UNITED STATES PATENT AND TRADEMARK OFFICE
`
`_______________________________
`
`BEFORE THE PATENT TRIAL AND APPEAL BOARD
`
`_______________________________
`
`SUN PHARMACEUTICAL INDUSTRIES, LTD.,
`SUN PHARMA GLOBAL FZE and
`AMNEAL PHARMACEUTICALS LLC,
`Petitioner
`
`v.
`
`ASTRAZENECA AB,
`Patent Owner
`
`___________________________
`
`Case No.: IPR2016-01104
`Patent No.: RE44,186
`
`___________________________
`
`
`PETITION FOR INTER PARTES REVIEW OF
`U.S. PATENT NO. RE44’186
`
`
`
`Mail Stop PATENT BOARD
`Patent Trial and Appeal Board
`U.S. Patent and Trademark Office
`P.O. Box 1450
`Alexandria, VA 22313-1450
`Submitted Electronically via the Patent Review Processing System
`
`

`
`Table of Contents
`
`Page
`
`I.
`
`INTRODUCTION ........................................................................................... 1
`
`A.
`
`B.
`
`C.
`
`Brief Overview of the ’186 Patent ........................................................ 2
`
`Brief Overview of the Prosecution History ........................................... 6
`
`Brief Overview of the Scope and Content of the Prior Art ................... 7
`
`1.
`
`2.
`
`3.
`
`The Dipeptide Substrate Targeted By The DP-IV Enzyme........ 7
`
`Substituting Hydroxyadamantyl onto the glycyl moiety ............ 9
`
`Adding Cyclopropyl to the Pyrrolidine Ring ............................ 11
`
`D. Overview of Differences Between the Prior Art and the Claims ........ 12
`
`E.
`
`Level of Skill in the Art ....................................................................... 13
`
`II. GROUNDS FOR STANDING ...................................................................... 17
`
`III. MANDATORY NOTICES UNDER 37 C.F.R. § 42.8 ................................. 18
`
`IV. PAYMENT OF FEES UNDER 37 C.F.R. §§ 42.15(A) AND 42.103.......... 19
`
`V.
`
`STATEMENT OF PRECISE RELIEF FOR EACH CLAIM
`CHALLENGED ............................................................................................ 19
`
`VI. CLAIM CONSTRUCTION .......................................................................... 21
`
`VII. BACKGROUND KNOWLEDGE IN THE ART PRIOR TO MARCH
`10, 2000 ......................................................................................................... 21
`
`VIII. DETAILED EXPLANATION OF GROUNDS FOR
`UNPATENTABILITY .................................................................................. 25
`
`A.
`
`[Ground 1] Claims 1, 2, 4, 6-11, 25-28, 32-35, 39 and 40 Are
`Obvious Under 35 U.S.C. § 103 Over Ashworth, Villhauer, Raag
`and Hanessian ...................................................................................... 25
`
`1.
`
`2.
`
`3.
`
`4.
`
`5.
`
`Skilled Workers Were Motivated to Make Better DP-IV
`Inhibitors ................................................................................... 26
`
`Ashworth Identified a Lead Compound .................................... 27
`
`Villhauer Identified a Large Adamantyl Group to Modify
`DP-IV Inhibitors ....................................................................... 29
`
`Raag Describes a Hydroxylated Adamantane Metabolite ........ 30
`
`Hanessian Describes Cyclopropyl Modification to the
`Proline Moiety ........................................................................... 31
`
`i
`
`

`
`6.
`
`7.
`
`8.
`
`9.
`
`The Compound of Claim 25 of the (cid:1932)186 Patent Was Obvious
`Over the Combined Teachings of the References .................... 34
`
`Claims 26-28 ............................................................................. 38
`
`Genus Claims 1, 2, 4, 6 and 8-11 Are Obvious As
`Encompassing The Compound Species of Claim 25 ................ 39
`
`Claims 32-35, 39 and 40: methods of treating type II
`diabetes mellitus ........................................................................ 48
`
`B.
`
`[Ground 2] Claims 12-16, 29, 30, 36, 37, 41 and 42 Are Obvious
`Under §103 Over Ashworth, Villhauer, Raag, Hanessian,
`Bachovchin and the GLUCOPHAGE Label ....................................... 51
`
`1.
`
`GLUCOPHAGE/ Metformin .................................................... 51
`
`a. Weight ratios ....................................................................... 53
`
`C.
`
`D.
`
`[Ground 3] Claims 12, 17, 18 and 22 Are Obvious Under §103
`Over Ashworth, Villhauer, Raag, Hanessian, Bachovchin and the
`XENICAL Label ................................................................................. 55
`
`[Ground 4] Claims 12 and 19-21 Are Obvious Under §103 Over
`Ashworth, Villhauer, Raag, Hanessian, Bachovchin and the
`MEVACOR Label ............................................................................... 59
`
`1. MEVACOR/Lovastatin ............................................................. 59
`
`a. Weight ratios ....................................................................... 60
`
`IX. CONCLUSION .............................................................................................. 63
`
`CERTIFICATE OF COMPLIANCE ....................................................................... 64
`
`
`
`
`
`ii
`
`

`
`
`
`Exhibit No.
`
`1001
`
`1002
`1003
`1004
`1005
`1006
`
`1007
`
`
`1008
`
`1009
`
`1010
`
`1011
`
`1012
`1013
`1014
`
`1015
`
`1016
`
`1017
`
`PETITIONER’S EXHIBIT LIST
`
`Description
`U.S. Reissue Patent 44,186 E to Robl et al. (reissued Apr. 30,
`2013)
`U.S. Patent No. 6,395,767 to Robl et al. (issued May 28, 2002)
`Declaration of David P. Rotella, Ph.D.
`Curriculum Vitae of David P. Rotella, Ph.D.
`File History of U.S. Patent No. 6,395,767 to Robl et al.
`File History of U.S. Reissued Patent 44,186 E to Robl et al.
`Doreen M. Ashworth et al., 2-cyanopyrrolidides as potent, stable
`inhibitors of dipeptidyl peptidase IV, 6 BIOORG. & MED. CHEM.
`LTRS. 1163 (1996)
`WO Patent App. Pub. No. 98/19998 to Villhauer (pub’d May
`14,1998)
`Reetta Raag & Thomas L. Poulos, Crystal Structure of
`Cytochrome P-450CAM Complexed with Camphane,
`Thiocamphor, and Adamantane: Factors Controlling P-450
`Substrate Hydroxylation, 30 BIOCHEMISTRY 2674 (1991)
`Stephen Hanessian et al., The Synthesis of Enantiopure (cid:550)-
`Methanoprolines and (cid:550)-Methanopipecolic Acids by a Novel
`Cyclopropanation Reaction: The “Flattening” of Proline, 36
`ANGEW. CHEM. ED. ENGL. 1881 (1997)
`WO Patent App. Pub. No. 99/38501 to Bachovchin et al. (pub’d
`Aug. 5, 1999)
`GLUCOPHAGE Label (available by FOIA Jan. 8, 1998)
`XENICAL Label (available by FOIA Aug. 9, 1999)
`MEVACOR Label (available by FOIA Sept. 15, 1994)
`Jian Lin et al., Inhibition of dipeptidyl peptidase IV by
`fluoroolefin-containing N-peptidyl-O-hydroxylamine
`peptidomimetics, 95 PROC. NATL. ACAD. SCI. USA 14020
`(1998)
`Howard E. Hoffman et al., Pharmacokinetics and Metabolism of
`Rimantadine Hydrochloride in Mice and Dogs, 32(11)
`ANTIMICROBIAL AGENTS AND CHEMOTHERAPY 1699
`(1988)
`Christopher A. Lipinski et al., Experimental and computational
`approaches to estimate solubility and permeability in drug
`discovery and development settings, 23 ADV. DRUG DELIV.
`
`iii
`
`

`
`Exhibit No.
`
`Description
`
`REV. 3 (1996)
`Hansch et al., Cluster Analysis and the Design of Congener Sets,
`in SUBSTITUENT CONSTANTS FOR CORRELATION ANALYSIS IN
`CHEMISTRY AND BIOLOGY 48 (John Wiley & Sons 1979)
`Lindley A. Cates, Calculation of Drug Solubilities by Pharmacy
`Students, 45 Am. J. Pharm. Educ. 11 (1981)
`Walter A. Korfmacher et al., HPLC-API/MS/MS: a powerful tool
`for integrating drug metabolism into the drug discovery process, 2
`Drug Disc. Today 532 (1997)
`C. Y. Chiou et al., The Cholinergic Effects and Rates of Hydrolysis
`of Conformationally Rigid Analogs of Acetylcholine, 166 J. Pharm.
`Exp. Ther. 243 (1969)
`Daniel E. Koshland, Jr., The Key-Lock Theory and the Induced Fit
`Theory, 33 ANGEW. CHEM. ED. ENGL. 2375 (1994)
`E.J. Ariëns & A. M. Simonis, Optimalization of Pharmacokinetics
`– An Essential Aspect of Drug Development – by Metabolic
`Stabilization, Pharmacochem. Lib., in 4 PHARMACOCHEM.
`LIB. 165 (1982)
`R. Scott Obach, Prediction of Human Clearance of Twenty-nine
`Drugs from Hepatic Microsomal Intrinsic Clearance Data: An
`Examination of In Vitro Half-life Approach and Nonspecific
`Binding to Microsomes, 27 DRUG METAB. DISPOS. 1350
`(1999)
`Yung-chi Cheng & William H. Prusoff, Relationship Between the
`Inhibition Constant (KI) and the Concentration of Inhibitor which
`Causes 50 Per Cent Inhibition (I50) of an Enzymatic Reaction, 22
`Biochem. Pharmacol. 3099 (1973)
`Debnath Pal & Pinak Chakrabarti, Cis Peptide Bonds in Proteins:
`Residues Involved, their Conformations, Interactions and
`Location, 294 J. of Mol. Biol. 271 (1999)
`US Provisional Patent Application No. 60/1888,555 to Robl
`
`1018
`
`1019
`
`1020
`
`1021
`
`1022
`
`1023
`
`1024
`
`
`1025
`
`1026
`
`1027
`
`iv
`
`

`
`I.
`
`INTRODUCTION
`
`On May 2, 2016, the Board instituted inter partes review (“IPR”) of claims
`
`1, 2, 4, 6-22, 25-30, 32-37, and 39-42 of U.S. Patent No. RE44,186 (the “’186
`
`patent,” Ex. 1001)
`
`in
`
`IPR2015-01340. Sun Pharma Global FZE, Sun
`
`Pharmaceutical Industries, Ltd. (together, “Sun”), and Amneal Pharmaceuticals
`
`LLC (“Amneal”) (collectively, “Petitioner”) submit
`
`this Petition for IPR
`
`(“Petition”) also seeking cancellation of claims 1, 2, 4, 6-22, 25-30, 32-37, and 39-
`
`42 of the ’186 patent on the grounds that those claims are unpatentable under 35
`
`U.S.C. §103(a) over the same art and arguments presented by petitioner Mylan
`
`Pharmaceuticals Inc. (“Mylan”) in its petition submitted in IPR2015-01340, and on
`
`which the Board instituted IPR. Petitioner also submits a Motion for Joinder to
`
`join this Petition with the IPR2015-01340 proceedings. This Petition is
`
`substantially identical to the petition for IPR filed by Mylan in in IPR2015-01340,
`
`and Petitioner’s intent to seek joinder with IPR2015-01340 will have no effect on
`
`the trial schedule in that action.
`
`For the reasons explained below, and for the reasons the Board instituted
`
`IPR in IPR2015-01340, there is a reasonable likelihood that claims 1, 2, 4, 6-22,
`
`25-30, 32-37 and 39-42 of the ’186 patent are unpatentable for failing to
`
`distinguish over prior art. Thus, claims 1, 2, 4, 6-22, 25-30, 32-37 and 39-42 of the
`
`’186 patent should be found unpatentable and canceled.
`
`

`
`A.
`
`Brief Overview of the ’186 Patent
`
`The (cid:1932)186 patent is entitled “Cyclopropyl-Fused Pyrrolidine-Based Inhibitors
`
`of Dipeptidyl Peptidase IV and Method.” Ex. 1001. In a general sense, the (cid:1932)186
`
`patent discloses compounds said to inhibit the enzyme dipeptidyl peptidase IV
`
`(“DP-IV” also referred to in the claims as “DP4”). This enzyme is responsible for
`
`the metabolic cleavage of certain peptides found in the body, including glucagon, a
`
`peptide of 29 amino acids. Id., at 1:30-34. The glucagon peptide has multiple
`
`actions in vivo, including the stimulation of insulin secretion, inhibition of
`
`glucagon secretion, promotion of satiety, and the slowing of gastric emptying. Id.,
`
`at 1:40-44. Glucagon is rapidly degraded in the body, and the DP-IV enzyme has
`
`been shown to be the primary degrader of glucagon. Id., at 1:49-54. Thus,
`
`inhibitors of DP-IV in vivo should increase endogenous levels of glucagon, and
`
`serve to attenuate the diabetic condition. Id., at 1:56-59.
`
`The ’186 patent discloses an extremely large genus of compounds which are
`
`termed “cyclopropyl-fused pyrrolidine-based compounds.” Id., at 1:65-66. In
`
`essence, these compounds are a cyclopropyl-fused pyrroline-based core with a
`
`wide variety of optional substituents. The ’186 patent also discloses various
`
`pharmaceutical compositions formed from the compounds, as well as methods of
`
`treatment for diabetes and an extremely wide variety of other diseases and
`
`conditions said to be related to diabetes. Id., at 3:4-18. The ’186 patent provides no
`
`2
`
`

`
`evidence of testing any of the compounds in in vivo animal trials or clinical trials in
`
`humans for any such diseases or related conditions.
`
`The original patent from which the ’186 reissued, US 6,395,767 (the “’767
`
`patent”), was based on an application filed February 16, 2001, which itself claimed
`
`the benefit of a provisional application, 60/188,555 (the “’555 application”), filed
`
`March 10, 2000. Ex. 1001, p. 1. Nine years after the ’767 patent issued, then-owner
`
`Bristol-Myers Squibb Company (“BMS”) filed a reissue application which, inter
`
`alia, added new claims 25-40. Ex. 1004 (reissue prosecution history) at [0612].
`
`BMS stated that the error it sought to correct was its failure to claim the compound
`
`of claim 25 specifically. Id. at [0129-30]. BMS subsequently amended or canceled
`
`other claims, and added more claims, 41-45. These claims were subsequently
`
`allowed and renumbered. Id. at [0038]. The reissued claims 1-43 are the claims
`
`presently in the ’186 patent. Claims 1, 2, 4, 6-22, 25-30, 32-37 and 39-42 of the
`
`’186 patent are shown in this petition to be unpatentable for failing to distinguish
`
`over prior art.
`
`Claim 1 of the (cid:1932)186 patent is directed to the large genus of compounds, and
`
`dependent claims 2-10 define various subgenera. Claim 12 is directed to a
`
`pharmaceutical combination comprising a compound of claim 1 and an anti-
`
`obesity agent, a lipid-modulating agent, or an anti-diabetic agent other than a DP-
`
`3
`
`

`
`IV inhibitor. Claims 13-20 depend directly or indirectly from claim 12 and are
`
`directed to various combinations of drug therapies.
`
`Independent claim 25 is directed to a specific compound that is encompassed
`
`by claim 1 [Ex. 1003, ¶13] and reads as follows:
`
`25. A compound that is
`
`or a pharmaceutically acceptable salt thereof.
`
`
`
`The compound of claim 25 is also known as (1S,3S,5S)-2-[(2S)-2-amino-2-
`
`(3-hydroxy-1-adamantyl) acetyl]-2-azabicyclo[3.1.0]hexane-3-carbonitrile.
`
`For convenience, the species compound defined by the structure set forth in
`
`claim 25 will hereafter be referred to as “saxagliptin.” Ex. 1003, ¶14. This petition
`
`and supporting evidence demonstrate that the species of claim 25 is obvious over
`
`the prior art. When a species is obvious over the prior art, broader claims which
`
`encompass the species are also obvious. In re Muchmore, 433 F.2d 824, 824-25
`
`(CCPA 1970) (“Since we agree with the board’s conclusion of obviousness as to
`
`these narrow claims, the broader claims must likewise be obvious.”); accord
`
`Soverain Software LLC v. Victoria’s Secret Direct Brand Mgmt., LLC, 778 F.3d
`
`1311, 1315 (Fed. Cir. 2015).
`
`4
`
`

`
`Independent claim 1 defines a genus of compounds with the following basic
`
`structure:
`
`
`Ex. 1001 at 86:24-87:47. Saxagliptin is but one species within this large genus. Id.,
`
`
`
`at 88:23-30; Ex. 1003, ¶149-150. Independent claim 8 defines an eight-member
`
`genus (counting structures), one of which is the saxagliptin species. Ex. 1001 at
`
`88:43-89:29; Ex. 1003, ¶12.
`
`Independent claim 10 defines a genus of compounds based on either of two
`
`structures (Ex. 1001 at 89:33-67), one of which (shown below) defines a subgenus
`
`that includes the saxagliptin species (because R1 may be a hydroxytricycloalkyl,
`
`which would include hydroxyadamantyl). Ex. 1003, ¶162.
`
`Independent claims 32 and 39 define methods of treating diabetes-related
`
`conditions in mammals using the saxagliptin compound. Ex. 1001, 91:51-92:16
`
`
`
`and 92:27-43; Ex. 1003, ¶171.
`
`5
`
`

`
`B.
`
`Brief Overview of the Prosecution History
`
`The challenged ’186 patent reissued on April 30, 2013, from the ’767 patent
`
`originally granted on May 28, 2002. The ’767 patent was based on application
`
`09/788,173 (the “’173 application”), filed on February 16, 2001, that claimed the
`
`benefit of the ’555 provisional application filed March 10, 2000. Ex. 1001, cover.
`
`Only one substantive Office Action was issued by the Office during prosecution of
`
`the ’173 application. In that action, certain claims were rejected under 35 U.S.C.
`
`102(b) as being anticipated by a Hiltmann reference. Ex. 1005, p. 0292. The
`
`Examiner’s rejection consisted of one sentence and no substantive reasons for the
`
`rejection were provided. Id. Following an amendment to claim 1, the Examiner
`
`allowed the claims.
`
`The reissue application filed by BMS in 2011 amended original claim 13,
`
`deleted original claims 23 and 24, and added claims 25-40. Ex. 1006 (reissue
`
`prosecution history) at [0612]. BMS stated that the error it sought to correct was its
`
`failure to claim the compound of claim 25 specifically. Id. at [0129-30]. BMS
`
`subsequently amended or canceled other claims, and added claims 41-45. Only one
`
`Office Action was issued by the Office against the reissue application. No prior art
`
`references were asserted against the claims in that Office Action, and the Examiner
`
`subsequently allowed the claims. Id. at [0038]. These claims, renumbered as claims
`
`1-22 and 25-43, are the claims presently in the ’186 patent.
`
`6
`
`

`
`C.
`
`Brief Overview of the Scope and Content of the Prior Art
`
`1.
`
`The Dipeptide Substrate Targeted By The DP-IV Enzyme
`
`Dipeptidyl peptidase IV, variously referred to in the art as DP-IV, DPP-IV,
`
`or DP-4, was well known by the mid-1990s as a serine protease enzyme. Ashworth
`
`(1996), Ex. 1007, p. 1163; Ex. 1003, ¶63. It cleaves two amino acid peptides, or
`
`dipeptides, from certain larger peptides or proteins. Id. The enzyme targets
`
`substrates having a proline or alanine amino acid as the second residue from the N-
`
`terminus. Id.
`
`DP-IV was known to inactivate glucagon-like peptide-1 (GLP-1), a major
`
`stimulator of pancreatic insulin secretion. Id. The art recognized that to inhibit DP-
`
`IV would result in increasing GLP-1 bioactivity. As GLP-1 was a major stimulator
`
`of pancreatic insulin secretion, DP-IV inhibitors would have direct benefits on
`
`glucose disposal. Villhauer (1998), Ex. 1008, p. 1. Thus, the art pursued inhibitors
`
`of DP-IV’s protease activity for GLP-1 as a potential treatment for type II diabetes
`
`mellitus and related conditions, including obesity. Ex. 1008 (Villhauer), pp. 1, 18;
`
`Ex. 1003, ¶40.
`
`DP-IV functions by recognizing as its substrate either proline or alanine in
`
`the second (carboxyl, or C-terminus) position from the N-terminus, and then
`
`cleaving the dipeptide from the peptide or protein chain. Analogues of dipeptides
`
`which inhibited DP-IV, were described by Ashworth (1996)(Ex. 1007), Villhauer
`
`7
`
`

`
`(1998)(Ex. 1008), and others (mentioned in Ashworth, Ex. 1007, at p. 1163-1164).
`
`Central to the substrate analogues described by both Ashworth and Villhauer is a
`
`modified first amino acid, glycyl, bonded to a modified proline as the second
`
`amino acid. Glycyl-proline is illustrated below, where glycyl is the portion in red
`
`and proline is in blue. Ex. 1007, p. 1163-1166; Ex. 1003, ¶100.
`
`
`
`Ashworth stated that substrates and inhibitors of DP-IV “require a free N-
`
`terminus.” Ex. 1007, p. 1163. Ashworth recognized, however, that a free amine at
`
`the N-terminus made the molecule prone to intramolecular cyclization, which
`
`would adversely affect stability of the analogue inhibitor. Ex. 1007, p. 1163; Ex.
`
`1003, ¶¶59,111. Consequently, Ashworth added bulky side groups near the N-
`
`terminus, such as a (S)-cyclohexyl or a cyclopentyl group, and found that this
`
`provided improved stability in an aqueous solution. Ex. 1007, pp. 1165-1166. One
`
`example is shown below, which differs from glycyl-proline by adding the bulky
`
`cyclohexyl group (red) on the (cid:533)-carbon of the glycyl, as described in Table II’s
`
`Compound 25 of Ashworth (“Chg”, abbreviation for Cyclohexylglycyl).
`
`8
`
`

`
`Ashworth’s Compound 25 (above) differs in another aspect from glycyl-
`
`
`
`proline in that the carboxy group on the proline has been replaced with a nitrile
`
`(CN; blue). Ashworth recognized that a nitrile group provided biological activity
`
`comparable to the best previously tested DP-IV inhibitors (“these compounds were
`
`potent inhibitors of DP-IV”). Ex. 1007, p. 1165, and p. 1166, referring to a series
`
`of dipeptide nitriles, compounds 24-29, in Table II.
`
`Thus, Ashworth published in 1996 two routes for optimizing a glycyl-
`
`proline based DP-IV inhibitor: placing large substituents such as cyclohexyl and
`
`cyclopentyl on the glycyl moiety, and modifying the pyrrolidine ring of the proline
`
`moiety by replacing the carboxyl group with a nitrile. Ex. 1003, ¶70. These
`
`substituents provided potent DP-IV inhibition and improved stability in an aqueous
`
`solution. Ex. 1007, 1163-64; Ex. 1003, ¶70.
`
`2.
`
`Substituting Hydroxyadamantyl onto the glycyl moiety
`
`Following Ashworth, Novartis AG (Villhauer, Ex. 1008) described other
`
`large substitutions on the glycyl moiety of a DP-IV dipeptide analog. Despite DP-
`
`9
`
`

`
`IV’s preference for a free amine on the N-terminal, Villhauer produced analogues
`
`with large substitutions on the amine itself (base structure (I) shown below). Ex.
`
`1008, cover page; Ex. 1003, ¶73.
`
`
`
`
`
`Adamantyl was among the substitutions Villhauer described for R, and
`
`adamantyl was identified as one of a small subset of “[e]ven more preferred
`
`compounds.” Ex. 1008, p. 5. The adamantyl-containing compound was made and
`
`characterized. Ex. 1008, pp. 11-13 (Example No. 47).
`
`Raag (1990) had previously described adamantane (below) and its
`
`metabolites. Ex. 1009, p. 2674; Ex. 1003, ¶70.
`
`
`
` Because adamantane is symmetric and its tertiary carbons (i.e. the carbons bound
`
`to three other carbons) are more reactive than its secondary carbons, it metabolizes
`
`to 1-hydroxyadamantane, i.e., a hydroxyl on any of the four tertiary carbons. Ex.
`
`1009, p. 2678; Ex. 1003, ¶80. Metabolites are known in the art to impart improved
`
`stability for therapeutic compounds, among other advantages. Ex. 1003, ¶129.
`
`10
`
`

`
`3.
`
`Adding Cyclopropyl to the Pyrrolidine Ring
`
`Proline’s pyrrolidine ring had been modified by both Ashworth and
`
`Villhauer to increase DP-IV inhibition by dipeptide analogues. Hanessian (1997)
`
`described adding a three-carbon cycle, cyclopropyl, (or “x,y-methano”) to
`
`pyrrolidine’s ring, thus creating 4,5-methanoproline, (trans-conformation depicted
`
`below, Fig. 8 in Hanessian’s Scheme 1; Ex. 1010, p. 1882). Hanessian noted that
`
`proline had “figured prominently as a component of therapeutic agents, in drug
`
`design, and in probing enzymatic activity.” Ex. 1010, p. 1881.
`
`Hanessian’s publication of conformationally altered ring variants of proline
`
`
`
`was described as having “important consequences in biological recognition, in cis-
`
`trans conformation changes, [and] in the susceptibility of the secondary amide
`
`bonds to enzymatic cleavage.” Ex. 1010, p. 1883.
`
`On the glycyl-2-cyanopyrrolidine modified as described in Ashworth (Ex.
`
`1007), the 3,4 and 4,5 locations on the proline ring are available for
`
`cyclopropanation as described in Hanessian without interfering with the other
`
`bonds on the ring. Ex. 1003, ¶82. Two possible enantiomers at each position results
`
`in only four possible cyclopropanations. Ex. 1003, ¶140.
`
`11
`
`

`
`To summarize, more than a year prior to the earliest priority date of the (cid:1932)186
`
`patent, those of ordinary skill in the art had all of the elements needed to make a
`
`compound glycyl-2-cyanopyrrolidine with an (S)-3-hydroxyadamantyl on the (cid:533)-
`
`carbon and with a 4S, 5S-cyclopropanation on
`
`the cyanopyrroline,
`
`i.e.,
`
`“saxagliptin.” Moreover, the skilled worker had strong reasons to combine those
`
`elements with a reasonable expectation of success in creating a dipeptide analogue
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`that inhibited DP-IV. Based on potent DP-4 inhibition and stability in aqueous
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`solution, attributes of analogues described by Ashworth, such a compound would
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`reasonably be expected by the skilled worker to be useful therapeutically,
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`including in the treatment of type II diabetes mellitus and its related conditions.
`
`D.
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`Overview of Differences Between the Prior Art and the Claims
`
`Pursuant to the requirements of Graham v. John Deere Co., 383 U.S. 1, 17,
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`36 (1966), Petitioner provides an overview of the differences between the prior art
`
`asserted against the (cid:1932)186 claims and the claims.
`
`Taking Ashworth Compound 25 (below) as a lead compound, the compound
`
`of claim 25 (saxagliptin) differs in two ways.
`
`
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`First, the claim 25 compound has a hydroxyadamantyl in place of the Ashworth’s
`
`cyclohexyl (in red). Ex. 1003, ¶101. Second, the claim 25 compound has a
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`cyclopropanation at
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`the 4 and 5 carbons (in green) of Ashworth’s 2-
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`cyanopyrrolidine. Ex. 1003, ¶101.
`
`For comparison, the compound of claim 25 of the (cid:1932)186 patent is reproduced
`
`below showing these modifications. Ex. 1001 at 91:20.
`
`The references are discussed more in depth in the context of the specific
`
`
`
`grounds of challenge.
`
`E.
`
`Level of Skill in the Art
`
`At the time of the invention, a person having ordinary skill in the art would
`
`have some combination of the following skills and experience: designing target
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`compounds towards drug discovery; designing and preparing formulations of drugs
`
`that exhibit inhibitory activity; understanding the biological aspects of drug
`
`development, including the drug’s effect on the whole animal; and understanding
`
`work presented or published by others in the field, such as references discussed by
`
`Dr. Rotella in his declaration in Ex. 1003, at, e.g., ¶¶59-84, representing the state
`
`13
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`of the art, and including the references asserted in grounds 1-4 in this Petition. Ex.
`
`1003, ¶59.
`
`Typically, a person of ordinary skill in the relevant field in March 2000
`
`would have an advanced degree (e.g., a Ph.D.) in pharmaceutics, pharmaceutical
`
`chemistry, medicinal chemistry or a related field and at least 2-3 years of practical
`
`experience in the design of drugs. Alternatively, a person of ordinary skill in the
`
`relevant field might have less education but considerable professional experience.
`
`Ex. 1003, ¶35.
`
`Petitioner’s expert, Dr. David P. Rotella, is a Professor of Chemistry at
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`Montclaire State University and an Adjunct Professor in Departments of
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`Pharmaceutical Sciences (University of Pittsburgh), Center for Drug Discovery
`
`(Northeastern University), and Medicinal Chemistry (University of Mississippi).
`
`Ex. 1003, ¶¶1-2; Ex. 1004. In addition, Dr. Rotella is a former registered
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`pharmacist in the Commonwealth of Pennsylvania. From 1991-2010, Dr. Rotella
`
`was a research scientist at multiple pharmaceutical companies, focused on drug
`
`discovery and development. He received his Ph.D. in Medicinal Chemistry in 1985
`
`from The Ohio State University, and then served as a post-doctoral fellow in the
`
`Department of Chemistry at The Pennsylvania State University. Ex. 1003, ¶4; Ex.
`
`1004. Dr. Rotella is well qualified as an expert, possessing the necessary scientific,
`
`technical, and other specialized knowledge to assist in an understanding of the
`
`14
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`
`evidence presented herein, as well as possessing the ability to address background
`
`art and common knowledge in the art.
`
`The lack of specific guidance in the specification of the (cid:1932)186 patent confirms
`
`the high level of skill in the art. For example, the (cid:1932)186 patent includes only limited
`
`description of the various pharmaceutical combinations that it claims. There are no
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`validated or tested dosages for those combinations and no examples describing any
`
`actual combinations produced by the inventors.
`
`Rather than providing specific guidance regarding dosages for the claimed
`
`combinations, the (cid:1932)186 patent invites those of ordinary skill in the art to turn to the
`
`knowledge and resources readily available to them when selecting and formulating
`
`appropriate combinations of known drugs. In one example, rather than providing
`
`specific guidance for the combination dosages, the patent provides extremely broad
`
`dosage ranges (Ex. 1001 at 4:48-53). This provides essentially no guidance for
`
`selecting actual dosages or treatment regimens. Hence, the (cid:1932)186 patent relies on a
`
`high level of skill in the art to enable practicing the invention. Ex. 1003, ¶36.
`
`In many instances, the (cid:1932)186 patent states that other known agents or
`
`treatment mechanisms can be used in combination with the selected compound,
`
`such as “other known mechanisms for therapeutically treating lipid disorders” (Ex.
`
`1001 at 4:43-45); “other known sulfonylureas or other antihyperglycemic agents
`
`which act on the ATP-dependent channel of the y-cells” (id. at 15:5-12); “squalene
`
`15
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`

`
`synthetase inhibitors suitable for use herein include, but are not limited to, (cid:302)-
`
`phosphono-sulfonates . . . as well as other known squalene synthetase inhibitors”
`
`(id. at 17:47-56); “hypolipidemic agents suitable for use herein include, but are not
`
`limited to, fibric acid derivatives . . . and other known serum cholesterol lowering
`
`agents” (id. at 18:1-20); and “[t]he beta 3 adrenergic agonist which may be
`
`optionally employed in combination with a compound of formula I may be AJ9677
`
`(Takeda/Dainippon), L750355 (Merck), or CP331648 (Pfizer) or other known beta
`
`3 agonists” (id. at 20:12-18). Furthermore, the (cid:1932)186 patent repeatedly defers to
`
`standard resources for guidance in determining dosages and other treatment
`
`parameters for the claimed combinations, including 15 citations to the Physician’s
`
`Desk Reference (“PDR”) (id. at 15:60-61; 16:4-5; 19:3 and 35; 20:43, 50, 57 and
`
`67; 21:9, 15, 24, 41, 47 and 54). The patent states that “[t]he amounts and dosages
`
`employed will be as indicated in the Physician’s Desk Reference[.]” Id. at 19:2-4.
`
`The PDR is well known in the art as a resource for established dosing and
`
`treatment regimens for approved drugs. Ex. 1003, ¶39.
`
`Villhauer (Ex. 1008) similarly indicates a high level of skill in the art by
`
`relying on that skill to select from the many options described as well as options
`
`known to those in the art. Ex. 1008 at, e.g., pp. 2-3 (large and diverse Markush R
`
`groups), p. 3 (pharmaceutically acceptable salts and isomers), p. 7 (“The process of
`
`the invention may be effected in conventional manner.”), p. 8 (starting materials
`
`16
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`

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`known or prepared in known or conventional manner) and p. 20 (pharmaceutically
`
`acceptable carriers, adjuvants and modes of administration, and conventional
`
`preparation of same). Villhauer reflects the conventional approach in the art of
`
`preparing promising variants of lead compounds and comparing the results. Ex.
`
`1003, ¶37.
`
`Thus, as shown above, the prior art confirms the high level of ordinary skill
`
`in the art as of March 10, 2000, the earliest date to which the (cid:1932)186 patent claims
`
`priority. See Okajima v. Bourdeau, 261 F.3d 1350, 1355 (Fed. Cir. 2001); In re
`
`GPAC Inc., 57 F.3d 1573, 1579 (Fed. Cir. 1995); accord Ex parte Jud, 85 USPQ2d
`
`1280, 1282 (BPAI 2007) (expanded panel) (holding the applicant’s disclosure, the
`
`cited references, and any declaration testimony may be used to establish the level
`
`of skill in the art).
`
`II. GROUNDS FOR STANDING
`
`Petitioner certifies that, under 37 C.F.R. § 42.104(a)) the (cid:1932)186 patent is
`
`available for inter partes review and that Petitioner is not barred or estopped from
`
`requesting inter partes review of the (cid:1932)186 patent on the grounds identified.1
`
`
`1 Petitioner is not barred from bringing this Petition, even though Sun and Amneal
`
`were each served with complaints asserting infringement of the ’186 patent more
`
`than one year before filing the Petition, as Petitioner is seeking joinder with
`
`IPR2015-01340. See 35 U.S.C. § 315(b)-(c).
`
`17
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`

`
`III. MANDATORY NOTICES UNDER 37 C.F.R. § 42.8
`
`Real parties-in-interest (§42.8(b)(1)): Petitioner certifies that Amneal
`
`Pharmaceuticals LLC, Amneal Pharmaceuticals of New York, LLC, Amneal
`
`Pharmaceuticals Co.
`
`India Pvt. Ltd., Amneal Holdings, LLC, Amneal
`
`Pharmaceuticals Holding Company, LLC, Sun Pharma Global FZE, Sun
`
`Pharmaceutical Industries Inc., and Sun Pharmaceutical Industries Ltd. are real
`
`parties-in-interest.
`
`Related Matters (§42.8(b)(2)): Judicial - Petitioner is aware of the
`
`following matters: The (cid:1932)186 patent is involved in AstraZeneca AB v. Mylan
`
`Pharmaceuticals Inc., 14-cv-00696 (D. Del. 2014); AstraZeneca AB v. Mylan
`
`Pharmaceuticals Inc., 14-cv-00094 (D.W. Va. 2014); AstraZeneca AB v.
`
`Aurobindo Pharma Ltd. et al., 14-cv-014696 and 14-cv-00664 (D. Del. 2014);
`
`AstraZeneca AB v. Actavis Laboratories FL, Inc., 14-cv-01356 (D. Del. 2014);
`
`AstraZeneca AB v. Sun Pharma Global FZE et al., 14-cv-00694 (D. Del. 2014);
`
`AstraZeneca AB v. Amneal Pharmaceuticals LLC., 14-cv-00697 (D. Del. 2014);
`
`and AstraZeneca AB v. Wockhardt Bio AG et al., 14-cv-00696 (D. Del. 2014).
`
`Administrative – Two petitions have been filed concerning th