`Trials@uspto.gov
`Paper 16
`Tel: 571-272-7822
`Entered: May 2, 2016
`
`
`
`
`
`
`UNITED STATES PATENT AND TRADEMARK OFFICE
`_______________
`
`BEFORE THE PATENT TRIAL AND APPEAL BOARD
`_______________
`
`MYLAN PHARMACEUTICALS INC.,
`Petitioner,
`
`v.
`
`ASTRAZENECA AB,
`Patent Owner.
`_______________
`
`Case IPR2015-01340
`Patent RE44,186 E
`_______________
`
`
`Before MICHAEL P. TIERNEY, RAMA G. ELLURU, and
`CHRISTOPHER G. PAULRAJ, Administrative Patent Judges.
`
`ELLURU, Administrative Patent Judge.
`
`
`
`
`DECISION
`Institution of Inter Partes Review
`37 C.F.R. § 42.108
`
`
`
`

`

`Case IPR2015-01340
`Patent RE44,186 E
`
`I. INTRODUCTION
`Mylan Pharmaceuticals Inc. (“Petitioner”) filed a Petition to institute
`an inter partes review of claims 1, 2, 4, 6–22, 25–30, 32–37, and 39–42
`(Paper 3, 1 “Pet.”) of RE44,186 E (Ex. 1001, “the ’186 patent”).
`Astrazeneca AB (“Patent Owner”) filed a Patent Owner Preliminary
`Response. Paper 7 (“Prelim. Resp.”). We subsequently ordered Petitioner
`to respond to certain arguments raised in the preliminary response. Paper
`10. Petitioner filed the authorized Reply to Patent Owner’s Preliminary
`Response. Paper 11 (“Reply”).
`We denied institution of an inter partes review of all the challenged
`claims. Paper 12, 14. Petitioner subsequently filed a Request for Rehearing
`(Paper 13), which we granted in an Order concurrently issued with this
`Decision. Paper 15.
`We have jurisdiction under 35 U.S.C. § 314, which provides that an
`inter partes review may not be instituted “unless . . . there is a reasonable
`likelihood that the petitioner would prevail with respect to at least 1 of the
`claims challenged in the petition.” 35 U.S.C. § 314(a). Upon considering
`the current record, we conclude that Petitioner has established a reasonable
`likelihood that it would prevail in showing the unpatentability of challenged
`claims 1, 2, 4, 6–22, 25–30, 32–37, and 39–42 of the ’186 patent. Therefore,
`we institute an inter partes review of the challenged claims of the ’186
`patent.
`
`A. Related Matters
`According to Petitioner, the ’186 patent is at issue in numerous district
`court actions. Pet. 16; Papers 2, 5.
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`Case IPR2015-01340
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`
`B. The ’186 patent (Ex. 1001)
`The ’186 patent is directed to “cyclopropyl-fused pyrrolidine-based
`inhibitors of dipeptidyl peptidase IV” (“DP-IV”). Ex. 1001, 1:19–20. DP-
`IV 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-IV-mediated
`enzymatic cleavage. Id. at 1:55–64. Inhibitors of DP-IV in vivo may,
`therefore, increase endogenous levels of glucagon, and serve to ameliorate
`the diabetic condition. Id. at 1:64–67.
`
`C. Illustrative Claim
`For the purposes of this Decision, claim 251 is illustrative of the
`challenged claims and is drawn to the compound shown below, or a
`pharmaceutically acceptable salt thereof.
`
`
`This 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
`
`
`1 All the challenged claims are directed to compounds, compositions, and
`methods relating to the specific compound recited in claim 25.
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`Case IPR2015-01340
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`“saxagliptin.” See Pet. 3; Prelim. Resp. 22–23; Ex. 1003 ¶ 15; Ex. 2047, 9.
`
`D. Prior Art Asserted by Petitioner
`Pursuant to 37 C.F.R. § 42.104(b), Petitioner identifies the following
`prior art as the basis for challenging claims 1, 2, 4, 6–22, 25–30, 32–37, and
`39–42 of the ’186 patent. See Pet. 5–6.
`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”).
`Petitioner also refers to the Declaration of David P. Rotella, Ph.D.
`(“Dr. Rotella”). Ex. 1003.
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`Case IPR2015-01340
`Patent RE44,186 E
`
` E. Asserted Grounds
`Petitioner challenges claims 1, 2, 4, 6–22, 25–30, 32–37, and 39–42 of
`the ’186 patent on the following grounds. Pet. 2–3, 22, 46, 50, 53.
`
`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, 19, 20, and 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
`
`II. ANALYSIS
`A. Claim Interpretation
`In an inter partes review, the Board interprets a claim term in an
`
`unexpired patent according to its broadest reasonable construction in light of
`the specification of the patent in which it appears. 37 C.F.R. § 42.100(b); In
`re Cuozzo Speed Techs., LLC, 793 F.3d 1268, 1278–79 (Fed. Cir. 2015),
`cert. granted sub nom. Cuozzo Speed Techs., LLC v. Lee, 136 S. Ct. 890
`(mem.) (2016). Under that standard, and absent any special definitions, we
`assign claim terms their ordinary and customary meaning, as would be
`understood by one of ordinary skill in the art at the time of the invention, in
`the context of the entire patent disclosure. In re Translogic Tech., Inc., 504
`F.3d 1249, 1257 (Fed. Cir. 2007).
`Petitioner contends that the claims use conventional terminology. Pet.
`18–19. Patent Owner does not contest the construction of any claim term.
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`For the purposes of this Decision, we need not expressly construe any claim
`terms.
`
`B. Ground 1 (claims 1, 2, 4, 6–11, 25–28, 32–35, 39, and 40)
`Petitioner contends that claims 1, 2, 4, 6–11, 25–28, 32–35, 39, and 40
`would have been obvious over Ashworth I, Villhauer, Raag, and Hanessian
`I. Pet. 22–46.
`Petitioner contends that each of claims 1, 2, 4, 6–11, 25–28, 32–35,
`39, and 40 either defines the saxagliptin compound or encompasses
`saxagliptin within its scope. Pet. 22–23. Petitioner further asserts that claim
`25 is directed to the saxagliptin compound, or a pharmaceutically salt
`thereof. Id. at 23. “Thus, if the saxagliptin compound (and its use to treat
`type II diabetes) is obvious under 35 U.S.C. § 103, then all of these claims
`are obvious.” Id. Accordingly, with respect to this asserted ground, we
`focus on whether Petitioner has established a reasonable likelihood that it
`would prevail in showing that claim 25 is unpatentable.
`In resolving the question of the obviousness of the claims, we
`consider the following underlying factual determinations: (1) the scope and
`content of the prior art; (2) any differences between the claimed subject
`matter and the prior art; and (3) the level of skill in the art; and (4) secondary
`considerations of non-obviousness. See Graham v. John Deere Co., 383
`U.S. 1, 17 (1966). 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
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`of success. See Otsuka Pharm. Co., Ltd., v. Sandoz, Inc., 678 F.3d 1280,
`1291–92 (Fed. Cir. 2012).
`Applying this analysis, Petitioner contends that one of ordinary skill
`in the art2 would have selected Ashworth I’s compound 25 (“compound 25”)
`as a lead compound in the development of DP-IV inhibitors “because of its
`superior combination of potency and stability.” Reply 1 (citing Pet. 24–25).
`Compound 25 is illustrated below.
`
`Pet 7, 25. 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.
`Pet. 7.
`The chemical structure of saxagliptin is shown below.
`
`
`2 At this stage of the proceeding, we accept Petitioner’s contention that a
`person of ordinary skill in the art would typically “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 less education but considerably more professional
`experience. Pet. 12; see Prelim. Resp. 31.
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`Prelim. Resp. 23. The structure of saxagliptin differs from compound 25 in
`having 3-hydroxyl adamantyl in place of the cyclohexyl group and a
`cyclopropyl fusion of the pyrrolidine ring3. Id.
`Petitioner argues that one of ordinary skill in the art would have been
`motivated to modify compound 25 by 1) replacing the 6-carbon cyclohexyl
`group at the 2-position with a 10-carbon adamantyl moiety;4
`2) hydroxylating the adamantyl moiety at a specific position; and 3) adding a
`cyclopyropyl ring to the pyrrolidine portion of compound 25 in the 4S,5S
`configuration. Pet. 25–33. As discussed in more detail below, at this point
`in the proceeding, we are persuaded that a skilled artisan would have made
`each of these modifications with a reasonable expectation of success in
`arriving at the compound.
`
`
`3 Patent Owner explains that DP-IV inhibitors were typically designed with
`two groups, generally referred to as a “P1 group” and “P2 group.” Prelim.
`Resp. 9 (citation omitted). Saxagliptin features a dipeptide format
`comprising P1 and P2 groups in which the “P1” core is made up of a
`cyclopropyl group fused to a pyrrolidine ring at the 4, 5 position and the
`pyrrolidine ring further has a cyano group in the S configuration. Id. at 22.
`The P2 group consists of an adamantyl group, with a hydroxy group in its 3
`position. Id. The “backbone” of P1 and P2 include a primary amine. Id.
`4 Adamantyl is a (C10) tricycloalkyl. Ex. 1003 ¶ 102.
`
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`
`As a preliminary matter, and for purposes of this Decision, we accept
`Petitioner’s assertion that a person of ordinary skill would have chosen to
`modify compound 25. At this point in the proceeding, we credit Dr.
`Rotella’s testimony that a skilled artisan would have selected compound 25
`as a lead compound. Ex. 1003 ¶¶ 105–107. 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). In determining whether a
`skilled artisan would have selected a prior art compound as a lead, our
`analysis is guided by evidence of the compound’s pertinent properties.
`Otsuka Pharmaceutical, 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.
`Patent Owner argues that at the time of the invention, researchers in
`the field of DP-IV inhibitors were pursuing a “broad range” of inhibitor
`structures. Prelim. Resp. 31. According to Patent Owner, “[t]he number of
`possibilities and combinations was vast.” Id. Patent Owner refers generally
`to other DP-IV inhibitors that were explored in the late 1990s as possible
`lead compounds that a skilled artisan would have chosen. Id. at 9–14. As
`analyzed further below, we disagree that Petitioner “fails to explain why a
`skilled artisan would have ignored the compounds [referenced by Patent
`Owner] . . . and, instead, would have focused on the Ashworth I
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`compounds.” Id. at 32. Indeed, even if the other compounds identified by
`Patent Owner were viable lead compound candidates, “the lead compound
`analysis must, in keeping with KSR, not rigidly focus on the selection of a
`single, best lead compound.” Daiichi Sankyo v. Matrix Labs., 619 F.3d
`1346, 1354 (Fed. Cir. 2010).
`Petitioner asserts that a skilled artisan would have reasonably selected
`Ashworth I’s compound 25 as a lead DP-IV inhibitor at the time of the
`invention “because of its superior combination of potency5 and stability.”6
`Pet. 24–26; Reply 1–4; Ex. 1007, Table II. Ashworth I evaluated chemical
`modifications in a series of DP-IV inhibitors having a 2-cyanopyrroline core
`and reported the effects of these modifications on potency and stability. Ex.
`1007, 1164–66, Table II. Based on the potency and stability data presented
`in Ashworth I’s Table II, we are persuaded on this record that a skilled
`artisan would have had reason to choose compound 25 as a lead compound.
`Specifically, Table II identifies compounds 24 and 25 as having the best
`
`5 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; Reply 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. Reply 1; Ex. 1003 ¶ 64; Prelim. Resp. 10 n.2. “Thus, an inhibitor
`with a Ki of 10-9 M is ten times more potent than one with a Ki of 10-8 M.”
`Prelim. Resp. 10 n.2. For the purpose 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).”).
`6 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;
`Reply 1–2.
`
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`
`DP-IV inhibition potencies, with both having the same lower Ki limit of 0.9
`nM, but of the two, compound 25 is illustrated as more stable with a half-life
`of >48. Ex. 1007, Table II; see Reply 2–3. Table II identifies compounds
`25 and 27 as being the most stable compound with both having half-lives of
`>48, but of the two, compound 25 is illustrated as having a higher potency.
`Id.
`
`Patent Owner argues that even if a skilled artisan focused on
`Ashworth I, compound 25 would not have been selected as a lead
`compound. Prelim. Resp. 32–34. Specifically, Patent Owner argues that
`Ashworth I identifies compounds 24–27 as having good potency and good
`stability, but a contemporaneous publication discussing Ashworth I reported
`that the most potent compound in Ashworth I is compound 24, and, thus, a
`skilled artisan would have chosen compound 24. Id. at 33. We are not
`persuaded by this argument because as discussed above, Ashworth I
`identified compounds 24 and 25 as having the same lower Ki limit, an
`indicator of potency. Thus, based on the data disclosed by Ashworth I itself,
`we are more persuaded by Petitioner’s argument on this record. Patent
`Owner also argues that Ashworth I only discloses in vivo data for compound
`26, and, thus, a skilled artisan would have chosen compound 26. Prelim.
`Resp. 33. We are not persuaded by this argument because Ashworth I does
`not explain why compound 26 was selected for in vivo testing, and, thus, we
`agree with Petitioner that without more there would have been no reason to
`select compound 26 as a lead compound over compound 25. Reply 3–4.
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`Further, Patent Owner argues that Ashworth II7 (Ex. 2001), which provides
`data for a series of DP-IV inhibitors with a different chemical core than the
`Ashworth I compounds, identified compounds that were up to “5-fold more
`active” than their Ashworth I 2-cyanopyrrolidine compounds and were
`characterized as containing the “optimum C-terminal [P1] residue.” Prelim.
`Resp. 34–35 (citing Ex. 2001, 2746) (emphasis omitted). Thus, contends
`Patent Owner, a skilled artisan without knowledge of the claimed compound
`at issue would have selected one of the Ashworth II compounds. Id. at 35.
`This argument is not persuasive because, as Petitioner responds (Reply 4),
`none of the compounds evaluated in Ashworth II exhibited both high
`potency and stability, as compared to compound 25.
`Lastly, Patent Owner argues that “no one in the prior art—Ashworth
`or otherwise—expressed or recognized a preference for compound 25.”
`Prelim. Resp. 33 (emphasis omitted). In support, Patent Owner refers to the
`“Ferring patent,” which Patent Owner asserts provides activity data for a
`total of 15 putative DP-IV inhibitors, but not for compound 25, and the
`potencies for other compounds disclosed exceed values reported for
`compound 25. Id. at 11, 33. Of all the DP-IV inhibitors illustrated in
`Ashworth I, the significance of compound 25’s potency and stability was
`recognized. For example, Ashworth I reported that “[a] number of dipeptide
`analogues, 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).” Ex. 1007, 1163. As Petitioner contends (Reply 3), only
`
`7 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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`compounds 25 and 27 satisfy these criteria highlighted by Ashworth I, but of
`the two, Ashworth I illustrates compound 25 as having better potency than
`compound 27. Id. at Table II. Therefore, at this stage in the proceeding, we
`are persuaded that a skilled artisan had reason to choose compound 25 as a
`lead compound.
`Accepting that compound 25 is a lead compound, it nevertheless
`“remains necessary to identify some reason that would have led a chemist to
`modify a known compound in a particular manner to establish prima facie
`obviousness of a new claimed compound.” Takeda Chem. Indus., 492 F.3d
`at 1357. 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 Pharms., Inc., 471 F.3d 1369, 1379
`(Fed. Cir. 2006). Furthermore, unexpected beneficial properties in the
`claimed compounds must be considered in the analysis. Id. at 1378. As
`discussed in more detail below, at this point in the proceeding, we are
`persuaded that a skilled artisan would have made each of Petitioner’s
`proposed modifications to arrive at saxagliptin with a reasonable expectation
`of success.
`
`1. Replacing the 6-carbon cyclohexyl group at the 2-position
`with a 10-carbon adamantyl moiety
`Petitioner refers to Ashworth I and Villhauer in arguing that a skilled
`artisan would have had reason to modify compound 25 by substituting its
`cyclohexyl substituent with an adamantyl group. Pet. 24–27. Based on the
`current record, we are persuaded by Petitioner’s argument.
`Ashworth I describes DP-IV inhibitors incorporating
`2-cyanopyrollindine. Ex. 1007, 1163–64. Ashworth I taught that DP-IV
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`inhibitors require a free N-terminus, but that these compounds are inherently
`unstable due to intramolecular cyclization. Ex. 1007, 1163. As Patent
`Owner acknowledges, “molecules with a ‘primary amine’ group in the
`backbone, particularly if the core included a ‘cyano’ group, were vulnerable
`to a reaction called ‘intramolecular cyclization,’ in which the nitrogen in the
`primary amine became linked to the carbon of the cyano group.” Prelim.
`Resp. 18 (citing Ex. 2007, 314).
`Petitioner’s witness, Dr. Rotella, opines that a skilled artisan “would
`have been motivated to limit intramolecular cyclization when optimizing
`Ashworth compound 25.” Ex. 1003 ¶ 111. Dr. Rotella explains that the
`cyclization reaction of the free N-terminus amino group with the reactive
`site of the inhibitor requires the molecule to assume the “cis” confirmation.
`Ex. 1003 ¶ 111 (citation omitted). According to Dr. Rotella, a skilled artisan
`“would have understood that intramolecular cyclization could be reduced by
`both selecting against a conformation that favors intramolecular cyclization
`(i.e., selecting against the cis conformation) and through the addition of a
`large, steric group to the compound.” Id. ¶ 112. Dr. Rotella reasons that
`“[s]election of the trans conformation advantageously places the reactive
`cyano and amine groups farther from each other” and “[a]dding a steric
`group to the compound would be expected to restrict its range of motion,”
`thereby limiting intramolecular cyclization. Id. Referring to compounds 28
`and 25 in Table II of Ashworth I, Dr. Rotella opines that changing the
`substituent at the 2-position of the acetylpyrrolidine-2-carbonitrile from a
`straight chain alkyl moiety (i.e,, a lysine moiety), in compound 28, to a more
`bulky cycloalkyl moiety (i.e., a cyclohexyl moiety) in compound 25,
`increased the stability of the compound from 24 hours to greater than 48
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`hours. Id. ¶ 115. Dr. Rotella concludes that “[g]iven this teaching, one of
`ordinary skill in the art would have been motivated to try even larger,
`bulkier alkyl groups” at the 2-position of the acetyl-pyrrolidine-2-
`carbonitrile compound, such as adamantyl, in order to bias the compound
`towards the trans configuration and increase stability. Id. ¶¶ 113, 115.8
`In addition, Petitioner argues that Ashworth II’s attempt to increase
`the potency of Ashworth I compounds 24 and 25, by modifying the
`pyrolidine ring to include a sulfur, decreased the stability of the compounds.
`Req. Reh’g 6–8 (citing Ex. 2001, 2748, Table II) (comparing half-lives of
`Ashworth I compound 24 to Ashworth II compound 13 and Ashworth I
`compound 25 to Ashworth II compound 14). Thus, contends Petitioner,
`based on this disclosure, a skilled artisan would have had reason to improve
`the stability of compound 25 while improving potency, despite the fact that
`Ashworth I described compound 25 as stable. Id. at 7. We are not
`persuaded by this argument. Petitioner itself acknowledges that Ashworth II
`attempted to improve the DP-IV inhibition potency of Ashworth I
`compounds 24 and 25 by modifying the pyrrolidine ring to include a sulfur.
`Req. Reh’g 7; see also Prelim. Res. 15–16 (discussing other modifications
`
`
`8 Referring to data from Table I from Ashworth I, Petitioner argues that a
`skilled artisan would have reason to substitute the cyclohexyl group with a
`larger alkyl group because Ashworth I allegedly teaches that “lipophilic
`amino acids” gave more potent compounds. Pet. 25 (citing Ex. 1003 ¶ 116;
`Ex. 1007, 1165, Table I). This argument is unpersuasive because as Patent
`Owner argues (Prelim. Resp. 44), this data relates to DP-IV inhibitors with a
`different chemical core than compound 25—one that lacks the cyano group.
`Given this composition difference, Petitioner has not sufficiently explained
`the relevance of this data to the modifications Petitioner proposes a skilled
`artisan would have made to compound 25 to arrive at saxagliptin.
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`discussed in Ashworth II, such as addition of a methyl group instead of one
`of the hydrogens on the cyanopyrrolidine core and replacing the five-
`membered pyrrolidine ring with a six-membered piperidine ring). Petitioner
`does not sufficiently explain the relevance of stability data resulting from the
`modification disclosed in Ashworth II (e.g., modifying the pyrrolidine ring
`to include a sulfur) to the modifications Petitioner proposes a skilled artisan
`would have made to compound 25 (replacing the cyclohexyl group with a
`hydroxylated adamantyl group and adding a cylopyropyl ring to the
`pyrrolidine portion). See Pet. 25–33.
`To the extent Petitioner argues that any modification to compound 25
`in an attempt to increase potency would diminish stability, we are not
`persuaded based on this evidence. See Req. Reh’g 6 (“Ashworth II
`highlights the potential instability of compound 25 when making changes to
`the pyrrolidine ring portion of the molecule (e.g., to improve potency) and
`motivates further improvement to the stability of compound 25 of the kind
`established in the Petition.”); id. at 7 (“In view of the teachings of Ashworth
`II, one of ordinary skill would have been highly motivated to improve the
`stability of compound 25 while improving potency”). In any event,
`Petitioner need not show that a skilled artisan had a reason to increase the
`stability of compound 25. It is sufficient that, based on this record, we are
`persuaded the prior art disclosed that adamantyl was a larger alkyl group
`than cyclohexyl and a suitable substitute on a DP-IV inhibitor, discussed
`further below, and a skilled artisan had a reasonable expectation that such a
`substitution on compound 25 would successfully yield a compound that was
`at least as stable as compound 25.
`Petitioner further argues that a skilled artisan would have had reason
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`to substitute the cyclohexyl group of compound 25 with the even larger
`cycloalkyl adamantyl group disclosed by Villhauer. Pet. 26. Dr. Rotella
`further opines that “the art taught adamantyl as an obvious alternative to
`cyclohexyl.” Ex. 1003 ¶ 118. Villhauer discloses examples of alkyl groups,
`a cyclohexyl group, and an adamantyl group, attached to the amino moiety
`of 2-cyano pyrrolidides. Ex. 1008, p. 12–13 (Example Nos. 28, 47, 52); Ex.
`1003 ¶ 118.
`Based on 1) Ashworth I’s recognition that a free N-terminus on a
`DP-IV inhibitor makes compound 25 prone to cyclization, and, thus,
`instability; 2) Dr. Rotella’s testimony that a skilled artisan would have had
`reason to add a large, steric group to compound 25 at the 2-postion to limit
`intramolecular cyclization; 3) the stability data disclosed in Ashworth I,
`Table II and relied upon by Dr. Rotella in opining that a larger alkyl group at
`the 2-position increased the stability of compound 25; and 4) the prior art
`teaching of adamantyl as a larger alkyl group that can be substituted for a
`cyclohexyl group, as disclosed in Villahauer, we are persuaded that
`Petitioner has made a sufficient showing that a skilled artisan would have
`had reason to modify Ashworth I’s compound 25 by substituting a larger,
`bulkier alkyl group at the 2- position of the acetyl-pyrrolidine-2-carbonitrile
`compound, such as an adamantyl group. With respect to predictable results,
`Dr. Rotella states that “[i]n the context of the ’186 patent, one of ordinary
`skill in the art would only need to verify the readily predicted results of
`adding an adamantyl group and removing the cyclohexyl group. Such a
`modification requires less experimentation than is invited by the
`specification of the ’186 patent.” Ex. 1003 ¶ 122. Based on the current
`record, particularly the unrebutted testimony of Dr. Rotella, we are
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`persuaded that a skilled artisan would have had a reasonable expectation of
`success in substituting the cyclohexyl group with an adamantyl group on
`compound 25.
`Patent Owner argues that a skilled artisan would not have reason to
`substitute the cyclohexyl group of compound 25 with an adamantyl group.
`Specifically, Patent Owner argues that Petitioner’s reliance on Ashworth I’s
`disclosure relating to the potency of DP-IV inhibitors with a chemical core
`that did not include a cyano group is not relevant because those compounds
`did not have an intramolecular cyclization problem. Prelim. Resp. 44; Pet.
`24 (Petitioner stating that “Ashworth found that lipophilic amino acids,
`particularly β-branched α-amino acid derivatives were the most potent.”).
`We do not find the evidence in Table I of Ashworth I persuasive because
`there is insufficient explanation as to the relevance of compounds that do not
`contain a cyano group to saxagliptin. We, thus, agree with Patent Owner
`that the potency data in Ashworth I, Table I does not sufficiently support
`Petitioner’s argument at this point in the proceeding. Patent Owner’s
`argument that the potency date is irrelevant, however, does not refute the
`stability data in Ashworth I, Table II and Dr. Rotella’s corresponding
`testimony, relied on by Petitioner.
`Patent Owner also argues that the stability data in Ashworth I, Table
`II, contradicts Petitioner’s theory because compounds 24–27 exhibit
`“comparable stability with half-lives of about 48 hours, no matter the
`substituent in the P2 position.” Prelim. Resp. 45 (citing Ex. 1007, 1165–66,
`Table II). The stability data in Table II of Ashworth I, however, is indicated
`by ranges. Thus, as Petitioner argues, Ashworth I indicates that
`cyclohexylated compound 25 is more stable (with a half-life of >48 hours)
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`than smaller cyclopentylated compound 24 (with a half-life of 48 hours).
`Req. Reh’g. 10. Petitioner asserts that “[t]he extent to which it is more
`stable is unknown based on the data presented in Ashworth I,” as the data
`shows only that compound 25 has a longer half-life than compound 24. Id.
`We agree with Petitioner, and, thus, are unpersuaded by Patent Owner’s
`argument.
`Referring to Ashworth II, Table II data, Patent Owner also argues that
`compounds with the more bulky liphophilic cyclohexane group and the
`cyclopentane group at the 2-position display lower stability, with a lower
`half-life, than the compounds with the less bulky isoleucine. Prelim. Resp.
`45–46 (citing Ex. 2001, Table II). Thus, concludes Patent Owner, this data
`indicates that by “increasing lipophilicity,” the compound’s potency and
`stability is decreased, contradicting the Petitioner’s proposed reason for
`modification. Id. at 46. We are not persuaded by Patent Owner’s argument
`because, as discussed above, the modifications discussed in Ashworth II are
`not proposed by Petitioner. Req. Reh’g. 7. Petitioner readily admits that
`stability was diminished by Ashworth II’s modifications to compound 25.
`Id. In sum, Patent Owner has not sufficiently explained, based on the
`current record, how the stability and potency data for compounds in
`Ashworth II are relevant to the modifications Petitioner proposes a skilled
`artisan would have had reason to make to compound 25 of Ashworth I.
`Although Patent Owner asserts that “[a]t worst, the data reinforce[s] the
`inability to