Federal Circuit: Lyophilized Prodrug Formed by API and Lyophilization Bulking Agent Not Obvious

On July 17, 2017, the Federal Circuit reversed a district court’s decision that Millennium’s U.S. Patent No. 6,713,446 (“the ’446 Patent”) covering the cancer drug Velcade^® was obvious.  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 district court failed to consider that the resulting product was a new chemical entity with superior properties.

The ‘446 Patent claims:

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

The inventors of the ‘446 Patent produced a lyophilized formulation using mannitol, a known bulking agent.  The lyophilization resulted in a formulation with improvement in dissolution and stability, which was the results of the formation of a new chemical compound during lyophilization: the claimed ester of bortezomib and mannitol.The mannitol ester of bortezomib acts as a “prodrug,” a compound that converts to or releases the active pharmaceutical ingredient upon administration to a patient.

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 reversed the district court, stating that “the question is whether a person of ordinary skill, seeking to remedy the known instability and insolubility and to produce an efficacious formulation of bortezomib, would obviously produce the D-mannitol ester of bortezomib, a previously unknown compound. The prior art contains no teaching or suggestion of this new compound, or that it would form during lyophilization.  Sandoz identifies no reference or combination of references that shows or suggests a reason to make the claimed compound. No reference teaches or suggests that such a new compound would have the long-sought properties of stability and solubility, and sufficiently dissociate to release bortezomib at an effective rate in the bloodstream, all critical to effective use for treating multiple myeloma. The D-mannitol ester of bortezomib is a new compound with distinct chemical properties. . . .The district court clearly erred in its obviousness analysis. … None of these references, alone or in combination, suggests or teaches that the solution to the problems of creating an efficacious formulation of bortezomib lay in freeze-drying bortezomib with mannitol to form an ester having the necessary properties for stability, storage, and treatment.”

The Federal Circuit also took issue with the district court’s identification of the closest prior art for a showing of unexpected results. “ Millennium presented expert testimony that the lyophilized mannitol ester of bortezomib yielded unexpected results as compared to bortezomib, viz., greatly improved stability, solubility, and dissolution.  However, the district court ruled that bortezomib itself was not the closest prior art, and declined to consider the advantages and benefits of the Velcade^® product. The district court’s error stems from its determination that Millennium should have compared the glycerol bortezomib ester, for the Adams Patent included glycerol as one of ten “[p]referred . . . dihydroxy compounds” for “boronate esters.” The bortezomib glycerol ester was not specifically disclosed, prepared, or tested in the Adams Patent. Although Sandoz now argues that the bortezomib glycerol ester is “generically” encompassed by the Adams Patent, Sandoz has not argued that any glycerol ester is specifically disclosed or actually identified in the Adams Patent (or in any other reference).  We conclude that the district court should have treated bortezomib as the closest prior art compound, and acknowledged the unrebutted evidence that the Dmannitol ester of bortezomib exhibited unexpected results compared with bortezomib, including unexpectedly superior stability, solubility, and dissolution.”

Millennium Pharmaceuticals v. Sandoz Inc., July 17, 2017.