On May 4, 2012, the District Court of New Jersey issued an amended memorandum opinion in relation to Sandoz’ paragraph IV challenge to U.S. Patents Nos. 4,910,214 and 6,716,867 listed in the Orange Book against Hospira’s PRECEDEX (dexmedetomidine hydrochloride) product. Since Sandoz had stipulated that its proposed ANDA product would infringe claims of the ‘214 and ‘867 patents, the only issues were the validity and enforceability of the ‘214 and ‘867 patents.
The ‘214 patent is generally directed to substantially pure, optically active dextrorotary stereoisomers of medetomidine. Claim 1 of the ‘214 patent reads as follows:
1. The d enantiomer of medetomidine or a non-toxic pharmaceutically acceptable acid addition salt thereof.
Medetomidine is an imidazoline containing selective α2-adrenoceptor agonist. The principle piece of prior art had disclosed the sedative and cardiovascular effects of racemic medetomidine, along with other related imidazoline compounds, and suggested that medetomidine enantiomers are “also to be studied”.
Anticipation – The Court concluded that the prior art piece was not anticipatory as it did not disclose the separated enantiomers of medetomine and as such did not teach the “substantially pure” limitation of any claims of the ‘214 patent.
Obviousness – The Court accepted that a person skilled in the art would have recognized that medetomidine is chiral and would have been motivated to separate the enantiomers of medetomidine. The skilled person would also have considered the stereoselectivity of other imidazoline α2-adrenoceptor compounds. However, the Court concluded that given the number of different ways of separating enantiomers, a skilled person would not have had a reasonable expectation of success in separating the individual medetomidine enantiomers, noting that there was considerable disagreement in the field regarding how difficult an enantiomeric resolution was at the relevant time. The Court accepted that in 1987, enantiomeric resolution was an iterative process in which trial and error was normal. The eventual success of a systematically designed enantiomeric resolution program does not make it obvious to isolate dexmedetomidine. The Court’s finding of nonobviousness was further supported by objective evidence demonstrating dexmedetomidine’s surprising stereoselective binding to the α2-adrenoceptor. The Court concluded:
On the facts here, the Court finds that dexmedetomidine’s especially strong affinity for the α2-adrenoceptor would not have been obvious to a person of ordinary skill in the art in July 1987. Rather, one would have predicted a weak stereoselectivity. Such an unexpectedly superior result, the Court’s conclusion that separation of medetomidine did not carry a reasonable expectation of success, and the moderate commercial success of Precedex are sufficient to demonstrate nonobviousness. Consequently, the Court holds that Defendants have failed to show clear and convincing evidence that the ’214 Patent is invalid as obvious under 35 U.S.C. § 103.
Inequitable Conduct – Sandoz had asserted that Table 2 of the 214 patent, which the patentee relied on in order to overcome a rejection during patent prosecution, contained incorrect and scientifically impossible results that were contradicted by later experiments performed by the patentee. The Court found that the Table 2 data was material but, following Therasense, Inc. v. Becton, Dickinson & Co., it could not conclude that one of the named inventors appreciated the materiality of the Table 2 data and deliberately withheld the data with the intent to deceive the PTO.
The 867 patent is generally directed towards the use of dexmedetomidine for sedation in the intensive care unit (“ICU”). Claim 1 of the ‘867 patent reads as follows:
1. A method of sedating a patient in an intensive care unit, which comprises administering to the patient an effective amount of dexmedetomidine of a pharmaceutically acceptable salt thereof, wherein the patient remains arousable and orientated.
Anticipation – the Court concluded that the prior art taught many of the limitations of the claims of the 867 patent. The Court narrowed the issues to whether the prior art discloses a method of sedating ICU patients and whether it discloses that those patients remain arousable and orientated. While acknowledging that it was probable that the patients in the prior art document were receiving intensive care, the prior art did not necessarily disclose this limitation. Similarly, the Court was not convinced that the prior art expressly or inherently disclosed that the patients remained arousable and orientated. As such, the Defendants’ claim failed because it relies on ”probabilities and possibilities”.
Obviousness – Sandoz asserted that it would have been obvious to try dexmedetomidine as an intensive care medication with the reasonable expectation that it would have the desired property of arousable and orientated sedation. The Court characterized the relevant prior art, as follows:
We can summarize the prior art specific to dexmedetomidine in 1998 as follows. A person of ordinary skill in the art would have recognized that sedation was an expected, dose-dependent side effect of intravenous dexmedetomidine. Moreover, dexmedetomidine induces a sedation from which patients typically are arousable and able to answer questions about their condition and participate in study tests. While the majority of the prior art references studied dexmedetomidine in healthy volunteers, Dr. Aho observed that dexmedetomidine was well-tolerated in patients undergoing surgery, and Dr. Talke observed that the expected sedative effect of dexmedetomidine carried over to patients with severe medical illnesses awaiting vascular surgery.
The Court concluded that any differences between the method of sedation in the ‘867 patent and the prior art are insignificant and all of the claims of the ‘867 patent would have been obvious to a person of skill in the art. The prior art provided a strong motivation to use dexmedetomidine for the claimed use and the skilled person would have had a reasonable expectation of success in achieving and maintaining arousable sedation in ICU patients. This conclusion was not displaced by objective evidence of nonobviousness.
Inequitable conduct – Sandoz’s theory of inequitable conduct was based on a failure to disclose a prior art reference (the Talke reference) which disclosed the intravenous administration of dexmedetomidine to surgery patients. The Court concluded that the withheld reference was material and was deliberately withheld from the PTO. However, given the inventors’ good faith belief that the reference was not material and following Therasense, the Defendants had not shown by clear and convincing evidence that the specific intent to deceive was the single most reasonable inference to be drawn from the inventors actions.
Having found the ‘214 patent valid and enforceable, the Court permanently enjoined the Defendants from the commercial manufacture, use, sale or offer for sale in the United States or importation into the United States of their generic dexmedetomidine HCl product until the ‘214 patent expires.
A copy of the Court’s amended memorandum opinion may be found here.