TAKEDA PHARMACEUTICAL COMPANY LTD. et al v. TORRENT PHARMACEUTICALS LTD. et al

Filing 136

Federal Circuit OPINION filed for the court by Dyk, Circuit Judge; Mayer, Circuit Judge and Chen, Circuit Judge re 133 Notice of Appeal (Federal Circuit), and 132 Notice of Appeal (Federal Circuit). Nonprecedential Opinion.(dam) Modified on 2/16/2021 (dam).

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NOTE: This disposition is nonprecedential.

United States Court of Appeals
for the Federal Circuit
______________________

TAKEDA PHARMACEUTICAL COMPANY LTD.,
TAKEDA PHARMACEUTICALS U.S.A., INC.,
TAKEDA PHARMACEUTICALS AMERICA, INC.,
TAKEDA IRELAND LIMITED,
Plaintiffs-Appellees
v.
TORRENT PHARMACEUTICALS LTD., TORRENT
PHARMA INC.,
Defendants-Appellants
INDOCO REMEDIES LTD.,
Defendant-Appellant
______________________
2020-1552, 2020-1598
______________________
Appeals from the United States District Court for the
District of New Jersey in Nos. 2:17-cv-03186-SRC-CLW,
2:17-cv-07301-SRC-CLW, Judge Stanley R. Chesler.
______________________
Decided: February 16, 2021
______________________
GREGORY A. CASTANIAS, Jones Day, Washington, DC,
argued for plaintiffs-appellees. Also represented by JASON
G. WINCHESTER, Chicago, IL; LISAMARIE LOGIUDICE, New

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York, NY.
H. KEETO SABHARWAL, Pillsbury Winthrop Shaw
Pittman LLP, Washington, DC, argued for defendants-appellants Torrent Pharmaceuticals Ltd., Torrent Pharma
Inc. Also represented by CEDRIC CHIA YANG TAN, YUN WEI.
IVAN MICHAEL POULLAOS, Winston & Strawn LLP, Chicago, IL, argued for defendant-appellant Indoco Remedies
Ltd. Also represented by ALISON MICHELLE HEYDORN,
GEORGE C. LOMBARDI, JOHN REYNOLDS MCNAIR.
______________________
Before DYK, MAYER, and CHEN, Circuit Judges.
CHEN, Circuit Judge.
Torrent and Indoco (collectively, Appellants) appeal
from the district court’s final judgment on Appellants’ invalidity challenges to claims 4 and 12 of U.S. Patent No.
7,807,689, owned by Takeda. 1 See Takeda Pharm. Co. Ltd.
v. Torrent Pharm. Ltd., No. 2:17-cv-03186-SRC-CLW, 2020
WL 549594, at *26 (D.N.J. Feb. 4, 2020) (Takeda). The
claims at issue are directed to alogliptin, a uracil-containing DPP-IV inhibitor useful for treating type II diabetes,
and pharmaceutical salts thereof. Following a two-day
bench trial and extensive testimony from three different
experts, the district court concluded Appellants had failed
to prove by clear and convincing evidence that the challenged claims are invalid for either statutory obviousness
or non-statutory obviousness-type double patenting. In
their appeal, Appellants challenge several different fact
Torrent refers to Torrent Pharmaceuticals Ltd. and
Torrent Pharma Inc. Indoco refers to Indoco Remedies Ltd.
Takeda refers to Takeda Pharmaceutical Company Ltd.,
Takeda Pharmaceuticals U.S.A., Inc., Takeda Pharmaceuticals America, Inc., and Takeda Ireland Limited.
1

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findings by the district court. Even assuming some of those
challenges have merit, we discern no clear error in the district court’s finding that a skilled artisan would not have
been motivated to make Appellants’ proposed scaffold and
isosteric replacements with a reasonable expectation of
success. On that basis, we affirm.
DISCUSSION
Relevant to “the assessment of [reasonable] expectation of success” in all three of Appellants’ invalidity theories, Takeda, 2020 WL 549594, at *11, is the undisputed
factual finding that “in the relevant art of pharmaceutical
development, very small changes in molecular structure
can have dramatic effects on the properties of the molecule,” id. at *10. Indeed, “the more distantly related two
chemical structures are, the less probable it will be that
they have the same biological effect.” J.A. 33375–76
(Böhm). Against this backdrop, we turn to the details of
Appellants’ invalidity theories.
A
Torrent presents two obviousness-type double patenting theories using Feng’s 2 F162 compound as the lead compound for further modification. First, Torrent argues that
a skilled artisan would have found it obvious to replace
F162’s pyrimidinone scaffold with uracil, citing Böhm and
Kim. 3 Böhm discloses that scaffold replacement techniques were known in the prior art as of the relevant priority date. Kim reports that administering uracil lowers
blood glucose in an animal model of diabetes but “[does] not
Feng refers to U.S. Patent No. 7,723,344.
Böhm refers to Böhm et al., “Scaffold Hopping,”
Drug Discovery Today: Technologies 1, No. 3 (December
2004): 217–23. Kim refers to Kim et al., “Anti-diabetic Activity of Constituents of Lycii Fructose,” The Journal of Applied Pharmacology 6 (1998): 378–82.
2
3

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mention DPP-IV or DPP-IV inhibitors or scaffold hopping
or the use of uracil as a scaffold.” See Takeda, 2020 WL
549594, at *27. Collectively, these references, along with
other evidence of record, do not demonstrate that uracil
was known to possess DPP-IV inhibitory activity or other
characteristics desirable in a scaffold for DPP-IV inhibition
as of the relevant priority date. 4 Given that Torrent fails
to establish that uracil was known at the time of invention
to lower blood glucose by inhibiting DPP-IV, or was otherwise understood to be a desirable scaffold for DPP-IV inhibition, we conclude that the district court did not clearly
err in finding that a skilled artisan would not have been
motivated to replace F162’s pyrimidinone scaffold with a
uracil scaffold with a reasonable expectation of success.
Second, Torrent contends that a skilled artisan would
have been motivated to replace a fluoro-olefin unit in
F162’s pyrimidinone scaffold with an amide unit. Torrent
argues that fluoro-olefin and amide were known isosteres
in the prior art, and “[b]ecause the [skilled artisans] are
medicinal chemists who are ‘always looking for a novel

At oral argument, Torrent’s counsel argued that
Kim need not disclose that uracil is a DPP-IV inhibitor because other prior art references of record purportedly teach
this feature. See Oral Arg. at 8:49–9:30; id. at 36:09–36:33.
None of the record evidence counsel directed us to discloses
that uracil was a known DPP-IV inhibitor. See, e.g., J.A.
33246–347 (“Kanstrup,” a PCT publication pertaining to
xanthine-based compounds, not uracil); J.A. 33496–715
(“Mark 2004,” another patent reference pertaining to xanthine-based compounds); J.A. 1473–74 (an excerpt from
Torrent’s post-trial briefing stating that “[x]anthine-based
compounds were known DPP-IV inhibitors” (emphasis
added)). Notably, moreover, Torrent’s expert agreed at
trial that the Kanstrup and Mark 2004 references “do[] not
say one word about using a uracil scaffold.” J.A. 911–12
4

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compound,’ the [skilled artisan] would have been motivated to replace [F162’s] fluoro-olefin . . . with its isostere
(an amide bond) with a reasonable expectation to develop
a new DPP-IV inhibitor.” J.A. 1484. We discern no clear
error in the district court’s contrary holding. Torrent has
not identified anything in the prior art that would have motivated a skilled artisan to dispose of F162’s fluoro-olefin
unit, let alone replace it with an amide, given myriad more
conservative and predictable modifications that were available for transforming F162 into a “novel” compound. See
Takeda, 2020 WL 549594, at *18–19. To the contrary, Torrent’s expert conceded at trial that he was unaware of any
prior art disclosing this specific modification, despite citing
references that taught the opposite modification—replacing an amide unit with a fluoro-olefin unit. J.A. 942–43.
Even the reference Torrent cites to establish that fluoroolefin and amide were known isosteres features fluoro-olefin compounds and is bereft of any suggestion to make the
replacement Torrent proposes. J.A. 33349, 33352.
B
As for statutory obviousness, Indoco argues that a
skilled artisan would have been motivated to use DCAX as
a lead compound and to replace DCAX’s xanthine scaffold
with uracil because xanthine and uracil are “interchangeab[le]” “naturally occurring nitrogenous bases.” See
Takeda, 2020 WL 549594, at *24. Even assuming, arguendo, that the prior art would have motivated a skilled
artisan to modify DCAX by replacing its xanthine scaffold
with uracil, we agree with the district court that Indoco
“failed to show that a [skilled artisan] who did so would
have [had] a reasonable expectation of success” with “this
particular scaffold replacement.” See id. at *24–25. The
interchangeability references on which Indoco relies do not
pertain to DPP-IV inhibitors or diabetes, nor do they, or
any other prior art of record, teach substituting an existing
xanthine scaffold for uracil, see Oral Arg. at 19:32–40 (acknowledging that Wiedeman does not show a xanthine to

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uracil swap). Moreover, Indoco’s expert, as the district
court observed, did not present any testimony or evidence
as to the predictability of the resulting properties from replacing DCAX’s scaffold with uracil. 5 See Takeda, 2020 WL
549594, at *25. We thus decline to disturb the district
court’s finding that Indoco failed to prove by clear and convincing evidence that a skilled artisan would have been
motivated to replace DCAX’s xanthine scaffold with uracil
with a reasonable expectation of success.
C
Lastly, we address Appellants’ contention that the district court materially erred with respect to the level of ordinary skill in the art. Appellants argue that the district
court improperly ignored the parties’ dispute over whether
a skilled artisan must have specific experience developing
DPP-IV inhibitors and/or type II diabetes drugs—experience Takeda’s expert did not have. 6 This specific experience, Appellants contend, is a material difference insofar
Unlike Indoco’s expert, Takeda’s expert addressed
this critical issue, testifying that a skilled artisan would
not have been able to predict the resulting properties from
the “wholesale” replacement of a lead compound’s scaffold
with uracil. See J.A. 1159–60.
6
At oral argument, Torrent’s counsel asserted that
the district court’s motivation analysis improperly relied
on testimony of Takeda’s expert to the exclusion of Torrent’s expert, specifically referencing a footnote in the opinion below. See Oral Arg. at 4:43–6:50 (discussing Takeda,
2020 WL 549594, at *12 n.3, which cites the trial transcript
at J.A. 1178–80, 910–11). That footnote refers to testimony
from both Takeda’s and Torrent’s experts, including testimony from Torrent’s expert agreeing that “the Kim reference doesn’t say one word about DPP-IV inhibition,” J.A.
910–11. Torrent’s counsel, moreover, could not identify anything factually inaccurate about the footnote.
5

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as it is critical to the district court’s findings regarding motivation and reasonable expectation of success. We disagree.
Rather than ignore the dispute, the district court considered the prior art from both perspectives—that of a
skilled artisan with and without specific experience with
DPP-IV inhibitors or type II diabetes drugs—and concluded that Appellants’ had failed to prove invalidity under
either definition of a skilled artisan. See Takeda, 2020 WL
549594, at *11 (finding that it “need not” resolve whether
the specific DPP-IV/type II diabetes experience urged by
Appellants was required “because it has no effect on the
outcome: even if [Appellants] are correct in this, they still
fail to provide invalidity by clear and convincing evidence”).
Given the substantive gaps in establishing motivation
and reasonable expectation of success identified above, the
record supports the district court’s conclusion that it would
have reached the same outcome under either definition of
a skilled artisan. Appellants, moreover, fail to show how
applying a level of ordinary skill that requires experience
with DPP-IV inhibitors or type II diabetes drugs would
have remedied its failures of proof. While motivation and
reasonable expectation of success need not be expressly disclosed by the prior art itself and may instead come from the
background knowledge of the skilled artisan, merely asserting that a given modification would have been obvious
to a skilled artisan does not make it so.
CONCLUSION
Because we conclude that the district court did not
clearly err in finding that a skilled artisan would not have
been motivated to make the proposed scaffold and isosteric
replacements with a reasonable expectation of success, we
need not reach the parties’ remaining arguments. For the
foregoing reasons, we affirm the district court’s judgment
upholding the validity of claims 4 and 12 of the ’689 patent.

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TAKEDA PHARMACEUTICAL COMPANY v. TORRENT
PHARMACEUTICALS LTD.

AFFIRMED