Filed on behalf of Petitioner COALITION FOR AFFORDABLE DRUGS II
`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 46-52 and 61-75) UNDER 35 U.S.C. §§ 311-319 and 37 C.F.R. §
`42.100 et seq.
`
`
`
`
`i
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`

`

`TABLE OF CONTENTS
`
`INTRODUCTION .......................................................................................... 1
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`
`
`I.
`
`II. MANDATORY NOTICES PURSUANT TO 37 C.F.R. § 42.8 ..................... 3
`
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`
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`III. PAYMENT OF FEES ..................................................................................... 6
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`IV. REQUIREMENTS UNDER 37 C.F.R. § 42.104 ............................................ 7
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`V.
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`A.
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`B.
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`C.
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`Real Party-In-Interest ............................................................................ 3
`
`Related Matters ...................................................................................... 5
`
`Lead and Backup Counsel ..................................................................... 5
`
`D.
`
`Service Information ............................................................................... 6
`
`A. Grounds for Standing ............................................................................ 7
`
`B.
`
`Identification of Challenge and Precise Relief Requested .................... 7
`
`
`
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`
`
`1.
`
`2.
`
`3.
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`4.
`
`Claims for Which Inter Partes Review is Requested ................. 7
`
`Statutory Ground on Which the Challenge is Based .................. 8
`
`Evidence Relief Upon to Support the Challenge ........................ 9
`
`How the Challenge Claims Are to be Construed ........................ 9
`
`SUMMARY OF THE '886 PATENT............................................................ 11
`
`A.
`
`B.
`
`C.
`
`Lineage of the '886 patent ................................................................... 11
`
`Litigation Relating to the '886 patent .................................................. 12
`
`Examination of the '886 patent ............................................................ 12
`
`D. Overview of the Cited Prior Art and the State of the Art ................... 16
`
`
`
`ii
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`

`

`
`
`A.
`
`Each Reference Relied on for Grounds 1-4 Is Prior Art ..................... 20
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`1.
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`2.
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`3.
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`4.
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`
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`Ground 1: Claims 46-50, 52, and 69-75 are obvious in view
`of Drucker '379 (Ex. 1029) and further in view of
`Kornfelt (Ex. 1027), and Osterberg (Ex. 1030) ........................ 20
`
`Ground 2: Claims 61-67 are obvious in view of Drucker
`'600 (Ex. 1028) and further in view of Kornfelt (Ex. 1027),
`Osterberg (Ex. 1030), and Holthuis (Ex. 1005) ........................ 20
`
`Ground 3: Claims 51 and 75 are obvious in view of
`Drucker '379 and further in view of Kornfelt, Osterberg,
`and Munroe ............................................................................... 21
`
`Ground 4: Claim 68 is obvious in view of Drucker
`'600 and further in view of Kornfelt, Osterberg, Holthuis,
`and Munroe. .............................................................................. 21
`
`VI. PETITIONER HAS A REASONABLE LIKELIHOOD OF
`
` PREVAILING ............................................................................................ 18
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`VII. CONCLUSION .............................................................................................. 57
`
`B. A Person of Ordinary Skill in the Art ................................................. 21
`
`C.
`
`Claims 46-52 and 61-75 are Obvious .................................................. 22
`
`
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`D.
`
`E.
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`F.
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`1.
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`2.
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`
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`Grounds 1 and 3: All of the limitations of Claims 46-52,
`and 69-75 are disclosed in the combination of the cited
`references .................................................................................. 22
`
`Grounds 2 and 4: The limitations of Claims 61-68
`directed to a Kit are disclosed in the combination of the
`prior art references .................................................................... 37
`
`There is a Reason to Combine the Cited References .......................... 49
`
`There is a Reasonable Expectation of Success ................................... 52
`
`There is no Evidence of Secondary Considerations ............................ 55
`
`
`
`iii
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`

`
`
`TABLE OF AUTHORITIES
`
`
`Page(s)
`
`
`Cases
`
`Galderma Labs., L.P. v. Tolmar, Inc.,
` 737 F.3d 731 (Fed. Cir. 2013) .................................................................... 56
`
`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, 49
`
`Merck & Co. v. Teva Pharms. USA, Inc.,
` 395 F.3d 1364, (Fed. Cir. 2005) .................................................................. 18
`
`Par Pharm., Inc. v. TWI Pharms., Inc.,
` 773 F.3d. 1186 (Fed. Cir. 2014) ................................................................. 54
`
`Pfizer, Inc. v. Apotex, Inc.,
` 480 F.3d 1348 (Fed. Cir. 2007) ...................................................... 49, 55, 56
`
`Statutes
`
`35 U.S.C. § 102 (b) .............................................................................. 9, 20, 21
`
`35 U.S.C. § 103(a) ............................................................................... 8, 18, 19
`
`35 U.S.C. § 112 ........................................................................................ 12, 14
`
`35 U.S.C. §§ 311-319 ........................................................................................
`
`35 U.S.C. § 318(a) ........................................................................................... 7
`
`
`Other Authorities
`
`37 C.F.R. § 42.100 ........................................................................................... 9
`
`
`
`
`iv
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`

`

`
`
`37 C.F.R. § 42.6(c) ........................................................................................ 19
`37 CPR. §42.6(c) ........................................................................................ 19
`
`37 C.F.R. § 42.8(b)(1) ..................................................................................... 3
`37 CPR. § 42.8(b)(1) ..................................................................................... 3
`
`37 C.F.R. § 42.8(b)(2) ..................................................................................... 5
`37 CPR. § 42.8(b)(2) ..................................................................................... 5
`
`37 C.F.R. § 42.10(b) ........................................................................................ 6
`37 CPR. § 42.10(b) ........................................................................................ 6
`
`37 C.F.R. § 42.15(a)(1-4) ................................................................................ 6
`37 CPR. §42.15(a)(1-4) ................................................................................ 6
`
`37 C.F.R. § 42.15(a)(3)) .................................................................................. 6
`37 CPR. §42.15(a)(3)) .................................................................................. 6
`
`37 C.F.R. § 42.15(a)(4)) .................................................................................. 6
`37 CPR. § 42.15(a)(4)) .................................................................................. 6
`
`37 C.F.R. § 42.102(a)(2) .................................................................................. 7
`37 CPR. § 42.102(a)(2) .................................................................................. 7
`
`37 C.F.R. § 42.104(a) ...................................................................................... 7
`37 CPR. § 42.104(a) ...................................................................................... 7
`
`37 C.F.R. § 42.104(b) ...................................................................................... 7
`37 CPR. § 42.104(b) ...................................................................................... 7
`
`
`
`
`
`v
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`

`

`
`
`I.
`
`INTRODUCTION
`
`
`
`Coalition for Affordable Drugs II LLC (“Petitioner” or “CFAD”)
`
`respectfully requests an Inter Partes (“IPR”) review for Claims 46-52 and 61-75
`
`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 claims 46 and 52 are directed to a formulation containing a
`
`peptide known as “glucagon-like peptide-2” (“GLP-2”) or an analog thereof.
`
`Independent claim 61 is directed to a kit containing the same GLP-2 formulation
`
`along with a vial of sterile water and instructions. Independent claim 69 is
`
`directed to a method of treatment comprising administering a GLP-2
`
`formulation to effect the growth or functioning of the gastrointestinal tract.
`
`There is a reasonable likelihood that at least one of these independent claims
`
`and those claims depending therefrom are unpatentable because they would
`
`have been obvious to a person of ordinary skill in the art.
`
`Formulations of GLP-2 and therapeutic use of such formulations for
`
`treatment of gastrointestinal disorders were well known before the earliest
`
`effective filing date of the ’886 patent. Storage stable formulations of a related
`
`peptide, glucagon, were also disclosed in the prior art. As shown herein, the
`
`
`
`1
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`

`

`
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`combination of the cited prior art references discloses all of the limitations of
`
`the claimed GLP-2 formulation, methods, and kits.
`
`A person of ordinary skill in the art would have been motivated to
`
`combine these prior art references in order to form a stable GLP-2 formulation
`
`for therapeutic use because there was a known design need for storage stable
`
`formulations. It was known that formulations of peptides, including peptides
`
`such as glucagon, lack storage stability. A solution to this problem, provided by
`
`the prior art, was to add L-histidine and sucrose or mannitol to the formulation
`
`to increase storage stability. Furthermore, GLP-2 and glucagon disclosed in the
`
`prior art are structurally similar leading one of ordinary skill in the art to
`
`combine disclosures in the prior art references with a view to forming a stable
`
`GLP-2 formulation.
`
`The combination of the prior art also provides a reasonable expectation of
`
`success in formulating GLP-2 in combination with L-histidine and sucrose or
`
`mannitol to create a storage stable formulation. Through routine experimentation, a
`
`person of ordinary skill in the art would easily substitute active ingredients having
`
`a similar physical and chemical profile to glucagon into stable formulations
`
`disclosed in the cited art. At the very least, storage stable formulations taught in the
`
`prior art for glucagon would be obvious to try with GLP-2.
`
`
`
`2
`
`

`

`
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`The claimed subject matter represents nothing more than the predictable use
`
`of known components having known functions, and represents a strong case for
`
`obviousness that overcomes any evidence of secondary considerations. The
`
`Patentee has not argued and cannot argue that the claimed subject matter provides
`
`unexpected results because similar results are shown for storage stable
`
`formulations of glucagon in the cited prior art. To the extent Patentee alleges
`
`commercial success to rebut the obviousness of claims 46- 52 and 69-75, no nexus
`
`between these claims and any alleged commercial success exists.
`
`Thus, the formulations of GLP-2, the claimed kit to deliver the GLP-2
`
`formulation as well as the claimed method of administering the GLP-2 formulation
`
`are obvious given the state of the art before the filing date of the ’886 patent. It is
`
`on this basis that claims 46-52 and 61-75 of the ’886 patent are not directed to
`
`anything inventive and merely demonstrate an attempt to capture that which was
`
`already in the prior art. As a result, claims 46-52 and 61-75 are 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
`
`Affordable Drugs II LLC (“CFAD”), Hayman Credes Master Fund, L.P.
`
`(“Credes”), Hayman Orange Fund SPC – Portfolio A (“HOF”), Hayman Capital
`
`
`
`3
`
`

`

`
`
`Master Fund, L.P. (“HCMF”), Hayman Capital Management, L.P. (“HCM”),
`
`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,
`
`“RPI”). The RPI hereby certify the following information: CFAD is a wholly
`
`owned subsidiary of Credes. Credes is a limited partnership. HOF is a
`
`segregated portfolio company. HCMF is a limited partnership. HCM is the
`
`general partner and investment manager of Credes and HCMF. HCM is the
`
`investment manager of HOF. HOM is the administrative general partner of
`
`Credes and HCMF. HI is the general partner of HCM. J Kyle Bass is the sole
`
`member of HI and sole shareholder of HOM. CFAD, Credes, HOF and HCMF
`
`act, directly or indirectly, through HCM as the general partner and/or
`
`investment manager of Credes, HOF and HCMF. nXnP is a paid consultant to
`
`HCM. Erich Spangenberg is 98.5% member of nXnP. IPNav is a paid
`
`consultant to nXnP. Erich Spangenberg is the 98.5% member of IPNav. Other
`
`than HCM and J Kyle Bass in his capacity as the Chief Investment Officer of
`
`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
`
`any other person in any of CFAD, Credes, HOF, HCMF, HCM, HOM, HI,
`
`nXnP or IPNav) has authority to direct or control (i) the timing of, filing of,
`
`
`
`4
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`

`

`
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`content of, or any decisions or other activities relating to this Petition or (ii) any
`
`timing, future filings, content of, or any decisions or other activities relating to
`
`the future proceedings related to this Petition. All of the costs associated with
`
`this Petition will be borne by HCM, CFAD, Credes, HOF and/or HCMF.
`
`B.
`
`Related Matters
`
`
`
`Pursuant to 37 C.F.R. § 42.8(b)(2), Petitioner is not aware of any judicial
`
`or administrative matters that could affect, or be affected by, a decision in this
`
`proceeding.
`
`C.
`
`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
`
`
`
`5
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`

`

`A Power of Attorney is being filed concurrently herewith in accordance with
`
`
`
`37 C.F.R. § 42.10(b).
`
`D.
`
`Service Information
`
`Papers concerning this matter should be served by EXPRESS MAIL, hand-
`
`delivery, or electronic mail at the following addresses:
`
`
`
`
`
`
`
`
`
`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
`Main Telephone: 404-954-5100
`Main Facsimile: 404-954-5099
`
`III. PAYMENT OF FEES
`
`Payment of $26,200.00 for the fees set forth in 37 C.V.R. § 42.15(a)(1-4) for
`
`this Petition for Inter Partes Review accompanies this request by way of credit
`
`card payment. Twenty-two claims are challenged and excess claim fees in the
`
`amount of $400.00 (under 37 C.F.R. § 42.15(a)(3)) and $2,800 (under 37 C.F.R. §
`
`42.15(a)(4)) are included. The undersigned further authorizes payment for any
`
`additional fees that might be due in connection with this Petition to be charged to
`
`Deposit Account No. 13-2725.
`
`
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`
`
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`6
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`

`

`
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`
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`IV. REQUIREMENTS UNDER 37 C.F.R. § 42.104
`
`A. Grounds for Standing
`
`Pursuant to 37 C.F.R. § 42.104(a), Petitioner hereby certifies that the ’886
`
`patent is available for Inter Partes review in accordance with 37 C.F.R. §
`
`42.102(a)(2), and that the Petitioner is not barred or estopped from requesting Inter
`
`Partes review challenging the claims of the ’886 patent on the grounds identified
`
`in this Petition. Neither Petitioner nor any privy of Petitioner has received a final
`
`written decision under 35 U.S.C. § 318(a) with respect to any claim of the ’886
`
`patent on any ground that was raised or could have been raised by Petitioner or its
`
`privies in any Inter Partes review, post grant review, or covered business method
`
`patent review.
`
`B.
`
`Identification of Challenge and Precise Relief Requested
`
`Pursuant to 37 C.F.R. § 42.104(b), Petitioner challenges Claims 46-52 and
`
`61-75 of the ’886 patent and requests that these claims be found unpatentable over
`
`the prior art for the reasons given herein.
`
`1.
`
`Claims for Which Inter Partes Review is Requested
`
`
`
`Petitioner requests Inter Partes review of Claims 46-52 and 61-75 of the
`
`’886 patent. The claims of the ’886 patent at issue are directed to GLP-2 peptide
`
`formulations (claims 46-52), a kit containing a GLP-2 formulation (claims 61-68) ,
`
`
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`7
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`

`

`
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`and a method of treatment using GLP-2 compositions (claims 69-75). Claims 46,
`
`52, 61, and 69 are independent claims. Claims 47-51 all depend directly or
`
`indirectly from Claim 46. Dependent Claims 62-68 all depend either directly or
`
`indirectly from claim 61. Dependent Claims 70-75 all depend either directly or
`
`indirectly from Claim 69.
`
`2.
`
`Statutory Ground on Which the Challenge is Based
`
`
`Claims 46-52 and 69-75 are unpatentable because they are obvious under 35
`
`
`
`U.S.C. § 103(a) in view of the combined teachings of U.S. Patent No. 5,789,379 to
`
`Drucker et al. (“Drucker ’379”) (Ex. 1029), U.S. Patent No. 5,652,216 to Kornfelt
`
`et al. (“Kornfelt”) (Ex. 1027), Osterberg et al., “Physical State of L-histidine after
`
`Freeze Drying and Long Term Storage,” European Journal of Pharmaceutical
`
`Sciences 8(1999)301-308 (“Osterberg”) (Ex.1030), and Munroe et al., Prototypic
`
`G-protein coupled receptor for the intestinotrophic factor glucagon –like peptide 2,
`
`Proc. Nat’l Acad. Sci. 96:1569 (1999)(“Munroe”)(Ex. 1022). Claims 61-68 are
`
`unpatentable because they would have been obvious under 35 U.S.C. § 103(a) in
`
`view of the combined teachings of PCT Publication W098/52600 to Drucker
`
`(“Drucker ’600”) (Ex. 1028), U. S. Patent No. 5,496,801 to Holthuis et al,
`
`(“Holthuis”)(Ex. 1005), Kornfelt, Osterberg, and Munroe.
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`8
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`

`
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`3.
`
`Evidence Relied Upon to Support the Challenge
`
`Petitioner relies upon each of the publications cited herein. Each of these
`
`publications has a publication date more than one year prior to the ’886 patent’s
`
`effective filing date of December 30, 2000. On this basis, they are available as
`
`prior art under 35 U.S.C. § 102 (b). Petitioner also relies upon the Declaration of
`
`Dr. Anthony Palmieri III, Ph.D., R.Ph., an Associate Scholar of Pharmaceutics at
`
`the University of Florida College of Pharmacy (Ex. 1001), and the documents cited
`
`therein (Exs. 1002-1030), including Dr. Palmieri’s curriculum vitae (Ex. 1002).
`
`4. How the Challenged Claims Are to be Construed
`
`The terms of the claims of the ’886 patent are to be given their broadest
`
`reasonable interpretation in light of the specification, as understood by a person of
`
`ordinary skill in the art. See 37 C.F.R. § 42.100(b).
`
`An “analog” of GLP-2 is construed to mean a peptide that incorporates one
`
`or more amino acid substitutions, deletions, additions, or modifications into a
`
`natural GLP-2 peptide and retains biological activity (Ex. 1003 at 4:33-36, 1:30-
`
`37; Ex. 1001 at ¶ 26). During prosecution, the Applicant overcame an
`
`indefiniteness rejection by confirming that term “analog” conformed to this
`
`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
`
`to enhance and maintain the functioning of the gastrointestinal tract and to promote
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`9
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`
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`the growth of intestinal tissue” to overcome a similar indefiniteness rejection (Ex.
`
`1008 at 4; Ex. 1001 at ¶ 26).
`
`“Medically useful amount” is defined in the specification to mean an amount
`
`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
`
`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
`
`preferably about 20 mg/ml (Ex. 1003 at 2:14-19,5:59-61, 6:12-19; Ex. 1001 at ¶
`
`27).
`
`“Medically useful amount” or “medically effective amount is construed to
`
`mean an amount which is useful either therapeutically or diagnostically (Ex. 1003
`
`at 5:59-61; Ex. 1001 at ¶ 27).
`
`“Therapeutically effective amount” is defined in the specification to mean an
`
`amount of GLP-2 or analog thereof including unit dosage amounts useful to treat a
`
`subject including multidose amounts (Ex. 1003 at 5:64-67, 6:5-7; Ex. 1001 at ¶
`
`28).
`
`“An amount sufficient to adjust the pH of the formulation to a physiological
`
`tolerable level” is defined in the ’886 specification, to mean an amount that
`
`buffers the formulation to a pH that elicits reactions, in a recipient, that are not so
`
`extreme to preclude further administration of the formulation (Ex. 1003 at 5:45-51;
`
`
`
`10
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`

`

`
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`Ex. 1001 at ¶ 29). The specification states that this includes a pH of greater than
`
`about 5.5, more preferably greater than about 6, even more preferably of about 6.9
`
`to about 7.9, and most preferably about 7.3 to about 7.4 (Ex. 1003 at 5:52-56; Ex.
`
`1001 at ¶ 29).
`
`“An amount sufficient to adjust the pH of the formulation to a
`
`pharmaceutically tolerable level” refers to an exemplary pH of “above about 6.0”
`
`as set forth in the specification (Ex. 1003 at 2:9-11; Ex. 1001 at ¶ 30).
`
`“An amount sufficient to stabilize the formulation” is defined in the
`
`specification, as an amount of histidine that increases “the length of time that the
`
`GLP-2 peptide remains intact prior to degradation” (Ex. 1003 at 5:30-32; Ex. 1001
`
`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 of GLP-2 or analogs thereof is
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`measured by determining the purity and quantity of the peak of GLP-2 using
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`reverse phase high pressure liquid chromatography. (Ex. 1003 at 9:65 to10:8; Ex.
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`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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`Litigation Relating to the ’886 patent
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`
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`The ’886 patent is not subject to any pending litigation of which Petitioner is
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`aware.
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`C. 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 cited.
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`
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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
`
`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).
`
`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).
`
`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
`
`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
`
`formulations, and that glucagon and GLP-2 were known to be related peptides (Id.
`
`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
`
`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 Kornfeld (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
`buffer, L-histidine for stabilizing the formulation and a bulking agent
`of mannitol and sucrose.
`
`(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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`D. Overview of the Cited Prior Art and the State of the Art
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`Formulations of GLP-2, methods of using formulations of GLP-2, and kits
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`containing GLP-2 formulations were known prior to the effective filing date of
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`the’886 patent (Ex. 1028 at p. 19:15-36; Ex. 1001 at ¶ 35). Drucker ’600 describes
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`formulations of GLP-2 and analogs for use in promoting the proliferation of
`
`intestinal tissue (Ex. 1028 at p. 2:25-32; Ex. 1001 at ¶ 35). Biologically active
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`analogs of GLP-2 with amino acid substitutions were also known as described
`
`extensively in Drucker ’379 (Ex.1029 at p. 4:6-7:20, p. 15:1-35; Ex. 1001 at ¶ 35).
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`Drucker ’379 teaches that GLP-2 was known to be susceptible to DPP-IV cleavage
`
`(Ex.1029 at p. 6:36-45; Ex. 1021 at 675; Ex. 1001 at ¶ 35). This led to the
`
`development of analogs with replacement of an amino acid at position 2; the DPP-
`
`IV cleavage site (Ex.1029 at p. 6:36-45; Ex. 1001 at ¶ 35). One such analog of
`
`human GLP-2, h[Gly2]GLP-2, was shown to be effective in an animal model of
`
`colitis (Ex. 1023 at G79; Ex. 1001 at ¶ 35). Munroe shows that GLP-2 analogs that
`
`stimulate intestinal cell proliferation were also known to bind to the GLP-2
`
`receptor (Ex.1022 at 1573, Table 2; Ex. 1001 at ¶ 35). 
`
`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,
`
`produced in intestinal enteroendocrine cells (Ex. 1018 at 885, Figure 8b; Ex. 1001
`
`at ¶ 36). GLP-2 exhibits 50% amino acid sequence similarity to glucagon and has a
`
`similar molecular weight (Ex. 1018 at 879, Fig.3; Ex. 1001 at ¶ 36). Despite some
`
`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
`
`an alpha helix region. Analogs of GLP-2 retain the alpha helix motif and as well as
`
`binding capacity to the GLP-2 receptor (Ex.1022 at 1573, Table 2; Ex. 1