The "Lead Compound" Approach to Obviousness and Obviousness-Type Double Patenting

In Otsuka Pharmaceutical Co. v. Sandoz, Inc., the Federal Circuit upheld the district court’s determination that the claims at issue were neither obvious nor invalid under the doctrine of obviousness-type double patenting based on a “lead compound” approach to the obviousness determinations. This case reaffirms the applicability of the “lead compound” analytical framework, and highlights subtle differences in its application to questions of obviousness and obviousness-type double patenting.

The Patent At Issue

The patent at issue was Otsuka’s U.S. Patent 5,006,528. Claims 12, 17, and 23 are specifically directed to aripiprazole, the active ingredient it Otsuka’s Abilify® product: 

7-{4-[4-(2,3-dichlorophenyl)-1-piperazinyl]-butoxy}-3,4-dihydrocarbostyril

The Obviousness Issue

The defendants alleged that the claims were obvious in view of any one of three lead compounds, an “unsubstituted butoxy” compound, a “2,3-dichloro propoxy” compound, and a compound named “OPC-3492.” 

The unsubstituted butoxy compound was the subject of an earlier Otsuka patent (U.S. Patent 4,734,416). During prosecution of that patent, Otsuka submitted the Nakagawa Declaration which provided experimental data on nine compounds, including the unsubstituted butoxy compound. The compounds that exhibited the greatest activity in the reported assay had propoxy linkers, not butoxy linkers.

The 2,3-dichloro propoxy compound was disclosed in two foreign counterparts of the ’416 patent.  For example, that compound was one of 96 compounds falling under one example of a Swedish patent.

OPC-3492 was another compound being developed by Otsuka. According to the Federal Circuit decision, “as of the priority date of the ’528 patent, [OPC-3492] was the only carbostyril derivative tested in humans as a potential antipsychotic.” Prior art articles described OPC-3492 in mixed terms, noting that “the anti-psychotic action was not strong but the strength of the activating action stood out,” that “improvements were observed in the negative symptoms,” that “the extra-pyramidal disturbances are extremely weak,” that it was “expected to have some advantageous effects different from those of conventional antipsychotic drugs,” and that while it was “expected to have fewer side effects than conventional drugs of the same class,” subjects receiving a 5 mg dose “experienced sleeplessness, stagger, weakness, fatigability, heavy headedness, lack of motivation and disturbed concentration, which were so severe that they were not able to perform daily routine work.”

The District Court Decision

With regard to obviousness, the district court determined that the cited prior art would not have led to the selection of one of the three compounds as a lead compound. Instead, the court found that compounds with a different core structure, such as clozapine or risperidone, which were approved anti-psychotics, were more likely candidates. Thus, the court concluded that “the Defendants had failed to prove obviousness by clear and convincing evidence.”

With regard to obviousness-type double patenting, the district court “considered whether aripiprazole and its uses are not patentably distinct from the unsubstituted butoxy” recited in claim 13 of the ’416 patent. The court noted “the structural differences” between the compounds, and “found that the prior art did not teach one of ordinary skill to achieve antipsychotic activity by modifying the unsubstituted butoxy with a 2,3-dichloro substitution on its phenyl ring to make aripiprazole.”  Thus, the court “concluded that the Defendants had failed to prove obviousness-type double patenting by clear and convincing evidence.

 The Federal Circuit Decision

The Federal Circuit rejected the defendants’ arguments that the “lead compound” framework was a ‘rigid obviousness analysis precluded by KSR.’” The Federal Circuit noted that the obviousness of chemical compounds need not always be evaluated under the “lead compound” framework, but the defendants’ arguments themselves relied on a lead compound analysis, e.g., the obviousness of aripiprazole over specific prior art compounds.  The Federal Circuit explained:

Our case law demonstrates that whether a new chemical compound would have been prima facie obvious over particular prior art compounds ordinarily follows a two-part inquiry. First, the court determines whether a chemist of ordinary skill would have selected the asserted prior art compounds as lead compounds, or starting points, for further development efforts. …. The second inquiry in the analysis is whether the prior art would have supplied one of ordinary skill in the art with a reason or motivation to modify a lead compound to make the claimed compound with a reasonable expectation of success.

The Federal Circuit noted the following characteristics of a “lead compound”:

• A lead compound … is “a compound in the prior art that would be most promising to modify in order to improve upon its . . . activity and obtain a compound with better activity.”
• [A] lead compound is “a natural choice for further development efforts.”
• A lead compound is identified by “evidence of the compound’s pertinent properties,” including positive properties (e.g., “activity and potency”) and negative properties (e.g., “toxicity”).
• Importantly, “[a]bsent a reason or motivation based on such prior art evidence, mere structural similarity between a prior art compound and the claimed compound does not inform the lead compound selection.”

The Federal Circuit reviewed the district court’s obviousness analysis, and found no clear error in its determinations that the asserted compounds were not lead compounds, and that, even if they were treated as lead compounds, it would not have been obvious to modify them to arrive at aripiprazole.

With regard to obviousness-type double patenting, the Federal Circuit noted that the “lead compound” analysis differs from the obviousness analysis because the analysis starts with the assumption that the compound claimed in the granted patent is a “lead compound.” Thus, the analysis turns on the identification in the prior art of “some reason that would have led a chemist to modify the earlier compound to make the later compound with a reasonable expectation of success.”

Turning to the district court’s analysis, the Federal Circuit agreed “that the prior art, including the Nakagawa Declaration, . . . did not teach the person of ordinary skill in the art to pursue a 2,3-dichloro substitution on the phenyl ring to achieve antipsychotic activity.” In affirming the district court, the Federal Circuit cited evidence of “the high degree of unpredictability in antipsychotic drug discovery” including evidence that “antipsychotic research at that time was ‘notoriously unsuccessful.’” The Federal Circuit emphasized that  ”KSR makes clear [that] predictability is a vital consideration in the obviousness analysis.”

Avoiding A Hindsight Determination

This decision highlights three parts of an obviousness analysis that can safeguard against a determination based on hindsight. First, the requirement for evidence of a reason to select the asserted compounds as lead compounds guards against hindsight based on structural similarity. Second, the requirement for evidence of a reason to modify a lead compound in the manner required to arrive at the claimed compound guards against hindsight based on the post-hoc identification of substitutions. Third, the relevance of evidence of unpredictability in the art guards against hindsight that would overlook the reasonable expectation of success required for obvoiuosness. Patent holders facing obviousness challenges should consider whether they can provide evidence on any or all of these points to strengthen their position, while patent holders facing obviousness-type double patenting challenges can focus on at least the last two points.