[W]hen analyzing obviousness-type double patenting in cases involving claimed chemical compounds, the issue is not whether a skilled artisan would have selected the earlier compound as a lead compound [because] the analysis must necessarily focus on the earlier claimed compound over which double patenting has been alleged, lead compound or not.

On May 7, 2012, in Otsuka Pharm. Co. v. Sandoz, Inc., the U.S. Court of Appeals for the Federal Circuit (Lourie,* Moore, Reyna) affirmed the district court judgment that U.S. Patent 5,006,528, which related to 7-{4-[4-(2,3-dichlorophenyl)-1-piperazinyl]-butoxy}-3,4-dihydrocarbostyril (aripiprazole) for the treatment of schizophrenia and bipolar disorder that Otsuka markets under the brand name Abilify®, was not invalid under 35 U.S.C. § 103 and under the doctrine of nonstatutory double patenting. The Federal Circuit stated:

In cases involving the patentability of a new chemical compound, prima facie obviousness under the third Graham factor generally turns on the structural similarities and differences between the claimed compound and the prior art compounds. The Defendants assert that the district court erred by employing a “lead compound” analysis as part of its determination under the third Graham factor. We reject that contention. New compounds may be created from theoretical considerations rather than from attempts to improve on prior art compounds. In this case, however, the parties’ arguments focus on selecting and modifying particular prior art compounds, designated as lead compounds. [W]hether 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. 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.” As such, a lead compound is “a natural choice for further development efforts.” . . .

In determining whether a chemist would have selected a prior art compound as a lead, the analysis is guided by evidence of the compound’s pertinent properties. Such properties may include positive attributes such as activity and potency; adverse effects such as toxicity, and other relevant characteristics in evidence. Absent 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. Were it otherwise, the analysis would impermissibly rely upon ex-post reasoning.

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. In keeping with the flexible nature of the obviousness inquiry, the reason or motivation for modifying a lead compound may come from any number of sources and need not necessarily be explicit in the prior art. Again, pertinent properties guide the analysis, for “it is the possession of promising useful properties in a lead compound that motivates a chemist to make structurally similar compounds.” “[I]t is sufficient to show that the claimed and prior art compounds possess a ‘sufficiently close relationship . . . to create an expectation,’ in light of the totality of the prior art, that the new compound will have ‘similar properties’ to the old.”

In the present case, in assessing whether aripiprazole would have been prima facie obvious in view of the prior art compounds asserted by the Defendants, the district court summarized the applicable law as requiring inquiry into 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 teachings 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.

We discern no error in the district court’s recitation of the applicable law. Moreover, the court did not require, as the Defendants allege, that only “the most obvious choice” could serve as the lead. Rather, the district court concluded that two compounds—clozapine and risperidone—would have been considered viable lead compounds. These were the only marketed antipsychotic compounds at the time the present inventors began their work. They were the natural and obvious lead compounds whose structures one would have considered to modify to obtain improved antipsychotic compounds. At the relevant time, 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, and the district court did not clearly err in concluding that they were not. [T]he district court’s careful analysis exposed the Defendants’ obviousness case for what it was—a poster child for impermissible hindsight reasoning. Because we agree with the district court that the Defendants failed to prove that claim 12 of the ’528 patent would have been prima facie obvious over the asserted prior art compounds, we need not address the court’s findings regarding objective evidence of nonobviousness. . . .

We now turn to the Defendants’ contention that the district court erred by failing to hold the asserted claims of the ’528 patent invalid for nonstatutory obviousness-type double patenting in view of the unsubstituted butoxy compound of claim 13 of the ’416 patent. An inventor may obtain “a patent” for an invention pursuant to 35 U.S.C. § 101; the statute thus “permits only one patent to be obtained for a single invention.” The double patenting doctrine “precludes one person from obtaining more than one valid patent for either (a) the ‘same invention,’ or (b) an ‘obvious’ modification of the same invention.” Nonstatutory double patenting is a judicially created doctrine grounded in public policy that “prevent[s] the extension of the term of a patent, even where an express statutory basis for the rejection is missing, by prohibiting the issuance of the claims in a second patent not patentably distinct from the claims of the first patent.”

As an initial matter, the parties disagree over the legal test for nonstatutory double patenting. Otsuka contends that there is no difference between obviousness under § 103 and obviousness-type double patenting. That is not entirely correct. We have noted that “a double patenting of the obviousness type rejection is analogous to [a failure to meet] the nonobviousness requirement of 35 U.S.C. § 103.” Important differences remain, however. The patent principally underlying the double patenting rejection need not be prior art. Moreover, when analyzing obviousness-type double patenting in cases involving claimed chemical compounds, the issue is not whether a skilled artisan would have selected the earlier compound as a lead compound. That is so because the analysis must necessarily focus on the earlier claimed compound over which double patenting has been alleged, lead compound or not.

The Defendants assert that, unlike an analysis under § 103, the test for obviousness-type double patenting never asks whether the prior art would have supplied a motivation to modify the earlier claimed compound. That is also incorrect. Unless the earlier claim anticipates the later claim under § 102, the question whether the two claimed compounds are “patentably distinct” implicates the question of obviousness under § 103, which in the chemical context requires identifying some reason that would have led a chemist to modify the earlier compound to make the later compound with a reasonable expectation of success. . . .

We agree with the district court that the asserted claims are not invalid for nonstatutory double patenting. [A]ripiprazole differs structurally from the unsubstituted butoxy of claim 13 of the ’416 patent. Aripiprazole has chlorine substituents at the 2 and 3 positions of its phenyl ring, whereas the unsubstituted butoxy has hydrogens at those positions—i.e., it is “unsubstituted.” In its double-patenting analysis, the court determined “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.” The evidence before the district court supports this finding. For example, the court credited evidence demonstrating the high degree of unpredictability in antipsychotic drug discovery as of the priority date. Experts testified that the discovery of new antipsychotic drugs in the 1980s was “very unpredictable,” and that antipsychotic research at that time was “notoriously unsuccessful.”