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
`Book1 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
`
`
`
`
`
`Cabazitaxel
`
`
`
`
`
`
` Docetaxel
`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-appellees3 (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, Hait5 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. Commerçon7 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 19948 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
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`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
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`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).
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`SANOFI-AVENTIS U.S., LLC v. FRESENIUS KABI USA, LLC
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`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
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`18
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`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 substitut