Millennium Pharms., Inc. v. Sandoz Inc.

Case Name: Millennium Pharms., Inc. v. Sandoz Inc., Civ. No. 12-1011-GMS (consolidated), 2015 U.S. Dist. LEXIS 110099 (D. Del. Aug. 20, 2015) (Sleet, J.) 

Drug Product and Patent(s)-in-Suit: Velcade^® (bortezomib); U.S. Patent No. 6,713,446 ("the '446 patent") 

Nature of the Case and Issue(s) Presented: Millennium sued defendants under the Hatch-Waxman Act. At trial, the primary issue presented was obviousness. Each asserted claim had three central elements: (i) freeze-drying bortezomib; (ii) using mannitol; and (iii) forming a bortezomib-mannitol ester. In addition to the three main elements, a further dependent asserted claim added the step of "reconstitution," which involves adding liquid to the freeze-dried cake to put the drug into solution for injection in to the patient. In view of the prior art, the court concluded that the asserted claims were invalid due to obviousness.

Why Defendants Prevailed: Millennium argued as a preliminary matter that defendants' expert did not identify any specific combination of references or any single reference that supposedly renders the asserted claims obvious, but instead cited seventeen references to support his obviousness opinion. The court was not concerned and held that defendants’ expert’s utilization of the references supported a "plausible rationale" as to why the prior-art references would have worked together and clearly articulated how and why a person of ordinary skill in the art ("POSA") would have been motivated to lyophilize bortezomib with mannitol to form an ester.

Defendants' most relevant prior-art reference was the '454 patent, which not only disclosed esters of bortezomib, but also claimed "pharmaceutical compositions" of the claimed esters, including the bortezomib ester.

The decision to freeze-dry bortezomib was obvious. Freeze-drying, according to both parties’ experts, was one of the "top-two" choices a formulator would consider to formulate a boronic acid compound. Defendants’ expert testified regarding three references that established freeze-drying as an industry-standard formulation option. It had been used for decades and a POSA at least would have considered the technique in developing a stable formulation. Plaintiff’s expert conceded that the ’454 patent disclosed the use of freeze-drying in a number of its examples.

The decision to freeze-dry bortezomib with mannitol was not inventive. Mannitol is a standard bulking agent. In correspondence among the inventors of the patent-in-suit, the idea to use mannitol was suggested as an "added insurance" policy if the solution work was not successful. Mannitol was referenced in a "disparate list of bulking agents" which one of the inventors expected to work based on his experience and knowledge of freeze-drying. It was an "obvious option" as the "most popular" bulking agent. Moreover, the ’454 patent explained that scientists should make esters using "preferably, a dihydroxy compound." Mannitol is a dihydroxy compound.

Millennium argued that none of the references cited by defendants’ expert taught the use of boronate esters to improve the stability of a boronic acid compound by preventing oxidation. Defendants responded that if the court were to find obvious the first two steps—freeze-drying bortezomib with mannitol—the patent would be necessarily invalid because ester formation is the inherent result of that combination. Defendants also assert that Millennium admitted inherency by excluding Dr. Adams, the inventor of the ’454 patent, as an inventor here even though he was the first to identify the ester formation. The court sided with defendants, and found that it would have been obvious to a POSA that freeze-drying bortezomib with mannitol would produce a bortezomib-mannitol ester.

Concerning secondary indicia of non-obviousness, and in particular unexpected results, the court found that Millennium’s experts testified that they did not know whether the bortezomib-mannitol ester was more stable or soluble than the closest prior-art bortezomib glycerol ester. Thus, Millennium failed to establish any difference between the claimed invention and the closest prior art. Millennium’s commercial-success and long-felt need arguments focused on the fact that bortezomib compound alone cannot be administered to patients, and therefore required a pharmaceutical formulation. But the evidence at trial suggested that other formulations provided a viable route to commercialization but were ultimately disregarded on economic rather than efficacy grounds. Moreover, the freeze-dried mannitol ester of bortezomib did not solve any problems’ persistence over a long period of time without resolution by the prior art.