On February 11, 2021 the Federal Circuit upheld a United States District Court for the District of Delaware decision finding that Amgen's function-only anti-PCSK9 monoclonal antibody claims were not  enabled under 35 U.S.C. § 112. This highly anticipated decision involved a suit between the makers of the LDL-cholesterol-lowering drugs, Repatha® (Amgen) and Praluent® (Sanofi/Regeneron), filed nearly seven years ago by Amgen. Amgen had argued that patents for its cholesterol drug, RepathaⓇ, which cover a genus of antibodies that bind to a protein known as PCSK9, were sufficiently specific to allow one “skilled in the art” to “make and use” the patented invention without “undue experimentation” under the Wands factors. Claim 1 from Amgen's ‘165 patent, which is representative of the asserted claims, reads in relevant part:

  1. An isolated monoclonal antibody, wherein, when bound to PCSK9, the monoclonal antibody binds to at least one of the following residues: S153, I154, P155, R194, D238, A239, I369, S372, D374, C375, T377, C378, F379, V380, or S381 of SEQ ID NO:3, and wherein the monoclonal antibody blocks binding of PCSK9 to LDLR.

This claim is directed to anti-PCSK9 antibodies, which are defined in terms of function only, namely that, (i) each monoclonal antibody in the claim scope must bind to “at least one” of the recited fifteen amino acid residues of PCSK9, i.e., corresponding to the “sweet spot” of PCSK9 defining a surface of the PCSK9 catalytic domain that binds to the EGFa domain of hepatocyte LDL-Rs.

Sanofi, also relying on the Wands  factors, argued that the claims were not enabled because the experimentation required to make and use the full scope of claimed antibodies would have been undue. The Federal Circuit affirmed the district court's ruling, agreeing with Sanofi, and held that “the patent does not provide significant guidance or direction to a person of ordinary skill in the art for the full scope of the claims,” and that “undue experimentation would be required to reach the full scope of claimed embodiments.”

The Patents at Issue

At issue in this appeal are claims 19 and 29 of the ‘165 patent and claim 7 of the ‘741 patent. Both patents, which issued in 2014, describe and claim antibodies that bind to the PCSK9 protein, which lowers LDL cholesterol levels in the blood by blocking the binding of PCSK9 to LDL receptors, preventing their degradation by the cell. The ‘165 and ‘741 patents share a similar disclosure, and its “specification discloses amino acids sequences for twenty-six antibodies, including the antibody...with the generic name of evolocumab, marketed by Amgen as RepathaⓇ.” The patents include various data around the disclosed antibodies, including amino acid sequences, PCSK9 domain binding assays, epitope mapping to determine which amino acid side chains in PCSK9 bind to antibodies, binning experiments to group antibodies based on common binding sites on PCSK9, and crystal structure determinations for at least two antibodies bound to PCSK9 to evaluate the binding interaction between epitope and antibody.

Procedural History

Amgen filed suit in the United States District Court for the District of Delaware on October 14, 2014, alleging that Sanofi had infringed its ‘165 and ‘174 patents, among others. At the close of trial, the jury found that the patents were not invalid for lack of enablement and written description. The district court granted JMOL for nonobviousness and no willful infringement and denied Sanofi's motion for JMOL of no written description and enablement. Sanofi appealed. The Federal Circuit affirmed the grant of Amgen's motion for JMOL of non-obviousness and the denial of Sanofi's motion for JMOL of no written description and enablement. The Federal Circuit, however, reversed the district court for errors made in evidentiary rulings and jury instructions, and remanded for a new trial on the issues of whether the patents lacked written description and enablement.

District Court Decision on Remand

On remand, the jury again found that Sanofi “failed to prove that the asserted claims were invalid for lack of written description and enablement.” Sanofi moved for JMOL for lack of enablement and written description. The district court granted JMOL for lack of enablement but denied JMOL for lack of written description.

The purpose of the enablement requirement is to ensure that the public is told how to carry out the invention, i.e., to make and use it. The requirement has been defined as not requiring that a person of ordinary skill in the art engage in “undue experimentation” to practice the claimed invention. In granting Sanofi's motion for JMOL for lack of enablement, the district court conducted its analysis based on the factual considerations set forth in In re Wands (also known as the Wands factors) for determining whether undue experimentation is needed. The Wands  factors are:

1) The quantity of experimentation necessary, 2) the amount of direction or guidance presented, 3) the presence or absence of working examples, 4) the nature of the invention, 5) the state of the prior art, 6) the relative skill of those in the art, 7) the predictability or unpredictability of the art, and 8) the breadth of the claims.

The district court compared the case at issue to various precedent involving claims similarly reciting compounds defined by functional limitations, such as Wyeth & Cordis Corp. v. Abbott Laboratories, Enzo Life Sciences, Inc. v. Roche Molecular Systems, Inc.,  and Idenix Pharmaceuticals LLC v. Gilead Sciences Inc. In each of these cases, the claimed compounds were defined by structure and function. The court noted in those cases it had held a lack of enablement due to the failure of the specification to teach how the full scope of the claims met the required functionality. For example, the court in Idenix  pointed to the vast scope of claimed compounds, noting that one skilled in the art would be required to screen “billions” of compounds to determine which ones exhibited the claimed functional limitations. The Federal Circuit found in these instances that undue experimentation was required.

The district court reviewed Sanofi's two key arguments: namely that (a) there were antibodies in the claim scope that were impossible to make and (b) that under In re Wands, the claims lacked enablement. As to the “impossibility” argument, the court reviewed the evidence regarding several alleged “impossible to make” antibodies (e.g., one which bound to only a single recited residue on PCSK9) and found that the evidence only supported that such antibodies “were unlikely” to make, but not impossible. As to In re Wands, the court analyzed the Wands  factors, including the claim scope, predictability in the art, and level of guidance. The court agreed with Sanofi that the claims were broad, potentially including millions of antibodies and rejected Amgen's position that the scope was much lower because the skilled person would have engaged in “intelligent substitutions.” The court also agreed with Sanofi that the art was highly unpredictable because, for instance, amino acid sequences alone could not predict three-dimensional antibody structures and/or whether a particular substitution would allow for the claimed functions. With a nod to similar outcomes in Wyeth, Enzo, and Idenix, the court held that the specification did not enable preparation of the full scope of the claimed antibodies.

Amgen appealed and the matter returned to the Federal Circuit for a second time.

The Federal Circuit's February 11, 2021 Decision

In its second review of the ‘165 and ‘741 patents, the Federal Circuit affirmed the district court's ruling that the asserted claims were not enabled and thus, were invalid. The decision largely turned on the court's analysis of the Wands  factors.

The court began by acknowledging that “[a]fter the challenger has put forward evidence that some experimentation is needed to practice the patented claim, the factors set forth in Wands then provide the factual considerations that a court may consider when determining whether the amount of that experimentation is either ‘undue' or sufficiently routine such that an ordinary skilled artisan would reasonably be expected to carry it out.”

In the instant case, Amgen argued that no undue experimentation was needed to obtain antibodies within the scope of the claims, pointing to expert testimony that “a person of skill in the art can make all antibodies within the scope of the claims by following a roadmap using anchor antibodies as described in the specification. . . ” and that the district court erred by focusing on the effort required to discover and make every embodiment of the claims. Sanofi countered by arguing 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,” and that instead of focusing on the number of antibodies actually known to satisfy the claims, “this court's precedents require examining the number of candidates that must be made and tested to determine whether they satisfy the claimed function.”    

The Federal Circuit agreed with the district court that cases such as Wyeth, Enzo,  and Idenix are instructive as to the present case. The Federal Circuit explained that the enablement inquiry for claims that include functional requirements can be particularly focused on the breadth of those requirements, especially where unpredictability is high and guidance falls short, as determined for the asserted claims. Consistent with its earlier decisions, the Federal Circuit confirmed that the amount of experimentation that is required to make and use the full scope of the claims - not just the limited number of embodiments that the patent discloses – is important to consider. Additionally, the court elaborated that in cases involving claims that contain both structure and functional recruitments (e.g., Idenix), undue experimentation can include the steps needed to sort from the total compounds meeting the structural requirements those compounds also satisfying the functional requirements.

The Federal Circuit agreed with the district court that the main concern with the “double-function claims” is not only the number of embodiments but also their “functional breadth.” The Federal Circuit determined that the claims are “far broader in functional diversity than the disclosed examples” of specific antibodies. The court noted that broad functional language in the claims “pose[s] high hurdles in fulfilling the enablement requirement,” and that the district court correctly determined that such requirement had not been met.  

The Federal Circuit further noted that their holding did not find that the “effort required to exhaust a genus is dispositive.” However, the court added that it is appropriate to “look at the amount of effort needed to obtain embodiments outside the scope of the disclosed examples and guidance. The functional limitations here are broad, and the disclosed examples and guidance are narrow. . . and substantial time and effort would be required to reach the full scope of claimed embodiments.”

Takeaways

  • Antibody claims that contain functional limitations “raise the bar for enablement.” The appeals court stated that “[w]hile functional claim limitations are not necessarily precluded in claims that meet the enablement requirement, such limitations pose high hurdles in fulfilling the enablement requirement for claims with broad functional language.”
  • Large amounts of “trial and error” needed to screen antibody candidates in order to know which antibodies meet claimed functional limitations and which ones do not may constitute undue experimentation.
  • The Amgen  decision does not prohibit epitope-based antibody claims or antibody claims defined in part by functional terms, but certainly highlights the challenges posed by such claims, and suggests how to possibly navigate enablement vulnerabilities, particularly when the functional limitations establish a vast scope. Tips include:
    • Describe as many species as possible in the scope of the claims, including data showing the desired functional requirements of the claims are met;
    • Disclosed species should be as diverse as possible, and where possible, provide guidance as to any common motifs, sequences, or other structural information in common that is tied to the recited functional aspects; and
    • Specification should include detailed guidance that is sufficient to make the full scope of antibodies in the claims in a predictable manner, and that the level of experimentation is not merely undue “trial and error.”

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