Filed: August 7, 2015
`
`UNITED STATES PATENT AND TRADEMARK OFFICE
`
`____________
`
`BEFORE THE PATENT TRIAL AND APPEAL BOARD
`
`____________
`
`COALITION FOR AFFORDABLE DRUGS II LLC
`Petitioner
`
`v.
`
`NPS PHARMACEUTICALS, INC.
`Patent Owner
`____________
`
`Case IPR2015-01093
`Patent 7,056,886
`
`
`____________
`
`PATENT OWNER’S PRELIMINARY RESPONSE
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`
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`

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`
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`TABLE OF CONTENTS
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`I. Introduction .................................................................................................... 1
`II. The Claimed Invention .................................................................................. 3
`III. The Petition Should Be Denied Because Petitioner Has Not
`Established a Reasonable Likelihood that Any of the Challenged
`Claims Are Obvious ....................................................................................... 5
`A. The Board Should Exercise Its Discretion under 35 U.S.C. §
`325(d) to Deny the Petition Because It Relies on Substantially
`the Same Art and Arguments Previously Considered by the
`Office ................................................................................................... 8
`1. The ’886 Patent Claims were Rejected During
`Prosecution over a Combination of a GLP-2 Formulation
`and Histidine Stabilization of Glucagon; The Rejection
`was Overcome ......................................................................... 11
`2. Petitioner Relies on Substantially the Same
`Combinations of Prior Art and the Same Argument as the
`Examiner Did during Prosecution ........................................... 18
`B. The Petition Fails to Articulate Sufficient Motivation to
`Combine the References to Arrive at the Claimed Invention
`with a Reasonable Expectation of Success ....................................... 22
`C. GATTEX®, the Commercial Embodiment of the Challenged
`Claims, Met a Long Felt Need and Is a Commercial Success .......... 28
`IV. The Petition Should Be Denied Because Petitioner Failed to
`Demonstrate that the ’886 Patent Is not Entitled to the Benefit of Its
`Priority Application ..................................................................................... 29
`V. The Petition Should Be Denied Because It Fails to Identify All Real
`Parties-in-Interest ......................................................................................... 31
`VI. The Petition Should Be Denied because the Real Parties-In-Interest
`Are Abusing and Misusing The IPR Process .............................................. 43
`VII. The Petition Should Be Denied If the Petition in Concurrent IPR2015-
`1103 Is Denied as a Sanction for Abuse of Process .................................... 44
`VIII. Conclusion ................................................................................................... 46
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`-i-
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`
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`TABLE OF EXHIBITS
`
`Description
`
`
`
`Ex.
`No.
`2001 NPS Pharmaceuticals, Inc.’s Requests for Production to Petitioner
`
`2002 NPS Pharmaceuticals, Inc.’s Interrogatories to Petitioner
`2003 NPS Pharmaceuticals, Inc.’s Topics for Examination of Petitioner
`2004 General Hedge Fund Structure & Regulation
`2005 RPI Diagram
`2006 Form ADV Brochure of HCM (Mar. 30, 2015)
`2007 Form ADV of HCM (Mar. 30, 2015)
`2008 Annual Report of HCM (July 8, 2013)
`2009 Amended Form D of HCOP (May 12, 2014)
`2010 Amended Form D of HCP (May 12, 2014)
`2011 Credes Onshore Form D (Jan. 14, 2015)
`2012 Credes Onshore Delaware Secretary of State Website Printout
`2013 HCMF Cayman Islands Search Report
`2014 Credes Offshore Form D (Jan. 14, 2015)
`2015 Credes Offshore Caymans Search Report
`2016 Form D of HOF (April 9, 2015)
`2017 Certificate of Formation of IPNav (Nov. 13, 2007)
`2018 Certificate of Formation of nXnP (Sept. 24, 2014)
`Ed Silverman, Innovate or Else: Kyle Bass Strikes Again and Challenges
`Shire Patents, Wall Street Journal (April 2, 2015)
`Robert Cyran, Kyle Bass Wields New Weapon in Challenging Drug
`Makers, The New York Times (February 11, 2015)
`Joseph Walker and Rob Copeland, New Hedge Fund Strategy: Dispute the
`Patent, Short the Stock, Wall Street Journal (April 7, 2015)
`Julia La Roche, Hedge Fund Manager Kyle Bass is Going After Big
`Pharma and Its “BS Patents,” Business Insider (Jan. 7, 2015)
`Julia La Roche, Hedge Fund Manager Kyle Bass is Going After Big
`Pharma and Its “BS Patents,” Business Insider Australia (Jan. 8, 2015)
`Delaware Secretary of State Business Entity Search Printout for Coalition
`Entities
`2024
`2025 Cayman Islands Search Report of HOM
`2026 Cayman Islands Search Report of HOF
`2027 GATTEX® Product Label
`Lehninger et al., Principles of Biochemistry, 2nd ed., Chapters 5-7 & 18, pp.
`111-197 & 542-597 (1993)
`
`2019
`
`2020
`
`2021
`
`2022
`
`2023
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`2028
`
`
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`
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`-ii-
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`
`
`Ex.
`No.
`
`Description
`
`Voet and Voet, Biochemistry, 2nd ed., Chapters 7 & 14, pp. 141-90 & 371-
`2029
`410 (1995)
`2030 Purves et al., Life: The Science of Biology, 3rd ed., Ch. 3, pp. 40-59 (1992)
`2031 NPS Pharmaceuticals , Inc. Form10-K 2014
`2032 Email from Jeff Blake to Counsel for Patent Owner
`2033 Declaration of Christopher E. Kirkpatrick
`2034 Declaration of Erich Spangenberg
`The Wall Street Journal – New Hedge Fund Strategy: Challenge the Patent,
`Short the Stock
`The Wall Street Journal – Innovate or Else: Kyle Bass Strikes Again and
`Challenges Shire Patents
`2036
`2037 Hayman Capital Management, L.P. Form ADV Part 2A Brochure
`Brubaker and Drucker, Structure-Function of the Glucagon Receptor
`Family of G-Protein Coupled Receptors: The Glucagon, GIP, GLP-1, and
`GLP-2 Receptors, Receptors and Channels, vol. 8, pp. 179-188 (2002)
`Chaturvedi, A Report on Stability of Polypeptides and Proteins, Birla
`Institute of Technology and Science Pilani (Rajasthan) (August 2009)
`Vassilatis et al., “The G protein-coupled receptor repertoires of human and
`mouse”, Proc Natl Acad Sci USA 100 (8): 4903–4908 (2003)
`
`2035
`
`2038
`
`2039
`
`2040
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`
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`-iii-
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`IPR2015-01093
`
`Pursuant to 35 U.S.C. § 313 and 37 C.F.R. § 42.107, Patent Owner NPS
`
`Pharmaceuticals, Inc. (“NPS” or “Patent Owner”) submits this Patent Owner’s
`
`Preliminary Response (“Response”) to the Petition for Inter Partes Review of U.S.
`
`Patent No. 7,056,886 (“Petition”) filed by Coalition for Affordable Drugs II LLC
`
`(“Petitioner”). Petitioner requests an inter partes review (“IPR”) of certain claims
`
`of U.S. Patent No. 7,056,886 (“the ’886 patent”). The Response is timely under 35
`
`U.S.C. § 313 and 37 C.F.R. § 42.107; it is filed within three months of the mailing
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`date of the May 7, 2015, Notice of Filing Date Accorded to Petition (Paper 6).
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`I.
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`Introduction
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`The inventor of the ’886 patent discovered GLP-2/GLP-2 analog
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`formulations “exhibiting superior stability following storage and/or exposure to
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`elevated temperatures.” Ex. 1003, Abstract. The challenged claims (claims 1-45)
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`are directed to formulations of GLP-2 or an analog that are stabilized with L-
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`histidine. The Petition should be denied because:
`
` 1 – it asserts substantially the same grounds of unpatentability that were
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`asserted by the Examiner during prosecution and were overcome by Patent Owner;
`
`2 – it does not rebut the arguments made during prosecution by the Patent
`
`Owner that successfully overcame these same rejections;
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`1
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`

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`IPR2015-01093
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`3 – it does not provide any motivation to combine references with any
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`reasonable expectation of success or without undue experimentation to reach the
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`invention of the challenged claims; and
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`4 – the Petitioner’s supporting expert declaration is unreliable because it
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`contains scientifically irrelevant “facts” and makes unsupported conclusory
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`statements.
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`Each ground for unpatentability proposed in the Petition relies upon a
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`combination of references disclosing that (1) GLP-2 formulations were known, and
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`(2) it was known to use histidine in formulations to improve the stability of the
`
`different molecule, glucagon. This is precisely the combination of teachings (albeit
`
`the Petition substitutes a different primary reference for the same teaching) and
`
`reasoning that the Examiner had used to reject the present claims as obvious. There
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`is nothing new in the Petition. The arguments made by the Patent Owner
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`overcame, and still overcome, these same grounds of unpatentability. Furthermore,
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`additional evidence is presented in this Response as to why teachings regarding
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`stabilization of glucagon are not predictive of results with GLP-2. The two
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`molecules are widely dissimilar in structure, properties, and function. There is
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`simply no motivation to combine references as Petitioner proposes. Petitioner has
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`failed to meet its burden of establishing that it has a reasonable success of
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`prevailing as to the patentability of at least one of the challenged claims. The
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`2
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`IPR2015-01093
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`Petition should be denied for this reason alone.
`
`However, the Petition should also be denied because:
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`5 – it fails to demonstrate that one reference upon which it relies is prior art;
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`6 – it fails to name all real parties-in-interest (“RPIs”);
`
`7 – it was not filed for a purpose that IPRs were established to address, and it
`
`hinders the ability of the Office to complete IPR proceedings timely; and
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`8 – comity, should the Board grant the pending motion for sanctions based
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`upon abuse of process in Coalition for Affordable Drugs VI LLC v. Celgene Corp.,
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`IPR2015-01103 (see IPR2015-01103, Paper 9), allows for the same sanction and
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`disposition, here, since the issue that is the subject of the motion in Celgene is also
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`an issue in the present Petition.
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`II. The Claimed Invention
`
`The challenged claims of the ’886 patent encompass L-histidine stabilized
`
`formulations of GLP-2/GLP-2 analog drug.
`
`The L-histidine stabilized GLP-2 analog, teduglutide (GATTEX®), is the
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`commercial embodiment of the ’886 patent. Each single-use vial of GATTEX®
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`contains 5 mg of teduglutide, 3.88 mg L-histidine, 15 mg mannitol, 0.644 mg
`
`monobasic sodium phosphate monohydrate, and 3.434 mg dibasic sodium
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`phosphate heptahydrate as a white lyophilized powder for solution for
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`subcutaneous injection. Ex. 2027, 5.
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`3
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`

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`IPR2015-01093
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`It is the first drug product for treating adult patients with Short Bowel
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`Syndrome (“SBS”) who are dependent on parenteral support. GATTEX® was
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`approved by the U.S. Food and Drug Administration (“FDA”) on December 21,
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`2012, as an orphan drug and has been sold by NPS since February 2013.1 The ’886
`
`patent is listed in the FDA’s
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`Approved Drug Products with Therapeutic
`
`Equivalence Evaluations (the “Orange Book”) for GATTEX®.
`
` SBS is a highly disabling condition that can lead to serious life-threatening
`
`complications and can severely impair a patient’s quality of life. It is associated
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`with intestinal failure and the inability to absorb sufficient nutrients and fluids
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`through the gastrointestinal tract. SBS typically arises after extensive resection of
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`the bowel due to Crohn’s disease, ischemia, trauma, or other conditions. Patients
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`with SBS are highly prone to malnutrition, diarrhea, dehydration, and an inability
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`to maintain weight due to the reduced intestinal capacity to absorb macronutrients,
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`water, and electrolytes.
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`Consequently, many SBS patients require chronic use of parenteral nutrition
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`(“PN”) and intravenous ( “IV”) fluids to supplement their nutritional needs and to
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`stabilize their hydration. PN/IV fluids bypass the digestive tract and are delivered
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`directly into the bloodstream through a central venous catheter. Although PN/IV
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`fluids can meet basic nutrition and fluid requirements, they do not improve the
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`1 NPS is now part of Shire PLC.
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`4
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`IPR2015-01093
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`body’s ability to absorb nutrients. The long-term use of PN/IV fluids is associated
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`with shortened life span and life-threatening complications such as blood clots and
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`liver damage. The development of PN-associated liver disease predisposes patients
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`to an increased incidence of sepsis, increased mortality rates, and the potential to
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`develop irreversible liver damage. Patients on parenteral support often experience
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`poor quality of life with difficulty sleeping, frequent urination, frequent bowel
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`movements, need for and problems with ostomy bags, and loss of independence.
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`There are an estimated 10,000 to 15,000 SBS patients in the U.S. who are
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`dependent on PN/IV fluids.
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`GATTEX® improves intestinal rehabilitation by promoting mucosal growth,
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`inhibiting gastric acid secretion and emptying, increasing intestinal barrier
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`function, and enhancing nutrient and fluid absorption. Treatment with GATTEX®
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`is associated with enhancement or restoration of the structural and functional
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`integrity of the remaining intestine thereby helping to improve absorption and to
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`reduce parenteral nutrition needs. Accordingly, GATTEX®
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` may allow these
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`patients more independence and the ability to lead rewarding personal, social, and
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`working lives, amounting to a significant improvement of their quality of life and
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`self esteem.
`
`III. The Petition Should Be Denied Because Petitioner Has Not Established
`a Reasonable Likelihood that Any of the Challenged Claims Are
`Obvious
`
`5
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`

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`IPR2015-01093
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`The Petition divides the challenged claims into four groups and then alleges
`
`one ground of obviousness for each grouping. 2 Ground 1 alleges that claims 1-27,
`
`33-35, 38, and 45 are obvious in view of Drucker, U.S. Patent No. 5,789,379
`
`(“Drucker ’379”) (Ex. 1029), in view of Kornfelt et al., U.S. Patent No. 5,652,216
`
`(“Kornfelt”) (Ex. 1027), and Osterberg et al., “Physical State of L-histidine after
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`Freeze Drying and Long Term Storage.” E. J. Pharm. Sci. 8(1999) 301-308
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`(“Osterberg”) (Ex. 1030). Petition (“Pet.”), 19. Claim 1 is the only independent
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`claim among all of the claims challenged in the Petition. It is directed to GLP-2
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`formulations that include,
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`inter alia , naturally occurring GLP-2 or an analog
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`thereof and L-histidine.
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`Ground 2 alleges that claims 31, 32, and 44 are obvious in view of Drucker
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`’379 in view of Kornfelt, Osterberg, and Munroe
`
`et al ., “Prototypic G protein-
`
`coupled receptor for the intestinotrophic factor glucagon-like peptide 2,” Pro. Natl.
`
`Acad. Sci. USA, Vol. 96, pp. 1569-1573 (Fe. 1999) (“Munroe”) (Ex. 1022). Pet.,
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`19-20. Dependent claim 31 is directed to the GLP-2 formulation of claim 1,
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`2 For the purposes of this Preliminary Response only, Patent Owner accepts
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`Petitioner’s claim constructions and description of one of ordinary skill in the art.
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`Patent Owner reserves the right to offer different constructions of claim terms and
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`a different description of one of ordinary skill in the art should the Petition be
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`granted.
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`6
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`

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`IPR2015-01093
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`wherein the analog is identified by screening against genetically engineered cells
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`that produce the GLP-2 receptor. Dependent claims 32 and 44 are directed to the
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`GLP-2 formulation of claim 1, in which the analog has at least one amino acid
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`substitution, addition, deletion, or modification and has GLP-2 receptor binding
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`activity.
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` Ground 3 alleges that claims 28-30 and 39-43 are obvious in view of
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`Drucker ’379 in view of Kornfelt, Osterberg, and Holthius, U.S. Patent No.
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`5,469,801 (“Holthius”) (Ex. 1005). Pet., 20. Claims 28-30 depend indirectly from
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`claim 1 and add stability criteria for the histidine-stabilized GLP-2 formulations of
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`claim 1. Claims 39 and 40 depend from dependent claim 38 (which claims a
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`lyophilized formulation of claim 1) and restrict the amount of water in the
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`lyophilized form. Claims 41-43 depend directly or indirectly from claim 1 and
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`also add stability criteria.
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` Ground 4 alleges that claims 36 and 37 are obvious in view of Drucker ’379
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`in view of Kornfelt, Osterberg, and Drucker, PCT patent publication no. WO
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`98/03547 (“Ducker ‘547”) (Ex. 1028). Pet., 20-21. Dependent claim 36 specifies
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`that the GLP-2 analog in the formulation of claim 1 is a GLP-2 receptor antagonist,
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`and dependent claim 37 specifies the amino acid substitutions in the analog of
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`claim 36.
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`
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`Each of Petitioner’s grounds for unpatentability relies upon substantially the
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`7
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`IPR2015-01093
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`same primary disclosure of GLP-2 or GLP-2 analog formulations and the identical
`
`secondary reference (Kornfelt) that discloses that L-histidine was used to stabilize
`
`formulations of a different molecule, glucagon. This is precisely the combination
`
`and reasoning that the Examiner used during prosecution to reject the present
`
`claims as obvious. There is nothing new in the Petition. The arguments made by
`
`the Patent Owner still overcome these grounds of unpatentability. Furthermore,
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`additional evidence is presented in this Response as to why teachings regarding
`
`stabilization of glucagon are not predictive of results with GLP-2 and provide no
`
`motivation to combine references.
`
`A. The Board Should Exercise Its Discretion under 35 U.S.C. §
`325(d) to Deny the Petition Because It Relies on Substantially the
`Same Art and Arguments Previously Considered by the Office
`
`
`
`Petitioner relies upon the same bases for unpatentability of the challenged
`
`claims over the prior art as did the Examiner during prosecution. Moreover,
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`Petitioner failed to rebut arguments from Patent Owner that successfully overcame
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`those rejections. Therefore, the Board should exercise its discretion under 35
`
`U.S.C. § 325(d) and deny the Petition.
`
`The primary reference during prosecution (Knudsen
`
`et al., WO 99/43361
`
`(“Knudsen”)) and the primary reference in the Petition (Drucker ’379) disclose the
`
`same thing, i.e., pharmaceutical formulations comprising a GLP-2 derivative or
`
`analog. Petitioner agrees. See Pet., 22 (Drucker ’379 discloses GLP-2 peptide
`
`8
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`IPR2015-01093
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`formulations); see also id. at 28. The first secondary reference relied upon by the
`
`Petitioner (Kornfelt) was also relied upon by the Examiner for the same thing, i.e.,
`
`use of a stabilizing amount of histidine in a glucagon pharmaceutical preparation.
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`Petitioner adds another secondary reference, Osterberg, which is less relevant than
`
`Kornfelt. Osterberg merely discloses that L-histidine functioned as a buffer and
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`stabilizer in lyophilized recombinant factor VIII formulations and how to prevent
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`L-histidine from crystallizing. Ex. 1030, 1. 3 Recombinant factor VIII is even more
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`remote from GLP-2 than is glucagon. 4 However, the substance of the Examiner’s
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`prior art rejections is unchanged by Petitioner.
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`3 The Petition and the supporting declaration (Ex. 1001) repeatedly cites to the
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`page numbers of the references as published rather than to the page number of the
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`exhibit inserted by Petitioner. For example, Petitioner cites to page 879 of Kieffer,
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`which is actually page 4 of that exhibit (Ex. 1018). For consistency, and in
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`accordance with the Office Trial Practice Guide, herein, Patent Owner cites to the
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`page numbers of the exhibits inserted by Petitioner rather than to the published
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`page number of the reference.
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`4 Petitioner’s declarant mischaracterizes Osterberg as disclosing that L-histidine is
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`a good stabilizer for all proteins. See Ex. 1001, ¶ 55 (“The excipient L-histidine
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`was very well known and widely used for stabilization of peptide formulations as
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`demonstrated by Osterberg
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`et al ., which recognizes L-histidine as a protein
`
`9
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`

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`IPR2015-01093
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`“In determining whether to institute or order a proceeding … the Director
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`may take into account whether, and reject the petition or request because, the same
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`or substantially the same prior art or arguments previously were presented to the
`
`Office.” 35 U.S.C. § 325(d). The Board has repeatedly exercised that authority to
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`deny institution of a trial based on art or arguments that are the same or
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`substantially the same as those presented to the PTO in prior Petitions,
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`reexaminations, and original prosecutions. See, e.g., Integrated Global Concepts,
`
`Inc. v. Advanced Messaging Tech., Inc.
`
`, IPR2014-01027, Paper 16, 6-8 (PTAB
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`Dec. 22, 2014 (denying institution of IPR because “the same prior art and
`
`substantially the same arguments were presented to the Office previously” during
`
`ex parte reexamination); Customplay, LLC v. Clearplay, Inc.
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`, IPR2014-00783,
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`Paper 9, 7-9, (PTAB Nov. 7, 2014) (denying institution of IPR because the petition
`
`“present[ed] substantially the same prior art, and substantially the same arguments”
`
`as the petition in another IPR); Prism Pharma Co. v. Choogwae Pharma Corp .,
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`IPR2014-00315, Paper 14, 12-13 (PTAB July 8, 2014) (denying institution of IPR
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`where “the same prior art and substantially the same arguments were presented to
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`stabilizer (Ex. 1030 at 307 (4. Conclusions)).” However, all that Osterberg says is
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`that L-histidine may have two different functions,
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`i.e., buffer or metal ion
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`scavenger, when the L-histidine is in an amorphous phase. Ex. 1030, 7. Osterberg
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`does not say or suggest that L-histidine can stabilize GLP-2 formulations.
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`10
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`

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`IPR2015-01093
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`the Office previously” during original prosecution); Excelsior Med. Corp. v. Lake ,
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`IPR2013-00494, Paper 8, 20 (PTAB Feb. 6, 2014) (denying institution of IPR in
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`view of the same combination of prior art references where the patent owner
`
`successfully argued during original prosecution that there was no motivation to
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`combine the references). Here, because Petitioner relies on the same arguments
`
`with substantially the same prior art disclosures that were before the Examiner
`
`during prosecution of the application resulting in the ’886 patent, the Board should
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`deny the Petition under 35 U.S.C. § 325(d).
`
`1.
`
`The ’886 Patent Claims were Rejected During Prosecution
`over a Combination of a GLP-2 Formulation and Histidine
`Stabilization of Glucagon; The Rejection was Overcome
`
` The Examiner of the application that issued as the ’886 patent rejected
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`patent application claims 1-8, 10, 22, 49-55, 58, 63-71, 73, and 78 (which include
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`the sole independent challenged claim (claim 1), here) 5 under 35 U.S.C. § 103(a)
`
`
`5 The following table corresponds the numbers of the challenged claims of the ‘886
`
`patent with the claim numbers of the application that issued as the ‘886 patent.
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`Issued ‘886 Patent Claim Number
`
`Application Claim Number
`
`1
`2
`3
`4
`5
`6
`7
`
`1
`2
`65
`3
`66
`4
`67
`
`11
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`

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`IPR2015-01093
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`IPR2015-01093
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`
`8
`5
`9
`68
`10
`6
`11
`69
`12
`7
`13
`70
`14
`8
`15
`71
`16
`9
`17
`72
`18
`10
`19
`73
`20
`11
`21
`74
`22
`12
`23
`75
`24
`13
`25
`76
`26
`14
`27
`15
`28
`25
`29
`26
`30
`27
`31
`16
`32
`17
`33
`18
`34
`19
`35
`20
`36
`21
`37
`59
`38
`22
`39
`23
`40
`24
`41
`28
`42
`26
`43
`27
`44
`58
`45
`64
`
`12
`12
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`

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`IPR2015-01093
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`as obvious over Knudsen in view of Kornfelt. The rejected application claims were
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`directed to GLP-2 formulations comprising a medically useful amount of GLP-2 or
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`a GLP-2 analog, a phosphate buffer sufficient to adjust the pH to a physiologically
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`tolerable level, L-histidine, and a mannitol or sucrose bulking agent.6
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`Pertinently, the Examiner explained that “Knudsen
`
`et al
`
`. teach a
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`pharmaceutical composition comprising a GLP-2 derivative or analog, an isotonic
`
`Compare Ex. 1016, 2-11 with Ex. 1003, 13-15.
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`6 Additionally, application claims 11-12 (specifying the mannitol concentration)
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`and 74-75 (which specified the mannitol concentration and the GLP-2 analog)
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`were rejected under 35 U.S.C. § 103(a) over Knudsen in view of Kornfelt further
`
`in view of Hora et al., U.S. Patent No. 5,997,856; application claims 13-15, 17-20,
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`and 76 (specifying the GLP-2 or analog) were rejected under 35 U.S.C. § 103(a)
`
`over Knudsen in view of Kornfelt further in view of Drucker
`
`et al ., PCT patent
`
`publication no. WO 97/39031 (“Drucker A”); application claims 16 (specifying
`
`how the GLP-2 analog was identified) and 21 (which specified that the GLP-2
`
`analog was a GLP-2 receptor antagonist) were rejected under 35 U.S.C. § 103(a)
`
`over Knudsen in view of Kornfelt further in view of Thin
`
`et al., U.S. Patent No.
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`5,912,229; and application claims 43-46 and 77 (directed to a kit) were rejected
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`under 35 U.S.C. § 103(a) over Knudsen in view of Kornfelt further in view of
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`Drucker et al., U.S. Patent No. 5,952,301 (“Drucker “B”)).
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`agent such as mannitol, a buffer of histidine or sodium phosphate, a
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`pharmaceutical [sic] acceptable carrier, a preservative and a surfactant … .
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`However, Knudsen et al. do not disclose using histidine as a stabilizing agent.” Ex.
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`1015, 5-6. The Examiner also explained that “Kornfelt
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`et al. disclose using [a]
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`stabilizing amount of a pharmaceutically acceptable ampholyte such as glycine,
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`histidine … or GlyGly in a pharmaceutical preparation comprising glucagon … .”
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`Id. at 6. 7 The Examiner concluded that the combination of references was proper
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`because “[a]t the time the invention was made, it would have been obvious that a
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`person of ordinary skill in the art is motivated to prepare a pharmaceutical
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`composition of GLP-2 as indicated by Knudsen et al. with the addition of histidine
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`as a stabilizing agent as taught by Kornfelt et al. because [sic, a] stabilizing amount
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`of histidine has been shown to stabilize glucagon in the formulation.” Id. at 6, ¶ 8;
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`see also id. at 7-9 citing ¶ 8.
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`7 The Examiner also explained that: “Hora et al. disclose 1-5% mannitol is used as
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`a bulking agent in protein preparation ….” (Ex. 1015, 7); “Drucker [A] disclose the
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`sequence of human GLP-2, h[Gly2]GLP-2 analog, and DPP-IV resistant GLP-2
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`analogs ….” ( id. at 8); “Thim et al . disclose a GLP-2 receptor is identified and
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`cloned, and a cell line stably expressing the receptor is used in a screening assay to
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`identify the antagonist of [the] GLP-2 receptor ….” ( id. at 8-9); and “Drucker [B]
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`disclose a kit comprising GLP-2 or GLP-2 analogs ….” (id. at 9).
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`Applicants overcame these rejections by explaining that:
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`[t]here is no teaching or suggestion in the prior art to combine the
`teachings of Knudsen with the teachings of Kornfelt to obtain the
`claimed invention. Kornfelt is directed to a pharmaceutical
`composition comprising glucagon and a stabilizing amount of a
`pharmaceutically acceptable ampholyte including, for instance,
`histidine. Despite similarities in their names, glucagon and a naturally
`occurring GLP-2, or an analog thereof, are not interchangeable and
`have different properties, characteristics, and functionality.
`
`For example, the physical properties of each protein are so different
`that it is not intuitive that excipients and formulations that stabilize
`glucagon would have the same effect on naturally occurring GLP-2,
`is very
`or an analog thereof. The following figure shows that there
`little structural equivalence between glucagon and GLP-2.
`
`***
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`
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`Moreover, the chart provided below shows some of the properties,
`characteristics, and functionality which are different between
`glucagon and LX-0600, an exemplary GLP-2 analog.
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`
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`As shown above, the solubility of glucagon and GLP-2 are
`dramatically different. Applicant teaches that [Gly2]hGLP-2
`precipitates from solution below about pH 5.5. See page 7, lines 3-6
`of the Application. In contrast, Kornfelt teaches that the preferred pH
`for glucagon is pH 2.8. See European Pharmacopoeia Commission,
`The European Pharmacopoeia (2nd. Ed.), page 612 (1989).
`
`Moreover, glucagon and GLP-2 are functionally distinct. GLP-2
`in vivo
`analogs that activate GLP-2 receptor signal transduction
`display intestinotrophic activity in vivo. See, e.g., Munroe et al., Proc.
`Natl. Acad. Sci. U.S.A. 96(4):1569-73 (1999) (“Munroe”). Glucagon
`does not. See page 1573, Table 2, of Munroe. Likewise, GLP-2, but
`not glucagon, is capable of high affinity binding to the GLP-2
`Receptor. See page 1573, Table 2, of Munroe.
`
`Accordingly, glucagon and a naturally occurring GLP-2, or an analog
`thereof, are not interchangeable as each peptide has different
`properties, characteristics, and functionality.
`
`Ex. 1016, 15-17 (emphasis in original).
`
`The Examiner allowed the ’886 patent claims for the following reasons:
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`The following references appear to be the closest art to the claimed
`invention. 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 5,654,216) disclose using [sic, a]
`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 GLP-2 or an
`analog thereof, a phosphate buffer, L-histidine for stabilizing the
`formulation and a bulking agent of mannitol or sucrose. Buhl et al. (J.
`Biol. Chem. 263, 8621-8624 (1988)) teach nucleotide and
`corresponding deduced amino acid sequences of cDNA encoding two
`anglerfish pre-proglucagons, where the GLP-2 sequence in the angler
`fish pre-proglucagon is different from the mammalian GLP-2.
`Therefore, the claims are allowable over the prior art.
`
`Ex. 1017, 5. The combination of a reference that disclosed GLP-2 formulations
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`with the disclosure of stabilizing glucagon with histidine could not render the ’886
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`patent claims unpatentable.
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`2.
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`Petitioner Relies on Substantially the Same Combinations of
`Prior Art and the Same Argument as the Examiner Did
`during Prosecution
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`Petitioner now makes the same arguments as did the Examiner with
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`substantially the same combinations of the prior art as relied upon by the Examiner
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`(i.e., that that glucagon (disclosed by Kornfelt and newly added, but less relevant,
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`Osterberg) is similar to GLP-2 (disclosed by Knudsen and newly added Drucker
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`’379).
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`Petitioner submits that ’866 patent GLP-2 formulation claims 1-45 are
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`obvious under 35 U.S.C. § 103(a) over Drucker ’379 in view of Kornfelt and
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`Osterberg alone or in combination with various tertiary references. Pet., 19-21.
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`Drucker ’379 is cited as disclosing “the same GLP-2 peptide formulations as set
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`forth in” independent claim 1. Pet., 22. However, Drucker ’379 does not disclose
`
`an L-histidine stabilizer for any molecule. Petitioner admits so by stating that “L-
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`histidine set forth in (c) of claim 1as well as mannitol in (d) of this claim (sucrose
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`is included under (d) in claim 1), were very well known and widely used for
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`stabilization of peptide formulations, including glucagon as disclosed by Kornfelt
`
`and Osterberg et al. … . In fact, Osterberg discloses L-histidine as a protein
`
`stabilizer in formulations containing sucrose … . Kornfelt teaches the [sic, that] L-
`
`histidine as a stabilizing amino acid is useful across a very broad range of pH
`
`levels … [and] Osterberg specifically teaches that both L-histidine and sucrose are
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`useful at the physiologically acceptable pH levels claimed in the ’886 patent … .”
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`Id. Petitioner argues that Kornfelt’s histidine-stabilized glucagon is motivation to
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`stabilize GLP-2 with histidine because FDA requires stability and:
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`1 – “glucagon and GLP-2 are closely related proteins sharing many of the
`
`same properties.” Id. at 50 (citing Ex. 1018 (Kieffer
`
`et al. , “The Glucagon-Like
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`Peptides,” Endocrine Reviews 20(6):876-913 (Dec. 1999)) (“Kieffer”));
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`2 – “GLP-2 was known to be a peptide hormone member of the glucagon
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`superfamily … .” Id.;
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`3 – “GLP-2 was also known to share amino acid sequence similarity of at
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`least 50% to that of glucagon and have a similar molecular weight … .” Id.;
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`4 – “GL