Case: 22-2153 Document: 71 Page: 1 Filed: 04/11/2024
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`
`
`United States Court of Appeals
`for the Federal Circuit
`______________________
`
`SALIX PHARMACEUTICALS, LTD., SALIX
`PHARMACEUTICALS, INC., BAUSCH HEALTH
`IRELAND LTD., ALFASIGMA S.P.A.,
`Plaintiffs-Appellants
`
`v.
`
`NORWICH PHARMACEUTICALS INC.,
`Defendant-Cross-Appellant
`______________________
`
`2022-2153, 2023-1952
`______________________
`
`Appeals from the United States District Court for the
`District of Delaware in No. 1:20-cv-00430-RGA, Judge
`Richard G. Andrews.
`______________________
`
`Decided: April 11, 2024
`______________________
`
`WILLIAM R. PETERSON, Morgan, Lewis & Bockius LLP,
`Houston, TX, argued for plaintiffs-appellants. Also repre-
`sented by MICHAEL J. ABERNATHY, KARON NICOLE FOWLER,
`MICHAEL SIKORA, Chicago, IL; JULIE S. GOLDEMBERG, Phil-
`adelphia, PA; JOSHUA DANIEL CALABRO, SHANNON KEOUGH
`CLARK, STEVEN C. KLINE, ALEXIS M. MCJOYNT, SCOTT K.
`REED, BECKY E. STEEPHENSON, Venable LLP, New York,
`NY.
`
` CHAD A. LANDMON, Axinn, Veltrop & Harkrider LLP,
`
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`SALIX PHARMACEUTICALS, LTD. v.
`NORWICH PHARMACEUTICALS INC.
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`Hartford, CT, argued for defendant-cross-appellant. Also
`represented by MATTHEW BECKER, REBECCA L. CLEGG,
`THOMAS K. HEDEMANN, MATTHEW S. MURPHY.
`
` IRENA ROYZMAN, Kramer Levin Naftalis & Frankel
`LLP, New York, NY, for amici curiae Regeneron Pharma-
`ceuticals, Inc., Ocular Therapeutix, Inc. Also represented
`by CHRISTINE WILLGOOS; PAUL BRZYSKI, Washington, DC.
`
` PAUL WHITFIELD HUGHES, III, McDermott Will & Em-
`ery LLP, Washington, DC, for amicus curiae Vanda Phar-
`maceuticals Inc. Also represented by CHRISTOPHER
`MICHAEL BRUNO, SARAH HOGARTH, APRIL ELISE
`WEISBRUCH.
`
`______________________
`
`Before LOURIE, CHEN, and CUNNINGHAM, Circuit Judges.
`Opinion for the court filed by Circuit Judge LOURIE.
`Opinion dissenting-in-part filed by Circuit Judge
`CUNNINGHAM.
`LOURIE, Circuit Judge.
`Salix Pharmaceuticals, Ltd., Salix Pharmaceuticals,
`Inc., Bausch Health Ireland Ltd., and Alfasigma S.P.A.
`(collectively, “Salix”) appeal from a final judgment of the
`United States District Court for the District of Delaware
`holding claim 2 of U.S. Patent 8,309,569, claim 3 of U.S.
`Patent 10,765,667, claim 4 of U.S. Patent 7,612,199, and
`claim 36 of U.S. Patent 7,902,206 invalid as obvious. See
`Salix Pharms., Ltd. v. Norwich Pharms., Inc., No. 20-cv-
`430, 2022 WL 3225381 (D. Del. Aug. 10, 2022) (“Decision”).
`Norwich Pharmaceuticals Inc. (“Norwich”) cross-ap-
`peals from an order that issued after the district court con-
`cluded that Norwich infringed claim 8 of U.S. Patent
`8,624,573, claim 6 of U.S. Patent 9,421,195, and claims 11
`and 12 of U.S. Patent 10,335,397 and had failed to prove
`
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`SALIX PHARMACEUTICALS, LTD. v.
`NORWICH PHARMACEUTICALS INC.
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`3
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`that those claims were invalid. That order, contained
`within the final judgment, instructed the FDA that the ef-
`fective approval date of Norwich’s Abbreviated New Drug
`Application (“ANDA”) may not precede the expiration dates
`of those claims. J.A. 51. Norwich also cross-appeals from
`a denial of its motion to modify the final judgment. See
`Salix Pharms., Ltd. v. Norwich Pharms., Inc., No. 20-430,
`2023 WL 3496373 (D. Del. May 17, 2023) (“Rule 60(b) Or-
`der”).
`For the following reasons, we affirm.
`BACKGROUND
`Rifaximin, the active ingredient in Salix’s commercial
`product Xifaxan®, has been widely used as an antibiotic for
`decades, having been first synthesized in the early 1980s
`in Italy and approved there as an antibiotic in 1985. Deci-
`sion at *8; J.A. 2532. The FDA approved Xifaxan nearly 20
`years later, in 2004, as 200 mg tablets for the treatment of
`travelers’ diarrhea. Decision at *1. The FDA subsequently
`approved 550 mg tablets for hepatic encephalopathy (“HE”)
`in 2010 and for irritable bowel syndrome with diarrhea
`(“IBS-D”) in 2015. Id.
`Norwich sought to market a generic version of rifaximin
`and, in 2019, filed an ANDA for 550 mg tablets with the
`same indications as Xifaxan, certifying pursuant to
`21 U.S.C. § 355(j)(2)(vii)(IV) that Salix’s rifaximin patents
`were invalid. Salix timely sued, asserting that Norwich’s
`ANDA infringed dozens of valid, Orange Book-listed pa-
`tents. By the time of trial, the case had been streamlined
`to three groups of patents:
`• the ’573, ’195, and ’397 patents, directed to treating
`HE (“the HE patents”);
`• the ’569 and ’667 patents, directed to treating IBS-D
`with 550 mg rifaximin three times a day (1,650
`mg/day) for 14 days (“the IBS-D patents”); and,
`
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`SALIX PHARMACEUTICALS, LTD. v.
`NORWICH PHARMACEUTICALS INC.
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`• the ’199 and ’206 patents, directed to rifaximin form
`β (“the polymorph patents”).
`Following a bench trial, the district court held that
`Norwich infringed the HE patents’ claims and had failed to
`establish their invalidity. Decision at *10−11. Norwich did
`not appeal those holdings. The court also held that Nor-
`wich’s ANDA infringed the IBS-D and polymorph patents,
`but that those patents’ claims would have been obvious
`over certain prior art. Id. at *2−3, 16−17. Salix appealed
`those invalidity holdings.
`As part of the entered judgment, the district court or-
`dered that the effective date of a final approval of Norwich’s
`ANDA should not precede October 2029, which is the latest
`expiration date associated with the HE patents. J.A. 51.
`Norwich then amended its ANDA in an attempt to remove
`the infringing HE indication and moved to modify the judg-
`ment under Federal Rule of Civil Procedure 60(b), assert-
`ing
`that
`the amendment negated any possible
`infringement. The court denied Norwich’s motion, and
`Norwich cross-appealed.
`We have jurisdiction under 28 U.S.C. § 1295(a)(1).
`DISCUSSION
`Salix first contends that the district court’s conclusion
`that the asserted claims of the IBS-D patents were invalid
`as obvious was reached in error. Subsumed within that
`challenge is a question of whether or not a background ref-
`erence discussed by the court was properly established as
`prior art. Salix also contends that the court erred in hold-
`ing that the asserted polymorph patent claims were invalid
`as obvious. Norwich’s cross-appeal asserts that the court
`erred in the phrasing of its order precluding final approval
`of its ANDA until expiration of the HE patents. Norwich
`further asserts that the court erred in denying its motion
`to modify after the ANDA was amended in an attempt to
`avoid infringement. We address each argument in turn.
`
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`SALIX PHARMACEUTICALS, LTD. v.
`NORWICH PHARMACEUTICALS INC.
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`I
`We turn first to Salix’s contention that the district
`court erred in concluding that the asserted claims of the
`IBS-D patents would have been obvious over the asserted
`prior art.
`Whether or not a claim would have been obvious is a
`question of law, based on underlying factual determina-
`tions. Hospira, Inc. v. Fresenius Kabi USA, LLC, 946 F.3d
`1322, 1328–29 (Fed. Cir. 2020). We review the ultimate
`legal question of obviousness de novo and the underlying
`factual determinations for clear error. Id. at 1328. A find-
`ing is clearly erroneous only if we are “left with a definite
`and firm conviction that the district court was in error.” Id.
`(citations omitted).
`The IBS-D patents are directed to treating IBS-D with
`550 mg rifaximin, thrice-daily (1,650 mg/day), for 14 days.
`For example, claim 2 of the ’569 patent depends from claim
`1 as follows:
`1. A method of providing acute treatment for diar-
`rhea-associated Irritable Bowel Syndrome (dIBS)
`comprising: administering 1650 mg/day of rifaxi-
`min for 14 days to a subject in need thereof,
`wherein removing the subject from treatment after
`the 14 days results in a durability of response,
`wherein the durability of response comprises about
`12 weeks of adequate relief of symptoms.
`2. The method of claim 1, wherein the 1650 mg is
`administered at 550 mg three times per day.
`’569 patent, col. 30 ll. 4–12 (emphases added); see also ’667
`patent, col. 46 ll. 29–33, 39–40 (claims 1 & 3, similar). The
`key limitation on appeal is the dosage amount that appears
`in the claims: 550 mg, three times per day (“TID”), for a
`total of 1,650 mg/day.
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`SALIX PHARMACEUTICALS, LTD. v.
`NORWICH PHARMACEUTICALS INC.
`
`Norwich challenged the IBS-D claims’ validity by as-
`serting as prior art references a clinical trial protocol that
`had been published on the ClinicalTrials.gov website in
`2005 (“the Protocol”)1 and a 2006 journal article (“Pimen-
`tel”).2 The Protocol describes a Phase II study evaluating
`twice-daily doses of 550 mg (1,100 mg/day) and 1,100 mg
`(2,200 mg/day) for 14 and 28 days for the treatment of IBS-
`D. See J.A. 7051. Pimentel teaches administering 400 mg,
`TID (1,200 mg/day), for the treatment of IBS,3 but further
`opines that the “optimal dosage of rifaximin may, in fact,
`be higher than that used in our study.” J.A. 4644.
`The district court found that those two references dis-
`close each and every limitation of the challenged IBS-D
`claims, and further found that a skilled artisan would have
`been motivated to combine those two references to arrive
`at what is claimed with a reasonable expectation of success.
`Decision at *17, *19–20. The court then concluded that the
`challenged IBS-D claims were invalid as obvious. Id. at
`
`
`1 ClinicalTrials.gov, History of Changes for Study:
`NCT00269412, Randomized, Double Blind, Placebo-Con-
`trolled Study to Assess the Efficacy and Safety of Three Dif-
`ferent Doses of Rifaximin Administered BID either Two or
`Four Weeks in the Treatment of Patients with Diarrhea-As-
`sociated Irritable Bowel Syndrome (December 22, 2005);
`J.A. 7047–55.
`2 M. Pimentel et al., The Effect of a Nonabsorbed
`Oral Antibiotic (Rifaximin) on the Symptoms of the Irrita-
`ble Bowel Syndrome, 145 ANN. INTERN. MED., 557 (2006);
`J.A. 4639–46.
`3 Salix did not argue a difference between a motiva-
`tion to use rifaximin to treat IBS versus IBS-D. Decision
`at *19 n.3. It concedes on appeal that “[r]oughly one-third
`of IBS patients suffer from IBS-D,” Appellants’ Br. at 6,
`and has not otherwise suggested that treatments for IBS
`would not inform treatments of IBS-D.
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`SALIX PHARMACEUTICALS, LTD. v.
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`*17–22. Salix appeals, asserting that the court erred in
`finding that a skilled artisan would have had a reasonable
`expectation of success in using the claimed 1,650 mg/day
`dosage to treat IBS-D. Appellants’ Br. at 39–48. Whether
`or not there would have been a reasonable expectation of
`success is a question of fact, IXI IP, LLC v. Samsung Elecs.
`Co., 903 F.3d 1257, 1262 (Fed. Cir. 2018), which we review
`for clear error, Hospira, 946 F.3d at 1328.
`Salix does not appear to dispute the district court’s
`finding that the Protocol and Pimentel “disclose all limita-
`tions of the IBS-D claims.” See Decision at *17. Rather, it
`contends that even if the asserted combination of refer-
`ences effectively discloses the claimed 1,650 mg/day dos-
`age, there remains insufficient evidence to support a
`finding of a reasonable expectation of success in using that
`particular dosage amount. See, e.g., Appellants’ Br. at 39–
`40. According to Salix, the highest prior art dosage amount
`that could have been supported with a reasonable expecta-
`tion of success was the 1,200 mg/day dose evaluated by Pi-
`mentel. Id. at 40. We disagree.
`The Protocol provides an outline of a planned Phase II
`clinical trial in which “three different doses (275, 550 and
`1100 mg) of rifaximin” were to be “administered BID [i.e.,
`twice-daily] for either two or four weeks in the treatment
`of patients with diarrhea-associated irritable bowel syn-
`drome.” J.A. 7050 (cleaned up). As an outline of that clin-
`ical trial plan, the Protocol provides only that those three
`specific, twice-daily dosage regimens were to be investi-
`gated for either two or four weeks. The Protocol does not
`include any efficacy or safety data, nor does it mention a
`1,650 mg/day dose or TID dosing.
`Although we have rejected the idea that “efficacy data
`[are] always required for a reasonable expectation of suc-
`cess,” OSI Pharms., LLC v. Apotex Inc., 939 F.3d 1375,
`1385 (Fed. Cir. 2019), we are hesitant to conclude as a gen-
`eral matter that the disclosure of a Phase II clinical trial
`
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`SALIX PHARMACEUTICALS, LTD. v.
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`plan, standing alone, provides an expectation of success
`sufficient to render obvious a dosage that was not included
`within the planned clinical trial. See Appellants’ Reply Br.
`at 13−14. But the Protocol was not asserted alone; it was
`asserted in combination with Pimentel.
`Pimentel teaches that administration of 400 mg rifaxi-
`min, TID (1,200 mg/day), “resulted in greater improvement
`in IBS symptoms” and “lower bloating score[s] after treat-
`ment.” J.A. 4639; see also id. at 4642–43 (providing sup-
`porting data). Pimentel explains that the 400 mg TID
`regimen was chosen “on the basis of a previous study that
`demonstrated the efficacy of rifaximin in bacterial over-
`growth.” Id. at 4640. However, Pimentel does not merely
`provide that daily rifaximin doses of 1,200 mg were likely
`to be successful in the treatment of IBS. Pimentel further
`teaches that “[r]ecent data suggest that the optimal dosage
`of rifaximin may, in fact, be higher than that used in our
`study.” J.A. 4644; Decision at *20 (emphases added).
`The district court did not clearly err in finding that a
`skilled artisan would have looked to both of those refer-
`ences, considered their limits, and had a reasonable expec-
`tation of success as to the efficacy of 550 mg TID dosing.
`The combined message that the skilled artisan would have
`discerned from the Protocol and Pimentel is that the opti-
`mal dosage for treating patients suffering from IBS disor-
`ders may be higher than 400 mg TID, and the next higher
`dosage unit from the Protocol was 550 mg. We see no clear
`error in the conclusion that there would have been a rea-
`sonable expectation of success in administering the
`claimed 1,650 mg/day to IBS-D patients. Indeed, certainty
`and absolute predictability are not required to establish a
`reasonable expectation of success. See Almirall, LLC v.
`Amneal Pharms. LLC, 28 F.4th 265, 275 (Fed. Cir. 2022)
`(“A finding of a reasonable expectation of success does not
`require absolute predictability of success.”); Acorda Thera-
`peutics, Inc. v. Roxane Lab’ys, Inc., 903 F.3d 1310, 1333
`(Fed. Cir. 2018) (“This court has
`long rejected a
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`SALIX PHARMACEUTICALS, LTD. v.
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`requirement of conclusive proof of efficacy for obviousness.”
`(cleaned up)).
`Moreover, references establishing the background
`knowledge of a person of ordinary skill in the art are con-
`sistent with the reasonable expectation of success provided
`by the combination of the Protocol with Pimentel. For ex-
`ample, Cuoco4 teaches the efficacy of 1,200 mg rifaxi-
`min/day for 14 days for the treatment of small intestinal
`bacterial overgrowth (“SIBO”). J.A. 4533. Salix has
`acknowledged that those of ordinary skill in the art identi-
`fied “bacterial alterations” as a potential underlying cause
`for IBS, Appellants’ Br. at 7, and the literature5 describes
`SIBO as a condition that is “highly prevalent in patients
`with irritable bowel syndrome (IBS),” such that “SIBO de-
`contamination is associated [with] a significant improve-
`ment of IBS symptoms.” J.A. 4664. We therefore agree
`with the district court that references describing the treat-
`ment of SIBO would have been pertinent to the skilled ar-
`tisan’s considerations as to what treatments would have a
`potential for success in treating individuals suffering from
`IBS.
`In addition to Cuoco, Lauritano6 teaches an increase in
`rifaximin efficacy for the treatment of SIBO as doses were
`increased from 600 mg/day to 1,200 mg/day, providing the
`
`4 L. Cuoco & M. Salvagnini, Small intestine bacterial
`overgrowth in irritable bowel syndrome: a retrospective
`study with rifaximin, 52 MINERVA GASTROENTEROL.
`DIETOL. (2006) 89; J.A. 4533–39.
`5 E. Scarpellini et al., High dosage rifaximin for the
`intestinal bacterial overgrowth,
`treatment of small
`25 ALIMENT. PHARMACOL. THER. 781 (2007); J.A. 4663−67
`(“Scarpellini”).
`6 E.C. Lauritano et al., Rifaximin dose-finding study
`for the treatment of small intestinal bacterial overgrowth,
`22 ALIMENT. PHARMACOL. THER., 31 (2005); J.A. 7267−71.
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`trend that Pimentel described as indicating that doses
`higher than 1,200 mg/day may be even more optimal for
`the treatment of IBS. J.A. 7267 (“Higher doses of rifaximin
`lead to a significant gain in terms of therapeutic efficacy in
`[SIBO] eradication without increasing the incidence of
`side-effects.”); see also id. at 4644. As evidenced by Scar-
`pellini and Lin,7 those in the art advanced on those find-
`ings, and subsequently evaluated higher doses. For
`example, Scarpellini reported that a 1,600 mg/day dose
`“showed a significantly higher efficacy” compared with
`1,200 mg/day for the treatment of SIBO. J.A. 4663; see also
`id. at 4666 (Table 1, noting study patients included those
`suffering from IBS-D); id. at 4747 (teaching that “[a]bout
`400 to about 600 mg of rifaximin may be administered TID
`for about 10 days” (i.e., 1,200 mg/day to 1,800 mg/day) for
`the eradication of bacterial overgrowth).
`The record further supports the finding that there
`would have been a reasonable expectation of success in ad-
`ministering higher doses of rifaximin without an intolera-
`ble increase in negative side effects. For example, Cuoco
`teaches that rifaximin was understood as having “a low
`risk of causing microbial resistance,” J.A. 4533, and that
`rifaximin was well known for its “profile of tolerability and
`safety widely described in the literature,” id. at 4538. Scar-
`pellini further reported that the 1,600 mg/day dose pro-
`vided a “similar compliance and side-effect profile”
`compared with the 1,200 mg/day dose. Id. at 4663. As the
`district court noted, the “[w]idespread off-label use” of
`rifaximin also supported the conclusion that rifaximin was
`safe and effective “for the treatment of IBS-D with a rea-
`sonable expectation of success.” Decision at *19; see also
`Appellants’ Br. at 17 (“There is no dispute that skilled
`
`
`International Patent Application Publication
`7
`2006/102536; J.A. 4721–47.
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`artisans knew of the general concept of trying off-label use
`of rifaximin to treat IBS-D.”).
`In view of the record before us, we see no clear error in
`the finding that a skilled artisan would have had a reason-
`able expectation of success in administering the claimed
`1,650 mg/day regimen for the treatment of IBS-D. We
`therefore affirm the district court’s holding that the chal-
`lenged IBS-D claims would have been obvious over the
`cited references. See In re Applied Materials, Inc., 692 F.3d
`1289, 1295 (Fed. Cir. 2012) (“[W]here the general condi-
`tions of a claim are disclosed in the prior art, it is not in-
`ventive to discover the optimum or workable ranges by
`routine experimentation.” (citation omitted)).
`Salix further contends that a Press Release8 issued by
`Salix in a filing with the Securities and Exchange Commis-
`sion less than a year before the patents’ priority date was
`not prior art because Norwich failed to establish that it was
`“by others” as required by pre-AIA 35 U.S.C. § 102(a). Ap-
`pellants’ Br. at 30−39. According to Salix, the district
`court’s inclusion of that allegedly non-prior art reference in
`its discussion of the skilled artisan’s expectation of success
`was harmful error. Id.
`Although the district court cited the Press Release in
`its discussion of the skilled artisan’s expectations, it ulti-
`mately held that the “Protocol and Pimentel [] disclose all
`limitations of the IBS-D claims” and that a skilled artisan
`“would have been motivated to combine the . . . Protocol
`and Pimentel [] with a reasonable expectation of success.”
`Decision at *17. We therefore need not decide whether or
`not the Press Release was prior art because, even assuming
`that it was not, the Protocol and Pimentel alone estab-
`lished the obviousness of the claims.
`
`
`8 Salix Pharms., Ltd., Current Report (Form 8-K)
`(Sept. 5, 2007); J.A. 7477–82.
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`SALIX PHARMACEUTICALS, LTD. v.
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`We accordingly affirm the district court’s determina-
`tion that Norwich established that the IBS-D claims would
`have been obvious in view of the Protocol and Pimentel.
`II
`We next turn to Salix’s contention that the district
`court clearly erred in finding that there would have been a
`reasonable expectation of success in obtaining the rifaxi-
`min form β recited in the polymorph patents’ claims.
`Whether or not there would have been a reasonable ex-
`pectation of success is a question of fact, IXI IP, LLC v.
`Samsung Elecs. Co., 903 F.3d 1257, 1262 (Fed. Cir. 2018),
`which we review for clear error, Hospira, 946 F.3d at 1328.
`We review the ultimate conclusion of obviousness de novo.
`Id.
`
`The polymorph patents are directed to rifaximin form
`β. For example, claim 4 of the ’199 patent recites:
`4. Rifaximin in polymorphic form β, wherein the
`rifaximin has x-ray powder diffraction pattern
`peaks at about 5.4°; 9.0°; and 20.9°2θ and wherein
`the rifaximin has a water content of greater than
`5%.
`’199 patent, col. 10 ll. 24–27; see also ’206 patent, col. 11 ll.
`33–37, 41–43 (claims 34 & 36, similar).
`Norwich challenged the polymorph claims’ validity by
`asserting, inter alia, Cannata,9 which discloses that rifaxi-
`min exists in crystalline form with “outstanding antibacte-
`rial properties.” J.A. 4528; Decision at *6. Cannata does
`not discuss rifaximin’s crystal structure in detail, but it
`does disclose several preparation protocols for rifaximin
`that include solvents used for crystallization. J.A. 4529–
`31; see also id. at 3408.
`
`
`9 U.S. Patent 4,557,866; J.A. 4526−32.
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`The district court held that expert testimony supported
`a conclusion that, in view of the prior art, (1) a skilled arti-
`san would have had good reason to characterize the crys-
`talline rifaximin obtained by following the Cannata
`protocols, (2) that such characterization was routine and
`could have been performed “in one day,” and (3) that doing
`so would have led the skilled artisan to have “detected
`rifaximin β.” Decision at *6–7. The district court subse-
`quently concluded that the challenged polymorph claims
`would have been obvious over the asserted prior art in view
`of the common knowledge of the skilled artisan. Id. at *7–
`8.
`
`Salix first challenges the district court’s conclusion of
`obviousness by asserting that Grunenthal GMBH v. Alkem
`Laboratories Ltd., 919 F.3d 1333 (Fed. Cir. 2019) and Phar-
`macyclics LLC v. Alvogen, Inc., No. 2021-2270, 2022 WL
`16943006 (Fed. Cir. Nov. 15, 2022) compel the opposite re-
`sult. Appellants’ Br. at 49–51. Salix further contends that
`the court “applied the wrong test” by not following a ra-
`tionale provided in the district court opinion from Pharma-
`cyclics. Id. at 55–57. We disagree.
`In Grunenthal, we held that it was not clear error for
`the district court to find that the record failed to establish
`by clear and convincing evidence a reasonable expectation
`of success in preparing the claimed polymorphic Form A of
`tapentadol hydrochloride. See 919 F.3d at 1341. In that
`case, the synthesis of tapentadol hydrochloride known in
`the prior art produced a particular form—Form B. Id. The
`district court found that there was a lack of evidence that
`a prior art synthesis would have resulted in the claimed
`Form A and that no prior art guidance existed to establish
`“what particular solvents, temperatures, agitation rates,
`etc., were likely to result” in the claimed polymorph. Id. at
`1343. We found no clear error in that analysis. Id. at
`1344–45.
`
`

`

`Case: 22-2153 Document: 71 Page: 14 Filed: 04/11/2024
`
`14
`
`SALIX PHARMACEUTICALS, LTD. v.
`NORWICH PHARMACEUTICALS INC.
`
`We also affirmed a conclusion of non-obviousness of a
`claimed polymorph in our non-precedential Pharmacyclics
`decision, which issued after the district court released its
`decision in this case. See 2022 WL 16943006, at *10–11.
`But the court here acted within its discretion when it de-
`clined to follow the district court decision in Pharmacyclics
`as though it was binding precedent. See Decision at *7 n.1
`(“Plaintiffs call to my attention [the district court’s decision
`in] Pharmacyclics LLC v. Alvogen Pine Brook LLC. I have
`considered that case but I do not agree with it on this
`point.”). And our later affirmance of the factual findings in
`Pharmacyclics did not retroactively override the district
`court’s analysis here.
`Moreover, a lack of clear error in Grunenthal and Phar-
`macyclics does not compel a conclusion of non-obviousness
`here. Indeed, Grunenthal underscored the factual nature
`of these types of inquiries and expressly held that it did
`“not rule out the possibility that polymorph patents could
`be found obvious.” 919 F.3d at 1344–45. “The determina-
`tion of obviousness is dependent on the facts of each case.”
`Sanofi-Synthelabo v. Apotex, Inc., 550 F.3d 1075, 1089
`(Fed. Cir. 2008); see also Pfizer, Inc. v. Apotex, Inc.,
`480 F.3d 1348, 1366 (Fed. Cir. 2007). In Grunenthal and
`Pharmacyclics, the issue was whether a skilled artisan
`would have had a reasonable expectation of success in pro-
`ducing a crystalline form of a compound. See 919 F.3d at
`1341–43; 2022 WL 16943006, at *10–11. Here, the prior
`art included a process to produce a crystalline form of rifax-
`imin, and the dispute centered around characterizing the
`crystalline form resulting from that process. See Decision
`at *13–14. These distinct factual predicates support the
`district courts’ factual findings in each of these three cases
`under the clear error standard of review.
`In Graham v. John Deere Co. of Kansas City, 383 U.S.
`1 (1966), the Supreme Court set forth the background
`against which obviousness is to be assessed: “Under § 103,
`the scope and content of the prior art are to be determined”
`
`

`

`Case: 22-2153 Document: 71 Page: 15 Filed: 04/11/2024
`
`SALIX PHARMACEUTICALS, LTD. v.
`NORWICH PHARMACEUTICALS INC.
`
`15
`
`and “differences between the prior art and the claims at
`issue are to be ascertained.” Id. at 17. The scope and con-
`tent of the prior art here includes preparations of crystal-
`line rifaximin, which expert testimony supports would
`have yielded the β form of rifaximin. Decision at *7; J.A.
`3391−92 (“[T]he as-synthesized form of rifaximin reported
`by Examples 1, 6, 7, and 9 [of Cannata] were necessarily
`rifaximin form Beta, because of the methods used, the sol-
`vent system used, and it was later confirmed by later work,
`including work from the named inventors.”); id. at 3408−09
`(similar testimony); id. at 3393−3404 (discussing the evi-
`dence of record that supports that conclusion); id. at
`4700−07, 4846−47, 5007−14 (providing supporting evidence
`for that conclusion). And the parties do not dispute that
`the methods for characterizing the resulting crystalline
`rifaximin were well known and readily available to the
`skilled artisan. Decision at *3. The difference between the
`prior art and the claims is thus effectively nothing more
`than the performance of routine characterization to iden-
`tify the polymorphic forms that result from the known Can-
`nata processes.
`In this regard, Salix does not appear to dispute that
`there would have been a motivation to explore potential
`polymorphic forms of rifaximin. Appellants’ Br. at 48–49.
`Rifaximin was, after all, a known compound with a known,
`useful activity. Salix further refers to the district court’s
`finding that “polymorph β is a commonly produced poly-
`morph and the most stable form of rifaximin” as an “undis-
`puted” fact. Id.; see also Decision at *7. There thus appears
`to be no dispute that the claimed polymorph can be readily
`produced from the crystallization conditions disclosed in
`Cannata and that it would have been well within the abil-
`ities of the skilled artisan to procure and characterize the
`β form of rifaximin.
`According to Salix, however, rifaximin’s β form consti-
`tuted a non-obvious invention because, although skilled ar-
`tisans
`“actually
`succeed[ed]”
`in
`producing
`and
`
`

`

`Case: 22-2153 Document: 71 Page: 16 Filed: 04/11/2024
`
`16
`
`SALIX PHARMACEUTICALS, LTD. v.
`NORWICH PHARMACEUTICALS INC.
`
`characterizing it, they would not have “expect[ed] to suc-
`ceed” because, as of the critical date, the polymorphic na-
`ture of rifaximin had not yet been reported and the identity
`of the β form remained undisclosed. Appellants’ Br. at 49.
`Salix further argues that there could have been no expec-
`tation of success because the skilled artisan would not have
`been able to predict what polymorphic forms might result
`from following the preparation protocols disclosed in the
`prior art. Id. at 20−21, 50−53. Salix’s framing of the issue
`suggests that no unknown entity could ever be obvious, as
`one cannot reasonably expect what was hitherto unknown,
`which is incorrect.
`Here, the district court found a reasonable expectation
`of success in characterizing the crystalline product of Can-
`nata for potential polymorphism using routine, conven-
`tional methods and skill. Decision at *6–7. We see no clear
`error in that conclusion. Indeed, Salix has done no more
`than combine known elements of the prior art to verify
`readily accessible information concerning a compound al-
`ready in the hands of those of ordinary skill in the art, and
`such routine efforts do not justify removing this polymorph
`from the public domain. See KSR Int’l Co. v. Teleflex Inc.,
`550 U.S. 398, 427 (2007); see also Pfizer, 480 F.3d at
`1367−68. To be sure, we do not hold that there is always a
`reasonable expectation of success in accessing or character-
`izing polymorphs. We are simply reviewing the district
`court’s decision before us as to its factual finding of a rea-
`sonable expectation of success, and in so doing, have not
`been left with a definite and firm conviction that a mistake
`was made in reaching that finding. See Scanner Techs.
`Corp. v. ICOS Vision Sys. Corp. N.V., 528 F.3d 1365, 1374
`(Fed. Cir. 2008).
`Having found no clear error in the district court’s fact
`findings as to the existence of a reasonable expectation of
`success, we affirm the court’s conclusion that the poly-
`morph patent claims were invalid as obvious. Because we
`affirm the court’s holding that the polymorph patent claims
`
`

`

`Case: 22-2153 Document: 71 Page: 17 Filed: 04/11/2024
`
`SALIX PHARMACEUTICALS, LTD. v.
`NORWICH PHARMACEUTICALS INC.
`
`17
`
`would have been obvious over the asserted prior art, we
`need not consider Norwich’s separate argument that the
`polymorph claims would have also been invalid as inher-
`ently anticipated.
`
`III
`On cross-appeal, Norwich raises two related but dis-
`tinct arguments that arose after the district court held that
`Norwich infringed the HE patents and failed to establish
`invalidity. See Decision at *10−16. Norwich first argues
`that, in issuing its final decision, the district court misin-
`terpreted 35 U.S.C. § 271(e)(4)(A), which directs a court,
`following a finding of infringement, to order the FDA to de-
`fer final approval of an ANDA until the expiration of the
`infringed patent. According to Norwich, that statute pre-
`cludes del