In Salix Pharmaceuticals. Ltd v. Norwich Pharmaceuticals Inc., [2022-2153, 2023-1952] (April 11, 2024), the Federal Circuit affirmed the district court determination 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 that those claims were invalid.

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. The FDA approved Xifaxan nearly 20
years later, in 2004, as 200 mg tablets for the treatment of travelers’ diarrhea. The FDA subsequently approved 550 mg tablets for hepatic encephalopathy in 2010 and for irritable bowel syndrome with diarrhea (“IBS-D”) in 2015.

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 patents. By the time of trial, the case had been streamlined to three groups of patents:

1. the ’573, ’195, and ’397 patents, directed to treating hepatic encephalopathy
2. the ’569 and ’667 patents, directed to treating irritable bowel syndrome with diarrhea with 550 mg rifaximin three times a day (1,650 mg/day) for 14 days; and,
3. the ’199 and ’206 patents, directed to rifaximin form β

Following a bench trial, the district court held that Norwich infringed the hepatic encephalopathy patents’ claims and had failed to establish their invalidity. Norwich did not appeal those holdings. The court also held that Norwich’s ANDA infringed the irritable bowel syndrome and polymorph patents, but that those patents’ claims would have been obvious
over the prior art. Salix appealed those invalidity holdings.

Norwich then amended its ANDA in an attempt to remove the infringing hepatic encephalopathy indication and moved to modify the judgment under Federal Rule of Civil Procedure 60(b), asserting that the amendment negated any possible infringement. The court denied Norwich’s motion, and Norwich cross-appealed.

Validity of the Irritable Bowel Syndrome Claims

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. Norwich challenged the IBS-D claims’ validity by asserting as prior art references a clinical trial protocol that had been published and a 2006 journal article by Pimentel. The Protocol described 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 irritable bowel syndrome. Pimentel taught administering 400 mg, TID (1,200 mg/day), for the treatment of irritable bowel syndrome but further opines that the “optimal dosage of rifaximin may, in fact, be higher than that used in our study.” The district court found that those two references disclose each and every limitation of the challenged irritable bowel syndrome 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.

Salix appealed, 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 irritable bowel syndrome. According to Salix, the highest prior art dosage amount
that could have been supported with a reasonable expectation of success was the 1,200 mg/day dose evaluated by Pimentel. The Federal Circuit disagreed, noting that while the Protocol alone might not support the reasonable expectation of success, in combination with Pimentel, which taught that “[r]ecent data suggest that the optimal dosage of rifaximin may, in fact, be higher than that used in our study,” it was not error for the district court to conclude that there was a reasonable expectation of success as to the efficacy of 550 mg TID dosing.

Validity of the rifaximin form β Claims

Norwich challenged the polymorph claims’ validity by asserting, inter alia, Cannata, which discloses that rifaximin exists in crystalline form with “outstanding antibacterial properties.”

The district court held that expert testimony supported a conclusion that, in view of the prior art, (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 noted that the scope and content of the prior art here includes preparations of crystalline rifaximin, which expert testimony supports would have yielded the β form of rifaximin. The difference between the prior art and the claims is thus effectively nothing more than the performance of routine characterization to identify the polymorphic forms that result from the known Cannata processes.

Salix argued that the rifaximin’s β form nonetheless constituted a non-obvious invention because, although skilled artisans actually succeeded in producing and characterizing it, they would not have expected to succeed because, as of the critical date, the polymorphic nature of rifaximin had not yet been reported and the identity of the β form remained undisclosed. Salix further argues that there could have been no expectation 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. The Federal Circuit disagreed, noting that Salix has done no more than combine known elements of the prior art to verify readily accessible information concerning a compound already 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.

The Federal Circuit noted that it was not holding that there is always a reasonable expectation of success in accessing or characterizing polymorphs. It was simply reviewing the district court’s decision before it as to its factual finding of a reasonable 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.

Norwich’s Cross Appeal

On cross-appeal, Norwich raises two related but distinct arguments that arose after the district court held that Norwich infringed the HE patents and failed to establish invalidity. Norwich first argues that the district court misinterpreted 35 U.S.C. § 271(e)(4)(A), which directs a court, following a finding of infringement, to order the FDA to defer final approval of an ANDA until the expiration of the infringed patent. According to Norwich, that statute precludes delaying final approval of an entire ANDA, and instead requires delaying only the approval of the infringing use.

The Federal Circuit said Section 271(e)(4)(A) instructs that, following a finding of infringement, “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 argued that the language of § 271(e)(4) requires courts to tie the restriction on FDA approval to the
indication for which the ANDA seeks approval when that indication was the source of infringement. The district court order concerned only the specific ANDA in question that included an infringing use, referred to the ANDA by its number, and enjoined the approval
of that ANDA.

Since the FDA does not approve drugs in the abstract, but rather approves drugs for particular uses (indications) of that drug, the statute is appropriately construed as directed to approval of particular infringing uses of the drug, not all uses of the drug including non-infringing uses. The statutory scheme makes clear that the relevant infringement is the submission of the ANDA that included an infringing use. That the ANDA further recited a non-patent-protected indication does not negate the infringement resulting from the ANDA’s submission. The order thus appropriately delayed the effective final approval date of “this
infringing ANDA” submission.

Norwich’s second argument arises from its decision to amend its ANDA to carve out the infringing HE use after final judgment. Following that amendment, Norwich filed a motion to modify the final judgment to allow for prompt approval of the amended ANDA that purportedly no longer sought approval for the infringing HE use. The district court denied that motion, holding that Norwich “fully litigated the merits of its non-infringement and invalidity case, lost, and now seeks a way around the final judgment through Rule 60(b).

The Federal Circuit said that a district court may reconsider its own finding of infringement
in light of an amended ANDA, but the court need not do so, and the Federal Circuit said that the court reasonably held that consideration of the amended ANDA would be inequitable
and inappropriate. The court noted that it 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 that what Norwich sought in its Rule 60(b) motion would essentially be a second litigation” following final judgment.

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