Opinion ID: 208728
Heading Depth: 3
Heading Rank: 2

Heading: District Court's Obviousness Analysis

Text: Altana challenges the district court's obviousness analysis on the merits. Altana argues that the district court clearly erred when it determined that the defendants' obviousness defense had substantial merit. In particular, Altana argues that the district court allowed the defendants to select compound 12 of the '518 patent as a lead compound when the prior art suggested the availability of numerous other compounds that were at least as promising to modify as compound 12. In addition, Altana contends that the district court's findings with respect to the teaching of Bryson are clearly erroneous. We examine each argument. Obviousness is ultimately a question of law, based on underlying factual determinations. Richardson-Vicks Inc. v. Upjohn Co., 122 F.3d 1476, 1479 (Fed. Cir.1997). The factual determinations that form the basis of the legal conclusion of obviousness include (1) the scope and content of the prior art; (2) the level of ordinary skill in the art; (3) the differences between the claimed invention and the prior art; and (4) evidence of secondary factors, known as objective indicia of non-obviousness. Graham v. John Deere Co., 383 U.S. 1, 17-18, 86 S.Ct. 684, 15 L.Ed.2d 545 (1966). This court recently explained that [w]here, as here, the patent at issue claims a chemical compound, the analysis of the third Graham factor (the differences between the claimed invention and the prior art) often turns on the structural similarities and differences between the claimed compound and the prior art. Eisai Co. Ltd. v. Dr. Reddy's Labs., Ltd., 533 F.3d 1353, 1356-57 (Fed.Cir.2008). Thus, to establish a prima facie case of obviousness in cases involving new chemical compounds, the accused infringer must identify some reason that would have led a chemist to modify a known compound in a particular manner. See Yamanouchi Pharm. Co., Ltd. v. Danbury Pharmacal, Inc., 231 F.3d 1339, 1344 (Fed.Cir.2000). This standard is consistent with the legal principles announced in the Supreme Court's decision in KSR Int'l Co. v. Teleflex Inc., 550 U.S. 398, 127 S.Ct. 1727, 167 L.Ed.2d 705 (2007). See Takeda Chem. Indus., Ltd. v. Alphapharm Pty., Ltd., 492 F.3d 1350, 1356 (Fed.Cir.2007); Eisai, 533 F.3d at 1359 (In other words, post-KSR, a prima facie case of obviousness for a chemical compound still, in general, begins with the reasoned identification of a lead compound.). Obviousness based on structural similarity may be proven by the identification of some motivation that would have led one of ordinary skill in the art to select and modify a known compound in a particular way to achieve the claimed compound. Eisai, 533 F.3d at 1357. The requisite motivation can come from any number of sources and need not necessarily be explicit in the art. Id. (citing Aventis Pharma Deutschland GmbH v. Lupin, Ltd., 499 F.3d 1293, 1301 (Fed.Cir.2007)). Instead, 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. Id. (quoting In re Dillon, 919 F.2d 688, 692 (Fed. Cir.1990) (en banc)). Our review of the district court's decision is limited, and it is important to place the district court's findings in perspective. Applications for preliminary injunctions are typically presented on an abbreviated record without the benefit of a full trial. In this case, the district court carefully explained that its obviousness findings were preliminary. In the district court, the defendants attempted to prove that the claims were vulnerable because one of skill in the art would have selected a number of compounds disclosed in the '518 patent, including compound 12, as a starting point for further development. Based on the record before it, the district court found that Defendants have raised a substantial argument that compound 12 was a natural choice for further development in this regard. Ample evidence supported this finding. First, the '518 patent claimed that its compounds, including compound 12, were improvements over the prior art, specifically omeprazole (the first successful PPI). In addition, compound 12 was disclosed as one of the more potent of the eighteen compounds of the '518 patent for which data was provided during prosecution. Moreover, the patent examiner relied on the compounds of the '518 patent during the prosecution of the '579 patent. Cf. Eisai, 533 F.3d at 1357 (Indeed, Teva's pharmacology expert ... declined to opine on lansoprazole's relevance to an examiner assessing the patentability of rabeprazole.). Beyond this evidence, the district court considered the opinions of qualified experts. The defendants supported their obviousness argument with the Declaration of Prof. Lester A. Mitscher, Ph.D. Dr. Mitscher was amply qualified to express opinions on the subject matter involved in this case. Dr. Mitscher expressed his opinion that Altana's '518 patent (which disclosed compound 12) was on the cutting edge of PPI development in June 1984. Dr. Mitscher provided the district court with an overview of the history of PPIs and the state of the art as of June 1984. In particular, Dr. Mitscher stated that one of skill in the art would have selected the 18 exemplary compounds (including compound 12) of the '518 patent over omeprazole from which to pursue further development efforts designed to improve the quality and effectiveness of PPIs. Although Altana's expert suggested that one of skill in the art would have selected omeprazole over the compounds of the '518 patent, in part because of toxicity concerns, the district court apparently accepted Dr. Mitscher's contrary opinion. The district court's reliance on Dr. Mitscher's opinion was not clearly erroneous. Beyond the finding that those of skill in the art would have pursued the 18 exemplary compounds in the '518 patent, the district court also found that one of skill in the art would have found compound 12, in particular, a natural choice for further development efforts. This finding is supported by evidence that compound 12 was one of the more potent PPI compounds disclosed in the '518 patent. Although potency is not dispositive, the district court believednot unreasonablythat the potency of the compound was a factor that would have led one of skill in the art to select compound 12 from the group for further study. It bears mention that Altana itself had selected compound 12 for further development efforts, although the inventor stated that he ultimately developed pantoprazole by using an unwanted by-product from his scale up work as a starting point, rather than compound 12. Altana suggests that the prior art would not have directed one of skill in the art to select compound 12 over the approximately 90 compounds claimed to be improvements in the '518 and other prior art patents, or, for that matter, over the thousands of other compounds included in the prior art disclosures. In light of Dr. Mitscher's declaration, however, the district court had a sufficient evidentiary basis for rejecting that position. Moreover, to the extent Altana suggests that the prior art must point to only a single lead compound for further development efforts, that restrictive view of the lead compound test would present a rigid test similar to the teaching-suggestion-motivation test that the Supreme Court explicitly rejected in KSR. Cf. KSR, 550 U.S. at 419, 127 S.Ct. 1727 (The obviousness analysis cannot be confined by a formalistic conception of the words teaching, suggestion, and motivation, or by overemphasis on the importance of published articles and the explicit content of issued patents. The diversity of inventive pursuits and of modern technology counsels against limiting the analysis in this way.). The district court in this case employed a flexible approachone that was admittedly preliminaryand found that the defendants had raised a substantial question that one of skill in the art would have used the more potent compounds of the '518 patent, including compound 12, as a starting point from which to pursue further development efforts. That finding was not clearly erroneous. The district court determined that the Sachs article taught those of skill in the art that an effective PPI should have a pKa of 4 because a pKa of 4 would lead to better stability of the compound within the body. Thus, according to the district court, one of skill in the art would have been motivated to modify the prior art compounds to reduce their pKa to 4. It is not disputed that the author of the Sachs article, Dr. George Sachs, is one of the leading researchers in the PPI development field. As such, the district court was entirely justified in selecting the Sachs article as relevant prior art. Moreover, although Altana disputed the teachings of Sachs before the district court, Altana does not challenge on appeal the district court's findings with respect to the Sachs teachings. Instead, Altana contends that the district court made a factual error in interpreting the Bryson article which requires reversal. We now turn to that issue. The Bryson article teaches the pKa values of various chemical groups, including methoxy groups, at the 3-position of a simple pyridine ring. The defendants argued that Bryson taught that a methoxy group at the 3-position of the pyridine ring would have a lower pKa value than if it had a methyl group at that position. The district court accepted this argument, but stated [a]ccording to Bryson, the pKa value of a methoxy group at such a position is 4; however, the pKa of a methyl group at this position is 5. The district court also stated: Bryson undisputably taught that a compound with a methoxy group at the 3 position of the pyridine ring would have a lower pKa value (namely a pKa of 4) that [sic] a compound with a methyl group at that position. The district court concluded that [w]hen Bryson's teachings are combined with the structure of compound 12 and combined with Dr. Sachs's teachings, Defendants have raised a substantial question that this combination was at the very least obvious to try and that such would lead to a predictable variation of compound 12, i.e., a compound with better pH5 stability. Altana correctly points out that the district court's findings that Bryson discloses lowering the pKa to 4 through the substitution of a methoxy group are in error. Bryson actually discloses values of 4.83 and 4.91 for simple pyridine rings containing a methoxy group in the 3-position. Because pKa values are measured on a logarithmic scale, there is a very substantial mathematical difference in the magnitude of a pKa value of 4 versus a pKa value of 4.83. A value of 4.83 is over 6.7 times larger than a value of 4. This error, however, does not require reversal unless Altana also shows that the district court's denial of the requested injunction was an abuse of discretion. New England Braiding Co., 970 F.2d at 882. Notwithstanding the district court's statements, the declaration of Dr. Mitscher clearly does not make such an error in its analysis of the Bryson reference. Rather, the evidence presented by the defendants supports a finding that one of skill in the art would read Bryson to teach the lowering of a pKa through the substitution of a methoxy group for a methyl group at the 3-position of the pyridine ring. Dr. Mitscher stated that Bryson indicates that the addition of a methoxy group at the 3-position decreases the pKa of pyridine by 0.27-0.35 pKa units (with an average pKa for 3-methoxy pyridine of 4.87). Consistent with Dr. Mitscher's statements, the Bryson article discloses precisely that. The expert also accurately described Bryson's disclosure of the pKa values of the pyridine ring with a methyl group at the 3-position: Bryson indicates that the addition of a methyl group at the 3-position of pyridine increases the pKa of pyridine by 0.34-0.53 pKa units (with an average pKa for 3-methyl pyridine of 5.66 compared to an average pKa of 5.18 for unsubstituted pyridine). Thus, the difference in the average pKa values of methyl and methoxy substituted pyridine rings disclosed by Bryson is 0.79. Under Bryson, the pKa of the methoxy substituted pyridine ring is substantially lower than the methyl substituted pyridine ring. The district court's references to pKa values of 5 and 4, although not technically accurate, in fact correlate with the difference in magnitude of the pKa values of the substituted pyridines described in Bryson. Indeed, elsewhere in the district court's opinion, the court stated that if Sachs teaches pH5 stability via lowering the pKa of the pyridine ring, and Bryson teaches how to lower such pKa, then the purportedly unexpected property of pantoprazole is in fact an expected property. The defendants as well as the district court understood that the obviousness position depended on Bryson's teaching of a way to substantially lower the pKa value of the pyridine ring. [4] The evidence thus supports the district court's overriding decision that the defendants had made out a sufficient case of obviousness to defer the matter for trial on the merits, as opposed to granting the preliminary relief sought by the plaintiffs. Moreover, the district court found that Altana had failed to prove irreparable harm. As we shall explain, that finding is not clearly erroneous and under this court's precedent is a prerequisite for preliminary relief. Accordingly, although we agree with Altana that some of the district court's findings with respect to Bryson were incorrect, we do not disturb the district court's decision on this ground.