Amgen Inc. v. Sanofi, No. 20-1074 (Fed. Cir. 2021)

Introduction

The Federal Circuit recently issued a precedential decision on the validity of antibody epitope claims covering Amgen's Repatha® (evolocumab) product. The court found that a genus of antibodies claimed only by specific functional properties (aspects of evolocumab's antigen binding and blocking) are invalid for lack of enablement.

Background

Repatha® is Amgen's blockbuster $20+ billion per year biologic that is indicated for lowering bad LDL bad cholesterol and reduces the risk of heart attack and stroke. Amgen owns U.S. Patents 8,829,165 (the "'165 patent")ⁱ and 8,859,741 (the "'741 patent")ⁱⁱ, which describe evolocumab antibodies that bind to proprotein convertase subtilisin/kexin type 9 ("PCSK9"). These antibodies purportedly block PCSK9 from binding to low-density lipoprotein ("LDL") receptors in order to prevent mediation of LDL receptor degradation, and to allow LDL receptors to remove LDL cholesterol from the blood stream.

The claims at issue (claims 19 and 29 of the '165 patent, and claim 7 of the '741 patent), claim a genus of antibodies that bind to amino acid residues of the PCSK9 protein, and block PCSK9 from binding to LDL receptors. Therefore, the antibodies are claimed by their function, rather than structure: binding to PCSK9 and blocking PCSK9/LDL receptor interaction. Representative claims of the '165 patent are provided below.

• 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.
• 19. The isolated monoclonal antibody of claim 1 wherein the isolated monoclonal antibody binds to at least two of the following residues S153, I154, P155, R194, D238, A239, I369, S372, D374, C375, T377, C378, F379, V380, or S381 of PCSK9 listed in SEQ ID NO:3.

Procedural History

Amgen asserted the '165 patent and the '741 patent again Sanofi, Aventisub, Regeneron, and Sanofi-Aventis (collectively, "Sanofi") in district court. The jury determined that the asserted claims were not invalid for lack of enablement and written description.

Sanofi appealed to the Federal Circuit, which held that the district court erred in its jury instructions regarding written description and enablement, and remanded for a new trial on those issues. Regarding written description, the Federal Circuit held that the written description requirement for a claimed genus of antibodies requires either a representative number species within the claimed genus, or structural features common to the genus. The Federal Circuit thus abolished the "Newly Characterized Antigen Test," which previously allowed patent applicants to claim a genus of antibodies by describing the structure of a corresponding antigen.

On remand from the Federal Circuit, the jury found that the asserted claims were not invalid for lack of written description or enablement. Sanofi moved for a judgment as a matter of law for a finding of invalidity due to lack of enablement and lack of written description. The district court granted the motion with regard to lack of enablement. Amgen appealed the decision to the Federal Circuit.

Federal Circuit Opinion

The Federal Circuit affirmed the decision of the district court that the claims at issue lack enablement.

The U.S. patent system, and other systems of major international markets modeled after it worldwide, are built upon a quid pro quo balance that is designed to ensure an incentive to innovate new products and services by way of time-limited exclusivity rights to the patent owner while also encouraging the wide dissemination of new ideas for public benefit and use upon expiration of the patented innovation. Specifically, in order for the patent owner to obtain the benefit of an exclusive right to prevent others from commercializing a patent eligible, novel, and inventive invention, including billion dollar biologic drug products, the patent owner must describe to those working in the field of invention how to "make and use" the patented claims. The courts have long clarified that this "enablement" requirement ensures that a person of skill in the art is able to practice the claimed invention without "undue experimentation." The determination of whether or not experimentation is undue is based on weighing a number of factual considerations, termed the "Wands factors." 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. In re Wands, 858 F.2d 731, 737 (Fed. Cir. 1988).

Enablement Inquiry for Functional Claim Limitations

When evaluating the Wands factors for claims including a functional requirement, the court noted that it is particularly important to consider the quantity of experimentation necessary to make and use the full scope of the claim, and that "broad functional claim limitations raise the bar for enablement" (emphasis added).

Regarding the breadth of the claims, the court emphasized that the concern is not simply with the number of embodiments falling within the claims, but also with the functional breadth of the claims. For the claims at issue, the court found that the claims are far broader in functional diversity than the disclosed examples, analogizing the genus to a plot of land where the disclosed species and guidance "only abide in a corner of the genus" (citing AbbVie Deutschland GmbH & Co. v. Janssen Biotech, Inc., 759 F.3d 1285, 1299-300 (Fed. Cir. 2014)).

Regarding the quantity of experimentation necessary, the court found that in view of the unpredictability of the art (e.g., it is not predictable from antibody sequence what antibody could bind to PCSK9 and where), and the lack of significant guidance to practice the full scope of the claims, the only way to discover undisclosed claimed embodiments is through trial and error or discovering such antibodies de novo by randomization and screening, which would take a substantial amount of time and effort. In support of this finding, the evidence showed that the scope of the claims encompasses millions of candidate antibodies, and it would be necessary to first generate and then screen each of these candidates to determine whether it meets the functional claim limitations.

In view of these considerations, the court affirmed that undue experimentation would be required to practice the full scope of the claims.

Summary

The patents at issue in this case claim a genus of antibodies based on their function: binding to PCSK9 amino acid residues and blocking PCSK9/LDL receptor interaction. The Federal Circuit invalided these claims for lack of enablement, finding that the binding limitation itself was sufficient for the claims to require undue experimentation.

This court noted that while functional claim limitations are not necessarily precluded from satisfying the enablement requirement, claims with broad functional limitations "pose high hurdles in fulfilling the enablement requirement." In applying the Wands factors to the broad functional claims of the present case, the court focused on the quantity of experimentation necessary to make and use the full scope of the claims. The experimentation that held to be undue encompassed generating and then screening millions of candidate antibodies to determine whether the candidate meets the functional limitation.

In support of its holding, the court cites Wyeth & Cordis Corp. v. Abbott Laboratories (Fed. Cir. 2013), where it held that claims having certain functionality requirements lack enablement because of the large number of possible candidates that would need to be synthesized and screened to determine which exhibit the claimed functionality. Similarly, the court cites Idenix Pharmaceuticals LLC. Gilead Sciences Inc. (Fed. Cir. 2019), where it held that undue experimentation would have been required to synthesize and screen billions of possible compounds, such that finding a functional compound would be akin to "finding a need in a haystack." In finding that the claims at issue would require undue experimentation, the court analogized the facts of the present case to those of Wyeth and Idenix. In a further discussion of precedential case law, the court upheld Wands, which held that claims to immunoassay methods using an antibody with a functional limitation was not invalid for lack of enablement, distinguishing Wands from the present case based on its facts.

The holding of the present case illustrates that careful consideration must be made of the "high hurdles" required to satisfy the enablement requirement for claims with broad functional limitations. We recommend that clients continue to carefully consider patenting strategies to biologic genus claims defined by functional properties. Functional claim limitations should be carefully considered and evaluated when developing and implementing a patent strategy for biologic therapeutic products, including during patent preparation and prosecution, transactional IP due diligence, licensing, and enforcement.

[i] Claims 1, 19 and 29 of U.S. Patent 8,829,165 (the “’165 patent”)

• 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.
• 19. The isolated monoclonal antibody of claim 1 wherein the isolated monoclonal antibody binds to at least two of the following residues S153, I154, P155, R194, D238, A239, I369, S372, D374, C375, T377, C378, F379, V380, or S381 of PCSK9 listed in SEQ ID NO:3.
• 29. A pharmaceutical composition comprising an isolated monoclonal antibody, wherein the isolated monoclonal antibody binds to at least two of the following residues S153, I154, P155, R194, D238, A239, I369, S372, D374, C375, T377, C378, F379, V380, or S381 of PCSK9 listed in SEQ ID NO:3 and blocks the binding of PCSK9 to LDLR by at least 80 percent.

[ii] Claims 1, 2, and 7 of U.S. Patent 8,859,741 (the “’741 patent”)

• 1. An isolated monoclonal antibody that binds to PCSK9, wherein the isolated monoclonal antibody binds an epitope on PCSK9 comprising at least one of residues 237 or 238 of SEQ ID NO: 3, and wherein the monoclonal antibody blocks binding of PCSK9 to LDLR.
• 2. The isolated monoclonal antibody of claim 1, wherein the isolated monoclonal antibody is a neutralizing antibody.
• 7. The isolated monoclonal antibody of claim 2, wherein the epitope is a functional epitope.