Salix Pharmaceuticals, Ltd. v. Norwich Pharmaceuticals Inc., No. 22-2153 (Fed. Cir. 2024)

“Schrödinger’s cat,” is a paradoxical thought experiment devised by physicist Erwin Schrödinger, while debating quantum superposition in 1935. Oversimplified, in the thought experiment, there is a cat in a box, and you have no way of knowing what physical state the cat is in, like a quantum wave function, until you open the box and observe it.

While studying polymorphic forms, like Schrödinger’s hypothetical [albeit a long stretch], you do not know what form a solid compound is until you measure it with x-ray crystallography. However, unlike Schrödinger’s hypothetical, you may have a reasonable expectation of succeeding to figure out what form your compound is depending on the prior art and knowledge of a person of ordinary skill.

Shifting from quantum to organic chemistry patent law, if there is a reasonable expectation of success in characterizing a known crystalline product for potential polymorphism using routine, conventional methods and skill, then a claim to that crystalline product would be invalid for obviousness. Such was the decision in Salix Pharmaceuticals, Ltd. v. Norwich Pharmaceuticals Inc., No. 22-2153 (Fed. Cir. 2024).

Salix claimed a specific crystalline form (form β) of rifaximin. The United States patent and Trademark Office (USPTO) granted Salix a patent on it.  However, when litigated, the United States Court of Appeals for the Federal Circuit (CAFC) affirmed the District Court of Delaware’s finding that Salix’s claims to rifaximin form β were invalid for obviousness.*

In other words, you cannot claim ownership of a compound just by making the expected crystalline form using someone else’s process and taking an x-ray crystal structure of it and giving a Greek letter name.

Background

• Salix markets Xifaxan® (rifaximin), and Norwich wanted to sell a generic version.
• Xifaxan® is a formulation of rifaximin crystalline form β.
  • Polymorph β is a commonly produced polymorph.
  • Polymorph β the most stable form of rifaximin.
• Disputed patent claims: Claim 4 of U.S. Patent No. 7,612,199 and Claim 36 of U.S. Patent No. 7,902,206.
  • Claim 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%.
• Prior art: Cannata et al. U.S. Patent No. 4,557,866.
  • Although Cannata does not discuss rifaximin’s crystal structure in detail, it does disclose several preparation protocols for rifaximin that include solvents used for crystallization.
  • Experts testified that Cannata’s preparation of crystalline Rifaximin would have yielded its β form. But they could not say it would every time.
• Rifaximin was a known compound with a known, useful activity (antibiotic).
  • While rifaximin was a known antibiotic, Salix owns rights to patents covering new method of use (hepatic encephalopathy). Salix won on appeal for such method-of-use claims.
• Experts testified that Cannata’s preparation of crystalline rifaximin would have easily made and taken an X-Ray diffraction pattern to determine that rifaximin was in its β form.
  • The experts could not convince the judge that the prior art process would produce rifaximin form β “every time.” If they could, then Salix’s claims would have been anticipated (not novel) as inherently present in the prior art.^‡
  • Although the experts could not convince the judge of the certainty of form β (novelty), they at least convinced the judge that form β was reasonably expected (obviousness).

CAFC Opinion Discussion

The CAFC decided that “the district court found a reasonable expectation of success in characterizing the crystalline product of Cannata for potential polymorphism using routine, conventional methods and skill [Salix Pharm., Ltd. v. Norwich Pharm., Inc., Civil Action No. 20-cv-430-RGA, (D. Del. Apr. 29, 2021), 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 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. See KSR Int’l Co. v. Teleflex Inc., 550 U.S. 398, 427 (2007); see also Pfizer, 480 F.3d at 1367−68.”

The District Court supported its factual determinations of obviousness with expert testimony that:

Salix argued that a person of ordinary skill in the art would not have “expect[ed] 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. They further argue that a skilled artisan would not have been able to predict which polymorphic form Cannata made. This argument was flawed. The CAFC states that Salix’s is incorrect in framing of the issue, as it suggests that no unknown entity could ever be obvious, as one cannot reasonably expect what was hitherto unknown.

* In the same appeal, The CAFC did affirm the District Court’s finding that Salix’s other claims to methods of treating hepatic encephalopathy were valid and nonobvious.

† Whether or not there would have been a reasonable expectation of success is a question of fact. “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. We review the ultimate conclusion of obviousness de novo.” Did the Justices themselves believe that the claims were obvious? Unknown. The CAFC perhaps equivocated or sidestepped the question. The justices did not say that they themselves believe that the polymorph claims were obvious. Rather, they merely said that they found no clear error in the District Court’s finding of obviousness. 

‡ The CAFC did not opine on whether or not the polymorph claims were invalid for being inherently anticipated (§102). The court said that they did not need to go that far since they already determined that the claims were invalid for obviousness (§103). The district court said that the polymorph claims were not anticipated as being inherent because Norwich did not prove with clear and convincing evidence that the prior art method would produce rifaximin form β “every time.” The inherency issue may deserve its own post. Question for discussion: Does the “every time” requirement go too high for “clear and “convincing evidence?” Perhaps requiring a specific result Every time may go up to the realm of “beyond a reasonable doubt,” which is not the level of burden of proof for patent law. Recall last year’s discussion of the Amgen case where there were arguments about how many examples enable the “full scope” of a claim. Stay tuned.

Additional Information

OrganicPatents.com page on Obviousness of Stereoisomers &Purified Compounds

See also PatentDocs’s post: https://www.jdsupra.com/legalnews/salix-pharmaceuticals-ltd-v-norwich-3362384/.

May 8, 2024