of
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`ordinary skill in the art would not attempt to design a formulation for GLP-2 based
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`on Kornfelt without providing any evidence or expert declaration that the
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`differences in amino acid sequence or solubility would affect the structure or
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`stability of GLP-2 in a formulation as taught by Kornfelt (Id. at 17).
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` On April 4, 2005, a Notice of Allowance issued for claims 1-51, 53-55, and
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`58-78 of the ’022 application (Ex. 1017). The alleged reasons for allowance were:
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`Knudsen et al. (WO 99/43361) teach a pharmaceutical composition
`comprising a GLP-2 derivative or analog, an isotonic agent such as
`mannitol, a buffer of histidine or sodium phosphate, a pharmaceutical
`acceptable carrier, a preservative and a surfactant; Kornfelt et al. (U.S.
`Patent 5,652,216) disclose using stabilizing amount of a
`pharmaceutically acceptable ampholyte such as glycine, histidine or
`GlyGly in a pharmaceutical preparation comprising glucagons.
`However, Knudsen et al. either alone or in combination with Kornfelt
`et al. do not teach or suggest a GLP-2 formulation comprising a
`medically useful amount of GLP2 or an analog thereof, a phosphate
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`buffer, L-histidine for stabilizing the formulation and a bulking agent
`of mannitol and sucrose.
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`(Id.at 2).
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`The ’022 application issued as the ’886 patent on June 6, 2006 (Ex. 1003).
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`C. Overview of the Cited Prior Art and the State of the Art
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`Formulations of GLP-2, and methods of preparing formulations of GLP-2
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`were known prior to the effective filing date of the’886 patent (Ex. 1028 at p.
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`19:15-36; Ex. 1001 at ¶ 35). Biologically active analogs of GLP-2 with amino acid
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`substitutions were also known as described extensively in Drucker ’379 (cited
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`herein;Ex.1029 at p. 4:6-7:20, p. 15:1-35; Ex. 1001 at ¶ 35). Drucker ’379 teaches
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`that GLP-2 was known to be susceptible to DPP-IV cleavage (Ex.1029 at p. 6:36-
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`45; Ex. 1021 at 675; Ex. 1001 at ¶ 35). This led to the development of analogs with
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`replacement of an amino acid at position 2, the DPP-IV cleavage site (Ex.1029 at
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`p. 6:36-45; Ex. 1001 at ¶ 35). One such analog of human GLP-2, h[Gly2]GLP-2,
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`was shown to be effective in an animal model of colitis (Ex. 1023 at G79; Ex. 1001
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`at ¶ 35). Analogs of GLP-2 that are antagonists were described in Drucker ‘574.
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`(cited herein; Ex.1028 at 4:3-10). Munroe shows that GLP-2 analogs, including
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`some known antagonists, were also known to bind to the GLP-2 receptor (cited
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`herein; Ex.1022 at 1573, Table 2; Ex. 1001 at ¶ 35).
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`It was known that GLP-2 was structurally related to glucagon. GLP-2 is a
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`peptide hormone member of the glucagon superfamily of peptide hormones and
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`has been described in the prior art since the 1980s (Ex. 1018 at 879; Ex. 1001 at ¶
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`36). GLP-2 and glucagon are generated from a single precursor, proglucagon,
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`produced in intestinal enteroendocrine cells (Ex. 1018 at 885, Figure 8b; Ex. 1001
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`at ¶ 36). GLP-2 exhibits 50% amino acid sequence similarity to glucagon and has a
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`similar molecular weight (Ex. 1018 at 879, Fig.3; Ex. 1001 at ¶ 36). Despite some
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`differences in amino acid sequence, glucagon (Ex.1019 at 254, Table V) and GLP-
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`2 (Ex. 1025 at p. 3:1-10; Ex. 1001 at ¶ 36) share a secondary structural feature of
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`an alpha helix region. Analogs of GLP-2 retain the alpha helix motif and as well as
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`binding capacity to the GLP-2 receptor (Ex.1022 at 1573, Table 2; Ex. 1020 at
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`8888, Abstract; Ex. 1001 ¶ 36). The GLP-2 receptor is a G coupled receptor and is
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`found in a class of G coupled receptors including the receptors for glucagon, GLP-
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`1 and parathyroid hormone (PTH). (Ex. 1018 at 896, col.2; Ex. 1001 ¶ 36).
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`It was known that pharmaceutical formulations of peptides for therapeutic
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`use need to be storage stable (Ex.1024 at 8; Ex. 1005 at 1:65-2:8; Ex. 1001 at ¶
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`37). At the time of filing of the ’886 patent, as taught by Osterberg, it was
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`standard in the art to prepare a lyophilized formulation to improve storage
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`stability of pharmaceutical compositions containing a peptide (cited
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`herein;Ex.1030 at 301; Ex. 1001 at ¶ 37). L-Histidine was well known as a
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`buffer and a stabilizing agent useful in lyophilized