The pharmaceutical industry can once again sleep at night, knowing the Federal Circuit has its back when compound patents are involved, after the court’s recent decision Millennium Pharms., Inc. v. Sandoz Inc., 2017 U.S. App. LEXIS 12702 (Fed. Cir. July 17, 2017). This case involved Velcade®, the blockbuster multiple myeloma treatment marketed by Takeda Oncology and Millennium Pharmaceuticals. The trial court had held that the patent claims were invalid because the compound was the inherent result of an allegedly obvious lyophilization process, but the Federal Circuit reversed. According to the Federal Circuit, the trial court applied the wrong legal framework; it should have applied the lead compound analysis espoused in Otsuka Pharm. Co. v. Sandoz, Inc., 678 F.3d 1280 (Fed. Cir. May 7, 2012).
Velcade® is a “boronate ester” formed when bortezomib is lyophilized with mannitol. The molecule was originally discovered in the early 1990s, but a stable and soluble formulation of the molecule did not come easy. According to the Court:
“Bortezomib and its properties as a proteasome inhibitor were previously known and are described in United States Patent No. 5,780,454 ("the Adams Patent"). However, despite its known efficacy against various cancers, bortezomib never achieved FDA approval and market status because of its instability, its rapid degradation in liquid formulations, and its insolubility. The record states that these problems remained unsolved despite extensive research effort by the inventor Dr. Adams and others at Millennium and its predecessor company.”
To solve these stability and solubility problems, Millenium turned to scientists at the University of Kanas and National Cancer Institute, who eventually produced a lyophilized product with improved stability and solubility using mannitol as the bulking agent. Dissolution and stability improved because a new chemical compound formed during lyophilization: the claimed ester of bortezomib and mannitol. Their patent, United Stated Patent No. 6,713,446, recites in claim 20:
The lyophilized compound D-mannitol N-(2-pyrazine)carbonyl-L-phenylalanine-L-leucine boronate.
Experts from Sandoz argued forcefully at trial that “lyophilization ‘was well-known in the field of formulation’ and that it was considered an obvious alternative ‘when a liquid formulation provided limited success.’” The trial court accepted this evidence, and ruled that Velcade® was the inherent result of an allegedly obvious process, but the Federal Circuit reversed. According to the Federal Circuit, the trial court applied the wrong legal framework; the trial court should have applied the lead compound analysis. Under this framework:
“We consider whether the prior art ‘would have supplied one of ordinary skill in the art with a reason or motivation to modify a lead compound to make the claimed compound with a reasonable expectation of success.’”
Sandoz’ proof fell short under this framework because:
“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.”
Sandoz offered proof that it was known that lyophilization was a well-known pharmaceutical technique, that mannitol was a well-known bulking agent used in lyophilization, and that bortezomib could form an ester, but that evidence was inadequate under the lead compound analysis. According to the Federal Circuit:
“No reference supports the district court's conclusion that ‘skilled formulators would be motivated to create a mannitol ester to improve bortezomib's stability and solubility.’ No reference suggests producing this ester for this purpose. The undisputed facts are of failed attempts to achieve a stable formulation with the necessary properties of solubility and dissolution in the bloodstream.”
The Federal Circuit demanded evaluation under its lead compound analysis, and the inventive activities simply did not fit that framework.
An interesting side note is the timing of the ‘446 patent. The application for the ‘446 was filed on January 25, 2002, and expires on January 25, 2022. FDA approved Velcade® on May 13, 2003. Millenium and Takeda will enjoy nearly nineteen years of patent exclusivity thanks to their persistence and dedication to this lifesaving treatment, and their solution to these vexing formulation issues.