Opinion ID: 799379
Heading Depth: 3
Heading Rank: 1

Heading: The District Court's Lead Compound Analysis

Text: 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. Daiichi Sankyo Co. v. Matrix Labs., Ltd., 619 F.3d 1346, 1352 (Fed.Cir. 2010). 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. 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. Eisai Co. v. Dr. Reddy's Labs., Ltd., 533 F.3d 1353, 1359 (Fed.Cir.2008) ([P]ost- KSR, a prima facie case of obviousness for a chemical compound still, in general, begins with the reasoned identification of a lead compound.). A lead compound, as we have explained, 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. Takeda Chem. Indus., Ltd. v. Alphapharm Pty., Ltd., 492 F.3d 1350, 1357 (Fed.Cir.2007). As such, a lead compound is a natural choice for further development efforts. Altana Pharma AG v. Teva Pharm. USA, Inc., 566 F.3d 999, 1008 (Fed.Cir.2009). In recent cases involving the alleged obviousness of a new chemical compound, the parties have frequently focused upon the notion that a chemist must select one or more lead compounds. E.g., Daiichi, 619 F.3d at 1352; Altana, 566 F.3d at 1007; Procter & Gamble Co. v. Teva Pharm. USA, Inc., 566 F.3d 989, 994 (Fed.Cir. 2009); Eisai, 533 F.3d at 1357; Takeda, 492 F.3d at 1357; Eli Lilly & Co. v. Zenith Goldline Pharm., Inc., 471 F.3d 1369, 1379 (Fed.Cir.2006); Yamanouchi Pharm. Co. v. Danbury Pharmacal, Inc., 231 F.3d 1339, 1345 (Fed.Cir.2000); cf. Unigene Labs., Inc. v. Apotex, Inc., 655 F.3d 1352, 1362 (Fed.Cir.2011) ([T]he term `reference composition' is more appropriate than `lead compound' when considering obviousness for a chemical composition.). In such cases our analysis focuses on those proposed lead compounds that the alleged infringer has attempted to prove, by clear and convincing evidence, that the skilled artisan would have had a reason to select from the panoply of known compounds in the prior art. Daiichi, 619 F.3d at 1354. 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. See Eli Lilly, 471 F.3d at 1378; In re Lalu, 747 F.2d 703, 707 (Fed.Cir.1984). Such properties may include positive attributes such as activity and potency, Altana, 566 F.3d at 1008; Eli Lilly, 471 F.3d at 1379; Yamanouchi, 231 F.3d at 1345; adverse effects such as toxicity, Takeda, 492 F.3d at 1358, and other relevant characteristics in evidence, see Eisai, 533 F.3d at 1358 (considering a prior art compound's lipophilicity and low molecular weight); Pfizer, Inc. v. Apotex, Inc., 480 F.3d 1348, 1363 (Fed.Cir.2007) (considering the strength, solubility, and other known chemical characteristics of a prior art salt-forming acid). 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. See Daiichi, 619 F.3d at 1354; In re Dillon, 919 F.2d 688, 692 (Fed.Cir. 1990) (en banc) ([S]tructural similarity between claimed and prior art subject matter, proved by combining references or otherwise, where the prior art gives reason or motivation to make the claimed compositions, creates a prima facie case of obviousness. (emphasis added)). Were it otherwise, the analysis would impermissibly rely upon ex post reasoning. See KSR Int'l Co. v. Teleflex, Inc., 550 U.S. 398, 421, 127 S.Ct. 1727, 167 L.Ed.2d 705 (2007) (A factfinder should be aware, of course, of the distortion caused by hindsight bias and must be cautious of arguments reliant 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. Takeda, 492 F.3d at 1357 ([I]n cases involving new chemical compounds, it remains necessary to identify some reason that would have led a chemist to modify a known compound in a particular manner to establish prima facie obviousness of a new claimed compound.); Pfizer, 480 F.3d at 1361 ([T]he challenger of the patent [must] show by clear and convincing evidence that a skilled artisan would have been motivated to combine the teachings of the prior art references to achieve the claimed invention, and that the skilled artisan would have had a reasonable expectation of success in doing so.); Dillon, 919 F.2d at 692. 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. Eisai, 533 F.3d at 1357 (citing KSR, 550 U.S. at 415, 127 S.Ct. 1727); Aventis Pharma Deutschland GmbH v. Lupin, Ltd., 499 F.3d 1293, 1301 (Fed.Cir. 2007). 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. Daiichi, 619 F.3d at 1354 (Potent and promising activity in the prior art trumps mere structural relationships.); see also Eli Lilly, 471 F.3d at 1378 ([P]atentability for a chemical compound does not depend only on structural similarity.); In re Stemniski, 58 CCPA 1410, 444 F.2d 581, 586 (1971). As we have explained, it 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. Aventis, 499 F.3d at 1301 (quoting Dillon, 919 F.2d at 692); see also In re Wilder, 563 F.2d 457, 460 (CCPA 1977). 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. Otsuka, 2010 WL 4596324, at , 2010 U.S. Dist. LEXIS 132595, at -53. 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. Id. at -24, 2010 U.S. Dist. LEXIS 132595 at . 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. As for the Defendants' purported lead compounds, the district court carefully considered each compound and correctly rejected the contention that a skilled artisan would have selected those compounds for further antipsychotic drug research efforts.