Opinion ID: 210543
Heading Depth: 4
Heading Rank: 2

Heading: Choice of the Claimed Compounds

Text: Even if Alphapharm had established that preliminary finding, and we have concluded that it did not, the record demonstrates that Alphapharm's obviousness argument fails on a second ground. The district court found nothing in the prior art to suggest making the specific molecular modifications to compound b that are necessary to achieve the claimed compounds. In reaching that conclusion, the court first found that the process of modifying lead compounds was not routine at the time of the invention. Takeda, 417 F.Supp.2d at 380. Dr. Mosberg opined that the steps of homologation and ringwalking were routine steps in the drug optimization process, but the court found that testimony unavailing in light of the contrary, more credible, testimony offered by Takeda's experts. Id. at 381. In addition, the court relied on Dr. Rosenberg's admission that a person of ordinary skill in the art would look at a host of substituents, such as chlorides, halides and others, not just methyls in modifying the pyridyl ring. Id. Pioglitazone differs from compound b in two respects, and one would have to both homologate the methyl group of compound b and move the resulting ethyl group to the 5-position on the pyridyl ring in order to obtain pioglitazone. With regard to homologation, the court found nothing in the prior art to provide a reasonable expectation that adding a methyl group to compound b would reduce or eliminate its toxicity. Based on the test results of the numerous compounds disclosed in Sodha II, the court concluded that homologation had no tendency to decrease unwanted side effects and thus researchers would have been inclined to focus research efforts elsewhere. Id. at 383. Indeed, several other compounds exhibited similar or better potency than compound b, and one compound in particular, compound 99, that had no identified problems differed significantly from compound b in structure. Id. at 376 n. 51. Moreover, Dr. Mosberg agreed with Takeda's expert, Dr. Danishefsky, that the biological activities of various substituents were unpredictable based on the disclosure of Sodha II. Id. at 384-85. The court also found nothing in the '200 and '779 patents to suggest to one of ordinary skill in the art that homologation would bring about a reasonable expectation of success. As for ring-walking, the court found that there was no reasonable expectation in the art that changing the positions of a substituent on a pyridyl ring would result in beneficial changes. Dr. Mosberg opined that the process of ring-walking was known to Takeda, but the court found that testimony inapt as it failed to support a reasonable expectation to one of ordinary skill in the art that performing that chemical change would cause a compound to be more efficacious or less toxic. Id. at 382. Moreover, Dr. Mosberg relied on the efficacy data of phenyl compounds in Sodha II, but the court found those data insufficient to show that the same effects would occur in pyridyl compounds. Alphapharm relies on In re Wilder, 563 F.2d 457 (CCPA 1977), for the proposition that differences in a chemical compound's properties, resulting from a small change made to the molecule, are reasonably expected to vary by degree and thus are insufficient to rebut a prima facie case of obviousness. In Wilder, our predecessor court affirmed the Board's holding that a claimed compound, which was discovered to be useful as a rubber antidegradant and was also shown to be nontoxic to human skin, would have been obvious in light of its homolog and isomer that were disclosed in the prior art. The evidence showed that the homolog was similarly nontoxic to the human skin, whereas the isomer was toxic. The court held that one who claims a compound, per se, which is structurally similar to a prior art compound must rebut the presumed expectation that the structurally similar compounds have similar properties. Id. at 460. While recognizing that the difference between the isomer's toxicity and the nontoxicity of the homolog and claimed compound indicate[d] some degree of unpredictability, the court found that the appellant failed to point out a single actual difference in properties between the claimed compound and the homologue, and thus failed to rebut the presumption. Wilder, 563 F.2d at 460. We would note that since our Wilder decision, we have cautioned that generalization should be avoided insofar as specific chemical structures are alleged to be prima facie obvious one from the other, Grabiak, 769 F.2d at 731. In addition to this caution, the facts of the present case differ significantly from the facts of Wilder. Here, the court found that pioglitazone exhibited unexpectedly superior properties over the prior art compound b. Takeda, 417 F.Supp.2d at 385. The court considered a report entitled Preliminary Studies on Toxicological Effects of Ciglitazone-Related Compounds in the Rats that was presented in February 1984 by Dr. Takeshi Fujita, then-Chief Scientist of Takeda's Biology Research Lab and co-inventor of the '777 patent. That report contained results of preliminary toxicity studies that involved selected compounds, including pioglitazone and compound b. Compound b was shown to be toxic to the liver, heart and erythrocytes, among other things, whereas pioglitazone was comparatively potent and showed no statistically significant toxicity. Id. at 356-57. During the following months, Takeda performed additional toxicity studies on fifty compounds that had been already synthesized and researched by Takeda, including pioglitazone. The compounds were tested for potency and toxicity. The results were presented in another report by Fujita entitled Pharmacological and Toxicological Studies of Ciglitazone and Its Analogues. Pioglitazone was shown to be the only compound that exhibited no toxicity, although many of the other compounds were found to be more potent. Id. at 358. Thus, the court found that there was no reasonable expectation that pioglitazone would possess the desirable property of nontoxicity, particularly in light of the toxicity of compound b. The court's characterization of pioglitazone's unexpected results is not clearly erroneous. As such, Wilder does not aid Alphapharm because, unlike the homolog and claimed compound in Wilder that shared similar properties, pioglitazone was shown to differ significantly from compound b, of which it was not a homolog, in terms of toxicity. Consequently, Takeda rebutted any presumed expectation that compound b and pioglitazone would share similar properties. Alphapharm also points to a statement Takeda made during the prosecution of the '779 patent as evidence that there was a reasonable expectation that making changes to the pyridyl region of compound b would lead to better toxicity than the prior art. During prosecution of the '779 patent, in response to an enablement rejection, Takeda stated that there should be no reason in the instant case for the Examiner to doubt that the claimed compounds having the specified substituent would function as a hypolipidemic and hypoglycemic agent as specified in the instant disclosure. That statement, however, indicates only that changes to the left moiety of a lead compound would create compounds with the same properties as the compounds of the prior art; it does not represent that lower toxicity would result. And even if the statement did so represent, it does not refer to any specific substituent at any specific position of TZD's left moiety as particularly promising. As the court correctly noted, the compounds disclosed in the '779 patent included a variety of substituents, including lower alkyls, halogens, and hydroxyl groups, attached to a pyridyl or thiazolyl group. As discussed supra, the district court found that the claims encompassed over one million compounds. Thus, we disagree with Alphapharm that that statement provided a reasonable expectation to one of ordinary skill in the art that performing the specific steps of replacing the methyl group of the 6-methyl compound with an ethyl group, and moving that substituent to the 5-position of the ring, would have provided a broad safety margin, particularly in light of the district court's substantiated findings to the contrary. We thus conclude that Alphapharm's challenges fail to identify grounds for reversible error. The court properly considered the teachings of the prior art and made credibility determinations regarding the witnesses at trial. We do not see any error in the district court's determination that one of ordinary skill in the art would not have been prompted to modify compound b, using the steps of homologation and ring-walking, to synthesize the claimed compounds. Because the court's conclusions are not clearly erroneous and are supported by the record evidence, we find no basis to disturb them. The court properly concluded that Alphapharm did not make out a prima facie case of obviousness because Alphapharm failed to adduce evidence that compound b would have been selected as the lead compound and, even if that preliminary showing had been made, it failed to show that there existed a reason, based on what was known at the time of the invention, to perform the chemical modifications necessary to achieve the claimed compounds. In light of our conclusion that Alphapharm failed to prove that the claimed compounds would have been prima facie obvious, we need not consider any objective indicia of nonobviousness. [5]