Otsuka Pharmaceutical Co. v. Sandoz, Inc. (Fed. Cir. 2012)

Otsuka Pharmaceutical Co. v. Sandoz, Inc., the Federal Circuit clarified the differences between obviousness and obviousness-type double patenting for a chemical composition-of-matter invention. Specifically, a new chemical compound is prima facie obvious if (1) a chemist of ordinary skill would have selected prior art compounds as a lead compounds, and (2) a reason or motivation for modifying the lead compounds to make the claimed compound with a reasonable expectation of success can be found in the prior art. On the other hand, for obviousness-type double patenting, the lead compound is the previously claimed compound, so the first inquiry is not necessary. However, the reason or motivation for modifying that previously claimed compound still needs to be found in the prior art. 

The compound at issue in this case is aripiprazole, the active ingredient of Abilify®: 

This compound is a "carbostyril derivative." For the purposes of the appeal, the significant features of the compound included (1) the two hydrogen atoms connected at the 3 and 4 positions of the carbostyril ring, instead of the double bond between the 3 and 4 carbon atoms as found in the carbostyril moiety, (2) the butoxy linker at the 7-position of the ring, which has four methylene units as opposed to three found in a propoxy linker, and (3) the terminal phenyl ring is 2,3-dichloro substituted (because of the chlorine atoms connected to the 2 and 3 positions of this ring). There were three asserted prior art "lead compounds" in this appeal. The first was the "unsubstituted butoxy" as disclosed and claimed in an earlier Otsuka patent: 

This compound differs from aripiprazole because it doesn't have the two chlorine substituents on the phenyl ring. The second asserted lead compound was the "2,3-dichloro propoxy" compound: 

This compound was disclosed in prior art foreign counterpart patents of Otsuka, and differs from aripiprazole because it has a propoxy linker at the 7-position of the carbostyril ring. The final asserted lead compound was OPC-4392, an Otsuka development compound that had been tested in humans as a potential antipsychotic: 

There are a few differences between this compound and aripiprazole: OPC-4392 has a 2,3-dimethyl substituted phenyl ring, a propoxy linker, and the carbostyril ring contains a double bind at the 3,4-position. 

Abilify® is marketed for the treatment of schizophrenia, bipolar disorder, irritability associated with autistic disorder in pediatric patients, and as an add-on treatment for depression. The first drug for the treatment of schizophrenia, chlorpromazine, was discovered in the early 1950s. It was found that this antipsychotic drug treated the "positive" symptoms of schizophrenia, including hallucinations and delusions (clearly "positive" in this case does not necessarily mean "desirable"). However, the "negative" symptoms of schizophrenia, such as flat affect, poverty of speech, inability to experience pleasure, lack of desire to form relationships, and lack of motivation, were not treated by the "typical" antipsychotics. The first "atypical" antipsychotic, clozapine, was discovered in the early 1960s, and treated both the positive and negative symptoms of schizophrenia. However, this drug had serious potential side effects. In 1994, the FDA approved the first post-clozapine atypical antipsychotic, risperidone, and since then, the FDA has approved seven others, including aripiprazole in 2002. However, aripiprazole is the only such compound that doesn't have a chemical structure related to either clozapine or risperidone. 

Otsuka is the assignee of the patent at issue in this case, which claims aripiprazole, pharmaceutical compositions for treating schizophrenia, and methods of treating schizophrenia. The Defendants in this case, Sandoz et al., Apotex Inc. and Apotex Corp., and Teva et al., all filed ANDAs to market generic versions of aripiprazole products. These cases were consolidated, and reduced to a validity determination of the asserted patent after the Defendants conceded infringement. The U.S. District Court for the District of New Jersey held a bench trial, and concluded that the Defendants failed to prove by clear and convincing evidence that the asserted claims would have been obvious to one of skill in the art, or that they were invalid for nonstatutory double patenting. The Defendants appealed. 

Obviousness of New Chemical Compounds 

The Federal Circuit first considered whether aripiprazole was obvious over the three asserted lead compounds. As indicated above, the first step of this inquiry is whether an asserted compound is, in fact, a lead compound, or in other words, whether the compound is "a natural choice for further development efforts," citing Altana Pharma AG v. Teva Pharm. USA, Inc., 566 F.3d 999 (Fed. Cir. 2009). However, mere structural similarity between two compounds is not sufficient to establish that a prior art compound would have been a "lead" compound; rather there must be evidence of a compound's pertinent properties that would have provided a reason or motivation to select it. Without such evidence, the analysis in no more than ex post reasoning. The second step is determining if the reason or motivation for modifying the lead compound can be found in the prior art. The Federal Circuit approved of the lower court's statement of the inquiry as: 

The hypothetical person of skill in the art's identification of a lead compound, structural differences between the proposed lead compound and the claimed invention, motivation or teaching in the prior art to make the necessary changes to arrive at the claimed invention, and whether the person of skill in the art would have a reasonable expectation of success in making such structural changes. 

The Court first considered whether the unsubstituted butoxy compound was a lead compound. This compound is disclosed and claimed U.S. Patent No. 4,734,416 ("the '416 patent"). Generally, the '416 patent taught a genus with about nine trillion compounds, and explained that the compounds have antihistaminic action and central nervous controlling action. However, Dr. Bryan Roth explained to the lower court that a skilled artisan would not have understood that all compounds in the genus would have potential antipsychotic activity. The unsubstituted butoxy compound was also disclosed in the "Nakagawa declaration," submitted by one of the co-inventors in the prosecution of the '416 patent. This declaration disclosed three sets of test data, the third of which was for "inhibiting jumping behavior in mouse induced by Methamphetamine and L-DOPA." Even though schizophrenia and antipsychotic activity were not mentioned in the declaration, evidence was presented that such data could be indicative of such activity to a skilled artisan. Nevertheless, out of the nine carbostyril derivatives tested, the two most potent had a 5-propoxy linker instead of a 7-butoxy linker. The unsubstituted butoxy compound was of only middling potency. At best, the Nakagawa declaration would have suggested that one of the two potent propoxy compounds would have been a potential lead compound. Because these were not suggested as lead compounds for the development of aripiprazole, neither the '416 patent nor the Nakagawa declaration supported the selection of the unsubstituted butoxy compound as a lead compound. 

The Federal Circuit also determined that the Defendants failed to prove that aripiprazole would have been obvious over the 2,3-dichloro propoxy. It is true that this compound was disclosed in a foreign application. However, the compound was disclosed "as one among hundreds of examples that may be useful for an extensive list of potential central nervous system controlling activities." Without a teaching that would tie the 2,3-dichloro propoxy to any meaningful suggestion of antipsychotic activity, this compound could not be considered a lead compound. The Court distinguished Pfizer, Inc. v. Apotex, Inc., 480 F.3d 1348 (Fed. Cir. 2007), because in that case the prior art reference not only provided ample motivation to narrow the prior art genus, it also predicted the results. There was no such analogous showing in this case. 

The Court similarly concluded that with respect to the final prior art compound, OPC-4392, it was not shown that it would have been selected as a lead compound because none of the evidence was sufficient to demonstrate this. For example, the Defendants alleged that a Murasaki 1987 reference disclosed that the compound was an anti-psychotic drug, but that reference instead taught that the anti-psychotic action of OPC-4392 was not very strong. Moreover, even if OPC-4392 was selected as a lead compound, there was no proof that the prior art taught or provided the motivation to modify this compound in the three specific ways required to arrive at aripiprazole. The Court rejected the argument that Otsuka took a very small amount of time to develop aripiprazole from OPC-4392 as evidence of its obviousness, because an inventor's own path can never lead to a conclusion of obviousness. Without the prima facia case of obviousness in view of these asserted three lead compounds, the Federal Circuit did not address the objective evidence of nonobviousness.