Filed on behalf of: Mylan Pharmaceuticals Inc.
`By: Steven W. Parmelee
`
`Michael T. Rosato
`WILSON SONSINI GOODRICH & ROSATI
`701 Fifth Avenue
`Suite 5100
`Seattle, WA 98104-7036
`Tel.: 206-883-2542
`Fax: 206-883-2699
`Email: sparmelee@wsgr.com
`Email: mrosato@wsgr.com
`
`
`
`
`
`
`UNITED STATES PATENT AND TRADEMARK OFFICE
`
`———————————————
`
`BEFORE THE PATENT TRIAL AND APPEAL BOARD
`
`———————————————
`
`MYLAN PHARMACEUTICALS INC.,
`Petitioner,
`
`v.
`
`ASTRAZENECA AB,
`Patent Owner
`
`———————————————
`Case No. IPR2015-01340
`Patent No. RE44,186
`———————————————
`
`PETITION FOR INTER PARTES REVIEW
`
`
`
`
`

`

`
`
`TABLE OF CONTENTS
`
`Page
`
`I.
`
`INTRODUCTION ........................................................................................... 1
`
`A.
`
`B.
`
`C.
`
`Brief Overview of the ’186 Patent ........................................................ 1
`
`Brief Overview of the Prosecution History ........................................... 5
`
`Brief Overview of the Scope and Content of the Prior Art ................... 6
`
`1.
`
`2.
`
`3.
`
`The Dipeptide Substrate Targeted By The DP-IV
`Enzyme ........................................................................................ 6
`
`Substituting Hydroxyadamantyl onto the glycyl moiety ............ 8
`
`Adding Cyclopropyl to the Pyrrolidine ring ............................... 9
`
`D. Overview of Differences Between the Prior Art and the Claims ........ 11
`
`E.
`
`Level of Skill in the Art ....................................................................... 12
`
`II.
`
`GROUNDS FOR STANDING ...................................................................... 15
`
`III. MANDATORY NOTICES UNDER 37 C.F.R. § 42.8 ................................. 16
`
`IV. STATEMENT OF PRECISE RELIEF FOR EACH CLAIM
`CHALLENGED ............................................................................................ 17
`
`V.
`
`CLAIM CONSTRUCTION .......................................................................... 18
`
`VI. BACKGROUND KNOWLEDGE IN THE ART PRIOR TO MARCH
`10, 2000 ......................................................................................................... 19
`
`VII. DETAILED EXPLANATION OF GROUNDS FOR
`UNPATENTABILITY .................................................................................. 22
`
`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............................................................................. 22
`
`-i-
`
`

`

`1.
`
`2.
`
`3.
`
`4.
`
`5.
`
`6.
`
`7.
`
`8.
`
`9.
`
`
`
`Skilled Workers Were Motivated to Make Better DP-IV
`Inhibitors ................................................................................... 23
`
`Ashworth Identified a Lead Compound .................................... 24
`
`Villhauer Identified a Large Adamantyl Group to Modify
`DP-IV Inhibitors ....................................................................... 25
`
`Raag Describes a Hydroxylated Adamantane Metabolite ........ 27
`
`Hanessian Describes Cyclopropyl Modification to the
`Proline Moiety ........................................................................... 28
`
`The Compound of Claim 25 of the ʼ186 Patent Was
`Obvious Over the Combined Teachings of the References ...... 30
`
`Claims 26-28 ............................................................................. 34
`
`Genus Claims 1, 2, 4, 6 and 8-11 Are Obvious As
`Encompassing The Compound Species of Claim 25 ................ 35
`
`Claims 32-35, 39 and 40: methods of treating
`type II diabetes mellitus ............................................................ 43
`
`B.
`
`C.
`
`D.
`
`[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 .................... 46
`a.
`GLUCOPHAGE/ Metformin .......................................... 47
`
`10. Weight ratios ............................................................................. 48
`
`[Ground 3] Claims 12, 17, 18 and 22 Are Obvious Under §103
`Over Ashworth, Villhauer, Raag, Hanessian, Bachovchin and
`the XENICAL Label ........................................................................... 50
`
`[Ground 4] Claims 12 and 19-21 Are Obvious Under §103
`Over Ashworth, Villhauer, Raag, Hanessian, Bachovchin and
`the MEVACOR Label ......................................................................... 53
`a. MEVACOR/Lovastatin .................................................. 53
`
`11. Weight ratios ............................................................................. 54
`
`VIII. CONCLUSION .............................................................................................. 57
`
`-ii-
`
`

`

`
`IX. PAYMENT OF FEES UNDER 37 C.F.R. §§ 42.15(A) AND 42.103.......... 58
`
`X. APPENDIX – LIST OF EXHIBITS .............................................................. 59
`
`-iii-
`
`

`

`
`
`I.
`
`
`
`INTRODUCTION
`
`Pursuant to the provisions of 35 U.S.C. § 311 and § 6 of the Leahy-Smith
`
`America Invents Act (“AIA”), and to 37 C.F.R. Part 42, Mylan Pharmaceuticals
`
`Inc. (“Petitioner”) hereby requests review of United States Reissue Patent No.
`
`RE44,186 to Robl (hereinafter “the ’186 patent,” Ex. 1001) that issued on April 30,
`
`2013, and is currently assigned to AstraZeneca AB (“Patent Owner”). This
`
`Petition demonstrates, by a preponderance of the evidence, that 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 ʼ186 patent is entitled “Cyclopropyl-Fused Pyrrolidine-Based Inhibitors
`
`of Dipeptidyl Peptidase IV and Method.” Ex. 1001. In a general sense, the ʼ186
`
`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 col. 1, l. 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 col. 1, l. 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 col. 1, l.
`
`49-54. Thus, inhibitors of DP-IV in vivo should increase endogenous levels of
`
`-1-
`
`

`

`
`
`glucagon, and serve to attenuate the diabetic condition. Id., at col. 1, l. 56-59.
`
`
`
`The ʼ186 patent discloses an extremely large genus of compounds which are
`
`termed “cyclopropyl-fused pyrrolidine-based compounds.” Id., col. 1, l. 65-66. In
`
`essence, these compounds are a cyclopropyl-fused pyrroline-based core with a
`
`wide variety of optional substituents. The ʼ186 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., col. 3, l. 44 – col. 3, l. 18. The ʼ186
`
`provides no 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 ʼ186 reissued, US 6,395,767 (the ʼ767
`
`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 ʼ186 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.
`
`-2-
`
`

`

`
`
`
`
`Claim 1 of the ʼ186 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-
`
`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, ¶14] 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, ¶15. 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
`
`-3-
`
`

`

`
`
`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).
`
`
`
`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, ¶150-151. 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, ¶13.
`
`
`
`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, ¶163.
`
`
`
`
`
`-4-
`
`

`

`
`
`
`
`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, ¶172.
`
`B.
`
`Brief Overview of the Prosecution History
`
`
`
`The challenged ʼ186 patent reissued on April 30, 2013, from the ʼ767 patent
`
`originally granted on May 28, 2002. The ʼ767 patent was based on
`
`application 09/788,173 (the ʼ173 application), filed on February 16, 2001, that
`
`claimed the benefit of the ʼ555 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 ʼ186 patent.
`
`-5-
`
`

`

`
`
`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 ¶64. 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, ¶41.
`
`
`
`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
`
`(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
`
`-6-
`
`

`

`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, ¶101.
`
`
`
`
`
`
`
`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, ¶60,112. 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 β-carbon of the glycyl, as described in Table II’s
`
`Compound 25 of Ashworth (“Chg”, abbreviation for Cyclohexylglycyl).
`
`NH2
`
`N
`
`CN
`
`
`
`O
`
`-7-
`
`

`

`
`
`
`
`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, ¶71. These
`
`substituents provided potent DP-IV inhibition and improved stability in an aqueous
`
`solution. Ex. 1007, 1163-64; Ex. 1003, ¶71.
`
`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-
`
`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, ¶74.
`
`
`
`
`
`-8-
`
`

`

`
`
`
`
`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, ¶71.
`
`
`
`
`
`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, ¶81. Metabolites are known in the art to impart
`
`improved stability for therapeutic compounds, among other advantages. Ex. 1003,
`
`¶130.
`
`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
`
`-9-
`
`

`

`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 at 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 ¶83. Two possible enantiomers at each position results
`
`in only four possible cyclopropanations. Ex. 1003, ¶141.
`
`
`
`To summarize, more than a year prior to the earliest priority date of the ʼ186
`
`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 β-
`
`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
`
`that inhibited DP-IV. Based on potent DP-4 inhibition and stability in aqueous
`
`solution, attributes of analogues described by Ashworth, such a compound would
`
`-10-
`
`

`

`
`
`reasonably be expected by the skilled worker to be useful therapeutically,
`
`including in the treatment of type II diabetes mellitus and its related conditions.
`
`D. 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,
`
`36 (1966), Petitioner provides an overview of the differences between the prior art
`
`asserted against the ʼ186 claims and the claims.
`
`
`
`Taking Ashworth Compound 25 (below) as a lead compound, the compound
`
`of claim 25 (saxagliptin) differs in two ways.
`
`
`
`N
`
`H2N
`
`O
`
`CN
`
` First, the claim 25 compound has a hydroxyadamantyl in place of the Ashworth’s
`
`cyclohexyl (in red). Ex. 1003, ¶102. Second, the claim 25 compound has a
`
`cyclopropanation at the 4 and 5 carbons (in green) of Ashworth’s 2-
`
`cyanopyrrolidine. Ex. 1003, ¶102.
`
`
`
`For comparison, the compound of claim 25 of the ʼ186 patent is reproduced
`
`below showing these modifications. Ex. 1001 at 91:20.
`
`-11-
`
`

`

`
`
`HO
`
`N
`
`H2N
`
`O
`
`CN
`
`
`
`
`
`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
`
`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., ¶¶60-85, representing the state
`
`of the art, and including the references asserted in grounds 1-4 in this petition.
`
`Ex. 1003, ¶60.
`
`
`
`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, ¶36.
`
`-12-
`
`

`

`
`
`
`
`Petitioner’s expert, Dr. David P. Rotella, is a Professor of Chemistry at
`
`Montclaire State University and an Adjunct Professor in Departments of
`
`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 registered 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, ¶5; 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 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 ʼ186 patent confirms
`
`the high level of skill in the art. For example, the ʼ186 patent includes only limited
`
`description of the various pharmaceutical combinations that it claims. There are no
`
`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 ʼ186 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
`
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`specific guidance for the combination dosages, the patent provides extremely broad
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`dosage ranges (Ex. 1001 at 4:48-53). This provides essentially no guidance for
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`selecting actual dosages or treatment regimens. Hence, the ʼ186 patent relies on a
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`high level of skill in the art to enable practicing the invention Ex. 1003, ¶37.
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`
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`In many instances, the ʼ186 patent states that other known agents or
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`treatment mechanisms can be used in combination with the selected compound,
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`such as “other known mechanisms for therapeutically treating lipid disorders”
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`(Ex. 1001 at 4:43-45); “other known sulfonylureas or other antihyperglycemic
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`agents which act on the ATP-dependent channel of the γ-cells” (id. at 15:5-12);
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`“squalene synthetase inhibitors suitable for use herein include, but are not limited
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`to, α-phosphono-sulfonates . . . as well as other known squalene synthetase
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`inhibitors” (id. at 17:47-56); “hypolipidemic agents suitable for use herein include,
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`but are not limited to, fibric acid derivatives . . . and other known serum cholesterol
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`lowering agents” (id. at 18:1-20); and “[t]he beta 3 adrenergic agonist which may
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`be optionally employed in combination with a compound of formula I may be
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`AJ9677 (Takeda/Dainippon), L750355 (Merck), or CP331648 (Pfizer) or other
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`known beta 3 agonists” (id. at 20:12-18). Furthermore, the ʼ186 patent repeatedly
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`defers to standard resources for guidance in determining dosages and other
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`treatment parameters for the claimed combinations, including 15 citations to the
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`Physician’s Desk Reference (PDR) (id. at 15:60-61; 16:4-5; 19:3 and 35; 20:43,
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`50, 57 and 67; 21:9, 15, 24, 41, 47 and 54). The patent states that “[t]he amounts
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`and dosages employed will be as indicated in the Physician’s Desk Reference[.]”
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`Id. at 19:2-4. The PDR is well known in the art as a resource for established dosing
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`and treatment regimens for approved drugs. Ex. 1003, ¶40.
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`
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`Villhauer (Ex. 1008) similarly indicates a high level of skill in the art by
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`relying on that skill to select from the many options described as well as options
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`known to those in the art. Ex. 1008 at, e.g., pp. 2-3 (large and diverse Markush R
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`groups), p. 3 (pharmaceutically acceptable salts and isomers), p. 7 (“The process of
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`the invention may be effected in conventional manner.”), p. 8 (starting materials
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`known or prepared in known or conventional manner) and p. 20 (pharmaceutically
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`acceptable carriers, adjuvants and modes of administration, and conventional
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`preparation of same). Villhauer reflects the conventional approach in the art of
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`preparing promising variants of lead compounds and comparing the results.
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`Ex. 1003, ¶38.
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`
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`Thus, as shown above, the prior art confirms the high level of ordinary skill
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`in the art as of March 10, 2000, the earliest date to which the ʼ186 patent claims
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`priority. See Okajima v. Bourdeau, 261 F.3d 1350, 1355 (Fed. Cir. 2001); In re
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`GPAC Inc., 57 F.3d 1573, 1579 (Fed. Cir. 1995); accord Ex parte Jud, 85 USPQ2d
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`1280, 1282 (BPAI 2007) (expanded panel) (holding the applicant’s disclosure, the
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`cited references, and any declaration testimony may be used to establish the level
`
`of skill in the art).
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`II. GROUNDS FOR STANDING
`
`
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`Petitioner certifies that, under 37 C.F.R. § 42.104(a)) the ʼ186 patent is
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`available for inter partes review and that Petitioner is not barred or estopped from
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`requesting inter partes review of the ʼ186 patent on the grounds identified.
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`III. MANDATORY NOTICES UNDER 37 C.F.R. § 42.8
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`Real parties-in-interest (§42.8(b)(1)): Mylan Pharmaceuticals Inc. is a real party-
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`in-interest. Mylan Pharmaceuticals Inc. is a subsidiary of Mylan Inc., which is a
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`subsidiary of Mylan NV. Mylan Laboratories Limited is a manufacturing
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`subsidiary of Mylan Inc.
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`Related Matters (§42.8(b)(2)): Petitioner is aware of the following matters:
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`The ʼ186 patent is involved in AstraZeneca AB v. Mylan Pharmaceuticals Inc., 14-
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`cv-00696 (D. Del. 2014); AstraZeneca AB v. Mylan Pharmaceuticals Inc., 14-cv-
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`00094 (D.W. Va. 2014); AstraZeneca AB v. Aurobindo Pharma Ltd. et al., 14-cv-
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`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).
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`Lead and Back-Up Counsel (§42.8(b)(3))
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`
`
`
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`Lead Counsel: Steven W. Parmelee (Reg. No. 31,990)
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`Back-Up Counsel: Michael T. Rosato (Reg. No. 52,182)
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`Service Information (§42.8(b)(4)) Mylan consents to electronic service.
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`Lead Counsel
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`Backup Counsel
`
`Steven W. Parmelee
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`sparmelee@wsgr.com
`
`Michael T. Rosato
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`mrosato@wsgr.com
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`WILSON SONSINI GOODRICH & ROSATI,
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`WILSON SONSINI GOODRICH & ROSATI,
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`
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`701 Fifth Avenue, Suite 5100
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`701 Fifth Avenue, Suite 5100
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`Seattle, WA 98104-7036
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`Seattle, WA 98104-7036
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`Tel.: 206-883-2542
`
`
`
`
`
`Tel.: 206-883-2529
`
`
`
`
`
`Fax: 206-883-2699
`
`Fax: 206-883-2699
`
`
`
`IV. STATEMENT OF PRECISE RELIEF FOR EACH CLAIM
`CHALLENGED
`
`
`
`Petitioner requests review of claims 1, 2, 4, 6-22, 25-30, 32-37 and 39-42 of
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`the ʼ186 patent under 35 U.S.C. § 311 and AIA § 6. Petitioner challenges claims 1,
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`2, 4, 6-22, 25-30, 32-37 and 39-42 on the grounds that each of the claims should
`
`be canceled as unpatentable under 35 U.S.C. § 103 (2012) as follows:
`
`Ground
`
`Claims
`
`Description
`
`1
`
`2
`
`1, 2, 4, 6-11, 25-28,
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`Obvious under 35 U.S.C. § 103 over Ashworth,
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`32-35, 39 and 40
`
`Villhauer, Raag and Hanessian
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`12-16, 29, 30, 36,
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`37, 41 and 42
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` Obvious under § 103 over Ashworth, Villhauer,
`
`Raag, Hanessian, Bachovchin and Glucophage®
`
`Label
`
`Obvious under § 103 over Ashworth, Villhauer,
`
`3
`
`12, 17, 18, 22
`
`Raag, Hanessian, Bachovchin and Xenical®
`
`Label
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`Obvious under § 103 over Ashworth, Villhauer,
`
`4
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`12, 19, 20, 21
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`Raag, Hanessian, Bachovchin and Mevacor®
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`Label
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`The ʼ186 patent claims the benefit of a provisional application filed March
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`10, 2000. Ashworth (Ex. 1007) was published in 1996; Villhauer (Ex. 1008) was
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`published on May 14, 1998; Raag (Ex. 1009) was published in 1991, and
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`Hanessian (Ex. 1010) was published in 1997. Each reference for ground 1 is
`
`available as prior art against the challenged claims under 35 U.S.C. § 102(b)
`
`(2012).
`
`
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`Bachovchin (Ex. 1011) published on August 5, 1999, and thus is prior art
`
`under §102(a). GLUCOPHAGE Label information (Ex. 1012) was publicly
`
`available from FDA under the Freedom of Information Act (“FOIA,” 5 U.S.C. §
`
`552) by January 8, 1998, and thus is available as prior art under §102(b).
`
`XENICAL Label information (Ex. 1013) was publically available from FDA under
`
`FOIA at least by August 9, 1999, and thus is prior art under §102(a). MEVACOR
`
`Label information (Ex. 1014) was publically available from FDA under FOIA by
`
`at least September 15, 1994, and thus is available as prior art under §102(b).
`
`V. CLAIM CONSTRUCTION
`
`
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`A claim subject to inter partes review receives the broadest reasonable
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`construction or interpretation in light of the specification of the patent in which it
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`appears, because among other reasons, the patent owner has an opportunity to
`
`amend the claims. See 37 C.F.R. § 42.100(b); In re Cuozzo Speed Techs., LLC,
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`778 F.3d 1271, 1279-82 (Fed. Cir. 2015).
`
`
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`The claims use conventional terminology. Ex. 1003, ¶42. The patent
`
`disclosure offers specific definitions (Ex. 1001 at 4:3-47), but these definitions are
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`conventional. Ex. 1003, ¶42. For example, the specification defines “[t] he term
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`‘lipid-modulating’ agent as . . . agents which lower LDL and/or raise HDL and/or
`
`lower triglycerides and/or lower total cholesterol and/or [sic, employ] other known
`
`mechanisms for therapeutically treating lipid disorders.” Ex. 1001 at 4:43-47. The
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`specification includes anti-atherosclerosis agents in this class. Ex. 1001 at 4:30-31
`
`(“one or more lipid-modulating agents (including anti-atherosclerosis agents)”).
`
`VI. BACKGROUND KNOWLEDGE IN THE ART PRIOR TO MARCH
`10, 2000
`
`
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`
`
`The Background section of the ’186 patent discloses that “inhibitors
`
`of dipeptidyl peptidase IV [(DP-IV) are known to] . . . treat[ ] diabetes, especially
`
`Type II diabetes.” Ex. 1001 col. 1, ll. 19-21. Lin (1998)(Ex. 1015) described
`
`common features of DP-IV inhibitors. For example, Lin reported that “[DP-IV]
`
`substrates require the presence of a proline at the P1 position as well as a
`
`protonated free N terminus.” Lin also described what was generally known in the
`
`art in March 2000 regarding DP-IV’s preference for substrates and inhibitors in the
`
`trans conformation: “[DP-IV] possesses a high conformational specificity for a
`
`trans amide bond between the P1 and N-terminal P2 residues.” Ex 1015, p. 14020.
`
`Ex. 1003, ¶46. Lin addressed the importance of the trans conformation for
`
`compound stability and its effect on DP-IV inhibition as follows:
`
`“Many of the problems associated with inefficient inactivation of [DP-IV] are a
`
`consequence of the importance of