Obviousness of Risedronate in Light of the Prior Art
To decide whether risedronate was obvious in light of the prior art, a court must determine whether, at the time of invention, a person having ordinary skill in the art would have had “reason to attempt to make the composition” known as risedronate and “a reasonable expectation of success in doing so.” PharmaStem Therapeutics, Inc. v. ViaCell, Inc., 491 F.3d 1342, 1360 (Fed. Cir. 2007).
The district court concluded that, even if 2-pyr EHDP were a lead compound, it would not render the ’122 patent’s claims on risedronate obvious because a person having ordinary skill in the art would not have had reason to make risedronate based on the prior art. The district court’s findings also support the conclusion that there could have been no reasonable expectation as to risedronate’s success.
The question of obviousness “often turns on the structural similarities and differences between the claimed compound and the prior art compound.” Eisai Co. Ltd. v. Dr. Reddy’s Labs., Ltd., 533 F.3d 1353, 1356-57 (Fed. Cir. 2008); see also Sanofi-Synthelabo v. Apotex, Inc., 550 F.3d 1075, 1086 (Fed. Cir. 2008) (“Precedent establishes the analytical procedure whereby a close structural similarity between a new chemical compound and prior art compounds is generally deemed to create a prima facie case of obviousness . . . .”); In re Mayne, 104 F.3d 1339, 1343 (Fed. Cir. 1997) (“Structural relationships often provide the requisite motivation to modify known compounds to obtain new compounds.”); In re Payne, 606 F.2d 303, 313-15 (CCPA 1979) (discussing the presumption of obviousness based on close structural similarity). In this case, risedronate and 2-pyr EHDP are positional isomers; they each contain the same atoms arranged in different ways. In risedronate, the hydroxy-ethane-diphosphonate group is connected to the #3 carbon of a pyridine ring, while in 2-pyr EHDP, the hydroxy-ethane-diphosphonate group is connected to the #2 carbon. Because the nitrogen atom is in a different position in the two molecules, they differ in three dimensional shape, charge distribution and hydrogen bonding properties.
To successfully argue that a new compound is obvious, the challenger may show “that the prior art would have suggested making the specific molecular modifications necessary to achieve the claimed invention.” Takeda, 492 F.3d at 1356 (quotation marks omitted). “In keeping with the flexible nature of the obviousness inquiry, the requisite motivation [to modify] can come from any number of sources.” Eisai, 533 F.3d at 1357 (citation omitted). Thus, in addition to structural similarity between the compounds, a prima facie case of obviousness may be shown by “adequate support in the prior art” for the change in structure. In re Grabiak, 769 F.2d 729, 731-32 (Fed. Cir. 1985). As we noted in Takeda:
A known compound may suggest its homolog, analog, or isomer because such compounds often have similar properties and therefore chemists of ordinary skill would ordinarily contemplate making them to try to obtain compounds with improved properties. . . . [However,] 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.
492 F.3d at 1356-57 (citation omitted).
At trial, P&G’s expert witnesses testified that, in 1985, a person having ordinary skill in the art realized that the properties of bisphosphonates could not be anticipated based on their structure. Additionally, the trial court relied on contemporaneous writings from Herbert Fleisch, the preeminent authority on bisphosphonates during the relevant time period. Dr. Fleisch wrote in 1984 that “every compound, while remaining a bisphosphonate, exhibits its own physical-chemical, biological and therapeutic characteristics, so that each bisphosphonate has to be considered on its own. To infer from one compound the effects in another is dangerous and can be misleading.” Herbert Fleisch, Chemistry and Mechanisms of Action of Bisphosphonates, in Bone Resorption, Metastasis, and Diphosphonates 33-40 (S. Garattini ed., 1985). In this case, P&G synthesized and tested 2-pyr EHDP, risedronate (3-pyr EHDP) and 4-pyr EHDP, another structural isomer. Confirming the unpredictability of bisphosphonates, test results for 4-pyr EHDP revealed that it was not active in inhibiting bone resorption despite its close relationship with potent compounds. In light of the Supreme Court’s instruction in KSR, the Federal Circuit has stated that, “[t]o the extent an art is unpredictable, as the chemical arts often are, KSR’s focus on  ‘identified, predictable solutions’ may present a difficult hurdle because potential solutions are less likely to be genuinely predictable.” Eisai, 533 F.3d 1353, 1359 (quoting KSR, 127 S. Ct. at 1742). The district court found that Teva failed to clear that hurdle, establishing insufficient motivation for a person of ordinary skill to synthesize and test risedronate. This finding was not clearly erroneous.
Additionally, there was an insufficient showing that a person of ordinary skill in the art would have had a “reasonable expectation of success” in synthesizing and testing risedronate. PharmaStem, 491 F.3d at 1360. In KSR, the Supreme Court stated that when an obvious modification “leads to the anticipated success,” the invention is likely the product of ordinary skill and is obvious under 35 U.S.C. § 103. 127 S. Ct. at 1742. “[O]bviousness cannot be avoided simply by a showing of some degree of unpredictability in the art so long as there was a reasonable probability of success.” Pfizer, 480 F.3d at 1364 (citing In re Corkill, 771 F.2d 1496, 1500 (Fed. Cir. 1985)). Here, the district court’s findings indicate that there was no reasonable expectation in 1985 that risedronate would be a successful compound.
Cases following KSR have considered whether a given molecular modification would have been carried out as part of routine testing. See, e.g., Takeda, 492 F.3d at 1360 (discussing the district court’s finding that a modification was not known to be beneficial and was not considered “routine”). When a person of ordinary skill is faced with “a finite number of identified, predictable solutions” to a problem and pursues “the known options within his or her technical grasp,” the resulting discovery “is likely the product not of innovation but of ordinary skill and common sense.” KSR, 127 S. Ct. at 1742. So too, “[g]ranting patent protection to advances that would occur in the ordinary course without real innovation retards progress.” Id. at 1741. In other cases, though, researchers can only “vary all parameters or try each of numerous possible choices until one possibly arrive[s] at a successful result, where the prior art [gives] either no indication of which parameters [are] critical or no direction as to which of many possible choices is likely to be successful.” In re O’Farrell, 853 F.2d 894, 903 (Fed. Cir. 1988). In such cases, “courts should not succumb to hindsight claims of obviousness.” In re Kubin, __ F.3d __, No. 2008-1184, slip op. at 14 (Fed. Cir. Apr. 3, 2009). Similarly, patents are not barred just because it was obvious “to explore a new technology or general approach that seemed to be a promising field of experimentation, where the prior art gave only general guidance as to the particular form of the claimed invention or how to achieve it.” In re
In this case, there is no credible evidence that the structural modification was routine. The district court found that the appellee’s expert was evasive on this topic, stating that the witness “did not directly respond to most questions posed to him about whether it would be common for a chemist who develops a pyridine compound to conceive of and make [2-pyr EHDP, 3-pyr EHDP, and 4-pyr EHDP] isomers.” Procter & Gamble, 536 F. Supp. 2d at 486. But evidence of evasion is not necessarily evidence that the testimony would otherwise have been favorable. The only direct evidence that
the structural modification was routine was presented by an expert witness that the district court judge discredited. Accordingly, we conclude that the district court did not clearly err in finding that Teva had not established a prima facie case of obviousness as to the challenged claims of the ’122 patent.
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