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ABILIFY compound patent attack a “poster child” for impermissible hindsight – CAFC

On May 7, 2012, the Court of Appeals for the Federal Circuit (CAFC) affirmed a judgment of the United States District Court for the District of New Jersey that held that U.S. Patent No. 5,006,528 was not invalid for obviousness or non-statutory double patenting.

A number of generic companies had challenged the obviousness of the chemical structure of aripiprazole, an atypical antipsychotic, largely in light of three prior art disclosures. The structures of aripiprazole and the prior art compounds are depicted below:

Claim 12 of the ‘528 patent claimed aripiprazole by its chemical name, 7-{4-[4-(2,3-dichlorophenyl)-1-piperazinyl]-butoxy}-3,4-dihydrocarbostyril.  Claim 17 of the ’528 patent is generally directed to a pharmaceutical composition containing aripiprazole. Claim 23 of the ‘528 patent (added during reexamination) was generally directed to treating schizophrenia with pharmaceutical compositions containing aripiprazole as the active ingredient.

Obviousness

The CAFC concluded that the “lead compound” analysis conducted by the District Court properly focussed on the differences between the claimed invention and the prior art.  The District Court’s lead compound analysis was not inconsistent with the flexible approach to obviousness adopted by the United States Supreme Court in 2007 in KSR Int’l Co v. Teleflex Inc . Rather, in cases of the patentability of new chemical compounds, the third Graham factor turns on the structural similarities between the claimed invention and the prior art. This, in turn, ordinarily follows the following two-part test:

  1. Would the person of skill in the art have selected the prior art compounds as lead compounds, or starting points for further development efforts?
  2. Would the prior art have supplied the skilled person with a reason or motivation to modify the lead compounds to make the claimed compounds with a reasonable expectation of success?

On the first point, the CAFC concluded that the District Court was correct in concluding that the lead compounds would be based on the structures of clozapine or risedronate as these were the only marketed atypical antipsychotics at the relevant time. At that time, no carbostyril compounds were known to have potent antipsychotic activity with minimal side effects. It is only in impermissible retrospect that carbostyrils were plausible lead compounds.

The CAFC, nevertheless, went on to consider the lead compounds proposed by the Defendants and rejected by the District Court. The “unsubstituted butoxy” compound was discounted as the prior art disclosed that this compound had an antihistamine effect.  Further, if a skilled person would have considered the prior art disclosing the “unsubstituted  butoxy” compound, they would have chosen other more potent compounds including those which contained a propoxy linker (-O-CH2-CH2-CH2-) and not the butoxy linker (-O-CH2-CH2-CH2-CH2-) found in aripiprazole. The 2,3-dichloro propoxy compound was only one among hundreds of examples and a skilled person would not have selected a 2,3 dichloro propoxy compound as a lead compound. OPC-4392, which was disclosed to only have weak antipsychotic action and as such was considered a failure, would have taught away from aripiprazole. Further, even if OPC-4392 was selected as a lead compound, there was nothing in the prior art that would have motivated the skilled person to convert OPC-4392 into aripiprazole.

Having concluded that the Defendants had failed to show that claim 12 of the ‘528 patent was prima facie obvious, the Court concluded it need not address any of the Plaintiff’s objective evidence of nonobviouness.

Double Patenting

The CAFC also affirmed that the ‘528 patent was not invalid by reason of non-statutory double patenting.  The CAFC held that the District Court did not err by relying in part on its obviousness findings in its subsequent double patenting analysis. The District Court was correct in finding that the prior art would not have provided a skilled person with a reason to make the necessary changes to convert the “unsubstituted butoxy” compound into aripiprazole.

A copy of the CAFC’s opinion may be found here.