The Federal Circuit held that a prima facie case of obviousness can be established by prior art ranges for solutions of structurally and functionally similar compounds that overlap with a claimed range in Valeant Pharmaceuticals International, Inc. v. Mylan Pharmaceuticals Inc. (Fed. Cir. April 8, 2020). Although it was well-established that a prima facie case of obviousness “typically exists when the ranges of a claimed composition overlap the ranges disclosed in the prior art,” this case extends that doctrine to instances where the cited prior art does not involve the same compound, but instead involves similar compounds.
If a range is claimed, the patent specification should contain sufficient support for the criticality of the claimed range, as well as support for narrower ranges, should amendment of the claims be needed to overcome the prior art. Demonstrating that a particular range is critical is generally achieved by showing that the claimed range achieves unexpected results relative to the prior art range, typically by test results. The showing of unexpected results should occur over the entire claimed range.
If the prior art is known prior to prosecution, the specification should also point out the differences in the structure between the compound subject to the range and the similar compounds addressed in the prior art. If the prior art is discovered during prosecution, the applicant can also submit an affidavit or declaration providing evidence of criticality and/or differences in structure between the compound that is the subject of the application and the compounds in the prior art.
A similar strategy can be used during litigation. The patent owner can, working with an expert, develop evidence of criticality and evidence that the structural difference between the disclosed compound and the prior art compounds results in unexpected beneficial properties. The patent challenger, of course, (again working with an expert) will want to demonstrate that the cited prior art discloses overlapping ranges involving compounds that are structurally and functionally similar to the compound involved in the challenged patent to establish a prima facie case of obviousness.
The District Court’s Determination
The asserted patent claimed stable methylnaltrexone pharmaceutical preparations, which can be used as an injectable drug to treat constipation as a side effect of taking opioid medication. Methylnaltrexone is unstable in aqueous solution. The inventors discovered that when the pH of a methylnaltrexone solution is adjusted, the percentage of total degradants drops significantly. Independent claim 1 disclosed “A stable pharmaceutical preparation comprising a solution of methylnaltrexone or a salt thereof, wherein the preparation comprises a pH between about 3.0 and about 4.0” Claim 8, dependent on claim 1, recites “[t]he pharmaceutical preparation of claim 1, wherein the preparation is stable to storage for 24 months at about room temperature.”
Mylan argued that claim 8 was obvious in light of three reference teaching formulations of either naloxone or naltrexone and in view of two treatises on pharmaceutical formulation, including one involving decomposition studies on naltrexone. The primary reference taught stable compositions of naloxone for injection with a pH of 3.0 to 3.5. Each of the three references “taught pH ranges that overlapped with the ‘about 3 to about 4’ range in claim 8, but those references detailed formulations of naloxone and naltrexone.” Mylan argued that the references established a prima facie case of obviousness because naloxone and naltrexone were structurally and functionally similar to methylnaltrexone.
The district court granted Valeant summary judgment that the asserted claim was not obvious, rejecting Mylan’s expert testimony and cited references as insufficient in large part because the references did not teach methylnaltrexone formulations but instead taught formulations of similar but different compounds, naloxone and naltrexone. The district court held that overlapping ranges only establish a prima facie case of obviousness when the only difference between the prior art is the “range or value of a particular variable.” The district court also rejected Mylan’s argument that the claimed pH range would have been obvious to try. The district court determined that there was not a finite number of options between pH 3 and 7 that a person of skill would try and that the evidence did not indicate that pH would be the first variable to be considered in improving stability. The district court also rejected Mylan’s assertion that long-term stability of methylnaltrexone was a predictable result of arriving at a pH range of 3 to 4.
The Federal Circuit’s Reversal of Summary Judgment
The Federal Circuit reversed the grant of summary judgment, finding that Mylan had established a prima facie case of obviousness, which “typically exists when the ranges of a claimed composition overlap the ranges disclosed in the prior art.” The pH range recited in claim 8 overlapped with the pH range in the cited prior art. Although none of the references disclosed the same drug as the one claimed, the Federal Circuit held that prior art ranges “for solutions of structurally and functionally similar compounds that overlap with a claimed range can establish a prima facie case of obviousness.” The Federal Circuit noted that its precedent “reflects an understanding that skilled artisans can expect structurally similar compounds to have similar properties” and that determinations of obviousness can rely on “prior art compounds with similar pharmacological utility….”
All three compounds at issue—naloxone, naltrexone, and methylnaltrexone—are well-known opioid antagonists that operate in the same manner and have very similar structures. The only structural difference between the molecules is the identity of the functional group attached to the nitrogen atom. “Because these three molecules bear significant structural and functionality similarity, and because the prior art of record teaches pH ranges that overlap with the pH range recited in claim 8, Mylan has at least raised a prima facie case of obviousness sufficient to survive summary judgment.” The Federal Circuit noted, however, that Valeant could rebut the prima facie case of obviousness by, for example, showing that the pH range was critical or that the difference in structure of methylnaltrexone results in unexpected beneficial properties.
With respect to Mylan’s obvious to try argument, the Federal Circuit held that the district court’s determination that there were an infinite number of pH ranges to try was inconsistent with precedent. There are a limited number of pH values between 3 and 4, and even if no reference listed pH as the “first variable” to alter, it was a reasonable inference that trying a pH of 3 to 4 would lead to a stable formulation at room temperature.
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