Velcade Patent Neither Inherently Obvious nor Obvious Under Lead Compound Analysis

In Millenium v. Sandoz,¹ the claim at issue recites a lyophilized compound that is an ester of bortezomib and D-mannitol. The Federal Circuit formulated the obviousness analysis by asking whether a person of ordinary skill, seeking to remedy the known instability of bortezomib “would obviously produce the D-mannitol ester of bortezomib, a previously unknown compound.”² Employing a lead compound analysis, the court concluded that the answer was no. Using bortezomib as the lead compound, the court found that no cited reference provided a reason to produce the claimed mannitol ester. The court also rejected the district court’s inherency analysis as impermissible hinsight.

Although the Federal Circuit agreed with Sandoz’s argument that lyophilization was known in formulating pharmaceutical products, and that bulking agents were known to be used in lyophilization, and that mannitol was a known bulking agent, the court concluded that the prior art does not teach or suggest that lyophilization of borezomib in the presence of mannitol would produce the claimed compound, or that the compound would solve the instability problems of bortezomib. ³

The Federal Circuit further found that the district court clearly erred in finding that the art did not teach away from the claimed compound. The patent holder persuaded the court that chemical modification of bortezomib would not have been desirable for fear of disturbing bortezomib’s anti-cancer functionality.⁴

The Federal Circuit also disagreed with the district court’s inherency analysis, characterizing it as hindsight. The district court found that the claimed ester is the natural result of freeze-drying bortezomib with mannitol. In rejecting this reasoning, the Federal Circuit cited prior case law, which stated that the inventor’s own path never leads to a conclusion of obviousness. The Federal Circuit further rejected Sandoz’s argument that the result of freeze drying bortezomib with mannitol was “‘inevitable’ and thus ‘inherent,’ and thus not ‘inventive’.”⁵ The Federal Circuit did not address the inevitability of ester formation, but rather focused on the fact that invention is not what the inventor intended, but rather viewed in terms of a person of ordinary skill. No expert asserted that they foresaw the reaction between bortezomib and mannitol, or that the resulting ester would have the long-sought advantages. ⁶

Finally, the Federal Circuit found that the district court clearly erred in its examination of unexpected results and long-felt need. Regarding unexpected results, the district court ruled that bortezomib was not the closest prior art, but rather the bortezomib glycerol ester.⁷ The Federal Circuit disagreed, finding that the prior art did not specifically disclose, prepare or test the bortezomib glycerol ester. The district court also clearly erred in finding that the mannitol ester of bortezomib did not meet a long felt need for a stable product to treat multiple myeloma. ⁸