UNITED STATES PATENT AND TRADEMARK OFFICE
`___________
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`BEFORE THE PATENT TRIAL AND APPEAL BOARD
`___________
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`MYLAN PHARMACEUTICALS INC.,
`Petitioner,
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`v.
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`ASTRAZENECA AB,
`Patent Owner.
`__________
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`Case IPR2015-01340
`Patent RE44,186
`__________
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`PATENT OWNER’S RESPONSE
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`Case No. IPR2015-01340
`Patent RE44,186
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`TABLE OF CONTENTS
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`Introduction ...................................................................................................... 1
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`Saxagliptin and the Applicable Dates of Invention ......................................... 4
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`I.
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`II.
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`III. Scope and Content of the Art .......................................................................... 5
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`A.
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`B.
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`Type-2 diabetes and DPP-4 inhibitors .................................................. 5
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`Structural requirements for a safe and effective DPP-4 inhibitor
`were largely unknown ........................................................................... 6
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`C. Ashworth-I’s compounds raised stability concerns .............................. 7
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`D.
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`The art sought ways to solve the problem of intramolecular
`cyclization and left the Ashworth-I compounds behind ..................... 11
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`E.
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`The most promising DPP-4 inhibitors were in the clinic .................... 14
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`1.
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`Novartis’s first clinical trial candidate NVP-DPP728 .............. 14
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`2. Merck’s first clinical trial candidate P32/98 ............................. 15
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`IV. The Invention of Saxagliptin ......................................................................... 17
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`A.
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`B.
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`Saxagliptin’s discovery ....................................................................... 17
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`The RE’186 patent............................................................................... 19
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`1.
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`2.
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`Saxagliptin-specific claims ....................................................... 19
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`Other challenged claims ............................................................ 19
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`V.
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`Level of Ordinary Skill in the Art ................................................................. 21
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`VI. The Differences Between Saxagliptin and the Prior Art Render The
`Saxagliptin-Specific Claims In Ground 1 Non-Obvious ............................... 21
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`A. A POSA would not have chosen Compound 25 as a lead .................. 22
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`1.
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`NVP-DPP728 and P32/98 were more plausible leads .............. 23
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`2.
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`Patent RE44,186
`Compound 25 would not have been selected over
`Ashworth-II’s compounds ........................................................ 26
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`B.
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`Even accepting Compound 25 as a lead, each of the additional
`proposed modifications would have been non-obvious ...................... 29
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`1.
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`2.
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`3.
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`There was no reason to add cyclopropyl to Compound 25
`in the cis-4,5 configuration ....................................................... 30
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`There was no reason to substitute an adamantyl group for
`the cyclohexyl of Compound 25 ............................................... 41
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`There was no reason to hydroxylate an adamantyl-
`substituted Compound 25 ......................................................... 49
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`C.
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`Petitioner’s failure to consider all of the proposed modifications
`together is legal error ........................................................................... 54
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`D. Objective evidence of non-obviousness demonstrates the
`patentability of saxagliptin .................................................................. 57
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`1.
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`2.
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`3.
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`4.
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`Development of a successful DPP-4 inhibitor was
`difficult and unpredictable ........................................................ 58
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`Saxagliptin’s properties were unpredictable and
`unexpected ................................................................................ 60
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`Saxagliptin met a long felt need ............................................... 65
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`Saxagliptin is a commercial success ......................................... 66
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`E.
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`Conclusion regarding saxagliptin ........................................................ 67
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`VII. The Cyclopropyl Fused Pyrrolidine Compounds of the Other
`Challenged Claims in Ground 1 Were Non-Obvious .................................... 68
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`VIII. Claims Directed To Pharmaceutical Combinations Were Non-Obvious ...... 69
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`IX. Conclusion ..................................................................................................... 69
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`Patent RE44,186
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`TABLE OF AUTHORITIES
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`Page(s)
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`Cases
`Bausch & Lomb, Inc. v. Barnes-Hind/Hydrocurve, Inc.,
`796 F.2d 443 (Fed. Cir. 1986) ............................................................................ 43
`
`Crocs, Inc. v. Int’l Trade Comm’n,
`598 F.3d 1294 (Fed. Cir. 2010) .......................................................................... 66
`
`In re Cyclobenzaprine Hydrochloride Extended-Release Capsule
`Patent Litig.,
`2010 WL 3766530 (D. Del. Sept. 21, 2010) ....................................................... 59
`
`Daiichi Sankyo Co. v. Matrix Labs., Ltd.,
`619 F.3d 1346 (Fed. Cir. 2010) .................................................................... 22, 27
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`Eli Lilly & Co. v. Zenith Goldline Pharm., Inc.,
`471 F.3d 1369 (Fed. Cir. 2000) .................................................................... 30, 56
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`In re Fine,
`837 F.2d 1071 (Fed. Cir. 1988) .......................................................................... 69
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`Graham v. John Deere Co.,
`383 U.S. 1 (1996) ................................................................................................ 22
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`Innopharma Licensing, Inc. v. Senju Pharm. Co., Ltd.,
`IPR2015-00902 ................................................................................................... 67
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`Knoll Pharms. Co. v. Teva Pharms. USA, Inc.,
`367 F.3d 1381 (Fed. Cir. 2004) .......................................................................... 59
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`KSR Int’l Co. v. Teleflex Inc.,
`550 U.S. 398 (2007) ...................................................................................... 38, 56
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`Leo Pharm. Prods. Ltd. v. Rea,
`726 F.3d 1346 (Fed. Cir. 2013) .......................................................................... 49
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`Life Tech., Inc. v. Clontech Labs., Inc.,
`224 F.3d 1320 (Fed. Cir. 2000) .......................................................................... 37
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`Mintz v. Dietz & Watson, Inc.,
`679 F.3d 1372 (Fed. Cir. 2012) .......................................................................... 58
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`Mylan Pharmaceuticals Inc. v. Gilead Sciences, Inc.,
`IPR2014-00888 ............................................................................................. 56, 57
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`Otsuka Pharm. Co. v. Sandoz, Inc.,
`678 F.3d 1280 (Fed. Cir. 2012) .............................................................. 22, 25, 33
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`Pfizer Inc., v. Mylan Pharm. Inc.,
`71 F. Supp. 3d 458, 473 (D. Del. 2014), aff’d 628 Fed. Appx. 764
`(Fed. Cir. 2016) ................................................................................................... 57
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`Procter & Gamble Co. v. Teva Pharm. USA, Inc.,
`566 F.3d 989 (Fed. Cir. 2009) ............................................................................ 65
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`Takeda Chem. Indus., Ltd. v. Alphapharm Pty., Ltd.,
`492 F.3d 1350 (Fed. Cir. 2007) .............................................................. 28, 30, 68
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`Torrent Pharm. Ltd. v. Merck Frosst Canada & Co.,
`IPR2014-00559 (2014) ....................................................................................... 56
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`Transocean Offshore Deepwater Drilling, Inc. v. Maersk Contractors
`USA, Inc.,
`617 F.3d 1296 (Fed. Cir. 2010) .......................................................................... 58
`
`Yamanouchi Pharm. Co. v. Danbury Pharmacal, Inc.,
`21 F. Supp. 2d 366 (S.D.N.Y. 1998), aff’d sub nom. Yamanouchi
`Pharm. Co. v. Danbury Pharmacal, Inc., 231 F.3d 1339 (Fed. Cir.
`2000) ................................................................................................................... 60
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`Yamanouchi Pharm. Co. v. Danbury Pharmacal, Inc.,
`231 F.3d 1339 (Fed. Cir. 2000) .......................................................................... 56
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`Statutes
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`35 U.S.C. § 103(a) ............................................................................................. 24, 56
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`35 U.S.C. § 316(e) ................................................................................................... 22
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`I.
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`Introduction
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`The patent at issue claims the compound saxagliptin. Saxagliptin is an
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`inhibitor of the enzyme dipeptidyl peptidase 4 (“DPP-4”) and is the active
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`pharmaceutical
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`ingredient
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`in
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`two FDA-approved drugs, Onglyza® and
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`Kombiglyze® XR, for the treatment of type-2 diabetes. Since entering the market
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`in 2009, there have been over 12 million dispensed prescriptions for the Onglyza®
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`family of products, totaling over 3.5 billion dollars in sales. That technical and
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`commercial success came in what has proven to be a highly unpredictable art,
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`where unpredictable in vivo effects of seemingly small structural variations led to
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`the failure of many seemingly promising compounds. Indeed, none of the putative
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`DPP-4 inhibitors in the prior art succeeded in attaining FDA approval.
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`Petitioner’s obviousness allegations ignore the prior art teachings and are
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`based on a hindsight reconstruction with full knowledge of the saxagliptin
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`invention. Nowhere is this hindsight bias more clear than in the selection by
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`Petitioner’s expert, Dr. Rotella, of Ashworth-I “Compound 25” as a lead
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`compound over other more fully characterized prior art compounds. No animal or
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`clinical data existed for Compound 25, it was abandoned in the prior art, and it
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`never made it into the clinic. Two structurally different compounds were much
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`more promising, had already advanced to the clinic, and had demonstrated
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`favorable diabetes results in humans. Those two clinical candidates, NVP-DPP728
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`and P32/98, were recognized as structural solutions to a long-standing stability
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`problem with the Ashworth-I-type compounds. Dr. Rotella admitted that he
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`improperly discounted these more advanced compounds as lead compounds
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`because he knows today, that they were not ultimately successful.
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`Even if one were to accept Compound 25 as a lead, arriving at saxagliptin
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`still requires no less than three distinct structural modifications: 1) adding a
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`“cyclopropyl” group to the “pyrrolidine” ring of Compound 25 in the particular
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`“cis-4,5” configuration; 2) substituting an “adamantyl” group through a carbon-
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`carbon bond (“C-linked”) for the cyclohexyl group on Compound 25; and 3)
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`hydroxylating the substituted adamantyl group in the 3-position. Petitioner’s
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`alleged motivations for making each of the modifications are undermined by Dr.
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`Rotella’s deposition admissions, and are further refuted by the opinions of Patent
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`Owner’s expert, Dr. Ann Weber1. Each individual modification to Compound 25
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`lacks the motivation proposed by Petitioner, is inherently unpredictable, and would
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`therefore have been non-obvious.
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`1 Dr. Weber was a Merck scientist who invented the FDA-approved DPP-4
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`inhibitor sitagliptin (Januvia®). Unlike Dr. Rotella, she has real-world experience
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`assessing lead compounds for development and designing an FDA-approved DPP-
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`4 inhibitor.
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`More significantly, Petitioner’s analysis fails to establish a motivation or
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`reasonable expectation of success for making all of the proposed structural changes
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`together. Focusing on the alleged obviousness of individual substitutions and
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`differences—instead of on the invention as a whole—is legally improper.
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`Finally, objective evidence of non-obviousness demonstrates
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`the
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`patentability of saxagliptin. The prior art squarely taught away from adding a
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`substituent to the pyrrolidine ring in the Ashworth-type compounds. Yet the
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`inventors’ addition of a cyclopropyl group in the “cis-4,5” orientation surprisingly
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`and unexpectedly improved the solution stability at physiologic temperatures by as
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`much as 440% compared to the Ashworth-I compounds. The further addition of a
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`C-linked hydroxy-adamantyl group to the remainder of the molecule, as compared
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`to a nitrogen-carbon “N-linked” bond taught in the prior art, surprisingly and
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`unexpectedly gave a 50 minute half-life of binding to DPP-4 (as compared to about
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`3 minutes for an N-linked inhibitor). This resulted in additional unpredictable
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`binding interactions with DPP-4 and led to the production in humans of a potent
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`and long-lasting active metabolite. As a result of this constellation of properties,
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`saxagliptin—the first-invented FDA-approved DPP-4
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`inhibitor—safely and
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`effectively treats type-2 diabetes in humans. Saxagliptin’s properties stand apart
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`from all compounds found in the prior art, as evidenced by the unpredictability of
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`structure-function relationships in this field, the resultant failure of others to
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`develop an FDA-approved DPP-4 inhibitor, saxagliptin’s satisfaction of a long-felt
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`need in the art for a new, efficacious class of type-2 diabetes treatment, and
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`saxagliptin’s commercial success in the market place.
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`II.
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`Saxagliptin and the Applicable Dates of Invention
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`The chemical structure of saxagliptin is shown below:
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`Adamantyl
`3-Hydroxy
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`C-linked
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`Primary amine
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`Cis-4,5-cyclopropyl
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`Pyrrolidine
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`Cyano (or “nitrile”)
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`“P2”
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`Saxagliptin is a dipeptide-based structure formed by a unique combination
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`of structural features in both its so-called “P1” and “P2” groups. The P1 group
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`includes a cyano (or nitrile) substituent and a cyclopropyl substituent in the
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`specific cis-4,5 configuration on a pyrrolidine ring. The P2 group is formed by an
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`adamantyl group which contains a hydroxy group in the 3-position and is attached
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`to a primary-amine-containing backbone through a carbon-carbon linkage (C-
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`linked). Ex. 2056 (Weber Decl.), ¶ 95.
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`Saxagliptin was first synthesized and tested for inhibitory activity in October
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`2000. Ex. 2173 (Robl Decl.), ¶13; Ex. 2190, 2 (completing the first synthesis on
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`October 18, 2000); Ex. 2189, 1 (reporting inhibitory data on October 30, 2000).
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`The non-provisional application upon which the RE44,186 patent (“the RE’186
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`patent”) is based was filed on February 16, 2001. Ex. 1001, 1.
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`III. Scope and Content of the Art
`A. Type-2 diabetes and DPP-4 inhibitors
`Type-2 diabetes is a complex metabolic disease characterized by high blood
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`glucose levels resulting from resistance to insulin. Ex. 2057 (Lenhard Decl.), ¶21,
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`24. It is a progressive disease that cannot be cured, often requiring combinations
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`of mechanistically distinct therapeutic interventions over the course of a patient’s
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`life. Ex. 2057, ¶25-26. In the late 1990s, available treatment options caused
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`serious side effects and new types of therapy were needed. Ex. 2057, ¶¶33-34.
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`DPP-4 is an enzyme responsible for cleaving glucagon-like peptide 1 (GLP-
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`1). Ex. 1001, col. 1, ll. 35-42. By the late 1990s, scientists understood that GLP-1
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`stimulates insulin release in response to increased blood glucose levels but has a
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`short half-life in vivo and is rapidly metabolized by DPP-4. Ex. 2056, ¶¶84-85; Ex.
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`2057, ¶¶35-36. Recognizing the limitations of administering GLP-1 itself, a 1998
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`article proposed inhibitors of DPP-4 as an alternative way of increasing levels of
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`GLP-1 to treat type-2 diabetes. Ex. 2005, 1; Ex. 2057, ¶36.
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`By the late 1990s, a variety of DPP-4 inhibitors with diverse structural
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`motifs were being explored. Ex. 2056, ¶98. At the time, use of DPP-4 inhibitors
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`to treat type-2 diabetes posed many questions and raised concerns of adverse
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`biological consequences in vivo because, inter alia, DPP-4 had other potential
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`substrates and was known to play a role in the immune system. Ex. 2057, ¶¶37-39.
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`It was unknown whether a DPP-4 inhibitor could protect endogenous GLP-1 in
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`vivo and be given safely and effectively to treat a chronic condition like type-2
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`diabetes. Ex. 2057, ¶¶37-39. Addressing such concerns would require extensive
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`characterization of any putative DPP-4 inhibitor, including in vivo evaluation. The
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`ultimate demonstration of safety and efficacy of such a compound would come
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`through FDA approval.
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`B.
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`Structural requirements for a safe and effective DPP-4 inhibitor
`were largely unknown
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`At the time of invention, the crystal structure of DPP-4 was unknown,
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`leaving scientists without detailed knowledge of its active site to aid inhibitor
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`design. Ex. 2056, ¶89. Much of what was known about DPP-4’s binding
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`requirements came from structure-activity relationship (“SAR”) studies with
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`substrates and inhibitors of varying structure in an attempt to characterize what
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`chemical features the enzyme would or would not tolerate. Ex. 2056, ¶90.
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`A number of putative DPP-4 inhibitors were designed as dipeptides, having
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`two groups generally referred to as the “P1 group” (or “C-terminal” residue) and
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`the “P2 group” (or “N-terminal” residue) poised to interact with the “S1 subsite”
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`and “S2 subsite” of DPP-4’s active site, respectively. Ex. 2056, ¶¶73, 91. Many of
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`these prior art dipeptide-based inhibitors showed good activity against DPP-4 in
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`vitro2, demonstrating that potency was not the major hurdle in this field. Ex. 2056,
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`¶142.
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`The greater hurdle was obtaining other necessary properties for a safe and
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`effective therapeutic DPP-4 inhibitor. Ex. 2056, ¶142. Those other properties
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`included
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`selectivity,
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`stability, pharmacokinetic
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`(“PK”) properties, oral
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`bioavailability, ADME
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`(absorption, distribution, metabolism, elimination)
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`properties, and pharmacodynamic (“PD”) properties including efficacy and safety.
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`Id. The structural features associated with these various properties were largely
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`unknown and unpredictable because, with the exception of two compounds that
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`had entered the clinic, the field generally lacked such data for the known DPP-4
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`inhibitors. Ex. 2056, ¶143.
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`C. Ashworth-I’s compounds raised stability concerns
`In 1996, the Ferring group published two articles reporting SAR for
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`dipeptide-based DPP-4 inhibitors designed for immunomodulatory purposes:
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`Ashworth-I (Ex. 1007) and Ashworth-II (Ex. 2001). They explored the SAR of the
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`P1 and P2 positions for inhibitors containing a pyrrolidine ring, a primary amine,
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`and a “C-linked” alkyl group. C-linkage means the alkyl group is attached to the
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`2 In vitro potency is typically expressed as “Ki” or “IC50”. The lower the Ki or
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`IC50, the more potent the inhibitor. Ex. 2056, ¶50.
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`carbon atom in the backbone, thereby positioning the entire P2 group to interact
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`with the S2 subsite of DPP-4 in a particular manner. Ex. 2056, ¶¶59, 198-199; see
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`Figures 2 and 18 infra.
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`By this time, scientists recognized serious stability concerns with C-linked
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`dipeptide compounds that contained an electrophile, such as a “cyano” group (CN),
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`in the P1 position. Ex. 2056, ¶116. With C-linkage, the free amine in the peptide
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`backbone reacts with the electrophile in an “intramolecular cyclization” reaction
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`that forms an inactive diketopiperazine compound. Id.; Figure 1 below.
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` cis-conformer cyclic amidine inactive diketopiperazine
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`Figure 1: Instability due to intramolecular cyclization
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`Ashworth-I explained that compounds with a free N-terminus are “inherently
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`unstable at neutral pH due to intramolecular cyclisation.” Ex. 1007, 1163.
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`Ashworth-I sought to “establish an optimal N-terminal residue” (or P2 position) by
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`“prepar[ing] a series of amino acid pyrrolidides.” Id., 1165. This pyrrolidide
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`series lacked an electrophile on the pyrrolidine ring in the P1 position and therefore
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`was not susceptible
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`to
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`intramolecular cyclization.
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` Ashworth-I
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`identified
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`compound 5 (having a cyclohexyl P2 group) from this series as most potent, and
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`went on to “appl[y] these findings to a series of 2-cyanopyrrolidides.” Id.
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`In applying the pyrrolidide data to the cyanopyrrolide series, Ashworth-I
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`concluded that “[t]he S.A.R. for the N-terminal residue developed in the
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`pyrrolidide series correlated well for the dipeptide nitrile series” and identified
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`compounds 24, 25, 26, and 27 as the most potent. Id. Ashworth-I reported that,
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`“[s]tability studies revealed excellent half-lives (t1/2) in aqueous solution (pH 7.4)
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`at room temperature (Table II) with several examples having t1/2 greater than 48h.”
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`Id. Stability, however, was not evaluated at physiological temperatures. Ex. 2056,
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`¶109. Having characterized the P2 position, Ashworth-I states that “[f]urther work
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`on optimisation of the pyrrolidide ring will be reported shortly.” Ex. 1007, 1163;
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`Ex. 2056, ¶105-106.
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`That optimization of the P1 position was reported in a subsequent
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`publication, Ashworth-II. Ex. 2056, ¶107. There, the authors explained that “[i]n
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`a quest to improve the potency of this class of inhibitors, we investigated replacing
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`the pyrrolidine ring with other nitrogen heterocycles.” Ex. 2001, 2746. Ashworth-
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`II found that compounds having a sulfur in the cyanopyrrolidine ring were the most
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`potent, and
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`specifically
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`that
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`the 4-cyanothiazolidide compounds were
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`approximately 5-fold more active than the 2-cyanopyrrolidides of Ashworth-I. Ex.
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`2056, ¶¶107-108.
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` Ashworth concluded
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`they had “established 4-
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`cyanothiazolidide as an optimum [P1] C-terminal residue.” Ex. 2001, 2745.
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`In identifying a cyanothiazolidide as optimal for the P1, Ashworth-II had
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`explored a variety of modifications to the pyrrolidine ring. The data showed that
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`increasing the size or adding substituents to the pyrrolidine ring in the P1 position
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`was detrimental for potency, suggesting that the S1 subsite of DPP-4 was not
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`generally tolerant to modification at this position. Ex. 2056, ¶¶107-108, 173-174.
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`The strict requirements for binding to the S1 subsite were reiterated a year
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`later when Augustyns-1997 (Ex. 2151) reported that increasing the pyrrolidine ring
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`size to a 6- or 7-membered ring, or adding a substituent (methyl, chlorine,
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`hydroxyl, azido, methoxy, or oxo) to the ring was not well tolerated. Ex. 2151,
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`303; Ex. 2056, ¶¶110-112, 173-174. Augustyns-1997 further reported that adding
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`a double bond, which was known to “flatten” and add rigidity to the pyrrolidine
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`ring, also decreased potency. Ex. 2056, ¶111. These data led to the conclusion
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`“that the S-1 subsite of DPP-IV ideally fits a five-membered saturated ring.” Ex.
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`2151, 303 (emphasis added).
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`At the time of invention in October 2000, no further data were available for
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`the cyanopyrrolidine compounds, other than what had been published in Ashworth-
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`I and -II. Of the Ashworth compounds, Ashworth-I reported that only Compound
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`26 (with an isoleucine P2 group) had been advanced into toxicity testing in mice
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`(Ex. 1007, 1166). The Ashworth-I compounds were never developed for use in
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`humans. Ex. 2056, ¶171. Compound 25, plucked from the prior art by Dr. Rotella
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`as an alleged lead compound, was not reported to have been tested further and was
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`effectively abandoned by the prior art.
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`D. The art sought ways to solve the problem of intramolecular
`cyclization and left the Ashworth-I compounds behind
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`Researchers in the prior art sought various ways to solve the stability
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`problems associated with the Ashworth-I-type compounds. For example, Novartis
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`explored a series of DPP-4 inhibitors all based on an “N-linked” dipeptide
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`backbone. Ex. 2056, ¶113. N-linkage means the alkyl group is attached directly to
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`the amine nitrogen in the peptide backbone, as opposed to a carbon atom in the
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`case of “C-linked” molecules. Ex. 2056, ¶59; Figure 2 below.
`C-linked
`N-linked
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`Figure 2: N-linkage versus C-linkage
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`The N-linked backbone provides the entire P2 group with access to a
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`different part of the S2 subsite for interaction with DPP-4. Ex. 2056, ¶¶198-199;
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`Figure 18 infra. N-linkage also reduces stability concerns because the more
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`sterically hindered secondary amine in the backbone is less likely to react with an
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`electrophile in the P1 group. Ex. 2056, ¶54. For this reason, the Novartis
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`compounds were viewed as a structural solution to the intramolecular cyclization
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`problem of Ashworth. Ex. 2056, ¶113, 125.
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` Novartis explored the SAR of a variety of N-linked P2 groups in
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`combination with various P1 cores. Ex. 2056, ¶113; Ex. 1008; Ex. 2158; Ex. 2157;
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`Ex. 2013. For example, the Villhauer-1998 publication (Ex. 1008) relied on by
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`Petitioner disclosed hundreds, if not thousands, of possible alkyl groups for its N-
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`linked cyanopyrrolidine-based inhibitors and provided potency and in vivo animal
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`data for 5 of the compounds, one of which was NVP-DPP728. Ex. 2056, ¶¶201-
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`203; Ex. 1008, 21. The chemical structure of NVP-DPP728 is shown in Figure 3
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`below. Ex. 2016, 11598; Ex. 2056, ¶155.
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`Figure 3: NVP-DPP728
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`In 1999, Novartis published further data for NVP-DPP728, including
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`binding data and improved stability, with a half-life of approximately 72 hours at
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`room temperature. Ex. 2056, ¶¶144, 156; Ex. 2016, 11599-11600. NVP-DPP728
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`advanced to clinical trials and, as discussed below, had positive data in humans
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`before the time of invention.
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`Recognizing the inherent instability of Ashworth-I’s compounds, Lin
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`developed a series of fluoroolefin-containing DPP-4 inhibitors to “obviate”
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`stability problems caused by intramolecular cyclization. Ex. 1015, 14021; Ex.
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`2056, ¶125. In 1998, they reported that “[t]he results of this study reveal that a
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`series of known inhibitors of DPP[-4] such as dipeptide boronic acids, dipeptide
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`phosphonates, peptidyl nitriles [citing Ashworth-I’s compounds], and others can be
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`modified by replacing the amide bonds with fluoroolefin moieties.” Ex. 1015,
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`14023.
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`Yet another option was to proceed without an electrophile in the P1 position,
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`thereby eliminating the risk of intramolecular cyclization altogether. Ex. 2056,
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`¶¶116-117. This was the case with Probiodrug’s compound P32/98. Id. P32/98 is
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`a C-linked compound with a thiazolidine ring (i.e., sulfur in the pyrrolidine ring
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`like the Ashworth II compounds) in the P1 position, and isoleucine in the P2
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`position. Ex. 2078, 308; Ex. 2056, ¶¶118, 155. The chemical structure is shown in
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`Figure 4 below. P32/98 was selected to advance to clinical trials and, as discussed
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`below, had positive data in humans before the time of invention.
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`Figure 4: Probiodrug P32/98
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`The most promising DPP-4 inhibitors were in the clinic
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`E.
`Of the various reported DPP-4 inhibitors in the prior art, only two had
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`entered the clinic for evaluation in humans: NVP-DPP728 and P32/98. Ex. 2056,
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`¶¶88, 143; Ex. 2057, ¶¶40-41. Because of the available data and ongoing clinical
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`trials, these two DPP-4 inhibitors were recognized as the most promising
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`compounds at the time. Ex. 2056, ¶¶154-159.
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`Novartis’s first clinical trial candidate NVP-DPP728
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`1.
`By the time of the invention, Novartis had selected NVP-DPP728 as a
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`clinical candidate, and it was reported to be safe and effective in initial studies in
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`humans. Ex. 2056, ¶88. Specifically, in a phase I clinical trial, NVP-DPP728
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`increased prandial active GLP-1 levels and reduced prandial glucose excursion
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`without causing low blood sugar (“hypoglycemia”) or causing serious adverse
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`events after a single dose of 100 mg in healthy volunteers. Ex. 2012, 2; Ex. 2056,
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`¶88; Ex. 2057, ¶41. These data “support[ed] the investigation of the glucose-
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`lowering potential of NVP-DPP728 for the treatment of type-2 diabetes,” and
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`indicated to a person of ordinary skill in the art (“POSA”) that NVP-DPP728
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`appeared safe and effective in initial studies in humans. Ex. 2012, 2; Ex. 2056,
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`¶156.
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`After the time of invention, Novartis discontinued NVP-DPP728 because it
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`was found to have a short half-life in vivo and progressed another N-linked
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`compound, vildagliptin, into the clinic. Ex. 2056, ¶¶146, 252; Ex. 2098, 4138.
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`Vildagliptin, described in the prior art U.S. Patent No. 6,166,063 (Ex. 2013), also
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`had the stabilizing N-linkage but ultimately failed to obtain FDA approval. It is
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`approved in Europe but only for administration twice-daily and with a requirement
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`for liver toxicity screening. Ex. 2056, ¶248; Ex. 2057, ¶¶67-70; Ex. 2050, 3-4.
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`The structure of vildagliptin is shown in Figure 5 below. See Ex. 2013, 5.
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`Figure 5: Vildagliptin
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`2. Merck’s first clinical trial candidate P32/98
`When Merck began medicinal chemistry on DPP-4 inhibitors, it performed a
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`real-world lead compound analysis. Ex. 2056, ¶¶116-118. Merck scientists were
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`concerned by the presence of a cyano group in the P1 position of Ashworth-I-type
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`compounds because of the potential for cyclization and for toxic cyanide release
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`should amide bond cleavage occur in vivo. Ex. 2056, ¶¶116-117; Figure 6 below.
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`Figure 6: Avoidance of the cyano for risk of toxic cyanide release
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`To eliminate these particular stability and toxicity concerns from their lead
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`compound, Merck chose to in-license P32/98 from Probiodrug for clinical
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`development. Ex. 2056, ¶118. P32/98 was not the most potent compound in the
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`prior art, as acknowledged by Ashworth-I. Ex. 1007, 2 (citing Ex. 2078, 308
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`(reporting an IC50 of 2.8 μM)); see also Ex. 2151, 304 (reporting a Ki of 1.8 μM for
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`compound 4b); Ex. 2056, ¶158. It nonetheless proved to be sufficiently potent to
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`enter the clinic. Ex. 2056, ¶159. By the late 1990s, P32/98 had been reported to
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`improve glucose tolerance in an animal model (Ex. 2056, ¶145; Ex. 2041), to be
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`well tolerated and to increase active GLP-1 in normal volunteers (Ex. 2056, ¶118;
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`Ex. 2160), and in June 2000, it was reported to enhance insulin secretion and
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`improve glucose tolerance in a clinical trial with diabetic patients after a single 60
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`mg dose. Ex. 2056, ¶118; Ex. 2010. These data indicated to a POSA that P32/98,
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`like NVP-DPP728, appeared safe and effective in initial studies in humans and
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`held promise for the treatment of type-2 diabetes. Ex. 2056, ¶159.
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`Like many other potential DPP-4 inhibitors, P32/98 was later discontinued
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`as a result of unforeseen safety issues. In this case, it was due to toxicities thought
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`to result from a lack of selectivity versus other DPP enzymes. Ex. 2056, ¶¶118,
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`146; Ex. 2161, 558-560.
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`IV. The Invention of Saxagliptin
`A.
`Saxagliptin’s discovery
`Scientists at Bristol Myers Squibb (“BMS”) discovered saxagliptin as a
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`result of their in-house DPP-4 research efforts. Ex. 2173, ¶13. In 1998, Dr. Robl
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`identified DPP-4 as a potential target for BMS to pursue for type-2 diabetes and
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`proposed a variety of previously unknown chemical structures as potential DPP-4
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`inhibitors. Ex. 2173, ¶¶4-5; Ex. 2169. Initially, BMS explored several series of
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`conformationally restrained bicyclic compounds designed to eliminate the ability
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`to cy