The Federal Circuit handed down an opinion last week that invalidated several asserted claims and found infringement under 35 U.S.C. § 271(e)(2) of the claims, while refusing to modify its judgment on infringement after Defendant Norwich submitted a revised ANDA containing a Section viii "carveout" in Salix Pharmaceuticals, Ltd. v. Norwich Pharmaceuticals Inc. The majority opinion raises issues in its invalidity analysis regarding the extent to which the prior art should be required to disclose the recited administered dose to satisfy the "reasonable expectation of success" prong for obviousness for pharmaceutical claims (wherein the standard adopted by the majority motivated Judge Cunningham to dissent in part). The reasoning provided by Judges Lourie and Chen appeared to be rooted in the broader scope of creativity imparted to the skilled artisan under KSR v. Teleflex as discussed below.

The case arose in ANDA litigation over rifaximin, the active ingredient in Salix's commercial product Xifaxan^®, which the opinion informs has been used as an antibiotic for 40 years. The use at issue was FDA-approved treatment of irritable bowel syndrome with diarrhea (IBS-D) and hepatic encephalopathy (HE), specified in each instance by treatment with 550 mg doses three times per day (TID) for a total of 1650 mg administered dose. Salix asserted three "groups" of patents:

• U.S. Patent Nos. 8,624,573, 9,421,195, and 10,335,397 directed to HE treatment;
• U.S. Patent Nos. 8,309,569 and 10,765,667 directed to treating IBS-D using the 550 mg TID administration protocol; and
• U.S. Patent Nos. 7,612,199 and 7,902,206 directed to rifaximin polymorph b

The District Court held* that claim 2 of U.S. Patent No. 8,309,569, claim 3 of U.S. Patent No. 10,765,667, claim 4 of U.S. Patent No. 7,612,199, and claim 36 of U.S. Patent No. 7,902,206 were obvious, and that claim 8 of U.S. Patent No. 8,642,573, claim 6 of U.S. Patent No. 9,421,195, and claims 11 and 12 of U.S. Patent No. 10,335,397 were not invalid and infringed, and entered judgment that the FDA not approve Norwich's ANDA for HE indications until the final patent in this group expired in October 2029. Norwich amended its ANDA to provide a Section viii "carveout" of indications related to HE treatment and filed a motion to modify the judgment under Fed. R. Civ. Pro. 60(b) which the District Court denied. This appeal by both parties of the adverse decisions below followed.

The Federal Circuit affirmed, in an opinion by Judge Lourie joined by Judge Chen in toto and by Judge Cunningham in part, who also dissented in part. Regarding obviousness of claims to IBS-D treatment, the opinion sets forth claim 2 of the '569 patent as being representative:

1. A method of providing acute treatment for diarrhea-associated Irritable Bowel Syndrome (dIBS) comprising: administering 1650 mg/day of rifaximin 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.

The District Court's decision was based on the combination of a Phase II clinical trial protocol disclosing twice-daily dosing of IBS patients with 550 mg doses (1100 mg total) or 1100 mg doses (2200 mg total) of rifaximin (the opinion noting that "the Protocol does not include any efficacy or safety data, nor does it mention a 1,650 mg/day dose or TID dosing"), taken in view of a scientific journal article to Pimentel that disclosed treating IBS with administration of 400 mg of rifaximin TID (for a total of 1,200 mg); significantly for the Federal Circuit's decision, this reference contained a speculative statement that "optimal dosage of rifaximin may, in fact, be higher than that used in our study." These references were used by the District Court to provide a motivation to combine them with a reasonable expectation of success, and the majority agreed (Judge Cunningham adducing here disagreement on this point in her dissent). Salix argued that the District Court erred in the reasonable expectation of success prong of this analysis, which as a question of fact required a showing of clear error on appeal. Curiously, Salix (according to the opinion) did not dispute the District Court's finding that all limitations of claims to IBS-D treatments were "effectively disclosed" in the cited art, despite there being no express disclosure of administering 550 mg rifaximin TID (for a total of 1650 mg) (other than the speculation in the scientific reference that higher doses may be optimal).

The Federal Circuit majority restricted the application of its conclusion that this prior art disclosure supports a finding that there is a reasonable expectation of success under these circumstances by asserting that:

Although we have rejected the idea that "efficacy data [are] always required for a reasonable expectation of success," OSI Pharms., LLC v. Apotex Inc., 939 F.3d 1375, 1385 (Fed. Cir. 2019), we are hesitant to conclude as a general matter that the disclosure of a Phase II clinical trial plan, standing alone, provides an expectation of success sufficient to render obvious a dosage that was not included within the planned clinical trial.

However, the majority distinguished the situation here by the combination of the clinical trial protocol with the Pimentel reference. For the majority, that speculative sentence, that "[r]ecent data suggest that the optimal dosage of rifaximin may, in fact, be higher than that used in our study" was sufficient to create in the skilled artisan sufficiently reasonable expectation of success to satisfy the requirement for finding obviousness (emphasis in opinion), at least in view of the clear error standard of review. The majority's reasoning was that Pimentel expressly disclosed 400 mg rifaximin TID and that "the next higher dosage unit from the Protocol was 550 mg" combined with the unsupported suggestion that higher doses may be optimal. This conclusion was supported in the majority's view by the Court's earlier precedent that "certainty and absolute predictability are not required to establish a reasonable expectation of success, citing Almirall, LLC v. Amneal Pharms. LLC and Acorda Therapeutics, Inc. v. Roxane Lab'ys, Inc. The majority also cited several "references establishing the background knowledge of a person of ordinary skill in the art" consistent with their finding of no clear error in the District Court's obviousness determination (although, as explicated in the dissent these references were not considered by the District Court). The majority appear to be satisfied that ex post facto verification of the skilled artisan's purported expectation of success using increased dosage amounts supports its reasonableness beforehand. The majority similarly uses this reasoning to credit the skilled artisan of apprehending that administering increased dosages would not create "an intolerable increase in negative side effects." And the majority also asserts that there had been "[w]idespread off-label use" of rifaximin for treating IBS-D that supported this safety expectation.

Similarly the Court (Judge Cunningham not dissenting from this aspect of the judgment) affirmed the District Court's determination that claims to the b-polymorph of rifaximin would have been obvious. Claim 4 of the '199 patent was set forth in the opinion as representative:

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%.

The prior art disclosed preparations of crystalline rifaximin (albeit not the b-polymorph expressly) and methods for preparing such crystalline forms including in particular solvents used to prepare them (it being recognized that in the arcane rituals of crystallization such solvent choice frequently determines the resulting crystalline product). The panel notes that the District Court's factual determinations supporting its obviousness conclusions were supported by expert testimony that "(1) a skilled artisan would have had good reason to characterize the crystalline 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.'" The Federal Circuit also distinguished prior precedent including Grunenthal GmBH v. Alkem Laboratories Ltd., 919 F.3d 1333 (Fed. Cir. 2019), and Pharmacyclics LLC v. Alvogen, Inc.; regarding Grunenthal, the panel asserts that the prior art produced one particular polymorph and that the art disclosed no evidentiary basis to expect that a second form would be produced using prior art guidance regarding "what particular solvents, temperatures, agitation rates, etc., were likely to result" in the claimed polymorphic form, which conclusion the Federal Circuit held was not clear error. The panel here maintained that this precedent merely showed the reliance on particular factual aspects involved in such decisions, citing Sanofi-Synthelabo v. Apotex, Inc. and Pfizer, Inc. v. Apotex, Inc. A particular distinction persuasive to the Court was that in Grunenthal there was a question of whether the skilled artisan could produce a crystalline form of the claimed compound, which was not the case here (the parties agreeing that methods for preparing crystalline rifaximin were established in the prior art, as well as there being an appreciation in the art that "polymorph β is a commonly produced polymorph and the most stable form of rifaximin"). While abjuring a conclusion that there would always be a reasonable expectation of success in producing the b-rifaximin polymorph the panel found no clear error in the District Court's fact finding here and thus affirmed.

(Regarding Pharmacyclics its status as a non-precedential decision put squarely within the District Court's discretion its decision not to follow its conclusions, as well as stating that the Court's "later affirmance of the factual findings in Pharmacyclics did not retroactively override the district court's analysis here.")

The panel assessed Norwich's appeal of the District Court's decision that, as a consequence of its ANDA constructively infringing Salix's claims to methods for treating HE it was correct in ordering that a final approval of Norwich's ANDA could not be effective before the HE patents expired under 35 U.S.C. § 271(e)(4)(A) as a question of statutory interpretation. In this regard, the opinion notes that the statute instructs that "the court shall order the effective date of any approval of the drug or veterinary biological product involved in the infringement to be a date which is not earlier than the date of the expiration of the patent which has been infringed." Norwich contended that this mandate includes the requirement that the order take into consideration (and is limited to) the indication for which an ANDA applicant seeks approval. The basis for this argument was that Norwich's original ANDA had indications for both HE and IBS-D and the District Court's infringement determination was limited to the HE indication. While Norwich voiced its concern that this Order would "unfairly precludes it from receiving final approval of a new non-infringing ANDA" the opinion flatly rejects this concern ("The district court did no such thing")(arguably thus receiving the Federal Circuit's imprimatur for any such filing of such an ANDA successfully). The statutory construction bases for this conclusion by the panel is that FDA approves drugs for specific and particular indications and thus proper construction is "directed to approval of particular infringing uses of the drug, not all uses of the drug including non-infringing uses." This limits the scope of infringement to submission of an ANDA to the infringing use under 35 U.S.C. § 271(e)(2)(A). But "[t]he order appropriately said nothing that would prevent approval of a new non-infringing ANDA."

Regarding the panel's affirmance of the District Court's denial of Norwich's Rule 60(b) motion, the Federal Circuit asserted that the question was whether that denial was an abuse of discretion under Third Circuit law, citing Amstar Corp. v. Envirotech Corp., 823 F.2d 1538, 1550 (Fed. Cir. 1987). The opinion states that a district court can reconsider its infringement finding when a defendant files an amended ANDA but is not compelled to do so, citing Ferring B.V. v. Watson Lab'ys, Inc. Fla. Here, the Federal Circuit appreciated that "[i]t is not a simple matter to determine whether an ANDA applicant has successfully carved out language from a label to turn infringement into non-infringement" and Norwich's motion would amount to "essentially" a second litigation. Because under Third Circuit law there is no obligation to grant such a motion the panel discerned no abuse of that discretion in this case.

Judge Cunningham's dissent was limited to the Court's affirmance that the asserted claims in the '569 and '667 patents were invalid for obviousness. In Judge Cunningham's opinion, Norwich has satisfied its burden to convince the Judge that she is "'left with the definite and firm conviction that a mistake has been committed' regarding these findings," citing Pfizer, Inc. v. Apotex, Inc. (quoting United States v. U.S. Gypsum Co., 333 U.S. 364, 395 (1948)). The basis of this conviction is the disconnect the Judge apprehends regarding the disclosure of the cited art (400 mg TID, 1200 mg/day in Pimentel or 550 mg BID or 1100 mg/day) and the scope of the claims (550 mg TID, 1650 mg/day). There is just a great a likelihood in the Judge's mind that the 1100 mg/day dose would have implied that higher doses would not lead to more successful results, inter alia because the tested 2200 mg/day dose did not. And the citations of the later-arising references don't cure these analytical deficiencies on the merits because they teach 1200 mg/day wherein the claimed invention recited dosages "almost 40% higher." Anecdotal reference to off-label use was also unavailing in the Judge's opinion to support the purported reasonable expectation of success because there was no disclosure of dosages therein. Requiring a correspondence between the recited dosages and the cited prior art is consistent with other Federal Circuit precedent including In re Cyclobenzaprine Hydrochloride Extended-Release Capsule Pat. Litig. and Ferring B.V. v. Watson Lab'ys, Inc.-Fla. The single sentence in the Pimentel reference also draws the Judge's attention, wherein "the lack of discussion of any actual dosage that may be optimal, the use of the word 'may,' and the fact that the RFIB 2001 Protocol discloses a specific dosing regimen of 2,200 mg/day rather than 1,650 mg/day all call into question the majority's finding" in Judge Cunningham's opinion. It has also not escaped the Judge's attention that this sentence was considered by the District Court for the motivation to combine requirement and not the reasonable expectation of success prong of the obviousness analysis. Finally, Judge Cunningham would decline to assess the significance and content of the after-arising art in the first instance, because none of this art provided any basis for the District Court's decision and thus had made no findings of fact regarding it, citing Golden Bridge Tech., Inc. v. Nokia, Inc., 527 F.3d 1318, 1323 (Fed. Cir. 2008). The first order of business for the district court on remand (if Judge Cunningham's views had prevailed) would be to consider the significance of this art, see, ACS Hosp. Sys., Inc. v. Montefiore Hosp., 732 F.2d 1572, 1578 (Fed. Cir. 1984).

* The totality of these claims at issue were:

U.S. Patent No. 8,309,569

2. A method of providing acute treatment for diarrhea-associated Irritable Bowel Syndrome (dIBS) comprising: administering 1650 mg/day of rifaximin 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, wherein the 1650 mg is administered as 550 mg three times per day.

U.S. Patent No. 10,765,667

3. A method of treating one or more symptoms of irritable bowel syndrome (IBS) in a subject 65 years of age or older, said method comprising administering, 550 mg of rifaximin TID for 14 days to the subject, thereby treating one or more symptoms of IBS in the subject 65 years of age or older, wherein the IBS is diarrhea-predominant IBS.

U.S. Patent No. 7,612,199

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%.

U.S. Patent No. 7,902,206

36. A solid pharmaceutical composition comprising rifaximin in polymorphic Form β and a pharmaceutically acceptable excipient or carrier, wherein the rifaximin Form β has x-ray powder diffraction pattern peaks at about 5.4°; 9.0°; and 20.9° 2-θ, wherein the rifaximin Form β has a water content of between about 4.5% to about 40%.

U.S. Patent No. 8,642,573

8. A method of maintaining remission of hepatic encephalopathy (HE) in a subject in need thereof comprising administering between about 1000 mg to about 1200 mg rifaximin daily to the subject for a period of 12 months or longer, thereby maintaining remission of HE, wherein remission is defined as a Conn score of 0 or 1.

U.S. Patent No. 9,421,195

6. A method of reducing the risk of hepatic encephalopathy (HE) recurrence in an adult subject in need thereof comprising:
orally administering between about 1000 mg to about 1200 mg of rifaximin daily to the adult subject for a period of 12 months or longer, thereby reducing the risk of hepatic encephalopathy (HE) recurrence,
comprising orally administering about 1100 mg of rifaximin per day to the adult subject,
and
orally administering about 550 mg of rifaximin twice daily to the adult subject.

U.S. Patent No. 10,335,397

11. A method of reducing a subject's risk of experiencing a breakthrough overt hepatic encephalopathy (HE) episode, comprising administering to the subject between about 1000 mg to about 1200 mg of rifaximin daily for a period of about 12 months or longer, wherein the subject has a Conn score of 0 or 1, wherein the rifaximin is administered orally, wherein 1100 mg of rifaximin is administered per day, and wherein 550 mg of rifaximin is administered twice daily.

12. A method of reducing a subject's risk of experiencing a breakthrough overt hepatic encephalopathy (HE) episode, comprising administering to the subject between about 1000 mg to about 1200 mg of rifaximin daily for a period of about 12 months or longer, wherein the subject has a Conn score of 0 or 1, further comprising administering lactulose.

In each instanced italics denotes independent claims from which the asserted claims depend.


Salix Pharmaceuticals, Ltd. v. Norwich Pharmaceuticals Inc. (Fed. Cir. 2024)
Panel: Circuit Judges Lourie, Chen, and Cunningham
Opinion by Circuit Judge Lourie; opinion dissenting-in-part by Circuit Judge Cunningham

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