Trials@uspto.gov
`571-272-7822
`
`Paper No. 79
`Entered: August 18, 2017
`
`UNITED STATES PATENT AND TRADEMARK OFFICE
`_______________
`
`BEFORE THE PATENT TRIAL AND APPEAL BOARD
`_______________
`
`MYLAN PHARMACEUTICALS INC.,
`WOCKHARDT BIO AG, TEVA PHARMACEUTICALS USA, INC.,
`AUROBINDO PHARMA U.S.A. INC., and SUN PHARMACEUTICALS
`INDUSTRIES, LTD., SUN PHARMA GLOBAL FZE
`and AMNEAL PHARMACEUTICALS LLC,
`Petitioners,
`
`v.
`
`ASTRAZENECA AB,
`Patent Owner.
`_______________
`
`Case IPR2015-01340
`Patent RE44,186 E1
`_______________
`
`Before MICHAEL P. TIERNEY, Vice Chief Administrative Patent Judge,
`RAMA G. ELLURU and CHRISTOPHER G. PAULRAJ, Administrative
`Patent Judges.
`
`Opinion for the Board filed by Administrative Patent Judge ELLURU.
`
`Opinion Concurring filed by Vice Chief Administrative Patent Judge
`TIERNEY.
`
`ELLURU, Administrative Patent Judge.
`FINAL WRITTEN DECISION
`35 U.S.C. § 318(a) and 37 C.F.R. § 42.73
`
`1 Wockhardt from IPR2016-01029, Teva from IPR2016-01122, Aurobindo
`from IPR2016-01117, and Sun/Amneal from IPR2016-01104 have each
`been joined as a Petitioner to this proceeding.
`
`

`

`IPR2015-01340
`Patent RE44,186 E
`
`
`I.
`
`INTRODUCTION
`Background
`A.
`Mylan Pharmaceuticals Inc. (“Mylan”) filed a Petition to institute an
`inter partes review of claims 1, 2, 4, 6–22, 25–30, 32–37, and 39–42 of U.S.
`Patent No. RE44,186 E (Ex. 1001, “the ’186 patent”). Paper 3, 17 (“Pet.”).
`Astrazeneca AB (“Patent Owner”) filed a Preliminary Response. Paper 7
`(“Prelim. Resp.”). We subsequently ordered Mylan to respond to certain
`arguments raised in the Preliminary Response. Paper 10. Mylan filed an
`authorized Reply to Patent Owner’s Preliminary Response. Paper 11.
`We initially denied institution of an inter partes review of all the
`challenged claims. Paper 12, 14. Mylan subsequently filed a Request for
`Rehearing. Paper 13. On May 2, 2016, we granted the Request for
`Rehearing in an Order (Paper 15) and concurrently instituted an inter partes
`review of all the challenged claims (Paper 16, 34–35 (“Dec.”)). Patent
`Owner timely filed a Response to the Petition. Paper 28 (“PO Resp.”).
`Mylan subsequently timely filed a Reply to Patent Owner’s Response.
`Paper 41 (“Pet. Reply”).
`Subsequent to our Institution Decision, Wockhardt Bio AG
`(“Wockhardt”), Teva Pharmaceuticals USA, Inc. (“Teva”), Aurobindo
`Pharma U.S.A., Inc. (“Aurobindo”), and Sun Pharmaceutical Industries,
`Ltd., Sun Pharma Global FZE, and Amneal Pharmaceuticals LLC
`(“Sun/Amneal”) (collectively, “follow-on Petitioners”) each filed separate
`follow-on Petitions for inter partes review challenging claims 1, 2, 4, 6–22,
`25–30, 32–37, and 39–42 of the ’186 patent based on the same grounds of
`unpatentability presented by Mylan. See IPR2016-01029, Paper 1
`(Wockhardt Petition); IPR2016-01122, Paper 1 (Teva Petition); IPR2016-
`
`2
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`IPR2015-01340
`Patent RE44,186 E
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`01117, Paper 1 (Aurobindo Petition); IPR2016-01104, Paper 3 (Sun/Amneal
`Petition). Each of the follow-on Petitioners also requested joinder with the
`inter partes review initiated based on Mylan’s Petition. Pursuant to 35
`U.S.C. § 315(c), we determined that the follow-on Petitions warranted
`institution and joined the follow-on Petitioners as parties to this proceeding,
`subject to the requirement that all Petitioners would present consolidated
`filings, evidence, and arguments, and not seek any additional discovery from
`Patent Owner.2 See Papers 34, 38, 39, and 53.
`Petitioners rely on the Declarations of Dr. David P. Rotella (Exs. 1003
`(in support of Pet.), 1074 (in support of Pet. Reply)), Dr. Robert J.
`Tanenberg (Ex. 1041), and Dr. Deforest McDuff (Ex. 1060). Patent Owner
`relies on the Declarations of Dr. Ann E. Weber (Ex. 2056), Dr. M. James
`Lenhard (Ex. 2057), Dr. Christine S. Meyer (Ex. 2059), and Dr. Jeffrey Robl
`(Ex. 2173).
`An oral hearing for this proceeding was held on January 25, 2017, a
`transcript of which has been entered in the record. Paper 77 (“Tr.”).
`We have jurisdiction under 35 U.S.C. § 6. This Final Written
`Decision is issued pursuant to 35 U.S.C. § 318(a) and 37 C.F.R. § 42.73.
`For the reasons that follow, we determine Petitioners have not
`established, by a preponderance of the evidence, that claims 1, 2, 4, 6–22,
`25–30, 32–37, and 39–42 of the ’186 patent are unpatentable.
`
`
`2 Mylan, Wockhardt, Teva, Aurobindo, and Sun/Amneal will be collectively
`referred to as “Petitioners” in this Decision.
`
`3
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`IPR2015-01340
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`
`Related Proceedings
`B.
`Petitioners and Patent Owner identify the following district court
`proceedings involving the ’186 patent: 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-01469 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). Pet. 16; Paper 2; Paper 5, 1. Patent Owner
`additionally identifies AstraZeneca AB v. Watson Laboratories, Inc., 14-cv-
`00666 (D. Del. 2014) as involving the ’186 patent. Paper 5, 1.
`
`The ’186 Patent (Ex. 1001)
`C.
`The ’186 patent is directed to “cyclopropyl-fused pyrrolidine-based
`inhibitors of dipeptidyl peptidase IV (DP-4) [“DP 4”], and to a method for
`treating diabetes.” Ex. 1001, 1:19–21. DP 4 is responsible for the metabolic
`cleavage of certain endogenous peptides including glucagon. Id. at 1:34–42.
`Glucagon is a peptide with multiple physiologic roles, including the
`stimulation of insulin secretion, the promotion of satiety, and the slowing of
`gastric emptying. Id. at 1:44–48. Glucagon is rapidly degraded in the body,
`primarily by DP 4-mediated enzymatic cleavage. Id. at 1:55–64. Inhibitors
`of DP 4 in vivo may, therefore, increase endogenous levels of glucagon, and
`serve to ameliorate the diabetic condition. Id. at 1:64–67.
`
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`
`Illustrative Claim
`D.
`We instituted a review of claims 1, 2, 4, 6–22, 25–30, 32–37, and 39–
`42. Claims 1, 8, 10, 25, 32, and 39 are independent claims. For purposes of
`this Decision, claim 25 is illustrative of the challenged claims and is drawn
`to the compound shown below, or a pharmaceutically acceptable salt
`thereof.
`
`
`Id. at 91:18–33. The illustrated compound is known as (1S,3S,5S)-2-[(2S)-
`2-amino-2-(3-hydroxy-1-adamantyl) acetyl]-2-azabicyclo[3.1.0]hexane-3-
`carbonitrile or “saxagliptin.”3 See Pet. 3; Ex. 1003 ¶ 15; Ex. 2047, 94.
`Petitioners state that each claim challenged under “Ground 1,” claims 1, 2, 4,
`6–11, 25–28, 32–35, 39, and 40, either defines the saxagliptin compound or
`includes saxagliptin within its scope. Pet. 22–23. Petitioners further
`contend that the species of claim 25 is obvious over the prior art, and thus,
`broader claims which also encompass the species are also obvious. Pet. 3–4
`(citation omitted). All the challenged claims are directed to compounds,
`compositions, and methods relating to the specific compound recited in
`claim 25. See Pet. 4–5, 22–23; PO Resp. 68–69; Tr. 7:12–8:5. Thus, our
`
`
`3 Saxagliptin is the active pharmaceutical ingredient in two FDA-approved
`drugs, Onglyza and Kombiglyze XR, for the treatment of diabetes. PO
`Resp. 1.
`4 Cites to exhibits refer to a document’s original page numbers.
`
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`IPR2015-01340
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`inquiry focuses on whether Petitioners have shown by a preponderance of
`the evidence that claim 25 would have been obvious to a skilled artisan. We
`determine, for the reasons explained below, that Petitioners have not carried
`their burden.
`
`E. Grounds of Unpatentability Instituted for Trial
`We instituted trial based on the following asserted references.
`
`Ashworth et al., 2-Cyanopyrrolidides as Potent, Stable Inhibitors of
`Dipeptidyl Peptidase IV, 6(10) BIOORGANIC & MED. CHEM. LETT.
`1163–66 (1996). Ex. 1007 (“Ashworth I”).
`Villhauer, WO 98/19998, published May 14, 1998. Ex. 1008
`(“Villhauer”).
`Raag, et al., Crystal Structures of Cytochrome P-450CAM Complexed
`with Camphane, Thiocamphor, and Adamantane: Factors
`Controlling P-450 Substrate Hydroxylation, 30 BIOCHEM. 2647–84
`(1991). Ex. 1009 (“Raag”).
`Hanessian et al., The Synthesis of Enantiopure w-Methanoprolines
`and w-Methanopipecolic Acids by a Novel Cyclopropanation
`Reaction: The “Flattening” of Proline, 36(17) ANGEW. CHEM. INT.
`ED. ENGL. 1881–84 (1997). Ex. 1010 (“Hanessian I”).
`Bachovchin et al., WO/99/38501, published Aug. 5, 1999. Ex. 1011
`(“Bachovchin”).
`Center for Drug Evaluation and Research, Application Number: NDA
`20-357, Revised Package Insert, available by FOIA Jan. 8, 1998.
`Ex. 1012 (“GLUCOPHAGE Label”).
`Center for Drug Evaluation and Research, Application Number: NDA
`20-766, Package Insert, available by FOIA Aug. 9, 1999. Ex. 1013
`(“XENICAL Label”).
`Center for Drug Evaluation and Research, Application Number: NDA
`19-643/S-033, Package Insert, available by FOIA Sept. 15, 1994.
`Ex. 1014 (“MEVACOR Label”).
`
`We instituted review of claims 1, 2, 4, 6–22, 25–30, 32–37, and 39–42
`
`based on the following grounds.
`
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`IPR2015-01340
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`
`Basis
`§ 103(a)
`
`§ 103(a)
`
`Claims Challenged
`1, 2, 4, 6–11, 25–28,
`32–35, 39, and 40
`12–16, 29, 30, 36,
`37, 41, and 42
`
` 103(a)
`
`12, 17, 18, and 22
`
` 103(a)
`
`12 and 19–21
`
` §
`
`
`
` §
`
`References
`Ashworth I, Villhauer, Raag, and
`Hanessian I
`Ashworth I, Villhauer, Raag,
`Hanessian I, Bachovchin, and
`GLUCOPHAGE Label
`Ashworth I, Villhauer,
`Raag, Hanessian I, Bachovchin,
`and XENICAL Label
`Ashworth I, Villhauer,
`Raag, Hanessian I, Bachovchin,
`and MEVACOR Label
`
`Dec. 34–35.
`
`II. ANALYSIS
`Claim Interpretation
`A.
`In an inter partes review, claim terms in an unexpired patent are
`interpreted according to their broadest reasonable constructions in light of
`the specification of the patent in which they appear. See 37 C.F.R.
`§ 42.100(b); Cuozzo Speed Techs., LLC v. Lee, 136 S. Ct. 2131, 2146
`(2016). Under the broadest reasonable construction standard, claim terms
`are presumed to have their ordinary and customary meaning, as would be
`understood by one of ordinary skill in the art in the context of the entire
`disclosure. In re Translogic Tech., Inc., 504 F.3d 1249, 1257 (Fed. Cir.
`2007).
`Petitioners contend that the claims use conventional terminology. Pet.
`18–19. Patent Owner does not contest the construction of any claim term.
`For purposes of this Decision, we need not expressly construe any claim
`terms.
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`
`Level of Ordinary Skill in the Art
`B.
`According to Petitioners’ expert, Dr. Rotella, a person of ordinary
`
`skill in the art, with respect to and at the time of the ’186 patent,
`would likely have some combination of the following skills and
`experience: (i) designing target compounds towards drug
`discovery; (ii) designing and preparing formulations of drugs
`that exhibit inhibitory activity; (iii) understanding the biological
`aspects of drug development, including the drug’s effect on the
`whole animal; and (iv) understanding work presented or
`published by others in the field, including the patents and printed
`publications discussed in this declaration
`and “could 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,” or, alternatively,
`“less education but considerable professional experience.” Ex. 1003 ¶ 35–
`36.
`According to Patent Owner’s expert, Dr. Weber, a person of ordinary
`
`skill in the art relevant to the ’186 patent “is a medicinal chemist with a
`Ph.D. in chemistry and several years of practical experience working with
`pharmaceutical chemical compounds for potential and eventual clinical use
`in patients,” “may also have a B.S. or M.S. degree in chemistry with
`significantly more experience,” and “also has familiarity with the spectrum
`of properties needed for a successful drug, the potential difficulties
`associated with attaining them, and the potential effects of pharmaceuticals
`in the human body.” Ex. 2056 ¶ 137.
`
`The parties’ formulations as to the level of ordinary skill in the art are
`similar, and neither side identifies with specificity an error in the opposing
`side’s formulation. See PO Resp. 21; Pet. Reply 10. On the record
`presented, we hold that the cited prior art is representative of the level of
`
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`IPR2015-01340
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`
`ordinary skill in the art. See Okajima v. Bourdeau, 261 F.3d 1350, 1355
`(Fed. Cir. 2001) (the level of ordinary skill in the art may be evidenced by
`the cited references themselves). Specifically, the references are consistent
`with the parties’ formulations and demonstrate the level of skill in the art.
`Our determinations regarding the patentability of the challenged claims
`would remain the same under either side’s proposed formulation.
`
`Credibility of the Experts
`C.
`We give more weight to the testimony of Patent Owner’s expert, Dr.
`
`Weber, over that of Petitioners’ expert, Dr. Rotella, with respect to
`testimony that is in direct conflict. We favor Dr. Weber’s testimony because
`of her extensive experience in the design and development of DP 4
`inhibitors for type-2 diabetes treatment. See Ex. 2056 ¶¶ 9–12; Ex. 2210, 1–
`2. Moreover, Dr. Weber entered the DP 4 field at the relevant time, i.e., the
`time of invention, around 2000. Ex. 1073, 108:16–21; Tr. 35:16–22. We
`find that her testimony has been consistent, not just throughout this
`proceeding, but also with evidence predating this proceeding. See, e.g., Ex.
`2056 ¶¶ 88, 115–118; 154–162; Ex. 1073, 51:2–54:14, 113:6–16, 119:19–
`121:9; Ex. 2161, 558.
`Starting in 2000, Dr. Weber spearheaded the chemistry effort and
`discovery program at Merck & Co. (“Merck”) that was targeting DP 4 as a
`type-2 diabetes treatment. Ex. 2056 ¶ 9; Ex. 1073, 40:5–8. In the early
`2000s, Merck and several other pharmaceutical companies were developing
`DP 4 inhibitors to treat type-2 diabetes. Ex. 2056 ¶¶ 119, 257. Dr. Weber’s
`work led to the development of sitagliptin, the first marketed and FDA-
`approved DP 4 inhibitor for treatment of type-2 diabetes. Ex. 2056 ¶ 9; Ex.
`1073, 40:13–21; Tr. 35:11–13. When she began working on the DP 4
`
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`program, Dr. Weber surveyed the scientific and patent literature, including
`Ashworth I, to select a lead compound for further development. Ex. 1073,
`43:2–11, 111:12–112:13; Tr. 35:19–36:5. That is, she “faced the problem
`the person of ordinary skill in the art would do,” “did it the way a person
`skilled in the art would,” and “went through the lead compound analysis” at
`the time of the invention. Tr. 36:1–5. Ultimately, Dr. Weber’s review of the
`prior art led her not to Ashworth I, but to P32/98, one of only two DP 4
`inhibitors that had advanced to clinical studies, for a lead compound. Ex.
`2056 ¶¶ 88, 116–118; Ex. 1073, 50:9–52:21; Ex. 2161, 558. Following the
`discovery of sitagliptin, Dr. Weber continued to lead Merck’s DP 4 inhibitor
`discovery program, resulting in further developments on DP 4 inhibitors for
`diabetes treatment. Ex. 1073, 40:22–41:9; Ex. 2056 ¶¶ 9–10. Dr. Weber has
`authored dozens of publications and has dozens of patents relating to DP 4.
`Ex. 1073, 110:19–111:10; Tr. 35:13–15; Ex. 2210, 3–13. In contrast, Dr.
`Rotella’s experience with DP 4 inhibitors is limited to working with co-
`inventors of the ’186 patent at Bristol-Meyers Squibb (“BMS”) after the
`invention of saxagliptin.5 Ex. 2221, 109:4–8, 113:7–116:25; Tr. 37:13–22.
`Therefore, for the reasons discussed above and because, as discussed
`below, Dr. Weber’s testimony is more consistent with the evidence, where
`there is a direct conflict between expert testimonies, we give more weight to
`Dr. Weber’s testimony.
`
`
`
`
`5 The subject matter of the ’186 patent (saxagliptin) was invented by
`researchers at BMS, the original owner of the ’186 patent. Prelim. Resp. 6
`n.1; Pet. 2. The ’186 patent was later purchased by Patent Owner. Prelim.
`Resp. 6 n.1.
`
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`
`Law of Obviousness
`D.
`“Section 103(a) forbids issuance of a patent when ‘the differences
`between the subject matter sought to be patented and the prior art are such
`that the subject matter as a whole would have been obvious at the time the
`invention was made to a person having ordinary skill in the art to which said
`subject matter pertains.’” KSR Int’l Co. v. Teleflex Inc., 550 U.S. 398, 405
`(2007). A determination of whether a new chemical compound would have
`been obvious over the prior art typically follows a two prong inquiry
`considering first, whether one of ordinary skill would have selected one or
`more lead compounds for further development and, second, whether the
`prior art would have supplied sufficient motivation to modify a lead
`compound to arrive at the compound claimed with a reasonable expectation
`of success. See Otsuka Pharm. Co., Ltd., v. Sandoz, Inc., 678 F.3d 1280,
`1291–92 (Fed. Cir. 2012). Identifying each element of a claimed compound
`in the prior art is insufficient to show that the compound as a whole would
`have been obvious. Eli Lilly and Co. v. Zenith Goldline Pharm., Inc., 471
`F.3d 1369, 1379 (Fed. Cir. 2006). “[W]here the prior art, at best, gives only
`general guidance as to the particular form of the claimed invention or how to
`achieve it, relying on an obvious-to-try theory to support an obviousness
`finding is impermissible.” In re Cyclobenzaprine Hydrochloride Extended–
`Release Capsule Patent Litigation, 676 F.3d 1063, 1073 (Fed. Cir. 2012)
`(internal citations and quotation marks omitted); see also Leo Pharm.
`Prods., Ltd. v. Rea, 726 F.3d 1346, 1357 (Fed. Cir. 2013). “Where . . . a
`defendant urges an obviousness finding by ‘merely throw[ing] metaphorical
`darts at a board’ in hopes of arriving at a successful result, but ‘the prior art
`gave either no indication of which parameters were critical or no direction as
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`to which of many possible choices is likely to be successful,’ courts should
`reject ‘hindsight claims of obviousness.’” Cyclobenzaprine, 676 F.3d at
`1070–71 (citing In re Kubin, 561 F.3d 1351, 1359 (Fed. Cir. 2009)
`(quoting In re O'Farrell, 853 F.2d 894, 903 (Fed. Cir. 1988)). An invention
`is not invalid for obviousness if all the prior art suggested “was to explore a
`new technology or general approach that seemed to be a promising field of
`experimentation, where the prior art gave only general guidance as to the
`particular form of the claimed invention or how to achieve it.” O’Farrell,
`853 F.2d at 903.
`
`E. Obviousness of Saxagliptin
`The chemical structure of saxagliptin is shown below.
`
`
`
`
`PO Resp. 4. The figure above is Patent Owner’s annotated illustration of
`saxagliptin. Patent Owner explains that saxagliptin is a dipeptide-based
`structure consisting of “so-called ‘P1’ and ‘P2’ groups.” Id. “The P1 group
`includes a cyano (or nitrile) substituent and a cyclopropyl substituent in the
`specific cis-4,5 configuration on a pyrrolidine ring.” Id. “The P2 group is
`formed by an adamantyl group6 which contains a hydroxy group in the 3-
`
`
`6 Petitioner explains that Adamantyl is a (C10) tricycloalkyl. Pet. 26 (citation
`omitted).
`
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`position and is attached to a primary-amine-containing backbone through a
`carbon-carbon linkage (C-linked).” Id. (citing Ex. 2056 ¶ 95).
`Lead Compound Analysis
`1.
`Petitioners contend that one of ordinary skill in the art would have
`selected Ashworth I’s compound 25 (“compound 25”) as a lead compound
`in the development of DP 4 inhibitors “because of its superior combination
`of potency7 and stability8.” Paper 11, 1 (citing Pet. 24–25).
`According to the Federal Circuit, a lead compound is “a compound in
`the prior art that would be most promising to modify in order to improve
`upon its . . . activity and obtain a compound with better activity.” Takeda
`Chem. Indus., Ltd. v. Alphapharm Pty., Ltd., 492 F.3d 1350, 1357 (Fed. Cir.
`2007). The lead compound analysis “requires the challenger to demonstrate
`. . . that one of ordinary skill in the art would have had a reason to select a
`proposed lead compound or compounds over other compounds in the prior
`art.” Daiichi Sankyo Co. v. Matrix Labs., Ltd, 619 F.3d 1346, 1354 (Fed.
`Cir. 2010). Our analysis as to whether a skilled artisan would have selected
`
`
`7 Inhibitor potency is measured in terms of disassociation constant (Ki),
`which indicates the propensity of an inhibitor to disassociate from its target
`with smaller Ki values indicating greater potency. Ex. 1003 ¶ 64; see Pet.
`31; Paper 11, 1. The parties agree that Ki, a measure of in vitro binding
`affinity, is indicative of inhibitor “potency,” wherein a smaller Ki indicates
`greater potency. Paper 11, 1; Ex. 1003 ¶ 64; PO Resp. 7 n.2; Ex. 2056 ¶ 50.
`For purposes of this Decision, therefore, we apply the convention of
`equating inhibitor “potency” with in vitro binding affinity, represented by
`Ki. See, e.g., Ashworth I (Ex. 1007, 1163) (“The most potent DP-IV
`inhibitors reported to date are the boroproline analogues 1, (Ki=2nM) and 2,
`(Ki =3nM).”).
`8 Inhibitor stability is measured in terms of an inhibitor’s half-life (t1/2), with
`longer half-lives indicating greater stability. Ex. 1003 ¶ 64; see Pet. 31;
`Pet. Reply 1–2.
`
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`a prior art compound as a lead is guided by evidence of the compound’s
`pertinent properties. Otsuka, 678 F.3d at 1292. Such relevant properties
`include positive attributes such as activity and potency, adverse effects, such
`as toxicity, and other relevant characteristics in evidence. Id. “Absent a
`reason or motivation based on such prior art evidence, mere structural
`similarity between a prior art compound and the claimed compound does not
`inform the lead compound selection.” Id. “[T]he lead compound analysis
`must, in keeping with KSR, not rigidly focus on the selection of a single, best
`lead compound.” Daiichi, 619 F.3d at 1354.
`Compound 25 of Ashworth I is illustrated below.
`
`
`Pet. 7, 25. The illustration shows that compound 25 comprises a glycyl
`moiety having a primary amine (NH2), a cyclohexyl group on the β-carbon
`(2-position) of the glycyl moiety, and a pyrrolidine ring having a cyano
`(nitrile) group, designated here as CN. See Pet. 7. Thus, the structure of
`saxagliptin (claim 25) differs from compound 25 in having 3-hydroxyl
`adamantyl in place of the cyclohexyl group and a cyclopropyl fusion of the
`pyrrolidine ring. See PO Resp. 29.
`DP 4 Inhibitors at the Time of Invention
`a)
`According to Dr. Weber, at the time of invention, the crystalline
`structure of DP 4 was unknown, leaving scientists without detailed
`knowledge of its active site for guidance in designing a DP 4 inhibitor. Ex.
`2056 ¶ 89. Much of what was known about DP 4’s binding requirements
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`came from structure-activity relationship (“SAR”) studies with substrates
`and inhibitors of varying structure in an attempt to characterize what
`chemical features the enzyme would or would not tolerate. Id. ¶ 90.
`b) Whether Ashworth I’s Compound 25 Would Have
`Been Selected as a Lead Compound
`
`According to Ashworth I, the “most potent DP-IV inhibitors” reported
`as of the date of Ashworth I were boroproline analogues, but they were
`considered unstable. Ex. 1007, 1163. Ashworth I discloses 2-
`cyanopyrrolidines as DP 4 inhibitors and focuses on their potency and
`stability. Pet. 24 (citing Ex. 1007, 1163–64). Ashworth I reported that “[a]
`number of dipeptide analogue, incorporating a 2-cyanopyrrolidide, were
`found to have Ki values of less than 5nM versus human DP-IV and half-lives
`of >48h in aqueous solution (pH 7.4).” Id. at 1163. Ashworth I also states
`that DP 4 inhibitors require a free N-terminus, and certain potential
`inhibitors, including C-terminal aldehydes, are inherently unstable at neutral
`pH due to intramolecular cyclization.9 Id. at 1163. Of the disclosed
`compounds, Ashworth I identifies compounds 24–27 as “possess[ing]
`activity comparable to the boroprolines” and having “excellent half-lives
`(t1/2) in aqueous solution (pH 7.4) at room temperature.” Id. at 1165. With
`respect to the disclosed compounds, Ashworth I states that “[f]urther work
`on optimization of the pyrrolidine ring will be reported shortly.” Id. at 1165.
`Petitioners argue that Ashworth I provided a skilled artisan “with reasons—
`specifically, potency and stability—to have selected compound 25
`
`
`9 As Patent Owner explains (PO Resp. 8), the free amine in the peptide
`backbone reacts with the electrophile, the “cyano” group (CN), in an
`intramolecular cyclization reaction to form an inactive compound.
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`(cyclohexylglycyl-2-pyrrolidine) as a lead compound and provided good
`reason to have expected that other β-branched α-amino acid derivatives
`would also be worth exploring.” Pet. 25.
`On the full record before us, we determine that Petitioners have not
`demonstrated by a preponderance of the evidence that a skilled artisan would
`have chosen Ashworth I’s compound 25 as a “lead compound.” Although
`Ashworth I indicates that compounds 24–29 were non-toxic in T cell assays
`up to 72 hours, and further indicates compound 25 was one among four
`compounds that were comparable to boroprolines, no further data is
`provided to guide the skilled artisan to select compound 25 among the other
`2-cyanopyrrolidides as a lead compound for further modification to develop
`a DP 4 inhibitor. Ex. 1007, 1165–66. More importantly, the data reported in
`Ashworth I was based on in vitro data at room temperature, not in vivo data.
`PO Resp. 25 (citing Ex. 2174, 82:23–83:11). Indeed, Dr. Rotella states,
`“those studies were carried out at room temperature, which is roughly 20
`degrees [Celsius]. I’ll point out that body temperature is higher than that,
`and that temperature has a direct effect on half-life. As you elevate
`temperature, you can expect half-life to decrease.” Ex. 2174, 82:23-83:11.
`Dr. Rotella further admits that he is not aware of any disclosure describing
`testing of Ashworth compounds in humans. Ex. 2174, 60:23-61:9. In
`addition, Ashworth I acknowledged that these compounds exhibited an
`intramolecular cyclization problem and that further work on optimization of
`the pyrrolidine ring was necessary and would be reported shortly. Ex. 1007,
`1163–65. Others in the prior art also continued to seek solutions to the
`problem of intramolecular cyclization, such as those posed by Ashworth I
`compounds. See PO Resp. 27–28.
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`The evidence shows that compound 25 would have presented
`additional concerns to the skilled artisan seeking to develop a DP 4 inhibitor.
`For example, the cyano group in the compound presented the concern of
`toxic cyanide release in vivo. Ex. 2056 ¶¶ 116–18, 162. Furthermore, as
`noted above, the known stability data of compound 25 was based on in vitro
`tests at room temperature, which would not have provided reliable
`information about in vivo stability. Indeed, as Dr. Rotella acknowledged,
`not much was known about the pharmaceutical properties of compound 25 at
`the time of the invention. Dr. Rotella testified that “nothing is known, at
`least at this point in time, about other properties associated with compound
`25, [and that] you’d want to understand what those properties were and
`adjust them as need be. Generally speaking, those properties are things we
`call, collectively, pharmaceutical properties.” Ex. 2174, 115:21–116:17; Ex.
`2056 ¶¶ 157, 171.
`Ashworth II10, which was a continuation of Ashworth I’s disclosure,
`and also considered prior art to the ’186 patent, does not further recognize
`compound 25 as a promising DP 4 inhibitor candidate and instead focuses
`on another series of compounds. Ex. 2056 ¶ 164 (Dr. Weber stating that
`Ashworth II was a continuation of Ashworth I and that a skilled artisan
`would have considered the teachings of both as a whole). Ashworth II states
`that “[a] series of stable, very potent inhibitors of [DP 4] has been
`developed.” Ex. 2001, Abstract. Ashworth II concludes that the 4-
`cyanothiazolidine (a sulfur-containing ring) was approximately 5-fold more
`
`
`10 Ashworth et al., 4-Cyanothiazolidides as Very Potent, Stable Inhibitors of
`Dipeptidyl Peptidase IV, 6(22) BIOORGANIC & MED. CHEM. LETT. 2745
`(1996). Ex. 2001 (“Ashworth II”).
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`potent than Ashworth I’s 2-cyanopyrrolidine inhibitors and concluded that
`the 4-cyanothiazolidides were the “optimum” P1 core. Ex. 2056 ¶ 165
`(citing Ex. 2001, 2746); see PO Resp. 26. We are persuaded by Dr. Weber’s
`opinion that a skilled artisan would not have had reason to choose compound
`25 as a lead compound given the disclosure in Ashworth II of a preference to
`cyanothiazolidides by the same authors that originally disclosed
`cyanopyrrolidines in Ashworth I. Ex. 2056 ¶ 170; see Daiichi, 619 F.3d at
`1353–54 (accepting as true all evidence that the proposed lead compounds
`exhibited remarkable potency and activity, but nevertheless rejecting the
`proposed leads over more potent second-generation compounds).11
`Petitioners’ Reply acknowledges that “[Ashworth II’s] [s]ulfur
`substitution at the 4-position on the proline ring made the inhibitor more
`potent” and preserved a saturated 5-membered ring. Pet. Reply 12.
`Nonetheless, Petitioners argue that cyclopropanation of the ring would also
`have preserved the saturated 5-membered ring, and, thus, Ashworth II did
`not teach away from compound 25, but rather was a modification consistent
`with cyclopropanating proline. Id. (citing Ex. 1074 ¶ 40). Petitioners’
`argument is unconvincing. Ashworth II does not disclose why the addition
`of sulfur in the proline ring made the compound more potent. Thus, Dr.
`Rotella’s testimony that the addition of sulfur to the proline ring is allegedly
`
`11 In support of its argument that a skilled artisan would have had reason to
`choose compound 25, Petitioners reply that “Ashworth [I] itself discloses
`several compounds in the prior art over which it improves, e.g.,
`boroprolines.” Pet. Reply 10 (citing Ex. 1007, 1163). This argument is
`unpersuasive because it does not take into account Ashworth II’s disclosure
`that 4-cyanothiazolidides were the “optimum” P1 core. In our assessment of
`obviousness, we have considered all the prior art and evidence of record,
`and not simply the disclosure of Ashworth I in isolation.
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`comparable to cyclopropanating because both modifications retain a statured
`5-membered pyrrolidine ring is, at best, tenuous and suggests improper
`hindsight bias. See Ex. 1074 ¶ 40.
`In addition to Ashworth II’s disclosure that 4-cyanothiazolidides were
`the “optimum” P1 core, other DP 4 inhibitor candidates in the prior art with
`significantly different P1 structures than compound 25 were already in
`clinical trials. As Patent Owner argues, “the [lead compound] analysis still
`requires the challenger to demonstrate . . . that one of ordinary skill in the art
`would have had a reason to select a proposed lead compound or compounds
`over other compounds in the prior art.” Daiichi, 619 F.3d at 1354
`(emphasis added).
`In particular, at the time of the invention, NVP-DPP728 and P32/98
`were the only DP 4 inhibitor candidates that had advanced to clinical trials
`for evaluation in humans. PO Resp. 14 (citing Ex. 2056 ¶¶ 88, 143; Ex.
`2057 ¶¶ 40–41). According to Dr. Weber, because of the available data on
`these two compounds and their ongoing clinical trials, NVP-DPP728 and
`P32/98 were recognized in the art as the most promising