Novartis v. West-Ward – Lead Compound Analysis v. Motivation to Combine
In Novartis Pharm. v. West-Ward Pharm., Appeal no. 2018-1434 (Fed. Cir., May 12, 2019), a three judge panel of Stoll, Plager and Clevenger affirmed the district court’s ruling that the claims of Novartis’ U.S. Pat. No. 8,410,131, directed to using a rapamycin analog 40-O-(2-hydroxyethyl) rapamycin (“everolimus”) to treat renal cell carcinoma (RCC) were valid over two prior art Novartis patents disclosing this analog and disclosing that it is generally useful to treat “tumors” and two papers disclosing phase I studies of another rapamycin analog, temsirolimus, which showed some efficacy against RCC.
The panel held that the district court erred in finding that the POSA “would have been motivated to pursue everolimus as one of several potential treatment options for…advanced RCC.” The panel continued:
“This finding should have affirmatively answered the question whether there would have been a motivation to combine. Yet, the district court continued its analysis and found that West-Ward ‘failed to prove by clear and convincing evidence that a POSA would have been motivated to select everolimus.’ The district court erred in applying this heightened standard. ‘[O]ur case law does not require that a particular combination must be the preferred, or the most desirable combination described in the prior art in order to provide motivation for the current invention.”
Does this sound like a subtle point? The panel went on to explain that this is not a “lead compound” case but is a new use for a known compound case:
“In lead compound cases, the court first determines whether a [POSA] ‘would have selected the asserted prior art compounds as lead compounds, or starting points for further development efforts….This requires the patent challenger to show by clear and convincing evidence that a [POSA] ‘would have had a reason to select a proposed lead compound or compounds over other compounds in the prior art…the court then determines ‘whether the prior art would have supplied the [POSA] with a reason or motivation to modify a lead compound to make the claimed compound with a reasonable expectation of success’”[italics added].
The difference between an obviousness rejection based on a lead compound analysis, e.g. is temsirolimus an appropriate lead compound, and a motivation to combine rejection of a claim to a new use for a known compound was explained by the panel:
“The [Novartis] patent claims methods of using everolimus to inhibit growth of solid tumors, including in patients having advanced RCC…It does not claim the everolimus compound itself, but rather methods of using the compound. This case therefore does not require lead compound analysis or analysis of whether a particular dose in a range of prior art doses would have been obvious….To the extent the district court required a showing that a [POSA] would have selected everolimus over other prior art compounds, it erred. The proper inquiry is whether a [POSA] would have been motivated to modify the prior art disclosing the use of temsirolimus to treat advanced RCC with the prior art disclosing everolimus.”
The last sentence is a bit awkward and might better have been presented as: “The proper inquiry is whether a POSA would have been motivated to try to treat RCC with everolimus, in view of the fact that everolimus had been disclosed to be useful to treat “tumors” and other references disclosed that temsirolimus, another rapamycin analog, showed anti-cancer activity against RCC.”
The panel held that the judge’s approach conflated the two approaches but answered the key question “affirmatively when the district court judge found that a [POSA] ‘would have been motivated to pursue everolimus as one of several potential treatment options for advanced sold tumors.’”
If everolimus was not in the prior art, the lead compound approach would have selected the closest rapamycin analog in the prior art, which was not temsirolimus, but 40-O-(3-hydroxypropyl) rapamycin, a compound disclosed in the ‘973 patent that is a homolog of everolimus that differs in having one more methylene group in the 40-O position. Without more, it would be prima-facie obvious to modify that substituent to arrive at everolimus, so the outcome of this inquiry would probably be the same.
The panel went on to hold that there was not a reasonable expectation of success in using everolimus to treat RCC, even given the somewhat promising Phase I trial data. (Temsirolimus went on to be approved to treat RCC.) While West-Ward argued that the district court judge erred by requiring clinical proof in the prior art that everolimus would be effective against RCC. The panel found that the weight of the evidence did not support a finding of a reasonable expectation of success:
“The district court reviewed the above evidence, determined that the molecular biology of advanced RCC was not fully understood, recognized the limitations in the temsirolimus phase I data, and found that such data did not provide a [POSA] with a reasonable expectation of success.”
Interestingly, the structural differences between temsirolimus and everolimus did not come into play, although I don’t see why they would not buttress an argument that everolimus would not be expected to have similar anti-cancer activity as temsirolimus, even though they are both mTOR inhibitors. The only reference to structure is on page 5 of the slip. opinion: “Everolimus is structurally similar to temsirolimus and is likewise a derivative of rapamycin.” However, from the standpoint of classical structural analysis, the two compounds are not “structurally similar.” Everolimus has a 40-O-hydroxy methyl group while temsirolimus has the more complex 40-O-(bis-1-(hydroxymethyl)) propanoyl substituent comprising an ester linkage to the 4O-0H group. Apparently neither side wanted to dust off their organic chemistry textbooks.