On March 28, 2012, the U.S. District Court for the District of New Jersey, in a 100 page opinion, held that AstraZeneca’s patent (US 5,948,437) covering sustained release quetiapine formulations was valid and infringed. The lawsuit arose out of a number of pIV certifications made by Anchen, Osmotica, Torrent and Mylan in respect of SEROQUEL XR. The claims of ‘437 patent read, in relevant part:
1. A sustained release formulation comprising a gelling agent and 11 -[4-[2-(2-hydroxyethoxy)ethyl]- 1 -piperazinyl]dibenzo-[b,f] [1,4]thiazepine or a pharmaceutically acceptable salt thereof, together with one or more pharmaceutically acceptable excipients.
2. A sustained release formulation according to claim 1 wherein the gelling agent is hydroxypropyl methylcellulose
13. A method of treating psychotic states or hyperactivity in a warm-blooded animal which comprises administering to said warm-blooded animal an effective amount of a formulation according to anyone of claims 1-12.
Torrent alleged that its proposed quetiapine products did not employ a gelling agent or HPMC as required by the claims, but rather contained non-gelling carageenan lambda as a sustained release agent. Based on an earlier Markman Order construing “gelling agent” to mean “any substance which forms a gel when in contact with water” and the expert evidence provided by AstraZeneca showing that carrageenan lambda forms a gel when in contact with water, the Court concluded that Torrent literally infringed claims 1, 10 and 11 of the ‘437 patent and infringed claim 2 of the ‘437 patent under the doctrine of equivalents.
Validity – Obviousness
The Defendants had all alleged that the ‘437 Patent was obvious in light of certain prior art documents, including US 4,879,288 which discloses pharmaceutical compositions containing quetiapine to treat psychosis and hyperactivity. In upholding the validity of the ‘437 patent, the Court found, among other things, that:
The skilled person: The Court accepted AstraZeneca position the skilled person, in addition to a pharmaceutical formulator, would include a clinician or antipsychotic drug researcher. The Court did not accept the Defendants’ evidence that the ‘437 patent “was all about formulation” and that no clinician is necessary.
Motivation to make a sustained release quetiapine formulation: The Court found that there was no motivation, as of 1997, to make a sustained release quetiapine formulation. Based on prior art teaching that quetiapine had a low dopamine D2 receptor occupancy, the Court accepted that a skilled person would have believed a sustained release formulation to be counterproductive. A sustained release formulation would slow down the release of quetiapine which would delay the ability to rapidly control the symptoms of schizophrenia. Thus, the skilled person would have been motivated away from sustained release and towards increasing the dose of the immediate release formulation.
General motivation of sustained release formulations: The Court did not accept general teachings of the benefits of sustained release formulations, including decreased side effects, better patient compliance and reduced blood level fluctuations, provided the requisite motivation to make a sustained release quetiapine formulation.
Combining prior art: The Court concluded that the Defendants had not shown, by clear and convincing evidence, any motivation to combine the `288 Patent with a number of general sustained release prior art documents, in part, because the various drugs disclosed in the general reference have different physical, therapeutic and pharmacological properties than those of quetiapine.
Reasonable expectation of success: The Court, in the event that it was wrong on the absence of motivation to combine the relevant prior art documents, concluded that the skilled person would nevertheless not have had a reasonable expectation of success. The Court noted that there were several technological ways to achieve sustained release other than a gel matrix system and that formulation science was unpredictable given the unique properties of quetiapine.
Secondary indicia: The Court concluded that Seroquel XR`s commercial success (it was the fastest growing atypical antipsychotic drug in 2010 from which AstraZeneca expects to earn about $3 Billion between 2013 and 2015) was primarily due to its unique combination of indications and such commercial success has the required nexus to the ‘437 Patent.
This is the third decision in less than a month on the validity of members of the same patent family. On March 7, 2012, the District Court of the Hague found the corresponding Dutch patent to be valid and non-obvious. On March 22, 2012 the U.K. High Court of Justice found the corresponding British patent to be invalid (see our previous report here).
A copy of the U.S. opinion may be found here.