Salix Pharms., Ltd. v. Norwich Pharms., Inc.

Xifaxan® (rifaximin)

August 10, 2022

GENERICally Speaking

Case Name: Salix Pharms., Ltd. v. Norwich Pharms., Inc., C.A. No. 20-cv-430-RGA, 2022 WL 3225381 (D. Del. Aug. 10, 2022) (Andrews, J.) 

Drug Product and Patent(s)-in-Suit: Xifaxan® (rifaximin); U.S. Patents Nos. 7,612,199 (“the ’199 patent”), 7,902,206 (“the ’206 patents”) (together, the ’199 and ’206 patents are referred to as the “Polymorph Patents”), 8,642,573 (“the ’573 patent”), 9,421,195 (“the ’195 patent”), 10,335,397 (“the ’397 patents”) (together, the ’573, ’195, and ’397 patents are referred to as the “HE Patents”), 8,309,569 (“the ’569 patent”), and 10,765,667 (“the ’667 patent”) (together, the ’569 and ’667 patents are referred to as the “IBS-D Patents”)

Nature of the Case and Issue(s) Presented: Norwich submitted an ANDA to the FDA for approval to market generic rifaximin. Salix filed suit alleging infringement under § 271(e)(2)(A). Norwich countersued alleging that the asserted claims were invalid. In 2004, FDA approved Xifaxan 200 mg tablets to treat travelers’ diarrhea. On March 24, 2010, the FDA approved Xifaxan 550 mg tablets to reduce the risk of overt hepatic encephalopathy (“HE”) recurrence in adults. On May 27, 2015, the 550 mg tablets were approved to treat irritable bowel syndrome with diarrhea (“IBS-D”) in adults. The asserted patents cover a polymorphic form of rifaximin and methods of treating HE and IBS-D in adults. After a found-day bench trial, the court found that Norwich’s ANDA will induce infringement of the HE, IBS-D, and Polymorph patent claims. The HE claims are nonobvious and Norwich has failed to show a lack of adequate written description. The asserted Polymorph and IBS-D claims are invalid as obvious.

Why Salix Prevailed: The Polymorph Patents. Norwich stipulated to infringement. It raised multiple arguments of invalidity: inherent anticipation, obviousness, and lack of adequate written description.

Norwich argued that the Cannata reference inherently anticipated claim 4 of the ’199 patent because it discloses a process that necessarily produces the claimed rifaximin β. Norwich could have shown anticipation either because (i) as a law of nature, rifaximin α, δ, and ϵ cannot exist without having been derived from rifaximin β, or (ii) a method disclosed in Cannata produces rifaximin β each and every time it is practiced. The court found that Norwich’s expert did not prove either by clear and convincing evidence. “Ultimately, it appears that Cannata left certain steps up to the discretion of the chemist preparing the rifaximin. To show that Cannata invariably produces rifaximin β, Norwich would have needed to show that, no matter how the chemist exercised his or her discretion, rifaximin β would be produced. I do not think Norwich has done so.”

Next, Norwich argued that the Polymorph Patents were obvious. The court held that the evidence is clear and convincing that a POSA would have been motivated to characterize the rifaximin produced by the Cannata processes. Cannata disclosed that rifaximin had strong antibacterial properties and low bioavailability, motivating a POSA to evaluate the substance as a potential drug candidate. Additionally, the evidence showed that a POSA would have a reasonable expectation of success in characterizing the polymorph β, as opposed to the other forms of rifaximin. “Although Norwich’s evidence failed to show that β was produced each and every time rifaximin was prepared according to Cannata, it did strongly suggest that polymorph β is a commonly produced polymorph and the most stable form of rifaximin.

Finally, the court rejected Norwich’s lack of adequate description argument. The asserted claims describe rifaximin β as having XRPD peaks “at about 5.4°, 9.0°, and 20.9° 2θ.” The specification states that rifaximin β is “characterized ... by a powder X-ray diffractogram (reported in FIG. 2) which shows peaks at the values of the diffraction angles 2θ of 5.4°; 6.4°; 7.0°; 7.8°; 9.0°; 10.4°; 13.1°; 14.4°; 17.1°; 17.90°; 18.30°; 20.9°.” The evidence shows that a subset of XRPD peaks can identify the polymorph. The “normal practice at the USPTO” is to claim a polymorphic form using “at least three powder diffraction pattern peaks,” which was accomplished here.

The HE Patents. HE is a liver disease that affects the brain. For patients with HE, the liver does not properly filter toxins from the blood. These toxins can cause changes to the patient’s mental state. In addressing infringement, the court found that it was more likely than not that Norwich’s label will encourage the drug’s administration for 12 months or longer in at least some patients, and that Norwich knows and specifically intends for this period of administration. HE is chronic. It must be managed until the patient gets a liver transplant or dies. The label described a study in which some patients used the product for 12 months or longer. The label also instructed as “maintaining remission of HE” as required by the asserted claims because the drug is indicated for the “reduction in risk of overt hepatic encephalopathy (HE) recurrence in adults.” Norwich’s label will also more likely than not induce use of rifaximin in patients with a Conn score of 0 or 1. The label encourages use to prevent an overt HE recurrence, which the Court has found means maintaining remission. The evidence showed that patients in remission of HE have a Conn score of 0 or 1. Norwich’s label encouraged co-administration with lactulose because in the Indications and the Clinical Studies section, the label notes that 91% of patients took rifaximin and lactulose concomitantly, and that lactulose did not alter the treatment effect of rifaximin. Finally, Norwich argued that its ANDA product has substantial non-infringing uses because most HE patients live less than 12 months after their first overt HE episode. Thus, a substantial number of patients taking Norwich’s ANDA as directed will not take rifaximin for 12 months or more, and these uses will not meet the 12-month-or-more claim limitation. But this is an off-label use and does not negate the teachings of the label.

In furtherance of its obviousness defense, Norwich argued that as of 2008, it was widely known that rifaximin was safe and effective for treating HE. Rifaximin was indicated abroad for HE in 2000. In 2004, the FDA approved Xifaxan for traveler’s diarrhea. From that time, there is evidence of widespread off-label use of Xifaxan by physicians to treat patients with HE. Market research conducted by Salix shows that, by January 2007, 77% of physicians who treated HE patients had prescribed Xifaxan for HE. But the Court did not adopt Norwich’s prior art combinations. It rejected combinations using “common knowledge” because a POSA would not have a reasoned basis to resort to the “common sense” that rifaximin could be used for 12 months or longer. Many of the sources Norwich relies upon to show long-term administration are not prior art and therefore were no in the common knowledge of the field.

The IBS-D Patents. The Court found that Norwich’s ANDA label induced administration to patients who are 65 years and older on the basis that the drug is indicated for “adults.” It also induced infringement of a 12-week adequate relief limitation because following the medication guide will induce such a response in at least some patients.

Prior to February 2008, there was widespread off-label use of Xifaxan to treat IBS in the United States. As of January 2008, 74% of gastroenterologists polled by Salix had prescribed Xifaxan for IBS. The prior art also discussed using rifaximin to treat IBS. The Court found that two prior art references in combination rendered the asserted claims obvious. Pimentel 2006 administered rifaximin, 400 mg TID for 10 days, to treat IBS patients aged 18-65. Pimentel 2006 taught, “rifaximin resulted in statistically greater global improvement in IBS than placebo,” and “Improvements were sustained through 10 weeks of follow-up” after 10 days of treatment. The “RFIB 2001 Protocol” was a Phase II trial designed to administer rifaximin to patients aged 18 and over, 550-2,220 mg per day for 14 days for the treatment of IBS-D. The protocol included the outcome measures of providing adequate relief of symptoms and evaluating a durability of response over a 12-week post-treatment period. Salix attacked these references by arguing there would be no motivation to combine or an expectation of success. But “obviousness does not require perfect evidence, however, and the available evidence persuaded a significant number of doctors who would have been qualified as POSAs to use rifaximin to treat IBS.”

Regarding secondary considerations, the Court found that evidence of skepticism is not as powerful when the skepticism is expressed by a source unfamiliar with the “prior art references that laid the groundwork for the inventors’ experiments.” “Ultimately, Salix has shown a small amount of skepticism but not enough to change the outcome of the obviousness analysis.”

Oren D. Langer


Managing Partner, New York Office

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