In Millennium Pharmaceuticals, Inc. v. Sandoz, the Federal Circuit reversed the district court decision that invalidated one of the Orange Book-listed patents covering the anti-cancer drug Velcade. In so doing, the court explained that a novel product with unexpected advantageous properties is not obvious just because the process by which it was made might have been.

The Velcade® Patent At Issue

The patent at issue was Millennium’s U.S. Patent No. 6,713,446, which is listed in the Orange Book for Velcade®, which is used to treat multiple myeloma and mantle cell lymphoma. The patent is directed to stable esters of boronic acid compounds, including the D-mannitol ester of bortezomib, which turned out to have surprising stability and overcame the problem of lack of stability of other bortezomib compounds and formulations.

The court discussed claim 20, which recites:

20. The lyophilized compound D-mannitol N-(2- pyrazine)carbonyl-L-phenylalanine-L-leucine boronate.

According to the Federal Circuit decision, the D-mannitol ester was discovered somewhat by accident. Researchers were trying to develop a stable, lyophilized formulation of bortezomib, and “produced a promising lyophilized formulation using mannitol,” a known bulking often use in lyophilization. They discovered that the formulation contained “a new chemical compound”—the D-mannitol ester of bortezomib, and that that compound was stable in the formulation and “acts as a ‘prodrug’ … that converts to [bortezomib] upon administration to a patient.” Since the instability of bortezomib had prevented FDA approval of previous products, this new compound paved the way for FDA approval of a product that “changed the decades-old standard of care for multiple myeloma and has saved thousands of lives.”

The ANDA Litigation

The ‘446 patent was the subject of ANDA litigation against a number of would-be generic manufacturers.

As summarized in the Federal Circuit decision:

The district court held that the claims were obvious because they were the inherent result of an allegedly obvious process, viz., lyophilizing bortezomib in the presence of the bulking agent mannitol.

The Federal Circuit Decision

The Federal Circuit decision was authored by Judge Newman and joined by Judges Mayer and O’Malley.

The Federal Circuit applied the “lead compound” analytical framework to assess the obviousness of the claimed compound, and found no evidence to support obviousness:

There is no teaching or suggestion in the references to produce the claimed mannitol ester. No reference shows or suggests ester formation at freeze-drying conditions, or that any such ester might solve the problems of instability and insolubility of the free acid while dissociating rapidly in the bloodstream. No reference provides a reason to make the mannitol ester of bortezomib.

Addressing Sandoz’s arguments regarding the obviousness of lyophilization with mannitol, the Federal Circuit emphasized:

[T]he prior art does not teach or suggest that lyophilization of bortezomib in the presence of mannitol would produce a chemical reaction and form a new chemical compound, or provide a reason to make this specific new chemical compound, or that this new compound would solve the previously intractable problems of bortezomib formulation.

Since it was not obvious that lyophilization with mannitol would form a new chemical compound with greatly improved stability, the standards for establishing obviousness were not met.

On the entirety of the record, we conclude that the district court clearly erred in finding that a person of ordinary skill would obviously make the D-mannitol ester in order to solve the problem of providing an effective form of bortezomib. The unexpected properties of an unexpectedly produced new compound, and the ensuing pharmaceutical efficacy and benefit, negate the district court’s ruling of obviousness

Thus, the Federal Circuit reversed the district court’s ruling on obviousness.

Obviousness and Inherency

It is not uncommon for an examiner to assert that a product claim is obvious because the product is the inherent result of a process that allegedly would have been obvious. Evidence of unexpected results is not always sufficient to overcome such a rejection, because the examiner may assert that the unexpected properties would have been inherent in the product that would have resulted from the obvious process. This decision is a reminder that the obviousness of novel products should be assessed under a “lead compound” analysis, and, as 35 USC § 103 reminds, “[p]atentability shall not negatived by on “the manner in which the invention was made.”