IN THE UNITED STATES DISTRICT COURT
`FOR THE DISTRICT OF DELAWARE
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`C.A. No. 14-cv-664-GMS
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`(CONSOLIDATED)
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`Plaintiff,
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`v.
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`AUROBINDO PHARMA LTD. and
`AUROBINDO PHARMA U.S.A., INC,
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`Defendants.
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`DEFENDANTS’ JOINT INITIAL INVALIDITY CONTENTIONS
`REGARDING U.S. PATENT NO. RE 44,186
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`Defendants (i) Aurobindo Pharma Ltd. and Aurobindo Pharma U.S.A., Inc.
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`(“Aurobindo”); (ii) Wockhardt Ltd. and Wockhardt USA LLC (“Wockhardt”); (iii) Actavis
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`Laboratories FL, Inc. and Watson Laboratories, Inc. (“Actavis”); (iv) Mylan Pharmaceuticals
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`Inc. (“Mylan); (v) Sun Pharma Global FZE and Sun Pharmaceutical Industries Ltd. (“Sun”); and
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`(vi) Amneal Pharmaceuticals LLC (“Amneal”) (collectively, Aurobindo, Wockhardt, Actavis,
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`Mylan, Sun and Amneal are referred to herein as “Defendants”), through their undersigned
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`counsel, hereby provide the following Joint Initial Invalidity Contentions Regarding U.S. Patent
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`No. RE 44,186 (“the RE ’186 patent”) to Plaintiff AstraZeneca AB (“Plaintiff” or
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`“AstraZeneca”). Defendants contend that each of the asserted claims of the RE ’186 patent are
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`invalid under at least 35 U.S.C. §§ 103 and/or 251. Defendants reserve the right to supplement
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`these Initial Invalidity Contentions pursuant to the Federal Rules of Civil Procedure, Local
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`Rules, Default Guidelines and/or Court’s Orders.
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`Discovery and investigation regarding the RE ’186 patent and potential grounds for
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`ASTRAZENECA AB,
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`Page 1 of 70
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`AstraZeneca Exhibit 2019
` Mylan v. AstraZeneca
` IPR2015-01340
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`invalidity is ongoing. This disclosure is made in good faith and based upon Defendants’ present
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`understanding of the claims being asserted by Plaintiff in Plaintiff’s initial infringement
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`contentions directed to each Defendant. In the absence of a claim construction order from the
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`Court, Defendants have based their Initial Invalidity Contentions on their preliminary
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`constructions of the asserted claims of the RE ’186 patent. Further, Defendants object to any
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`attempt to imply claim construction from their identification or discussion of prior art in the
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`attached exhibits. In addition, if Plaintiff revises those contentions to add additional claims, then
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`Defendants reserve the right to amend their contentions to include invalidity contentions for
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`those newly added claims. Defendants reserve the right, without prejudice, to supplement these
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`Initial Invalidity Contentions as additional research is conducted, prior art is discovered,
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`discovery is obtained, supplements or modifications are made to the infringement theories
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`advanced by Plaintiff, claim construction positions are taken or orders issued, expert discovery is
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`obtained, and for any other reason permitted under the Federal Rules of Civil Procedure, Local
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`Rules, and/or the Court’s Orders.
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`INVALIDITY OF ASSERTED CLAIMS OF THE RE ’186 PATENT
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`Plaintiff has asserted claims 8, 9, 25 and 26 of the RE ’186 patent (the “Asserted
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`Claims”) against each of the Defendants. Each of the Asserted Claims is invalid as obvious
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`under 35 U.S.C. § 103, or alternatively, as invalid under 35 U.S.C. § 251. Claim charts
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`demonstrating Defendants’ invalidity contentions for the Asserted Claims are provided in
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`Exhibit A.
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`The RE ’186 patent, entitled “Cyclopropyl Fused Pyrrolidine-Based Inhibitors of
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`Dipeptidyl Peptidase IV and Method,” issued on April 20, 2013 from U.S. Patent Application
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`No. 13/308,658 (“the ’658 application). The ’658 application, filed on December 1, 2011 is a
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`reissue application of U.S. Patent No. 6,395,767 (“the ’767 patent”), which issued on May 28,
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`2
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`2002 to Bristol-Myers Squibb Company. The ’767 patent issued from the U.S. Patent
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`Application No. 09/788,173 (“the ’173 application”) which was filed on February 16, 2001. The
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`’173 application claims priority to U.S. Provisional Application No. 60/188,555 filed on March
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`10, 2000. Therefore, the earliest possible priority date for the RE ’186 patent is March 10,
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`2000.1
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`The RE ’186 patent generally relates to cyclopropyl-fused pyrrolidine-based inhibitors of
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`dipeptidyl peptidase IV, pharmaceutical combinations, and methods of treatment involving such
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`inhibitors and/or pharmaceutical combination. All of the Asserted Claims of the RE ’186 patent
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`recite compounds including saxagliptin or pharmaceutically acceptable salts thereof.
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`I.
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`The Asserted Claims of the RE ’186 Patent are Invalid as Obvious
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`Each of Asserted claims 8, 9, 25 and 26 of the RE ’186 patent would have been obvious
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`to a person of ordinary skill in the art at the time of the invention. The obviousness inquiry takes
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`into account the following factors: (1) the level of ordinary skill in the art at the time the
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`invention was made; (2) the scope and content of the prior art; (3) the differences between the
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`prior art and the claims at issue; and (4) objective evidence of nonobviousness. Graham v. John
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`Deere Co., 383 U.S. 1, 17-18 (1966). Each of these factors is discussed below.
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`1 Less than one week before the March 12, 2015 deadline for Defendants’ service of initial
`invalidity contentions regarding the RE ’186 patent, on March 6, 2015, AstraZeneca served a
`supplemental response to Defendants’ Joint Interrogatory No. 1 in which AstraZeneca has
`indicated that it may allege that the “assertable dates of invention for the asserted patents” may
`be prior to March 10, 2000. As of March 12, 2015, AstraZeneca has produced no
`documentation to support the claims set forth in its March 6, 2015 supplemental response to
`Defendants’ Joint Interrogatory No. 1. Further, AstraZeneca has not formally asserted a date of
`invention for the asserted claims of the RE ’186 patent prior to the March 10, 2000 earliest
`priority date of the RE ’186 patent. Defendants reserve the right to supplement and revise their
`contentions based on AstraZeneca’s possible future assertion of prior invention and identification
`of documents supporting any such claim or other reasons.
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`3
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`A.
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`The Level of Ordinary Skill in the Art
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`The court conducts the obviousness analysis from the perspective of a person of ordinary
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`skill in the art. The level of skill in the art is a fact-specific inquiry determined on a case-by-case
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`basis. Based on the currently available facts, for purposes of these Initial Invalidity Contentions,
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`Defendants assert that a person of ordinary skill in the art relevant to the RE ’186 patent, is an
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`organic chemist, a medicinal chemist, a pharmaceutical chemist or a related scientist with a
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`Ph.D. or an equivalent advanced degree in their field of practice with several years’ practical
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`experience designing, discovering, testing and/or optimizing new pharmaceutical chemicals for
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`potential and eventual human use. The person of ordinary skill also has familiarity with
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`dipeptidyl-peptidase IV (“DPP-IV”) inhibitors, as well as with amino acids and amino acid
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`analogs as well as the chemistry of peptides and peptidomimetics, and enzyme-substrate
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`interactions and chemical homology of substrates interacting with a given enzyme or protein.
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`Defendants’ definition of a person of ordinary skill in the art may change, depending on
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`what is discovered during litigation, including evidence related to the type of problems
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`encountered in art; prior art solutions to those problems; rapidity with which innovations were
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`made; sophistication of the technology; and educational level of active workers in the field. The
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`conclusions set forth in these Initial Invalidity Contentions would not change even if this
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`definition is changed substantially and significantly.
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`B.
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`The Scope and Content of the Prior Art
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`Each asserted claim of the RE ’186 patent would have been obvious to a person of
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`ordinary skill in the art at the time of the invention, based on the collective teachings of the prior
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`art.
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`The scope and content of the prior art generally is determined by examining “the field of
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`the inventor’s endeavor” and “the particular problem with which the inventor was involved” at
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`“the time the invention was made.” Monarch Knitting Mach. Corp. v. Sulzer Morat GmbH, 139
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`F.3d 877, 881 (Fed. Cir. 1998). In determining the scope and content of the prior art, the court
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`first obtains an understanding of the asserted invention and claimed in the application or patent
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`by reading the specification, including the claims, to understand what the applicant or patentee
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`has invented. Id.; Manual of Patent Examination Procedure (MPEP) § 904.
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`Prior to the filing date of the RE ’186 patent, there existed several oral anti-diabetic
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`agents with different mechanism of action, such as hepatic glucose suppressors, insulin
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`secretagogues, glucose absorption inhibitors, and insulin sensitizers. A person of ordinary skill
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`knew, however, that each had significant limitations and side effects. Therefore, there existed a
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`motivation to develop a new oral anti-diabetic agent that would not only provide an efficacious
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`alternative mechanism for lowering blood glucose and glycosylated hemoglobin (HbA1c) levels,
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`but also would have acceptable safety and tolerability profiles. A drug that worked through an
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`alternative mechanism would also allow it to be combined with existing treatment agents for
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`combined and synergistic effects. As of this time period, the use of multiple oral anti-diabetic
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`agents was an emerging standard of treatment paradigm for type-2 diabetes therapy.
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`Also as of this time period, a person of ordinary skill in the art knew that glucagon like
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`peptide-1 (GLP-1) was a desired target for diabetic patients. GLP-1 is a 30-amino acid peptide
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`incretin hormone derived from processing of pro-glucagon, and is secreted by the L-cells of the
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`intestinal mucosa in response to glucose stimulation. Since the early 1990’s, the GLP-1 had
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`been known to be a potent insulin secretagogue and glucagon suppressor, with robust anti-
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`diabetic and pro-satiety effects in diabetic humans.2 Parenteral versions of GLP-1 receptor
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`agonists, such as Byetta (exenatide) and Victoza (liraglutide), have been developed.
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`2 See M.A. Nauck et al., Effects of subcutaneous glucagon-like peptide 1 (GLP-1 [7-36 amide])
`in patients with NIDDM, Diabetologia, 39 (12), 1546-53 (1996).
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`A person of ordinary skill also understood, prior to the critical date, that a DPP-IV was
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`the primary peptidase responsible for the in vivo degradation of GLP-1. A person of ordinary
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`skill in the art knew, therefore, that if one could decrease or inhibit the function of DPP-IV, one
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`could increase the amount of endogenous GLP-1 in the body.3 For chemists, the concept of
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`generating targeted protease/peptidase inhibitors as therapeutic agents was well known.4
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`Therefore, a person of ordinary skill would have known that DPP-IV inhibitors could be used to
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`beneficially affect the amount of GLP-1 in the body.5
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`1.
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`Identification of the Relevant Prior Art References
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`Relevant prior art includes, without limitation, the following as understood in the context
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`of what was known as of the March 10, 2000 priority date of the RE ’186 patent. Each of the
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`references below (produced bearing production numbers SAXA-DEF-00001 – SAXA-DEF-
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`00459) qualifies as prior art under Pre-AIA 35 U.S.C. §§ 102(a), (b) and/or (e).6 To the extent
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`any reference described below is not expressly incorporated into the later discussion or claim
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`chart of the obviousness of the RE ’186 patent, it is included here because Defendants are
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`currently aware of the art and may use the reference to rebut arguments made by Plaintiff as to
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`the non-obviousness of the RE ’186 patent.
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`a) U.S. Patent No. 5,939,560 to Jenkins et al., PCT published June 8, 1995 (“the
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`3 J.J. Holst et al., Perspectives in Diabetes: Inhibition of the Activity of Dipeptidyl-Peptidase IV
`as a Treatment for Type 2 Diabetes, Diabetes, 47: 1663 (1998).
`4 For example, neutral endopeptidase (NEP) proteolytically degrades the endogenous vasodilator
`atrial natriuretic peptide (ANP) to inactive fragments. By inhibiting this degradation, NEP
`inhibitors have been useful in the treatment of hypertension.
`5 Moreover, through experimentation in rats, a person of ordinary skill in the art would have
`known that inhibition of DPP4 could be both safe and efficacious. Thompson et al., A Fischer
`rat substrain deficient in dipeptidyl peptidase IV activity makes normal steady-state RNA levels
`and an altered protein: Use as a liver-cell transplantation model, Biochem. J., 273: 497-502
`(1991).
`6 Pre-AIA 35 U.S.C. § 102 applies because the ’173 application was filed prior to the March 16,
`2013 effective date of the AIA.
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`6
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`’560 patent”);
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`b) International Patent Application Publication No. 95/15309 to Jenkins et al.,
`published June 8, 1995 (“the 309 publication”);
`
`c) International Patent Application Publication No. 98/19998 to Villhauer, published
`May 14, 1998 (“the ’998 publication”);
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`d) U.S. Patent No. 6,011,155 to Villhauer, filed October 31, 1997 and published
`January 2, 2000 (“the ’155 patent”);
`
`e) J. Li et al., “Aminoacylpyrrolidine-2-nitriles: Potent and Stable Inhibitors of
`Dipeptidyl-Peptidase IV (CD 26),” Archives of Biochemistry and Biophysics, Vol.
`323, No. 1, 148-154 (1995) (“Li”);
`
`f) D. Ashworth et al., “2-Cyanopyrrolidides as Potent, Stable Inhibitors of
`Dipeptidyl Peptidase IV,” Bioorganic and Medicinal Chemistry Letters, Vol. 6,
`No. 10, 1163-1166 (1996) (“Ashworth”);
`
`g) R. Hiltmann et al., “2-Acylaminopyridine-Derivatives with Morphine Agonistic
`and Morphine Antagonistic Properties,” Arzneim.-Forsch., 24(4), 584-600 (1974)
`(Abstract only) (“Hiltmann”);
`
`h) U.S. Patent No. 4,591,598 to Urbach et al., published May 27, 1986 (“the ’598
`patent”);
`
`i) German Patent No. DE 25 21 895 to Hromadko, published on April 8, 1976
`(“Hromadko”);
`
`j) U.S. Patent No. 3,325,478 to Hermann et al., published June 13, 1967 (“the ’478
`patent”);
`
`k) S. Hanessian et al., “The Synthesis of Enantiopure ω-Methanoprolines and ω-
`Methanopipecolic Acids by a Novel Cyclopropanation Reaction: The ‘Flattening’
`of ‘Proline’,” Angew. Chem. Int. Ed. Engl., Vol. 36, No. 17, 1881-1883 (1997)
`(“Hanessian 1997”);
`
`l) S. Hanessian et al., “Probing the Importance of Spacial and Conformational
`Domains in Captopril Analogs for Angiotensin Converting Enzyme Activity,”
`Bioorg. Med. Chem. Lett., Vol. 8, 2123-2128 (1998) (“Hanessian 1998”);
`
`m) K. Gerzon et al., “The Adamantyl Group in Medicinal Agents. I. Hypoglycemic
`N-Arylsulfonyl-N’-adamantylurcas,” J. Med. Chem., Vol. 6, 760-763 (1963)
`(“Gerzon”)
`
`n) U.S. Patent No. 6,166,063 to Villhauer, issued from Application No. 09/458,224,
`filed December 9, 1999 as a continuation of Application No. 09/209,068, filed
`December 10, 1998, and granted December 26, 2000 (“the ’063 patent”);
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`o) Fischer et al., “The conformation around the peptide bond between the P1- and
`P2- positions is important for catalytic activity of some proline-specific
`proteases,” Biochim. Biophys. Acta 742:452 (1983) (“Fischer”);
`
`p) Augustyns et al., “The unique properties of dipeptidyl-peptidase IV (DPP IV /
`CD26) and the therapeutic potential of DPP IV inhibitors,” Curr Med Chem.,
`6(4):311-27 (1999) (“Augustyns”);
`
`q) Rubio et al., “Urinary Metabolites of Rimantadine in Humans,” Drug Metabolism
`and Disposition, Vol. 16, 773-777 (1988) (“Rubio”);
`
`r) Raag et al., “Crystal Structures of Cytochrome P-450CAM Complexed with
`Camphane, Thiocamphor, and Adamantane: Factors Controlling P-450 Substrate
`Hydroxylation,” Biochemistry, Vol. 30, 2674-2684 (1991) (“Raag”);
`
`s) U.S. Patent No. 4,954,158 to Stammer et al., published September 4, 1990 (“the
`158 patent”);
`
`t) Lipinski et al., “Experimental and Computational Approaches to Estimate
`Solubility and Permeability in Drug Discovery and Development Settings,”
`Advanced Drug Delivery Review, 23, pp. 3-25 (1997) (“Lipinski”);
`
`u) Hansch et al., “Cluster Analysis and the Design of Congener Sets,” Substituent
`Constants for Correlation Analysis in Chemistry and Biology, John Wiley &
`Sons: New York, 48-54 (1979) (“Hansch”);
`
`v) Cates, L., “Calculation of Drug Solubilities by Pharmacy Students,” American
`Journal of Pharmaceutical Education, 45, pp. 11-13 (1981) (“Cates”); and
`
`w) Korfmacher et al., “HPLC-API/MS/MS: a powerful tool for integrating drug
`metabolism into the drug discovery process,” DDT, Vol. 2, no. 12, pp. 532-537
`(1997) (“Korfmacher”).
`
`Defendants reserve the right to amend this list as more references are revealed during
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`discovery and in response to arguments that Plaintiff may make as to why the invention is not
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`obvious.
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`2.
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`Disclosures of the Relevant Prior Art References
`
`A brief summary of the disclosures of each of the prior art references listed above is set
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`forth below.
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`a)
`
`The ’560 Patent
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`The ’560 patent issued August 17, 1999, with a 102(e) date of August 27, 1996 and
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`qualifies as prior art under at least 35 U.S.C. §§ 102(a) and 102(e). The ’560 patent claims
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`priority to a PCT application published on June 8, 1995 as the ’309 publication (further discussed
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`below), which qualifies as prior art under at least 35 U.S.C. § 102(b). The ’560 patent was
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`before the U.S. Patent Office during the prosecution of the RE ’186 patent, but was not cited or
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`discussed by the examiner to reject the claims.
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`The ’560 patent discloses dipeptidyl peptidase IV (DPP-IV) inhibiting compounds having
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`the following general structure:
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`
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`(’560 patent, col. 42, ll. 45-53; see also ’309 publication at 5-6, 48.) Claim 1 of the ’560 patent
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`sets forth the possible substitutions of the general formula for the disclosed compounds. In
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`particular, when, n=1, m=1, X=CH2, R=CN, Y=N, and A is an α-amino acyl group bearing a
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`cycloaliphatic side chain, the compounds disclosed in the ’560 patent (and the ’309 publication)
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`resemble the structure of saxagliptin as claimed in the RE ’186 patent, as follows:
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`’560 Patent/’309 Publication Compounds
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`Saxagliptin
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`
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`Thus, the compounds disclosed in the ’560 patent (and the ’309 publication) differ from the
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`saxagliptin compound claimed in the RE ’186 patent in that they (i) lack a specific identification
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`of the hydroxy-adamantyl group representing the aliphatic side chain, and (ii) lack a fused
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`cyclopropyl group.
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`The ’560 patent (and the ’309 publication) further discloses that DPP-IV has a major role
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`in human physiology and pathophysiology, and that potent inhibitors of DPP-IV may be useful
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`as drugs for the treatment of a variety of human diseases, including immunosuppressants,
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`prevention of HIV, prevention of metastases, treatment of dermatological diseases, male
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`contraception, and benign prostate hypertrophy. (’560 patent, at col. 1, ll. 23-26; col. 2, l. 50-col.
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`3, l. 2; ’309 publication at 1-3.)
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`b)
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`The 309 publication
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`The 309 publication was published on June 8, 1995, more than one year before the
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`earliest U.S. filing date of the RE ’186 patent, and qualifies as prior art under at least 35 U.S.C.
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`§ 102(b). The ’309 publication was not before the U.S. Patent Office during the prosecution of
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`the RE ’186 patent.
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`As discussed above, the ’309 publication discloses numerous DPP-IV serine protease
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`inhibitor compounds. Moreover, all three inventors listed on the 309 publication (and the ’560
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`patent) are also authors of the Ashworth reference (Paul D. Jenkins, D. Michael Jones, and
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`Michael Szelke).
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`c)
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`The ’998 Publication
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`The ’998 publication was published on May 14, 1998, more than one year before the
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`earliest U.S. filing date of the RE ’186 patent, and qualifies as prior art under at least 35 U.S.C.
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`§102(b). The ’998 publication was not before the U.S. Patent Office during the prosecution of
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`the RE ’186 patent.
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`The ’998 publication discloses N-(N’-substituted glycyl)-2-cyanopyrrolidine compounds
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`that are useful as inhibitors of DPP-IV (dipeptidyl-peptidase-IV) activity of the following
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`formula:
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`
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`(’998 publication at Abstract.) The ’998 publication discloses that R may be R5, wherein R5 is
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`“…adamantyl; or (C1-8)alkyl…optionally mono- or
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`independently plurisubstituted with
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`hydroxy….” (’998 publication at 3.) Thus, the ’998 publication discloses compounds that
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`resemble the structure of saxagliptin as claimed in the RE ’186 patent, as follows:
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`’998 Publication Compounds
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`Saxagliptin
`
`HO
`
`N H
`
`N
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`O
`
`CN
`
`
`
`
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`(Id.) Thus, the differences between the compounds disclosed in the ’998 publication and
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`saxagliptin are the lack of a fused cyclopropyl group on the former that is present in the latter,
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`and the hydroxy-adamantyl group attached to the glycyl alpha-carbon in the latter rather than to
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`the amine as in the former. The ’998 publication further discloses that DPP-IV inhibition
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`“appears to represent an attractive approach for treating non-insulin-dependent diabetes
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`mellitus.” (Id. at 1.)
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`d)
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`The ’155 Patent
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`The ’155 patent issued January 2, 2000, and qualifies as prior art under at least 35 U.S.C.
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`§ 102(a). The ’155 patent was before the U.S. Patent Office during the prosecution of the RE
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`’186 patent, but was not cited or discussed by the examiner to reject the claims.
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`The ’155 patent discloses compounds “indicated for use as pharmaceuticals in inhibiting
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`DPP-IV and in the treatment of conditions mediated by DPP-IV, such as non-insulin-dependent
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`diabetes mellitus, arthritis, obesity, osteoporosis and further conditions of impaired glucose
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`tolerance.” (’155 patent at Abstract.) The ’155 patent discloses N-(N’-substituted glycyl)-2-
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`cyanopyrrolidine compounds that are useful as inhibitors of DPP-IV activity of the following
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`formula:
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`
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`(’155 patent at Abstract.) The ’155 patent discloses that R may be R5, wherein R5 is
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`“…adamantyl; or (C1-8)alkyl…optionally mono- or
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`independently plurisubstituted with
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`hydroxy….” (’155 patent at col. 2, ll. 28-35.) Thus, the ’155 patent discloses compounds that
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`resemble the structure of saxagliptin as claimed in the RE ’186 patent, as follows:
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`’155 Patent Compounds
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`Saxagliptin
`
`HO
`
`N H
`
`N
`
`O
`
`CN
`
`
`
`
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`(Id.) Thus, the differences between the compounds disclosed in the ’155 patent and saxagliptin
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`are the lack of a fused cyclopropyl group on the former that is present in the latter, and the
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`hydroxy-adamantyl group attached to the glycyl alpha-carbon in the latter rather than to the
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`amine as in the former. The ’155 patent further discloses that DPP-IV inhibition “appears to
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`represent an attractive approach for treating non-insulin-dependent diabetes mellitus.” (Id. at
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`col. 1, ll. 30-32.)
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`The ’155 patent further discloses several compounds and provides data for these
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`compounds in inhibiting DPP-IV. Of the compounds disclosed, compound of Example 47 was
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`found to be one of the most potent compounds when tested in human and rat plasma DPP-IV:
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`
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`The data also showed that having an adamantyl group increases the potency of a drug by
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`more than 10-fold. Compound of Example 47 with an adamantyl side chain was significantly
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`more potent than an identical compound of Example 28 with a cyclohexyl side chain:
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`Example No.
`
`Activity data (Ki values)7 (nM)
`Human
`DPPIV
`
`Caco-2 cells
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`Rat DPPIV
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`7 The inhibitor constant, Ki value, is an indication of how potent an inhibitor is. Ki is the
`concentration required to produce half maximum inhibition, thus the smaller the Ki value, the
`more potent the inhibitor is.
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`Ex. 28
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`N
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`NH
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`O
`
`N
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`Ex. 47
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`NH
`
`O
`
`N
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`
`
`N
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`
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`e)
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`Li
`
`90
`
`180
`
`60
`
`10
`
`11
`
`5
`
`Li was published in 1995, more than one year before the earliest U.S. filing date of the
`
`RE ’186 patent, and qualifies as prior art under at least 35 U.S.C. § 102(b). Li was before the
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`U.S. Patent Office during the prosecution of the RE ’186 patent, but was not cited or discussed
`
`by the examiner to reject the claims.
`
`Li discloses a series of amino acylpyrrolidine-2-nitriles in which the carboxyl group of
`
`proline is replaced by a nitrile group, which were synthesized as inhibitors of dipeptidyl-
`
`peptidase IV. (Li, at Abstract.) Li further discloses that such compounds, “by virtue of their
`
`ease of synthesis, stability, specificity, and inhibitory potency appear to be superior to other
`
`described dipeptidyl-peptidase IV inhibitors.” (Id.) The structure of the amino acylpyrrolidine-
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`2-nitrile compounds disclosed in Li is as follows:
`
`
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`14
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`
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`where R represents phenyl, alanyl or arginine. (Id. at 150-51.) The data disclosed in Li also
`
`show that optimization of the R group which is attached to the alpha carbon can increase the
`
`inhibitory potency. (Id. at 152, Table 1.)
`
`f)
`
`Ashworth
`
`Ashworth was published in 1996, more than one year before the earliest U.S. filing date
`
`of the RE ’186 patent, and qualifies as prior art under at least 35 U.S.C. § 102(b). Ashworth was
`
`before the U.S. Patent Office during the prosecution of the RE ’186 patent, but was not cited or
`
`discussed by the examiner to reject the claims.
`
`In Ashworth, a group of researchers from the Ferring Research Institute, disclosed a
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`novel series of stable, potent inhibitors of dipeptidyl peptidase IV (which were known to be
`
`compounds that were useful for treating diabetes) of the following formula:
`
`
`
`Ashworth discloses a series of 2-cyanopyrrrolidide compounds that are stable, potent
`
`inhibitors of DPP-IV. (Ashworth, at Abstract.) Ashworth further discloses that it was necessary
`
`to develop such inhibitors because of their therapeutic potential in a number of disease states,
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`including inflammation, graft versus host disease, cancer and AIDS. (Id. at 1164.)
`
`Ashworth reported that tests of its compounds revealed excellent half-lives in aqueous
`
`solution (pH 7.4) at room temperature (Table II) with several examples having half-lives greater
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`than 48 hours. The following Table II describes the structures of the compounds, their potencies,
`
`and stabilities:
`
`15
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`
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`Specific 2-cyanopyrrolidines disclosed by Ashworth in Table II include the following
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`
`
`compounds:
`
`;
`
`
`
`(See Ashworth, at 1166 (Table II, compounds 24 (cyclopentyl glycine substitution for “Xaa”)
`
`and 25 (cyclohexyl glycine substitution for “Xaa”)).) Ashworth further discloses that the
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`compounds in Table II were potent inhibitors of DPP-IV. (Id. at 1165.) Ashworth thus singled
`
`out as the “most potent” the “compounds 24, 25, 26, and 27.”
`
`Of these compounds, only compounds 25 and 27 showed stability with half-lives greater
`
`than 48 hours and compound 25 showed the best combination of potency (Ki = 1.4 nm) and
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`stability.
`
`Cyclohexylglycine (Compound 25)
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`
`
`16
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`Page 16 of 70
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`
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`Ashworth suggests that “further work on optimization of the pyrrolidine ring” is possible
`
`and that they will be reported shortly. Therefore, a person of ordinary skill in the art would have
`
`been motivated to further increase Compound 25’s potency and stability through optimization.
`
`Therefore, a person of ordinary would have focused on compound 25 as the lead compound
`
`given its stability and great potency.
`
`Two of the authors of Ashworth also are the named inventors of the WO 95/15309
`
`publication (published June 8, 1995), which also discloses compound 25 as Example 16, 1-(2-
`
`amino-2-cyclohexyl-acetyl)pyrrolidine-2-carbonitrile. In a later publication,8 the Bristol-Myers
`
`Squibb Research and Development team specifically referenced Ashworth et al. articles and
`
`disclosed that the compounds reported in those references (among others) were chosen as the
`
`front runners for the design optimization approach that lead to the discovery of the saxagliptin
`
`compound. In particular, they stated that “[f]rom a potency perspective, the nitrilo-pyrrolidines
`
`were deemed to be highly attractive.”9
`
`Ashworth, in the context of earlier work from Novartis, may also disclose that the
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`position of the substituents is important. Both Ashworth and the ’155 patent disclose compounds
`
`that are DPP-IV inhibitors, but the ’155 patent discloses compounds with substitution of the
`
`lipophilic group at the terminal nitrogen of the N-terminal amino acid, whereas Ashworth
`
`
`8 Jefferey A. Robl & Lawrence G. Hamman, The Discovery of the Dipeptidyl Peptidase-4
`(DPP4) Inhibitor Onglyza™: From Concept to Market, in Accounts in Drug Discovery: Case
`Studies in Medicinal Chemistry, 1 (RSC 2011).
`9 Id. at 6-7.
`
`17
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`Page 17 of 70
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`
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`discloses compounds with the corresponding substitution at the alpha carbon atom. In viewing
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`the IC50 values of the compounds in the ’155 patent and those in Ashworth, a person of ordinary
`
`skill in the art would have understood that the substitution of the lipophilic group at the alpha
`
`carbon atoms, as in Ashworth, could lead to a change in potency or a substantially improved
`
`potency. The following compounds, for example, are substantially the same except for the
`
`position of the cyclohexyl group:
`
`18
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`Page 18 of 70
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`
`
`
`
`Example No.
`
`Compound 25 of Ashworth
`N
`
`O
`
`N
`
`NH2
`
`Ex. 28 of U.S. Patent No. 6,011,155
`N
`
`
`
`NH
`
`O
`
`N
`
`
`
`
`
`g)
`
`Hiltmann
`
`Activity data (Ki values) (nM)
`Human DPP-IV
`
`1.4
`
`180
`
`Hiltmann was published in 1974, more than one year before the earliest U.S. filing date
`
`of the RE ’186 patent, and qualifies as prior art under at least 35 U.S.C. § 102(b).
`
`Hiltmann discloses a series of 2-acylamino pyridine derivatives that have potent
`
`analgesic properties. (Hiltmann, at Abstract.) Hiltmann further discloses the structure of such
`
`derivatives, including the following compound:
`
`
`
`CH3
`
`O
`
`N
`
`NH
`
`N
`
`X
`
`(Id., at 590 (Table 3).)
`
`19
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`Page 19 of 70
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`
`
`h)
`
`The ’598 Patent
`
`The ’598 patent issued May 27, 1986, more than one year before the earliest U.S. filing
`
`date of the RE ’186 patent, and qualifies as prior art under at least 35 U.S.C. § 102(b). The ’598
`
`patent was not before the U.S. Patent Office during the prosecution of the RE ’186 patent.
`
`The ’598 patent discloses derivatives of 2-azabicyclo[3.1.0]hexane-3-carboxylic acids
`
`and processes to prepare them, including starting with compounds of the following formula:
`
`
`
`wherein W is hydrogen and R1 is a (C5 to C9)-cycloalkyl. (See ’598 patent at col. 1, ll. 26-40,
`
`col. 3, ll.35-63.) The ’598 patent further discloses that such compounds “have a long-lasting and
`
`strong hypotensive effect” and are “potent inhibitors of angiotensin converting enzyme (ACE
`
`inhibitors) and can be employed to control hypertension of a variety of etiologies.” (See ’598
`
`patent at col. 7, ll. 61-65.) Like DPP-IV, angiotensin converting enzyme was also known as a
`
`proline-specific peptidase.10
`
`i)
`
`Hromadko
`
`Hromadko published on April 8, 1976, more than one year before the earliest U.S. filing
`
`date of the RE ’186 patent, and qualifies as prior art under at least 35 U.S.C. § 102(b).
`
`Hromadko was before the U.S. Patent Office during the prosecution of the RE ’186 patent, but
`
`was not cited or discussed by the examiner to reject the claims.
`
`Hromadko discloses α-amino-2-adamantyl acetic acid of the following structure:
`
`
`10 See, e.g., Yoshioka et al., Role of rat intestinal brush-border membrane angiotensin-converting
`enzyme in dietary protein digestion. Am J Physiol. 1987 Dec; 253(6 Pt 1):G781–G786.
`
`20
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`Page 20 of 70
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`
`
`(Hromadko at 1.) Hromadko further discloses that the α-amino-2-adamantyl acetic acid can be
`
`used for organic synthesis in the production of drugs, in particular, penicillin. (Id.) Hromadko
`
`also states that the use of the α-amino-2-adamantyl penicillin can be used instead of previously
`
`known penicillins when resistance against such penicillins has built up. (Id. at 2.) Thus,
`
`Hromadko teaches the improvement of the penicillin compound to overcome penicillin
`
`resistance through the a