  United States Court of Appeals
      for the Federal Circuit
                ______________________

SANOFI-AVENTIS U.S., LLC, SANOFI MATURE IP,
                 SANOFI,
            Plaintiffs-Appellants

                           v.

DR. REDDY'S LABORATORIES, INC., DR. REDDY'S
     LABORATORIES, LTD., SANDOZ, INC.,
              Defendants-Appellees

      FRESENIUS KABI USA, LLC, ACCORD
  HEALTHCARE, INC., APOTEX CORP., APOTEX
 INC., ACTAVIS LLC, ACTAVIS ELIZABETH LLC,
        MYLAN LABORATORIES LIMITED,
           Defendants-Cross-Appellants
             ______________________

            2018-1804, 2018-1808, 2018-1809
                ______________________

    Appeals from the United States District Court for the
District of New Jersey in Nos. 3:14-cv-07869-MAS-LHG,
3:14-cv-08079-MAS-LHG, 3:14-cv-08082-MAS-LHG, 3:15-
cv-00287-MAS-LHG, 3:15-cv-00290-MAS-LHG, 3:15-cv-
00776-MAS-LHG,      3:15-cv-01835-MAS-LHG,       3:15-cv-
02520-MAS-LHG,      3:15-cv-02522-MAS-LHG,       3:15-cv-
02631-MAS-LHG,      3:15-cv-03107-MAS-LHG,       3:15-cv-
03392-MAS-LHG,      3:16-cv-02259-MAS-LHG,       3:16-cv-
05678-MAS-LHG, Judge Michael A. Shipp.
                ______________________

               Decided: August 14, 2019
2         SANOFI-AVENTIS U.S., LLC v. FRESENIUS KABI USA, LLC




                 ______________________

   WILLIAM E. SOLANDER, Venable LLP, New York, NY,
argued for plaintiffs-appellants. Also represented by
KATHERINE ADAMS, DOMINICK A. CONDE, WHITNEY LYNN
MEIER, DANIEL JOHN MINION.

    EMILY L. RAPALINO, Goodwin Procter LLP, Boston, MA,
argued for all defendants-cross-appellants. Defendants-
cross-appellants Fresenius Kabi USA, LLC, Actavis LLC,
Actavis Elizabeth LLC also represented by DARYL L.
WIESEN, ERIC ROMEO; AVIV ZALCENSTEIN, New York, NY.

    ANDREW M. ALUL, Taft, Stettinius & Hollister, LLP,
Chicago, IL, argued for all defendants-cross-appellants.
Defendants-cross-appellants Apotex Corp., Apotex Inc.
also represented by ROSHAN SHRESTHA.

    FRANK RODRIGUEZ, Windels Marx Lane & Mittendorf
LLP, Madison, NJ, for defendants-appellees Dr. Reddy's
Laboratories, Inc., Dr. Reddy's Laboratories, Ltd. Also rep-
resented by JAMES BARABAS.

    LAURA A. LYDIGSEN, Brinks Gilson & Lione, Chicago,
IL, for defendant-appellee Sandoz, Inc. Also represented
by MARK HERBERT REMUS, JOSHUA JAMES.

    IMRON T. ALY, Schiff Hardin, Chicago, IL, for defend-
ant-cross-appellant Accord Healthcare, Inc. Also repre-
sented by HELEN H. JI.

   MATTHEW R. REED, Wilson, Sonsini, Goodrich & Rosati,
PC, Palo Alto, CA, for defendant-cross-appellant Mylan La-
boratories Limited. Also represented by WENDY L. DEVINE,
KRISTINA M. HANSON, San Francisco, CA.
                 ______________________

    Before LOURIE, MOORE, and TARANTO, Circuit Judges.
SANOFI-AVENTIS U.S., LLC v. FRESENIUS KABI USA, LLC        3



LOURIE, Circuit Judge.
     Plaintiffs-Appellants (collectively, “Sanofi”) appeal
from the judgment of the U.S. District Court for the Dis-
trict of New Jersey holding, after a bench trial, claims 7,
11, 14–16, and 26 of U.S. Patent 8,927,592 (the “’592 pa-
tent”) invalid as obvious. Sanofi-Aventis U.S. LLC v. Frese-
nius Kabi USA, LLC, No. 14-7869 (D.N.J. Dec. 19, 2017)
(“Decision”). Defendants-Cross-Appellants (collectively,
“Fresenius”) cross-appeal from the same judgment holding
claims 1 and 2 of U.S. Patent 5,847,170 (the “’170 patent”)
not invalid as obvious. Because there was no case or con-
troversy with respect to claims 7, 11, 14–16, and 26 of the
’592 patent when the district court issued its decision, we
vacate the court’s decision concerning those claims. We af-
firm the court’s judgment that the ’170 patent is not invalid
as obvious.
                       BACKGROUND
    Sanofi owns the ’170 and ’592 patents, respectively
claiming the compound cabazitaxel and methods of using
it. Sanofi markets cabazitaxel under the trade name Jev-
tana® to treat certain drug-resistant prostate cancers.
Both the ’170 and ’592 patents are listed in the Orange
Book 1 as covering cabazitaxel.
    Cabazitaxel belongs to a family of compounds called
taxanes and is the third and most recent taxane drug to
gain approval by the Food and Drug Administration
(“FDA”). The other two are paclitaxel, approved in 1992,
and docetaxel, approved in 1996. The chemical structures
of docetaxel and cabazitaxel are depicted below:




    1   This publication is formally entitled “Approved
Drug Products with Therapeutic Equivalence Evalua-
tions.”
4         SANOFI-AVENTIS U.S., LLC v. FRESENIUS KABI USA, LLC




        Docetaxel                           Cabazitaxel
As annotated above, cabazitaxel differs from docetaxel in
the substitution of two methoxy groups for hydroxyl
groups. The carbon atoms to which the right and left meth-
oxy groups are bound are referred to as C7 and C10, respec-
tively. A fully numbered cabazitaxel is depicted in
Appendix A, and the carbon positions are numbered in the
same way in docetaxel. 2
    Cabazitaxel was the product of a multi-year research
program aimed at identifying taxane analogs with better
activity than docetaxel in resistant tumors. By making
substitutions at multiple positions on docetaxel with vari-
ous functional groups, Sanofi scientists synthesized several
hundred compounds and tested their activities. Of this
group, cabazitaxel was one of two compounds that entered
into human studies. It obtained FDA approval in 2010.
    Fresenius and the other defendants-appellees 3 (collec-
tively, “Defendants”) filed Abbreviated New Drug Applica-
tions (“ANDAs”) to market generic versions of cabazitaxel
prior to the expiration of the ’592 and ’170 patents, prompt-
ing Sanofi to sue the Defendants for infringement in the
District of New Jersey. Defendants counterclaimed for a



    2   In contrast to docetaxel, paclitaxel, the other FDA-
approved prior art taxane, has an acetoxy group at C10 in-
stead of a hydroxyl. It also has a different sidechain group
at C3′.
    3   Three defendants have not joined Fresenius’s
cross-appeal.
SANOFI-AVENTIS U.S., LLC v. FRESENIUS KABI USA, LLC         5



declaratory judgment of invalidity of the ’592 patent. The
case ultimately proceeded to a bench trial concerning both
patents.
    However, while the district court case was pending, the
Patent Trial and Appeal Board (the “Board”) of the United
States Patent and Trademark Office instituted inter partes
review of the ’592 patent. Soon after the district court trial
began, the Board held claims 1–5 and 7–30 unpatentable
as obvious and denied Sanofi’s motion to amend its claims.
Although Sanofi did appeal from the Board’s denial of its
motion to amend, it did not appeal from the Board’s deci-
sion with respect to claims 7, 11, 14–16, and 26. And on
December 8, 2017, Sanofi filed a statutory disclaimer of
those claims (the “disclaimed claims”) in the Patent and
Trademark Office and so informed the district court. J.A.
14135–36; see 37 C.F.R. § 1.321(a).
     Soon after the disclaimer, the district court entered a
post-trial order reaching two conclusions relevant to this
appeal. First, despite the statutory disclaimer of the dis-
claimed claims, the court concluded that a case or contro-
versy still existed with respect to those claims and that
they were invalid as obvious. Decision, slip op. at 45–46,
79–83. Second, the court held that the Defendants failed
to prove that claims 1 and 2 of the ’170 patent, claiming the
cabazitaxel compound and related pharmaceutical compo-
sitions (and set forth in Appendix B), would have been ob-
vious over the prior art. Id. at 42–43. 4



    4   Over one year after the district court’s judgment,
and after the parties completed briefing in this appeal, we
vacated the Board’s decision denying Sanofi’s motion to
amend and remanded the case to the Board for further pro-
ceedings. See Sanofi Mature IP v. Mylan Labs. Ltd., 757 F.
App’x 988, 994 (Fed. Cir. 2019). We held that the Board
erroneously placed the burden on Sanofi to prove the
6         SANOFI-AVENTIS U.S., LLC v. FRESENIUS KABI USA, LLC




    Sanofi appealed from the district court’s conclusion
that a case or controversy still existed over the disclaimed
claims after Sanofi’s statutory disclaimer. Fresenius cross-
appealed from the court’s judgment of nonobviousness of
claims 1 and 2 of the ’170 patent. We have jurisdiction over
both appeals under 28 U.S.C. § 1295(a)(1). We first ad-
dress Sanofi’s jurisdictional appeal and then turn to Frese-
nius’s cross-appeal.
                        DISCUSSION
                             I
    We review de novo whether a case or controversy ex-
isted for the district court to enter a declaratory judgment
of noninfringement or invalidity, Prasco, LLC v. Medicis
Pharm. Corp., 537 F.3d 1329, 1335 (Fed. Cir. 2008), and
apply Federal Circuit law, 3M Co. v. Avery Dennison Corp.,
673 F.3d 1372, 1377 (Fed. Cir. 2012).
    Sanofi argues that after it disclaimed the particular
claims, there was no longer a case or controversy regarding
those claims, and the district court thus lacked authority
to invalidate them. Accordingly, Sanofi requests that we
vacate the court’s judgment invalidating the disclaimed
claims.
    Defendants respond that there may still have been a
case or controversy over the disclaimed claims depending
on the merits of their potential future issue or claim pre-
clusion defense, which Defendants could raise if Sanofi suc-
ceeds in amending claims of the ’592 patent and then



patentability of the amended claims, and “decline[d] to
speculate as to how the Board would resolve this case un-
der the correct legal standard.” Id. at 991. The case re-
mains pending before the Board. See Mylan Labs. Ltd. v.
Aventis Pharma S.A., No. IPR2016-00712, 2019 WL
1559904 (P.T.A.B. Apr. 9, 2019), Paper No. 108.
SANOFI-AVENTIS U.S., LLC v. FRESENIUS KABI USA, LLC        7



asserts the amended claims against Defendants. That is,
Defendants insist we must resolve this potential preclusion
issue in the first instance in order to decide whether the
district court had jurisdiction over the disclaimed claims.
     Article III empowers federal courts to adjudicate only
“Cases” and “Controversies,” U.S. Const. art. III, § 2, “ap-
propriately resolved through the judicial process,” Lujan v.
Defs. of Wildlife, 504 U.S. 555, 560 (1992) (quoting
Whitmore v. Arkansas, 495 U.S. 149, 155 (1990)). To sat-
isfy the case or controversy requirement in the declaratory
judgment context, the parties’ dispute must be “‘real and
substantial’ and ‘admi[t] of specific relief through a decree
of a conclusive character, as distinguished from an opinion
advising what the law would be upon a hypothetical state
of facts.’” MedImmune, Inc. v. Genentech, Inc., 549 U.S.
118, 127 (2007) (alteration in original) (quoting Aetna Life
Ins. Co. v. Haworth, 300 U.S. 227, 240–41 (1937)). The case
or controversy analysis is highly similar to that of Article
III standing. See Apotex, Inc. v. Daiichi Sankyo, Inc., 781
F.3d 1356, 1362 (Fed. Cir. 2015). “To have standing, a
plaintiff must ‘present an injury that is concrete, particu-
larized, and actual or imminent; fairly traceable to the de-
fendant’s challenged behavior; and likely to be redressed
by a favorable ruling.’” Dep’t of Commerce v. New York, 139
S. Ct. 2551, 2565 (2019) (quoting Davis v. Fed. Election
Comm’n, 554 U.S. 724, 733 (2008)). The injury must be
“‘concrete and particularized’ and ‘actual or imminent, not
conjectural or hypothetical.’” Spokeo, Inc. v. Robins, 136 S.
Ct. 1540, 1548 (2016) (quoting Lujan, 504 U.S. at 560).
     Further, “an actual controversy must be extant at all
stages of review, not merely at the time the complaint is
filed.” Steffel v. Thompson, 415 U.S. 452, 459 n.10 (1974)
(emphasis added). We focus our analysis on whether there
was an actual controversy when the district court entered
final judgment. See Janssen Pharmaceutica, N.V. v. Apo-
tex, Inc., 540 F.3d 1353, 1362–63 & n.9 (Fed. Cir. 2008).
8         SANOFI-AVENTIS U.S., LLC v. FRESENIUS KABI USA, LLC




    We agree with Sanofi that its disclaimer of the dis-
claimed claims mooted any controversy over them. As we
explain, at the time the district court entered final judg-
ment, the relief requested by Defendants was both specu-
lative and immaterial to its possible future defenses, and
Defendants thus failed to demonstrate an Article III case
or controversy.
    When Sanofi disclaimed the disclaimed claims, it “ef-
fectively eliminated those claims from the . . . patent,” Vec-
tra Fitness, Inc. v. TNWK Corp., 162 F.3d 1379, 1383 (Fed.
Cir. 1998), leaving the ’592 patent “as though the dis-
claimed claim(s) had ‘never existed,’” Genetics Inst., LLC v.
Novartis Vaccines & Diagnostics, Inc., 655 F.3d 1291, 1299
(Fed. Cir. 2011) (quoting Vectra, 162 F.3d at 1383)). By
leaving the ’592 patent as if the disclaimed claims had
never existed, Sanofi’s disclaimer mooted any infringe-
ment-based dispute concerning those claims. See Fresenius
USA, Inc. v. Baxter Int’l, Inc., 721 F.3d 1330, 1340 (Fed.
Cir. 2013) (“[I]n general, when a claim is cancelled, the pa-
tentee loses any cause of action based on that claim, and
any pending litigation in which the claims are asserted be-
comes moot.”).
     Nonetheless, Defendants contend that the district
court’s invalidity judgment with respect to the disclaimed
claims must be preserved to provide them with “patent cer-
tainty,” relying principally on our decision in Teva Phar-
maceuticals USA, Inc. v. Novartis Pharmaceuticals Corp.,
482 F.3d 1330 (Fed. Cir. 2007). In that case, Teva brought
a declaratory judgment action against four Orange Book-
listed patents owned by Novartis. Id. at 1335. We con-
cluded that there was a case or controversy sufficient for
declaratory judgment jurisdiction concerning those patents
because Teva had submitted an ANDA certifying that the
patents were invalid or not infringed, and Novartis had al-
ready sued Teva on another listed patent covering the same
product. Id. at 1340–44. The controversy in Teva thus re-
lated to a concrete and realistic threat posed by existing
SANOFI-AVENTIS U.S., LLC v. FRESENIUS KABI USA, LLC         9



patent claims. Defendants point to no such threat created
by the effectively nonexistent disclaimed claims, so Defend-
ants’ reliance on Teva is misplaced.
    In some circumstances, patent claims may create a con-
troversy sufficient for declaratory judgment jurisdiction
even when there is no risk of infringement, but the party
seeking such judicial relief must demonstrate some other
concrete and imminent harm traceable to the claims. See
Daiichi Sankyo, 781 F.3d at 1361–62; see also Amerigen
Pharm. Ltd. v. UCB Pharma GmbH, 913 F.3d 1076, 1083–
84 (Fed. Cir. 2019). Defendants have not done so in this
case.
    Defendants allege that if we vacate the district court’s
judgment of invalidity of the disclaimed claims, then De-
fendants will lose the possible benefit of an issue preclusion
defense based on that judgment should Sanofi obtain
amended claims and assert them against Defendants. We
conclude that this alleged injury did not provide a case or
controversy at the time of the court’s judgment for at least
two reasons.
     First, the relevance of the disclaimed claims to a possi-
ble issue preclusion defense was speculative. An Article III
court may not “advis[e] what the law would be upon a hy-
pothetical state of facts.” MedImmune, 549 U.S. at 127 (in-
ternal quotation marks omitted). When the district court
issued its decision, there were no enforceable amended
claims. The Board had denied Sanofi’s motion to amend,
so any future assertion of amended claims was premised on
a hypothetical appellate reversal or vacatur and remand of
the Board’s inter partes review decision.
    Second, even assuming that Defendants’ stake in the
district court’s judgment concerning the disclaimed claims
was sufficiently imminent, they have not established that
the judgment pertaining to those claims is material to a
possible future suit. Defendants contend that they have an
interest in preserving, for possible issue preclusion
10        SANOFI-AVENTIS U.S., LLC v. FRESENIUS KABI USA, LLC




purposes, the court’s purported finding “[i]n connection
with disclaimed claim 11” that “dosages of cabazitaxel be-
yond 20 mg/m2 were in the prior art and used to treat docet-
axel-resistant prostate cancer.” Cross-Appellants’ Br. 47–
48. They cite two sections of the court’s decision as relevant
to that finding. However, the first section addresses only
claims 21 and 30, not disclaimed claim 11, and thus would
be entirely unaffected by vacatur of the court’s decision re-
garding the disclaimed claims. See Decision, slip op. at 75
(discussing claims 21 and 30 and finding that “[t]he
TROPIC trial was a trial done at a dose of 25 mg/m2 of cab-
azitaxel”). And while the second section does discuss claim
11, it does not examine dosages above 20 mg/m2. Defend-
ants have thus failed to demonstrate that vacatur of the
court’s judgment regarding the disclaimed claims would
matter to its potential issue preclusion argument.
    Somewhat relatedly, Defendants ask us to consider in
the first instance the claim preclusion arguments that they
intend to make—based on Sanofi’s previous assertion of
certain non-disclaimed claims—should Sanofi secure
amended claims at the Board and then assert them against
Defendants. Defendants do not allege, however, that this
hypothetical defense in any way depends on the district
court’s judgment concerning the disclaimed claims. We
cannot issue an advisory opinion on such a theoretical dis-
pute and we decline to do so here. Defendants will have
ample opportunity to raise a claim preclusion defense at
the district court should Sanofi sue them again.
    For these reasons, Defendants have not shown the ex-
istence of a case or controversy over the disclaimed claims
at the time the district court entered judgment. The court
thus lacked authority to disinter the already disclaimed
claims and declare them invalid. Accordingly, we vacate
the court’s judgment concerning the disclaimed claims.
SANOFI-AVENTIS U.S., LLC v. FRESENIUS KABI USA, LLC         11



                              II
     We now turn to Fresenius’s cross-appeal from the dis-
trict court’s judgment that cabazitaxel, claimed in claims 1
and 2 of the ’170 patent, would not have been obvious over
docetaxel, which has been determined to be the lead com-
pound and, in effect here, the closest prior art. On appeal
from a bench trial, we review a district court’s conclusions
of law de novo and its findings of fact for clear error.
Braintree Labs., Inc. v. Novel Labs., Inc., 749 F.3d 1349,
1358 (Fed. Cir. 2014). A factual finding is clearly erroneous
if, despite some supporting evidence, we are left with the
definite and firm conviction that a mistake has been made.
United States v. U.S. Gypsum Co., 333 U.S. 364, 395 (1948).
“The burden of overcoming the district court’s factual find-
ings is, as it should be, a heavy one.” Polaroid Corp. v.
Eastman Kodak Co., 789 F.2d 1556, 1559 (Fed. Cir. 1986).
A patent is presumed valid, and overcoming that presump-
tion at the district court requires clear and convincing evi-
dence. Microsoft Corp. v. i4i Ltd. P’ship, 564 U.S. 91, 95
(2011); Ferring B.V. v. Watson Labs., Inc.-Fla., 764 F.3d
1401, 1407 (Fed. Cir. 2014).
     Obviousness is a question of law based on underlying
facts, including the scope and content of the prior art, dif-
ferences between the prior art and the claims at issue, the
level of ordinary skill, and relevant evidence of secondary
considerations. Graham v. John Deere Co. of Kan. City, 383
U.S. 1, 17–18 (1966). “[I]n cases involving new chemical
compounds, it 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). The reason need not be the same as the patentee’s
or expressly stated in the art. KSR Int’l Co. v. Teleflex Inc.,
550 U.S. 398, 419 (2007); see In re Dillon, 919 F.2d 688,
693–94 (Fed. Cir. 1990) (en banc). But charting a path to
the claimed compound by hindsight is not enough to prove
12        SANOFI-AVENTIS U.S., LLC v. FRESENIUS KABI USA, LLC




obviousness. “Any compound may look obvious once some-
one has made it and found it to be useful, but working back-
wards from that compound, with the benefit of hindsight,
once one is aware of it does not render it obvious.” Ameri-
gen, 913 F.3d at 1089.
     In its obviousness analysis, the district court consid-
ered the testimony of seven witnesses and seventeen prior
art references and ultimately concluded that Defendants
failed to prove that claims 1 and 2 of the ’170 patent would
have been obvious. Decision, slip op. at 43. The court found
that a person of ordinary skill would have selected docet-
axel as a lead compound, and the key issue was thus
whether a skilled artisan would have been motivated to re-
place the C7 and C10 hydroxyl groups of docetaxel with the
methoxy groups of cabazitaxel. Id. at 30. We summarize
the court’s extensive findings on this issue as pertinent to
this appeal.
    Defendants argued at the district court that a skilled
artisan would have been motivated to increase the lipo-
philicity of docetaxel to interfere with a protein called Pgp
and thereby thwart drug resistance. Generally, the district
court credited undisputed expert testimony that Pgp was
involved in one of several possible mechanisms for drug re-
sistance. Id. at 36. Functioning as a protein pump, Pgp
can remove drug compounds from a cell and thereby hinder
their therapeutic effect.        The court made findings
SANOFI-AVENTIS U.S., LLC v. FRESENIUS KABI USA, LLC       13



concerning two references relating to Pgp, Hait 5 and Lam-
pidis, 6 which we review here.
    Hait discussed how Pgp could contribute to multi-drug
resistance and proposed a binding model for Pgp inhibitors.
J.A. 25093–94. The reference studied a group of Pgp inhib-
itors called phenothiazines, which have a tricyclic ring
structure quite different from taxanes, and found that in-
creasing lipophilicity increased sensitivity of a cancer cell
line to a non-taxane therapeutic. J.A. 25093. The district
court found that Hait would not have motivated a skilled
artisan to modify docetaxel for several reasons. The court
found that Hait addressed the effect of phenothiazines, not
taxanes, on Pgp, and that phenothiazines were structurally
quite different from taxanes. Decision, slip op. at 34. Con-
sistent with that fact, the court observed that no prior art
taxane reference of record cited Hait. Id. Additionally, the
court found that Hait only presented a hypothetical model
of Pgp binding based on the binding site of a different pro-
tein. Id.
    The district court found similarly with respect to Lam-
pidis. Lampidis reported that increasing the lipophilicity
of a positively-charged dye beneficially increased accumu-
lation of the dye in drug resistant cells. J.A. 16954. As
with Hait, however, the district court found that Lampidis
never discussed taxanes. Decision, slip op. at 34. Further,
the court determined that the reference focused on increas-
ing the lipophilicity of positively-charged compounds, but
taxanes do not have a positive charge. Id.; see Lampidis,


    5   William N. Hait & Dana T. Aftab, Rational Design
and Pre-Clinical Pharmacology of Drugs for Reversing
Multidrug Resistance, 43 Biochemical Pharmacology 103
(1992).
    6   Theodore J. Lampidis et al., Relevance of the Chem-
ical Charge of Rhodamine Dyes to Multiple Drug Re-
sistance, 38 Biochemical Pharmacology 4267 (1989).
14        SANOFI-AVENTIS U.S., LLC v. FRESENIUS KABI USA, LLC




J.A. 16954 (“If our hypothesis is correct, then it would ap-
pear that, in general, as we increase the lipophilicity of pos-
itively charged (delocalized) compounds we increase their
abilities to accumulate in, and subsequently kill, MDR
cells.” (emphasis added)).
    The district court also considered the teachings of two
articles that identified possible positions for substitution
on taxanes. Commerçon 7 identified the C3′, C7, C9, and
C10 positions on paclitaxel as “flexible” and suitable for
modification and also identified C2′ as a possible site for
certain modifications if the configuration of the group is
maintained. J.A. 25161. Kingston 1994 8 was similar.
    In addition to these articles, the district court ad-
dressed numerous references that investigated the activity
of specific taxane analogs. We review these here.
    European Patent Application 0 639 577 (“Golik”) sub-
stituted a methylthiomethoxy group for the C7 hydroxyl of
paclitaxel and reported that the compound had increased
activity in vitro compared to docetaxel and paclitaxel in a
drug-resistant cell line. J.A. 25205–06, 25229; Decision,
slip op. at 23. Golik also modified the C2′ position with a
prodrug moiety, and this analog showed promising results
in vivo. J.A. 25208, 25261; Decision, slip op. at 30. The
court found no evidence that Golik’s methylthiomethoxy
substitution at C7 would lead a skilled artisan to make a




     7  A. Commerçon et al., Practical Semisynthesis and
Antimitotic Activity of Docetaxel and Side-Chain Ana-
logues, in Taxane Anticancer Agents: Basic Science and
Current Status 233 (G. I. Georg et al. eds., 1994).
    8   David G. I. Kingston, Recent Advances in the Chem-
istry and Structure-Activity Relationships of Paclitaxel, in
Taxane Anticancer Agents: Basic Science and Current Sta-
tus 206 (G. I. Georg et al. eds., 1994).
SANOFI-AVENTIS U.S., LLC v. FRESENIUS KABI USA, LLC      15



methoxy substitution at that position. Decision, slip op. at
31.
    The other reference studying the activity of taxane an-
alogs against drug-resistant cell lines was Ojima 1994. 9
Ojima 1994 reported that modifying C3′ with certain sub-
stitutions produced much better activity than paclitaxel
and docetaxel against a drug-resistant cell line.
J.A. 25114–15. The reference disclosed neither a C7 nor a
C10 methoxy substitution. The court found that Ojima
1994 did not teach increasing lipophilicity of C7 and C10
against drug resistant cells. Decision, slip op. at 34–35.
    U.S. Patent 6,201,140 (“Wong”) disclosed a paclitaxel
derivative with a methoxy substitution at C7. J.A. 25324.
However, the district court found that Wong disclosed a
more potent paclitaxel derivative with a C2′ modification
and a different ether substitution at C7. Decision, slip op.
at 31. Further, the court found that Wong did not disclose
any compound with the C10 hydroxyl of docetaxel or the
C10 methoxy of cabazitaxel and did not disclose activity
data from resistant cell lines. Id.
    Another reference considered by the district court,
Kant, 10 focused on substitutions at C10, including a C10
methoxy substitution. Kant did not evaluate the activity
of C10 analogs in drug resistant cell lines and compared
the C10-methoxy-substituted docetaxel only to paclitaxel,
not docetaxel. J.A. 25311–12. Kant also did not study any



    9    Iwao Ojima et al., Syntheses and Structure-Activity
Relationships of New Taxoids, in Taxane Anticancer
Agents: Basic Science and Current Status 262 (G. I. Georg
et al. eds., 1994).
    10   Joydeep Kant et al., A Chemoselective Approach to
Functionalize the C-10 Position of 10-Deacetylbaccatin III.
Synthesis and Biological Properties of Novel C-10 Taxol®
Analogues, 35 Tetrahedron Letters 5543 (1994).
16        SANOFI-AVENTIS U.S., LLC v. FRESENIUS KABI USA, LLC




C7 substitutions. Although the court observed that the
C10 methoxy substitution (along with another analog)
showed good results in one assay, another compound per-
formed better in a different assay. Decision, slip op. at 32.
     The district court proceeded to Klein, 11 which focused
on substitutions at C9. Klein reported that certain C9-sub-
stituted taxanes “have increased water solubility and sta-
bility as compared to [paclitaxel] and also exhibit excellent
activity in tumor models.” J.A. 25173. Klein also disclosed
simultaneous C7 and C9 substitutions, including a C7
methoxy with good activity, but no C10 substitutions.
J.A. 25178. As with Wong and Kant, the court observed
that Klein did not investigate the activity of these substi-
tuted taxanes on drug resistant cell lines. Decision, slip op.
at 33.
    Ultimately, the district court found Defendants’ ex-
perts cherry-picked data in the references to reach caba-
zitaxel and were not credible. Id. at 36. The court credited
Sanofi’s expert’s testimony that taxane modifications were
considered at C2, C4, C5, C7, C8, C9, C10, C11, C12, C13,
C14, C2′, and C3′, id. at 37, and concluded that it would not
have been obvious to make simultaneous methoxy substi-
tutions at C7 and C10 of docetaxel, id.
    In addition, the district court found that some second-
ary considerations evidence supported nonobviousness and
that there was a nexus between claims 1 and 2 and the
marketed product Jevtana®. Id. at 37–38. Despite at-
tempts by research groups around the world to develop ef-
fective taxane cancer treatments, the court recognized that
cabazitaxel was only the third taxane to obtain FDA



     11 L. L. Klein et al., Chemistry and Antitumor Activity
in 9(R)-Dihydrotaxanes, in Taxane Anticancer Agents:
Basic Science and Current Status 276 (G. I. Georg et al.
eds., 1994).
SANOFI-AVENTIS U.S., LLC v. FRESENIUS KABI USA, LLC      17



approval. Id. at 40–41. The court thus determined that
“[Sanofi’s] success, where others had failed,” supported
nonobviousness. Id. at 41. The court also found that Jev-
tana® achieved commercial success. Id. at 42. In light of
all the evidence, the court concluded that Defendants failed
to prove obviousness by clear and convincing evidence. Id.
at 43.
     In its cross-appeal, Fresenius argues that the district
court committed a “cascading series of factual and legal er-
rors.” Cross-Appellants’ Br. 67. Specifically, Fresenius al-
leges that the court erred in rejecting its theory that a
skilled artisan would have: (1) been motivated to modify
docetaxel to reduce Pgp-related drug resistance; (2) knew
that this could be accomplished by increasing lipophilicity
of the C7 and C10 positions; and (3) determined that meth-
oxy substitutions were the “smallest, most conservative”
modification to achieve that goal. Id. Fresenius further
argues that the evidence of secondary considerations does
not overcome the evidence of obviousness.
    Sanofi responds that Fresenius’s obviousness theory
was hindsight-driven and that the district court did not err
in rejecting it.
     We agree with Sanofi and conclude that Fresenius’s
convoluted obviousness theory lacks merit. We begin with
Fresenius’s contention that the district court clearly erred
in finding that Hait and Lampidis would not have provided
a reason to make docetaxel more lipophilic. Not only did
these references not contemplate taxanes, they investi-
gated compounds that are structurally very different from
taxanes. Lampidis focused on positively-charged dyes and
suggested that increasing lipophilicity of positively-
charged molecules could be beneficial, but docetaxel is not
positively charged. Likewise, Hait studied phenothiazines,
which are much smaller than taxanes and have a three-
ring structure bearing no resemblance to taxanes. Fur-
thermore, Hait only presented a hypothetical binding site
18        SANOFI-AVENTIS U.S., LLC v. FRESENIUS KABI USA, LLC




model based on a different protein than Pgp. And the evi-
dence showed that no prior art taxane reference cited Hait.
Decision, slip op. at 34. We conclude that the court did not
clearly err in its assessment of these references or in find-
ing that they would not have motivated a skilled artisan to
modify docetaxel to obtain cabazitaxel.
     Even assuming there was some general motivation to
make docetaxel more lipophilic to combat drug resistance,
the district court also did not clearly err in finding that
Fresenius failed to establish a motivation to do so by spe-
cifically making simultaneous methoxy substitutions at C7
and C10. The court found that taxane researchers investi-
gated substitutions at many positions, and the voluminous
references in this case support that finding. For example,
Commerçon disclosed that C3′, C7, C9, and C10, and to a
more limited extent C2′, were modifiable. And as summa-
rized above, the other references investigated a diverse set
of substitutions. Fresenius reads this panoply of teachings
as rendering obvious simultaneous C7 and C10 methoxy
substitutions. But despite the apparent interest in taxane
analogs, not a single reference relied on by Fresenius made
simultaneous substitutions of any kind at C7 and C10. And
of the references that made individual methoxy substitu-
tions at C7 or C10, none tested those taxane analogs
against drug resistant cell lines or taught that the analogs
would overcome drug resistance. On this record, the court
did not clearly err in finding no motivation to make C7 and
C10 methoxy substitutions on docetaxel to improve its ac-
tivity against drug-resistant cancers.
    Considering Fresenius’s reference-specific arguments,
we agree with the district court that they are emblematic
of hindsight reasoning. Fresenius contends that Com-
merçon would have pointed a skilled artisan towards C7,
C10, and (less desirably) C9 substitutions because those
positions were “flexible,” and away from C2′ and C3′ sub-
stitutions because those positions were “crucial.” Cross-
Appellants’ Br. 57–58. However, this argument plainly
SANOFI-AVENTIS U.S., LLC v. FRESENIUS KABI USA, LLC         19



mischaracterizes the reference. Commerçon expressly
identified the sidechain position C3′ as “flexible,” and indi-
cated that C2′ could be modified with certain substitutions
if the configuration was maintained. J.A. 25161–62.
    That teaching is consistent with references such as
Ojima 1994 that investigated sidechain substitutions on
taxanes. See Ojima 1994, J.A. 25104 (C3′ substitutions);
Wong, J.A. 25327 (C2′ substitution). Fresenius, however,
contends that Ojima 1994 would motivate a skilled artisan
to make a C10 methoxy substitution because it showed that
“changing a hydrophilic hydroxy group to a more lipophilic
methoxy group at C-10 resulted in a significant increase in
potency against drug resistant cells.” Cross-Appellants’
Br. 62. As with its argument concerning Commerçon,
Fresenius’s position is premised on an incorrect character-
ization of the reference. The portions of Ojima 1994 in the
record nowhere investigated a methoxy-substituted tax-
ane, at C10 or anywhere else. While two of the compounds
tested did have paclitaxel’s C10 acetoxy group, Ojima 1994
did not even mention that fact. Rather, it emphasized the
“excellent” or “noteworthy” activity associated with C3′ iso-
butyl and isobutenyl substitutions. J.A. 25114–15. We
conclude that the district court did not clearly err in reject-
ing Fresenius’s selective reading of the reference.
    Although no cited reference shows that C7 or C10
methoxy-substituted taxanes have improved properties
with respect to drug resistance, Fresenius argues that a
skilled artisan would have made simultaneous C7 and C10
methoxy substitutions because they are “small, conserva-
tive changes” that increase lipophilicity. Cross-Appellants’
Br. 65–67 (citing Bristol-Myers Squibb Co. v. Teva Pharm.
USA, Inc., 752 F.3d 967, 974–75 (Fed. Cir. 2014)). Frese-
nius’s arguments concerning Golik are illustrative. As pre-
viously discussed, Golik disclosed a taxane analog with a
methylthiomethoxy substitution at C7, which had promis-
ing qualities against drug-resistant cell lines. Rather than
simply motivate a skilled artisan to investigate C7
20        SANOFI-AVENTIS U.S., LLC v. FRESENIUS KABI USA, LLC




methylthiomethoxy substitutions, Fresenius argues that
this teaching really supports making a C7 methoxy substi-
tution.
    This argument stands on little more than hindsight.
The district court found no evidence that the methoxy
group would provide a similar benefit as the sulfur-contain-
ing methylthiomethoxy group. Decision, slip op. at 30–31.
In contrast to the reported advantageous features of the
methylthiomethoxy group in Golik and the absence of any
evidence showing equivalent properties of a methoxy sub-
stitution, Fresenius directs us on appeal only to its experts’
vague testimony that sulfur has some unspecified “meta-
bolic liabilities” or “other complications.” J.A. 12361–62,
13160. We conclude that the court did not clearly err in
rejecting this weak testimony.
    Fresenius’s position concerning Ojima 1994 is similar.
Fresenius argues that Ojima 1994’s supposed implicit
teaching of the benefits of a C10 acetoxy group against
drug-resistant cells would actually motivate a skilled arti-
san to make a C10 methoxy substitution because it is
smaller and more conservative. As with Golik, Fresenius
cites no non-conclusory evidence that the methoxy group
would have the same purported benefits as the acetoxy
group, and offers no persuasive explanation of how the
methoxy group, which was not tested in Ojima 1994, would
be a more conservative choice than the C10 acetoxy already
present in the FDA-approved drug paclitaxel. We consider
Fresenius’s argument exemplary of hindsight reasoning.
    Many of Fresenius’s arguments cite our decision in
Bristol-Myers Squibb. There, we affirmed a district court’s
conclusion that it would have been obvious to make a single
chemical change to a lead compound where there were a
“small, finite number of changes to try,” and the particular
claimed change had already been shown to have desirable
properties in a similar context. Bristol-Myers Squibb Co.,
752 F.3d at 975–76 (quoting In re Cyclobenzaprine
SANOFI-AVENTIS U.S., LLC v. FRESENIUS KABI USA, LLC       21



Hydrochloride Patent Litig., 676 F.3d 1063, 1072 (Fed. Cir.
2012)). As our review above shows, the district court’s find-
ings in this case are quite different and demand a different
outcome. The court here found that numerous docetaxel
modifications were under investigation, and there was no
showing that making individual or simultaneous methoxy
substitutions at C7 and C10 improved activity against
drug-resistant cells, the sole motivation relied on by Frese-
nius. We also disagree with Fresenius that small changes
to a compound are necessarily prima facie obvious. We did
not adopt such a bright-line legal rule in Bristol-Myers
Squibb, and doing so would be inconsistent with the flexi-
ble analysis inherent to the highly contextual obviousness
inquiry. See KSR, 550 U.S. at 415.
    Fresenius last challenges the district court’s weighing
of the evidence of secondary considerations, although it
does not point to any error in the court’s reasoning. We see
no clear error in the court’s finding that “[m]ultiple groups
around the world tried unsuccessfully to develop taxanes
into effective therapies and only [Sanofi] succeeded in de-
veloping a compound that showed superior activity over
docetaxel, namely cabazitaxel, and obtained FDA ap-
proval.” Decision, slip op. at 41 (citations omitted). And
we agree with the court that, in this case, this finding war-
rants significant weight in the ultimate obviousness anal-
ysis. We also conclude that the court did not clearly err
with respect to Sanofi’s evidence of commercial success.
    Ultimately, we agree with Sanofi that the district court
correctly concluded that claims 1 and 2 of the ’170 patent
would not have been obvious over docetaxel. We have also
considered Fresenius’s other arguments but find them un-
persuasive. We thus affirm the court’s judgment.
                        CONCLUSION
    For the foregoing reasons, we vacate the district court’s
judgment of obviousness concerning claims 7, 11, 14–16,
and 26 of the ’592 patent and affirm the court’s judgment
22         SANOFI-AVENTIS U.S., LLC v. FRESENIUS KABI USA, LLC




of nonobviousness concerning claims 1 and 2 of the ’170 pa-
tent.
     AFFIRMED-IN-PART AND VACATED-IN-PART
                            COSTS
     Costs to Sanofi.
SANOFI-AVENTIS U.S., LLC v. FRESENIUS KABI USA, LLC   23



                        APPENDIX A




                        Cabazitaxel
24        SANOFI-AVENTIS U.S., LLC v. FRESENIUS KABI USA, LLC




                        APPENDIX B
’170 Patent Claim 1
     1. 4α-Acetoxy-2α-benzoyloxy-5β,20-epoxy-1β-hy-
     droxy-7β,10β-dimethoxy-9-oxo-11-taxen-13α-
     yl(2R,3S)-3-tert-butoxycarbonylamino-2-hydroxy-
     3-phenylpropionate.
’170 Patent Claim 2
     2. A pharmaceutical composition comprising at
     least the product according to claim 1 in combina-
     tion with one or more pharmaceutically acceptable
     diluents or adjuvants and optionally one or more
     compatible and pharmacologically active com-
     pounds.
