Obviousness in Pharmaceutical and Medical Patent Cases: Making Sense of Motivation to Combine

In 2007, the Supreme Court rejected the Federal Circuit’s rigid application of the so-called "TSM test"—that there must be an explicit teaching, suggestion, or motivation in the prior art—in order to find a claimed invention is obvious. While the Supreme Court adopted a more flexible approach to obviousness, it nevertheless acknowledged that the finder of fact must identify "a reason that would have prompted a person of ordinary skill in the relevant field to combine the elements in the way the claimed new invention does." KSR International Co. v. Teleflex Inc. et al., 550 U.S. 398 (2007). Recent Federal Circuit cases provide guidance for determining whether sufficient motivation to combine exists in life sciences cases where an explicit teaching, suggestion, or motivation is lacking in the prior art.

The Federal Circuit’s recent In re: Nuvasive Inc., No. 2015-1670 (Fed. Cir. Dec. 7, 2016) decision is particularly instructive. The Nuvasive case involved claims to a spinal fusion implant that required first and second radiopaque markers placed at certain positions relative to the medial plane. In response to a petition by Medtronic, Inc., the PTAB instituted an inter partes review and determined that the claims at issue were obvious over a combination of references. On appeal, Nuvasive argued that the PTAB did not adequately explain why a person having ordinary skill in the art ("PHOSITA") would have been motivated to combine the prior art references to locate the radiopaque markers on the medial plane as required by the claims. According to Nuvasive, the PTAB relied solely on conclusory testimony by Medtronic’s expert that a skilled artisan would modify the prior art to obtain "additional information." Nuvasive, slip op at 8.

The Federal Circuit agreed that this was not sufficient: "the PTAB must articulate a reason why a PHOSITA would combine the prior art references," and that reason must have "a foundation in the prior art." Nuvasive, slip op. at 9, 10 (emphasis in the original). In Nuvasive, however, "the PTAB never articulated why the additional information would benefit a PHOSITA when implanting . . . the implants disclosed in [the prior art]," "never actually made an explanation-supported finding that . . . the PHOSITA would have sought this additional information," and "failed to explain the type of additional information a PHOSITA would obtain or how the PHOSITA would use that information." Id. at 12. Significantly, the PTAB failed to articulate a reason why a PHOSITA would have modified the prior art implants to place radioplaque markers proximate to said medial plane. Although the modification resulted in improved alignment of the implant, there was no evidence that a PHOSITA would have sought or appreciated the improvement prior to the priority date of patent-in-suit. Id. at 12-13.

The Nuvasive decision thus focused on two elements for a motivation to combine: A well-articulated reason to make a modification that has its foundation in the prior art, and an explanation that one of skill in the art would have recognized that the specific combination of prior art references relied upon would provide the reason to modify the art to arrive at the claimed invention. Invoking "common sense," "common knowledge," or "the high level of skill in the art" without more, is not enough to establish motivation to combine. Id. at 11.

Other recent Federal Circuit decisions in the life sciences arena have followed a similar approach. In Millennium Pharmaceuticals v. Sandoz, Inc. et al., Nos. 2015-2066, 2016-1008, 2016-1009, 2016-1010, 2016-1109, 2016-1110, 2016-1283, 2016-1762 (Fed. Cir. July 17, 2017), the Federal Circuit reversed the district court’s holding that the claims to a boronate ester of bortezomib and D-mannitol were obvious as the inherent (or natural) result of an allegedly obvious process of lyophilizing bortezomib in the presence of mannitol, a known bulking agent that had been previously used in the lyophilization of other substances. In Millennium, the Federal Circuit found insufficient evidence of both motivation and a reasonable expectation of success. As to motivation, the Federal Circuit identified the problem as the known instability and insolubility of bortezomib, which were severe enough to prevent the FDA from approving that drug for clinical use, despite its known efficacy against various cancers. But there was no evidence that one of ordinary skill in the art recognized that the lyophilization of bortezomib in the presence of mannitol would cause a chemical reaction that would result in a previously unknown ester, let alone that the resulting ester would solve bortezomib’s insolubility and instability problems. Millennium, slip op. at 12 ("None of these references, alone or in combination, suggests or teaches that the solution to the problems of creating an efficacious formulation of bortezomib lay in freeze-drying bortezomib with mannitol to form an ester having the necessary properties for stability, storage, and treatment.").

Similarly, in Eli Lilly and Company v. Teva Parenteral Medicines, Inc., et al., No. 2015-2067 (Fed. Cir. Jan. 12, 2017), claims to an improved method of administering pemetrexed, a chemotherapeutic agent, comprising pretreatment of the patient within specific dose ranges of both folic acid and vitamin B12, were not obvious because one of skill in the art would not have been motivated to use vitamin B12 pretreatment with pemetrexed, let alone in accordance with the claimed dosage regimens. Eli Lilly, slip op. at 24. Again, the problem was known–pemetrexed toxicity–but the cited prior art did not provide evidence of a relationship between vitamin B12 and pemetrexed toxicity and thus "would not have motivated a skilled artisan to administer vitamin B12 to patients to address pemetrexed toxicity." Id. at 26. In other words, a skilled artisan would not have recognized that vitamin B12 therapy, as disclosed in the prior art, would address the pemetrexed toxicity problem and arrive at the claimed vitamin B12 pretreatment invention.

In all of three of these cases, the Federal Circuit required more than mere "common sense" or a desire to improve upon what is known. In fact, the court seems to have taken a two-step approach to motivation: (1) identifying a problem, grounded in the prior art, and (2) explaining why one of skill in the art would have recognized that the cited combination of prior art references would solve that problem through modifications that arrive at the claimed invention. These two elements provide at least one approach for analyzing the issue of motivation in the context of life science patents.