In an opinion that referred to a Defendant’s obviousness case for a small-molecule drug as “a poster child for impermissible hindsight reasoning,” the Federal Circuit affirmed a decision of the District Court for the District of New Jersey that upheld the validity of U.S. Patent No. 5,006,528, which provides composition of matter protection for the antipsychotic agent Abilify® (aripiprazole). The case, decided on May 7, 2012, is Otsuka Pharmaceutical Co., LTD. v. Sandoz, Inc., et al. The ‘528 patent claims the aripiprazole compound, as well as pharmaceutical compositions and methods of treating schizophrenia using this compound:

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In the opinion, the court invoked the “lead compound analysis,” (see, e.g., Yamanouchi Pharm. v. Danbury Pharmacal (CAFC 2000)), which provides a twostep analysis for small-molecule obviousness: 1) determine whether one of ordinary skill in the art would select a particular compound(s) to serve as a starting point for chemical modification (a “lead compound”); 2) consider whether a chemist of ordinary skill would have had some reason to modify the known compound in the particular manner necessary to achieve the new compound. The court examined the following proposed lead compounds, as well as what was known about these compounds at the time of filing, in determining whether the aripiprazole structure was obvious. Like aripiprazole, the cited compounds all fall within the carbostyril class of molecules:

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The “unsubstituted butoxy” compound, which lacks the chlorine substituents of aripiprazole, and the “2,3-dichloro propoxy” compound, which differs from aripiprazole by one methylene group (butoxy vs. propoxy), were described in earlier Otsuka patents. “OPC-4392” has dimethyl substitution on the phenyl ring, a propoxy linker, and a saturated carbon-carbon bond on the quinonlin-one ring, and was characterized as “an anti-psychotic drug being developed” in a scientific journal article. After re-emphasizing that the lead compound analysis is consistent with the Supreme Court’s obviousness principles in KSR Int’l Co. v. Teleflex, Inc.(2007) (See also Takeda v. Alphapharm (Fed. Cir. 2007) and Eisai Co. v. Dr. Reddy’s Labs. (Fed. Cir. 2008)), the court individually considered each of the proposed lead compounds employing the test. For the first proposed lead, the court determined that the unsubstituted butoxy compound was described during prosecution of an earlier Otsuka patent as inferior to similar compounds having a propoxy linker, and that another, structurally dissimilar, compound from that patent had a higher potency. With respect to the second alleged lead, the court found that the patent covering the 2,3-dichloropropoxy compound “fails to tie the 2,3-dichloro propoxy to any meaningful suggestion of antipsychotic activity,” and any allegations of motivation to combine the unsubstituted butoxy compound and the 2,3- dichloropropoxy compound to arrive at aripiprazole would constitute improper hindsight. Finally, the court found that OPC-4392 could be considered “a failure insofar as it did not treat the positive symptoms of schizophrenia and was not welltolerated in modest doses,” and that, even if this compound could have been considered a lead, there existed no motivation in the art to make the molecular changes necessary to arrive at aripiprazole. These factors, among others, led the court to determine that none of these compounds qualified as leads. In fact, the court noted that “there were no carbostyril compounds that were marketed as antipsychotics or were publicly known to have potent antipsychotic activity with minimal side effects. Carbostyrils were thus not plausible lead compounds, except in retrospect” (emphasis added).  

Finally, the court affirmed the lower court’s ruling that the ‘528 patent was not invalid for obviousness-type double patenting in view of Otsuka’s prior patent claiming the unsubstituted butoxy compound. In its analysis, the court noted that traditional obviousness analysis should be used when determining nonstatutory obviousness-type double patenting in the context of small-molecules: “[t]here is no other way to consider the obviousness of compound B over compound A without considering whether one of ordinary skill would have had reason to modify A to make B.” With this foundation, the court reiterated that there existed no evidence that one of skill in the art would be motivated to modify the unsubstituted butoxy compound to arrive at aripiprazole. According to the court, this was particularly true in view of “the high degree of unpredictability in antipsychotic drug discovery as of the priority date”, as well as expert testimony establishing that, at the time of filing, there existed no known successful antipsychotic drug having a 2,3- dichlorophenyl substituent.  

Prior to Otsuka v. Sandoz, the Federal Circuit last ruled on the obviousness of a novel chemical entity in September of 2010 (Daiichi Sankyo Company, Ltd. et al. v. Matrix Laboratories, LTD., in which the court upheld the non-obviousness of Olmesartan medoxomil). The Federal Circuit has not wavered from its approval of the use of the lead compound analysis during this almost two-year period. In fact, the court’s opinion focuses significantly more on dismissing the prior art structures as “leads” than the structural differences between the prior art structures and aripiprazole, and makes no mention of any secondary considerations of nonobviousness associated with aripiprazole. As discussed in our article Pharmaceutical Innovation and the Use of the Lead Compound Analysis (Intellectual Property Today, Dec. 2011), the lead compound analysis is a commonsense guide in determining obviousness for new pharmaceuticals, and plays an important role in defending pharmaceutical development from improper hindsight bias. Indeed, such bias is exactly what the court avoids in its determination of nonobviousness in the Otsuka case: “[t]he inventor’s own path itself never leads to a conclusion of obviousness; that is hindsight.”  

You can view the Federal Circuit’s decision here: http://www.cafc.uscourts.gov/images/stories/opinions-orders/11-1126.pdf