In a decision issued November 19, 2019, in Sanofi-Aventis Deutschland GMBH v. Mylan Pharm. Inc., 791 F. App'x 916 (Fed. Cir. 2019), the Federal Circuit affirmed the PTAB’s decision to invalidate Sanofi’s U.S. formulation patents for recombinant insulin glargine (a/k/a Lantus®). By way of background, FDA first approved Lantus® in 2000, without including a surfactant in the formulation. Previously approved insulins had included surfactants to prevent the insulin from aggregating, but Sanofi apparently concluded that its recombinant insulin glargine did not suffer a similar risk.
Sanofi subsequently changed course. After receiving several patient reports of white particles in Lantus® vials, Sanofi reformulated the product to include a surfactant, and was eventually awarded U.S. Patent Nos. 7,476,652 and 7,713,930 directed to the formulation. Claim 1 of the '652 patent is illustrative of the claimed subject matter and recites:
1.A pharmaceutical formulation comprising Gly(A21), Arg(B31), Arg(B32)-human insulin;
at least one chemical entity chosen from polysorbate 20 and polysorbate 80;
at least one preservative; and
water,
wherein the pharmaceutical formulation has a pH in the acidic range from 1 to 6.8.
Two points here are worth remembering. First, it is unclear why this formulation patent was such a problem for Mylan, since Mylan filed its application with FDA under 21 U.S.C. 505(b)(2). If Mylan had filed the application under 21 U.S.C. 505(j), it would have been obligated to use the same surfactant Lantus® under FDA’s exception excipient rules, but those rules do not apply to applications filed under 505(b)(2).
Second, if Sanofi’s patents had survived, Sanofi would have ended up with 24 years of patent exclusivity for its drug. The patent could potentially have prevented generic competition until January 2024, for a drug product first approved on April 20, 2000. One can’t help but wonder if this fact influenced the Court’s decision.
We read the case with interest wondering how the use of a surfactant could have been obvious when Sanofi -- the originator of insulin glargine -- had itself determined that a surfactant was not necessary. We also wondered whether patient reports of precipitation might have been cited as prior art in the court’s decision.
As it turns out, the decision was far more mundane. The PTAB simply disagreed with the Examiner who had granted the patents, and determined that a person of ordinary skill in the art would have been concerned with aggregation for insulin glargine for the same reason that other insulins aggregate. Motivated by such a concern, a POSA would have been motivated to add a surfactant to insulin glargine. As explained by the Federal Circuit:
evidence reasonably supports the Board's finding that a relevant artisan would have understood glargine to come within the general recognition of an aggregation problem for insulins. The Lantus® Label discloses glargine formulated as a solution with an acidic pH [which contributes to aggregation], and both the Lantus® Label and Owens teach glargine formulations in vials known to contain hydrophobic surfaces and an air-water interface [which also contribute to aggregation for other insulins]. [Record citations omitted]
The PTAB was clearly the best venue for challenging these patents, with its preponderance of the evidence standard of proof. These patents would have been much more likely to survive if challenged in Federal Court, given the significant deference the judiciary gives to decisions at the Patent Office.
Hopefully this decision will lead to more competition in the insulin market, and a reduction of prices for insulin in the United States. To our understanding, Mylan still has not secured U.S. FDA approval for its generic version of Lantus®, reportedly due to manufacturing issues at a plant in Malaysia, even though the product has been approved for marketing in Europe and Australia.
