Mylan Pharmaceuticals Inc. and others ("Mylan") appealed from the District Court's grant of summary judgment that claim 8 of U.S. Patent 8,552,025 owned by Valeant Pharm. Int'l, Inc.was not invalid. Valeant Pharm. Int'l, Inc. v. Mylan Pharm., Inc., No. 2:15-cv-08180 (SRC), 2018 WL 2023537 (D.N.J. May 1, 2018). The Court of Appeals for the Federal Circuit ("the Court") reversed the decision of the district court.

The '025 patent claims stable methylnaltrexone pharmaceutical preparations. Methylnaltrexone, a quaternary amine opioid antagonist derivative, is useful for reducing side effects of opioids but is unstable in aqueous solution. The inventors discovered that when the pH of a methylnaltrexone solution is adjusted to about 3.0-3.5, the percentage of total degradants dropped significantly.

Claim 1 of the '025 patent reads: 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 of the '025 patent reads: The 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 invalid as being obvious over solutions with overlapping pH values of similar antiopioids. Valeant moved for summary judgment that claim 8 would not have been obvious, and the district court granted Valeant's motion. The court noted that the references did not teach methylnaltrexone formulations but instead formulations of similar but different compounds, naloxone and naltrexone, and that there was nothing in the record suggesting that a pH of 3–4, "without added stabilizers," was associated with 24-month stability for injectable pharmaceutical solutions.

Mylan argued that a person of skill in the art would have been motivated to prepare and would have arrived at the preparation of claim 8 via routine optimization of the pH, because the references relied upon by Mylan each taught pH ranges that overlapped with the "about 3 to about 4" range in claim 8. Even if the references detailed formulations of naloxone and naltrexone, they "still established a prima facie case of obviousness because naloxone and naltrexone were structurally and functionally similar to methylnaltrexone." Mylan also argued that the pH range in the claim would have been obvious to try. The district court disagreed, because none of the references taught methylnaltrexone formulations and because the overlapping ranges only establish a prima case of obviousness when the only difference between the prior art is the "range or value of a particular variable."

The district court expressly rejected Mylan's view that the range was just one of a finite number of options between pH 3 and 7 that a person of skill would try. "[T]he evidence did not support that 'adjusting pH would be the first variable formulators [one] would consider to improve stability.'" The district court further rejected that "long-term stability of methylnaltrexone was a predictable result of arriving at a pH range of 3 to 4." The district court detailed how the prior art references and expert testimony failed to establish that methylnaltrexone could be stabilized based on pH alone. Mylen appealed.

On appeal, Mylan maintained that the references established a prima facie case of obviousness because they described overlapping pH ranges and methylnaltrexone bears significant structural and functional similarity to naloxone and naltrexone "such that a person of skill in the art would seek to use prior disclosed pHs for naloxone and naltrexone when formulating solutions of methylnaltrexone."

In response, Valeant pointed out that overlapping ranges for different chemical compounds that fail to meet claim 8's stability requirement did not establish obviousness and the structural and functional similarities of the compounds were "not relevant because claim 8 recites a solution of methylnaltrexone with a stability profile unrecognized and unattained in the prior art." Valeant argued that methylnaltrexone, naloxone, and naltrexone functioned differently because of their structural differences, and "nothing about the shared function of the drugs is relevant to their stability in solution."

The Court agreed with Mylan. "Our case law reflects an understanding that skilled artisans can expect structurally similar compounds to have similar properties." Daiichi Sankyo Co. v. Matrix Labs., Ltd., 619 F.3d 1346, 1352 (Fed. Cir. 2010).  The Court pointed out that "an obviousness analysis can rely on prior art compounds with similar pharmacological utility in addition to structural similarity. See, e.g., In re Merck & Co., Inc., 800 F.2d 1091, 1097 (Fed. Cir. 1986)." "When compounds share significant structural and functional similarity, those compounds are likely to share other properties, including optimal formulation for long-term stability."

The Court noted that naloxone, naltrexone, and methylnaltrexone were well-known opioid antagonists that operate by binding to the body's opioid receptors without activating them, each is an oxymorphone derivative, and three molecules have remarkably similar structures with a difference in the identity of the functional group attached to the nitrogen atom. The Court concluded that "a person of skill could expect similar stability of the molecules at similar pH ranges in solution." The Court held that summary judgment was granted in error.

The Court, however, expressly warned that the holding "should not be misconstrued to mean that molecules with similar structure and similar function can always be expected to exhibit similar properties for formulation." The Court suggested that "the factfinder should consider whether Valeant has rebutted Mylan's prima facie case, by, for example, establishing that the claimed pH range is critical or that the quaternary nitrogen results in unexpected beneficial properties." "Valeant may also attempt to rebut Mylan's case by showing that the prior art teaches away from the claimed invention in any respect." 

Originally published Apr 27, 2020.

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