Mylan Pharmaceuticals Inc.v.AstraZeneca AB

Patent Trial and Appeal Board

Dec 9, 2015

13308658 (P.T.A.B. Dec. 9, 2015)

Trials@uspto.gov Paper 12
Tel: 571-272-7822 Entered: December 9, 2015

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 RAMA G. ELLURU, CHRISTOPHER G. PAULRAJ, and
ROBERT A. POLLOCK, Administrative Patent Judges.

POLLOCK, Administrative Patent Judge.

DECISION
Denying Institution of Inter Partes Review
37 C.F.R. § 42.108

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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, “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 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 Petition, Preliminary Response, and Reply, we conclude that Petitioner
has not established a reasonable likelihood that it would prevail in showing
the unpatentability of any challenged claim of the ’186 patent. Therefore,
we deny 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.
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
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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 25 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 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 of 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 (1996). Ex. 1007 (“Ashworth I”).
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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
(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 (1997). Ex. 1010 (“Hanessian”).
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”).
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, 38–58.
References Basis Claims challenged
Ashworth I, Villhauer, Raag and,
Hanessian
§ 103(a)
1, 2, 4, 6–11, 25–28,
32–35, 39, and 40
Ashworth I, Villhauer, Raag,
Hanessian, Bachovchin, and
Glucophage Label
§ 103(a)
12–16, 29, 30, 36, 37,
41, and 42
Ashworth I, Villhauer,
Raag, Hanessian, Bachovchin and,
Xenical Label

§ 103(a) 12, 17, 18, and 22
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References Basis Claims challenged
Ashworth I, Villhauer,
Raag, Hanessian, Bachovchin, and
Mevacor Label

§ 103(a) 12, 19, 20, and 21
II. ANALYSIS
Petitioner contends that each of the challenged claims encompasses
the compound of claim 25, saxagliptin, its pharmaceutically acceptable
salt[s], or the use of those compounds. Pet. 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, we focus on
whether Petitioner has established a reasonable likelihood that it would
prevail in showing that claim 25 is unpatentable.
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, 778 F.3d 1271, 1278–81 (Fed. Cir. 2015).
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.
For the purposes of this Decision, none of the terms requires express
construction.
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B. Patentability Analysis
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).
Applying this analysis, Petitioner contends that one of ordinary skill
in the art
1
would have selected Ashworth I 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 has the structure shown below:
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

1
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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pyrrolidine ring having a cyano (nitrile) group, designated here as CN. Pet.
7. The chemical structure of saxagliptin is shown below.

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 pyrroline ring. 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; 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.
For the purpose of this Decision, we accept Petitioner’s assertion that
a personal of ordinary skill would have chosen 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., Ltd. v.
Alphapharm Pty., Ltd., 492 F.3d 1350, 1357 (Fed. Cir. 2007). Here, we
focus on whether the evidence of record supports Petitioner’s contention that
one of ordinary skill in the art would have been motivated to replace the 6-
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carbon cyclohexyl group at the 2-position of compound 25 with a 10-carbon
adamantyl moiety.
1. Stability
Petitioner points to the stability of compound 25 as an important
reason for selecting it as a lead compound. See, e.g., Pet. 25; Reply 3–4.
For example, Petitioner argues that Ashworth I teaches the advantages of a
large cycloalkyl moiety, such as the cyclohexyl group of compound 25, in
promoting both stability (by preventing cyclization of the primary amine)
and affinity (by biasing the molecule toward the trans configuration). Pet.
25; see also Ex. 1003 ¶¶ 111–121. Petitioner further argues, however, that
one of ordinary skill in the art would have been motivated to substitute the
cyclohexyl group of compound 25 with the even larger cycloalkyl adamantyl
group taught by Villhauer to increase its stability and potency (affinity).
2

Ex. 1003 ¶ 113; Pet. 26. Petitioner does not, however, explain why one of
ordinary skill in the art would have sought to further increase the stability of
compound 25. In light of the evidence of record, we agree with Patent
Owner that such motivation is lacking. Prelim. Resp. 44–47.

2
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 opinion, 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).”).

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According to Petitioner’s own assertions and evidence, the prior art
characterized compound 25 as a stable compound. In particular, Ashworth I
characterizes stable DP-IV inhibitors, compared to unstable inhibitors, as
those having half-lives of 48 hours or more. For example, Ashworth I
teaches that the free amino-terminus of DP-IV inhibitors renders them
“inherently unstable at neutral pH due to intramolecular cyclisation.”
Ex. 1007, 1163. Illustrating this instability, Ashworth I teaches that the most
potent of these inhibitors to date are boroproline analogues with half-lives
(t½) at neutral pH of only 30 and 90 minutes, respectively. Id.
In contrast to the shorter half-lives of boroproline analogs, Ashworth I
discloses “stable” inhibitors of DP-IV as having half-lives of 48 hours or
greater. Id., Title, Abstract; see also id. at 1164 (“superior stability”);
Ex. 1003 ¶ 62; Prelim. Resp. 32–33. In particular, Ashworth I states that
“[a] number of dipeptide analogues, incorporating a 2-cyanopyrrolidide,
were found to have Ki values of less than 5 nM versus human DP-IV and
half-lives of >48h in aqueous solution (pH 7.4)” Ex. 1007, Abstract. These
analogs, identified in Ashworth I, Table II, as having “excellent half-lives
(t½) in aqueous solution (pH 7.4),” expressly include compound 25. Id. at
1165, 1166, Table II.
Ashworth I provides further disclosure that DP-IV inhibitors having
half-lives of 48 hours or more are “stable.” For example, Ashworth I Table
II reports the half-life of compound 24 as equal to 48 hours. See Ex. 1007,
1166. A subsequent review of DP-IV inhibitors by other authors noted that
this compound exhibited “excellent stability at pH = 7.4 (t½ = 48 h).”
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Ex. 2007,
3
314–15, 325 (cited reference 40); see also Prelim. Resp. 33
(confirming identity of compound 24 in Ex. 2007).
Despite the “excellent” stability of Ashworth I’s compounds, the
authors continued to optimize the pyrrolidine ring of their inhibitor series.
Ex. 1007, 1165. Not surprisingly, the resulting publication, Ashworth II,
4

was not directed to increasing stability, but “to improv[ing] the potency of
this class of inhibitors.” Ex. 2001, 2746. Indeed, Ashworth II identified as
“stable” compounds having half-lives of from as little as 5 to 27 hours.
Ex. 2001, Title, Abstract, 2748; see also id. at 2746 (“good stability”).
Ashworth II, therefore, further suggests that compound 25 is stable in its
original form. Accordingly, Petitioner has failed to establish sufficient
motivation for modifying compound 25 to increase its stability.
Even were we to find some motivation to increase the stability of
compound 25, we are not persuaded that Petitioner has identified a sufficient
rationale, based on the cited art, for increasing stability by substituting a
larger cycloalkane—in particular, adamantane—for the cyclohexyl group of
compound 25. Petitioner argues that because Ashworth I teaches the
stability benefits of a large lipophilic substituent at the 2-position, one of
ordinary skill in the art would reasonably turn to an even larger lipophilic
substituent like adamantyl. Pet. 27–28. But, as Patent Owner points out,
Ashworth I compounds 24–27 exhibit comparable stabilities with half-lives

3
Augustyns et al., The Unique Properties of Dipeptidyl·peptidase IV (DPP
IV I CD26) and the Therapeutic Potential of DPP IV Inhibitors, 6 CURR.
MED. CHEM. 311 (1999). Ex. 2007 (“Augustyns”).
4
Ashworth et al., 4-Cyanopyrrolidides as Potent, Stable Inhibitors of
Dipeptidyl Peptidase IV, 6(22) BIOORGANIC & MED. CHEM. LETT. 2745
(1996). Ex. 2001 (“Ashworth II”).
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of at least 48 hours despite having substituents of varying size and
composition in the 2-position. See Prelim. Resp. 45. Moreover, Table II
shows no discernable difference between the stability of compound 25
(having a 6-carbon cyclohexyl ring at the 2-position) as compared to
compound 27 (having a 4-carbon tert-butyl group at the 2-position).
Ex. 1007, 1166, Table II. In addition, Ashworth II suggests that, in a related
series of nitrile compounds, those having cyclohexane or cyclopentane rings
at the 2-position “display lower stability (lower t½) than the less bulky
lipophilic group of isoleucine.” Prelim. Resp. 45 (citing Ex. 2001, 2748,
Table II (comparing compounds 13 and 14 with compound 3)).
Petitioner’s reliance on Villhauer fails to cure the lack of rationale for
substituting adamantyl at the 2-position of compound 25. See Pet. 25–28,
31. Villhauer, as Patent Owner points out, is directed to secondary amine
compounds, and does not address the stability of the primary amine
backbone of compound 25. Prelim. Resp. 4–5, 19, 46; see Pet. 25. Indeed,
Villhauer does not mention stability as a reason to choose any particular
moiety. And although Villhauer identifies adamantyl as a possible moiety in
“[e]ven more preferred compounds,” adamantyl groups are conspicuously
absent from the preferred examples of Villhauer—“Examples 1, 3, 5, 8, and
12 [,which] are the preferred agents of the invention.” Ex. 1008, 5, 21; see
Pet. 26.
2. Potency
Petitioner also asserts that a person of ordinary skill would have been
motivated to substitute a larger cycloalkane—in particular, adamantane—for
the cyclohexyl group of compound 25 because such a substitution would
increase the compound’s affinity to DP-IV. Specifically, Petitioner’s expert
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contends that one of ordinary skill in the art would have been motivated to
substitute the cyclohexyl group at the 2-position of compound 25 with the
larger adamantyl group because Ashworth I “shows increased potency for
compounds having larger substituents at the 2-position.” Ex. 1003 ¶ 113. In
support of this opinion, Petitioner’s expert points to the comparative
affinities of Ashworth I compounds 24 and 25. Id.
Compound 24 has a 5-member cyclopentyl (Cpg) ring at the 2-
position and a Ki of 1.1 ±0.2 nM. Ex. 1007, 1166, Table II. Compound 25
has a larger, 6-member cyclohexyl ring (Chg) and a Ki of 1.4±0.5 nM. Id.
In addressing Patent Owner’s argument that compound 24 is, in fact, more
potent (i.e., has a lower Ki) than compound 25, Petitioner asserts that
“because the potencies are presented as ranges, both compounds 24 and 25
have the same lower Ki limit of 0.09 nM.” Reply 1–2 (citing Prelim. Resp.
33) (emphasis added).
5

Under either interpretation, the record does not establish persuasively
that an even larger cycloalkyl moiety, i.e., adamantyl, at the 2-position will
increase potency. To the contrary, according to Petitioner’s argument that
compounds 24 and 25 have the same lower Ki limit, increasing the size of
the cycloalkyl ring at the 2-position has no effect on potency. Conversely,
under Patent Owner’s interpretation, increasing the size of the cyclopentyl
ring of compound 24 by a single carbon, leads to an increase in Ki, and
hence, a reduction in affinity. See generally Prelim Resp. 33 (citing
Ex. 2007, 314). Moreover, consistent with Patent Owner’s interpretation,

5
We recognize that Petitioner’s argument is contrary to Augustyns, which
characterizes compound 24, rather than compound 25, as “the most potent”
of Ashworth I’s compounds. See Ex. 2007, 314–315; Prelim. Resp. 33.
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Ashworth II shows similar effects with a related series of compounds where
a 5-carbon cyclopentyl ring at the 2-position of compound 13 (Ki = 0.5±0.10
nM) provides a more potent DP-IV inhibitor than the larger cyclohexyl of
compound 14 (Ki = 0.8±0.20 nM). Ex. 2001, 2748, Table II.
Petitioner also appears to suggest that one of ordinary skill in the art
would have been motivated to explore larger lipophilic substitutions such as
adamantane at the 2-position in light of Ashworth I’s statement that “as can
be seen in Table I, lipophilic amino acids gave more potent compounds.”
Ex. 1007, 1165; Pet. 24–25; Ex. 1003 ¶¶ 71, 116. However, the data in
Ashworth Table I itself shows that “the generalization that greater
bulk/lipophilicity is better for potency does not invariably hold.” Prelim.
Resp. 44–45. For example, as noted by Patent Owner, “the amino acid
valine is less lipophilic and contains less “beta-branching” (having one less
CH3 group) than tertbutyl, yet the valine compound (Compound 9) is more
potent than the tert-butyl compound (Compound 11).” Id. We further note
that compound 5, having cyclohexylglycine at the 2-position, has a lower Ki
than compound 17, which has a larger cyclohexylalanine moiety at that
position. See Ex. 1007, 1164, Table I. Moreover, because the compounds
identified in Ashworth Table I lack the cyano group of saxagliptin, we
consider them less pertinent to Petitioner’s position than, for example,
compounds 24 and 25, discussed above. In light of Ashworth I’s teaching
that a 6-carbon cyclohexyl ring at the 2-position provides no better potency
than a 5-carbon cyclopentyl ring in more closely related cyano compounds,
we do not find this argument persuasive.
For the reasons set forth above, the evidence of record does not
convince us that one of ordinary skill in the art would have had reason to
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increase either the stability or potency of compound 25 by substituting the
10-carbon adamantyl ring for the less bulky 6-carbon cyclohexane ring.
3. Additional Cited Art
As set forth above, Petitioner’s asserted grounds further rely on the
teachings of Raag, Hanessian, Bachovcin, Glucophage Label, Xenical Label,
and Mevacor Label in asserting that the challenged claims are unpatentable.
Petitioner’s contentions regarding the motivation for one of ordinary skill in
the art to replace the cyclohexyl group at the 2-position of compound 25
with adamantyl, however, is the same with respect to each asserted ground.
As explained above, we are not persuaded by Petitioner’s arguments on this
issue. Accordingly, we conclude that Petitioner has not established a
reasonable likelihood it would prevail in showing any of the challenged
claims would have been obvious based on any one of the asserted grounds.
III. CONCLUSION
For the foregoing reasons, the information presented in the Petition
and accompanying evidence does not establish a reasonable likelihood that
Petitioner would prevail in showing the unpatentability of claims 1, 2, 4, 6–
22, 25–30, 32–37, and 39–42 of the ’186 patent.
IV. ORDER
Accordingly, it is
ORDERED that Petitioner’s request for an inter partes review of
claims 1, 2, 4, 6–22, 25–30, 32–37, and 39–42 of the ’186 patent is denied.

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PETITIONER:
Steven Parmelee
sparmelee@wsgr.com

Michael Rosato
mrosato@wsgr.com

PATENT OWNER:
Charles Lipsey
charles.lipsey@finnegan.com

Eric Grondahl
egrondahl@mccarter.com

David Weingarten
david.weingarten@finnegan.com