Insulin Glargine - USA

On Nov. 19, 2019, Federal Circuit affirmed PTAB’s decision & found formulation patents covering insulin glargine (Lantus®) invalid under obviousness.

Sanofi-Aventis Deutschland GMBH’s owns U.S. Patent Nos. 7,476,652 and 7,713,930, which describe and claim certain formulations of a particular kind of insulin ie —insulin glargine. Mylan filed IPR petitions & board finally concluded that the subject matter of the claims is unpatentable for obviousness. Sanofi appealed.

Claim 7 of the ’652 patent is illustrative for present action:

 7. A pharmaceutical formulation comprising Gly(A21), Arg(B31), Arg(B32)-human insulin, at least one chemical entity chosen from polysorbate and poloxamers; at least one preservative; and water, wherein the pharmaceutical formulation has a pH in the acidic range from 1 to 6.8.

Sanofi first commercially sold glargine in the U.S. in May 2001 (before priority), under the trade name Lantus®, whose product label identifies, among other things, a pH of 4. Some patients soon began reporting problems with turbidity in the vials, i.e., before injection. Sanofi determined that the turbidity was caused by undesirable “non-native” aggregation of the glargine protein while still in solution. Sanofi then resolved the vial-turbidity problem by adding a nonionic surfactant to the glargine formulation to prevent non-native aggregation.

During appeal Sanofi challenged the Board’s finding based on (1) KSR International Co. v. Teleflex Inc., 550 U.S. 398 (2007), required the Board to find that the prior art disclosed an aggregation problem for glargine specifically (not just insulins in general); (2) the Board improperly relied on each patent’s own (shared) specification in finding a motivation to combine; and (3) substantial evidence does not support the Board’s finding because key evidence cited by the Board concerned insulins in general rather than glargine specifically.

With respect to first point, Sanofi argued that the Board was required, under KSR, to find in the prior art a recognition of an aggregation problem for glargine specifically, not just for insulins generally. But Federal Circuit said that in KSR, the Supreme Court criticized a rigid approach to determining obviousness based on the disclosures of individual prior-art references, with little recourse to the knowledge, creativity, and common sense that an ordinarily skilled artisan would have brought to bear when considering combinations or modifications. Nothing in KSR demands the kind of prior-art identifications of a problem at the level of specificity that Sanofi urges. The Board thus properly examined the evidence in this particular case to determine whether a relevant artisan would have recognized an insulin aggregation problem in the prior art and expected glargine to share that problem.

With respect to second point, Federal Circuit also rejected Sanofi’s contention that the Board committed legal error when it cited the shared patent specification, specifically background section. Sanofi challenged the Board’s reliance on this material as legally improper, invoking court’s longstanding recognition that a tribunal should not “look to knowledge taught by the inventor . . . and then use that knowledge against its teacher.” But Federal Circuit said that the Board did not violate that principle, because it did not use the specification for its teachings about the inventor’s discovery. Rather, it used the specification for its teachings about prior-art knowledge, and that use of a specification is not just common, given patent drafters’ standard practice of reciting prior art in setting out the background of the invention, but permissible. Moreover, the Board used the cited material not as the sole support for any finding but in conjunction with support from other sources. The Board found evidence of insulin aggregation on hydrophobic surfaces and at air/water interfaces in a handful of other prior-art references.

With respect to third point, Federal Circuit said that the Board’s findings with respect to the motivation to combine are detailed and well supported. The Board correctly found that insulins “had a known tendency to aggregate in the presence of hydrophobic surfaces” and at air-water interfaces and that a relevant artisan would have expected glargine to behave similarly to other insulins when in contact with hydrophobic surfaces and at air-water interfaces. The Board also found that nonionic surfactants, including the claimed ones, were well known and had been used successfully to stabilize insulin formulations, and so would have been looked to by a relevant artisan concerned about aggregation in glargine. Sanofi argued that the prior art discloses aggregation only in insulin pumps, but the Board disagreed, finding instead that “it is the air-water interfaces and interactions with hydrophobic surfaces that promote insulin aggregation, and not the type of device used to deliver the insulin formulation.”  Prior art & expert testimony supports the Board’s determination. The evidence also supports the Board’s finding that the prior art taught use of nonionic surfactants like those claimed in the present patents to address the aggregation problem.

Sanofi also challenged the Board’s finding that a relevant artisan would have had a reasonable expectation of success in adding the claimed surfactants to the existing glargine preparation in the way claimed in the patents at issue here. Sanofi specifically argued that, although surfactants were known to stabilize insulins generally, a relevant artisan would not have expected the same result for glargine specifically because its mechanism of action depends on some favorable native aggregation. Federal Circuit said that nonionic surfactants—were shown in the prior art to have been successfully used to prevent aggregation of various types of insulins and other peptides. Moreover, presence of phenols in a glargine formulation would not have dissuaded a relevant artisan from expecting success in using nonionic surfactants. Therefore, Board’s finding is supported by substantial evidence. Finally, Federal Circuit also rejected Sanofi challenge with respect to commercial success.

Federal Ciruit thus affirmed the Board’s decisions that all claims of the ’652 and ’930 patents are unpatentable for obviousness.