The Federal Circuit considered its 35 U.S.C. § 112 enablement case law and found that “the enablement inquiry for claims that include functional requirements”—in this case, claims to antibodies defined by their function—“can be particularly focused on the breadth of those requirements, especially where predictability and guidance fall short.” Dkt. 132 at 10. In Amgen Inc. et al. v. Sanofi, Aventisub LLC, et al., 20-1074 (Fed. Cir.), the Federal Circuit affirmed the district court’s finding of non-enablement for claims asserted by Amgen Inc., Amgen Manufacturing, Ltd., and Amgen USA, Inc. (collectively, “Amgen”). Id. at 3. U.S. Patent Nos. 8,829,165 and 8,859,741 were reviewed by the Federal Circuit for the second time, after Sanofi, Aventisub LLC, Regeneron Pharmaceuticals Inc., and Sanofi-Aventis U.S. LLC (collectively, “Sanofi”) previously successfully appealed a jury determination “that the patents were not shown to be invalid for lack of enablement and written description.” Id. at 5. In the first appeal, the Federal Circuit remanded for a new trial because it found that the “district court erred in its evidentiary rulings and jury instructions,” in particular related to the written description requirement for functional antibody claims. Id. On remand, following a new trial, the jury ruled for Amgen but the district court, on motion for JMOL, overturned the jury’s verdict and found Amgen’s functional antibody claims invalid for lack of enablement as a matter of law. On appeal, the Federal Circuit affirmed.

The patents in suit “describe antibodies that purportedly bind to the PCSK9 protein and lower LDL levels by blocking PCSK9 from binding to LDL receptors.” Id. at 3. Amgen’s patents, related to its Repatha (evolocumab) product, were alleged to cover Sanofi’s Praluent (alirocumab) product as well. The patents “claim antibodies that bind to one or more of fifteen amino acids . . . of the PCSK9 protein and block PCSK9 from binding to LDL receptors.” Dkt. 132 at 4. The Federal Circuit homed in on the functional requirements of Amgen’s claims—i.e., the antibodies of the claims are defined not by their structure (i.e., amino acid sequence), but by their binding and blocking functions: “binding to . . . combinations of sites (residues) on the PCSK9 protein, in a range from one residue to all of them; and blocking the PCSK9/LDLR interaction.” Id. at 5. The question was whether the specification—which provided 26 examples of antibodies that meet the claims, as well as techniques for screening to find more such examples—enabled ordinarily skilled artisans to make and use the claimed antibodies without undue experimentation.

To assess whether undue experimentation would be needed, the Court considered the so-called Wands factors, first laid out in In re Wands, 858 F.2d 731, 736-37 (Fed. Cir. 1988). These factors include, among others, assessments of the quantity of experimentation required, the amount of guidance in the patent specification, and the level of predictability in the art, in considering whether the experimentation necessary to make and use an invention is “undue.”

The enablement concern here, as Sanofi argued, is that “there are millions of antibody candidates within the scope of the claims, the disclosures do not provide sufficient guidance, antibody generation is unpredictable, and practicing the full scope of the claims requires substantial trial and error.” Id. at 8. While the Court recognized that the parties disputed the exact number of antibodies within the scope of Amgen’s claims, the issue was not the precise number of embodiments, but the claims’ “functional breadth.” Id. at 12. In other words, according to the Court, “[r]egardless of the exact number of embodiments, it is clear that the claims are far broader in functional diversity than the disclosed examples.” Id.

The Federal Circuit also emphasized the unpredictability of structure-function relationships in antibodies. For example, the Court quoted Amgen’s own expert’s concession that “substitutions in the amino acid sequence of an antibody can affect the antibody’s function, and testing would be required to ensure that a substitution does not alter the binding and blocking functions.” Dkt. 132 at 12-13. This level of unpredictability led the Federal Circuit to agree with the district court that:

the only ways for a person of ordinary skill to discover undisclosed claimed embodiments would be through either “trial and error, by making changes to the disclosed antibodies and then screening those antibodies for the desired binding and blocking properties,” or else “by discovering the antibodies de novo” according to a randomization-and-screening “roadmap.”

Id. at 13. Either way, “the required experimentation would take a substantial amount of time and effort.” Id.

The Court cautioned that “the effort required to exhaust a genus is [not] dispositive.” Id. Nevertheless, the Court made clear that “[i]t is appropriate . . . to look at the amount of effort needed to obtain embodiments outside the scope of the disclosed examples and guidance.” Id. Ultimately, the Federal Circuit found that, on the facts of this particular case, “the evidence showed that the scope of the claims encompasses millions of candidates claimed with respect to multiple specific functions, and that it would be necessary to first generate and then screen each candidate antibody to determine whether it meets the double-function claim limitations.” Dkt. 132 at 14. As a result, the Federal Circuit affirmed “the district court’s determination that the asserted claims are invalid for lack of enablement.” Id.