The Future of Enablement for Antibody Genus Claims

The dispute centers on Amgen’s Repatha^® and Sanofi-Regeneron’s Praluent^® products for the treatment of high cholesterol. Amgen sued Sanofi-Regeneron in the District of Delaware, alleging patent infringement. The parties stipulated to infringement, and a jury returned a verdict in favor of Amgen, failing to find invalidity. Judge Andrews overturned the verdict on a motion for judgment as a matter of law (JMOL), finding certain claims to a genus of monoclonal antibodies invalid for lack of enablement. Amgen appealed. Major pharmaceutical companies filed amicus curiae briefs in support of both parties, including Bristol-Myers Squibb and Merck in support of Amgen’s position, and Pfizer in support of Sanofi-Regeneron’s position, with each side expressing concerns regarding the potential impact on innovation and demonstrating the potential significance of the outcome of the appeal.

Amgen v. Sanofi Background

Asserted Technology

As discussed in the district court opinion and appeal briefs, the asserted patents disclose a class of antibodies that lowers the levels of LDL cholesterol in the bloodstream.¹ These antibodies bind to a small region—referred to by Amgen as the “sweet spot”—on a protein called PCSK9 and block it from binding to LDL receptors (LDLRs). This spares LDLRs from destruction, reducing LDL cholesterol levels.

The claims are directed to a genus of monoclonal antibodies that bind to the 15 residues of the “sweet spot” of PCSK9 and block its binding to LDLRs. The patents characterize 26 antibodies and provide what Amgen calls a “roadmap” for obtaining other antibodies. The specification further discloses Table 1 regarding another method of making variants through amino acid substitutions to disclosed antibodies.

District Court Enablement Opinion

The enablement requirement provides that a patent specification “must teach those skilled in the art how to make and use the full scope of the claimed invention without ‘undue experimentation.’”² In assessing whether a patent meets this requirement, the Federal Circuit considers several factors as outlined in the seminal In re Wands opinion, including, but not limited to, the breadth of the claim, the predictability of the art, the amount of direction or guidance provided, and the quantity of experimentation required.³

Judge Andrews considered the Wands factors and held that a reasonable fact finder could only conclude that undue experimentation would be needed to practice the full scope of the claims.⁴ He found that a jury could only conclude that the claim scope is “vast,” citing Sanofi-Regeneron’s expert testimony as showing that the Table 1 substitutions would lead to “millions” of new candidate antibodies.⁵ Judge Andrews further found that a jury could only conclude that the art is unpredictable, and the specification did not provide any guidance on how to predict whether an antibody, from its sequence, will bind to the claimed PCSK9 residues—thus, a person of ordinary skill in the art (POSA) would have to test a newly generated antibody to determine if it meets the functional limitations of the claims.⁶ He found that even though the techniques employed to identify antibodies within the scope of the genus are routine, a POSA would still be required to do the same work as the inventors to generate large pools of antibodies or engage in “trial and error”—time and effort a jury could only find would be “substantial.”⁷

Amgen’s Appellate Position

Amgen argues that the district court improperly made its own findings regarding the claim scope—the jury, based on evidence of “actual” antibodies, could find it to be in the range of 400 antibodies.⁸ Amgen further reasons that, “[b]ecause the ‘sweet spot’ on PCSK9 is a small region with a unique structure, only a limited number of antibodies have the physical and chemical structure to bind there,”⁹ and the Table 1 substitutions do not yield “millions” of new antibodies but variants with predictable activity.¹⁰ Amgen also argues that the patents provide “a wealth” of enabling information with the characterization of 26 antibodies and a “roadmap” that allows a POSA to produce all claimed antibodies through routine techniques that are “highly predictable.”¹¹ Moreover, Amgen argues, the substantial evidence showed that any process to confirm an antibody’s activity would be “predictable and easy.”¹²

Sanofi-Regeneron’s Appellate Position

Sanofi-Regeneron argue that the undisputed evidence showed the claims encompass “millions” of possible antibodies.¹³ Sanofi-Regeneron criticize Amgen’s claim of narrow breadth as focused on the number of antibodies “known” versus the candidates that must be made and tested to determine whether they satisfy the functional requirements.¹⁴ Sanofi-Regeneron further argue that the testimony confirms a POSA cannot know whether an antibody will meet the claims’ functional requirements of binding and blocking without testing.¹⁵ Sanofi-Regeneron argue that even if the methods for generating and testing the antibodies are routine, testing the “vast” number of antibodies would be a significant task for a POSA, and the specification discloses at best a starting point for trial-and-error experimentation.¹⁶

Amici Weigh In

Bristol-Myers Squibb and Merck emphasize the need for the patent system to protect pharmaceutical inventions without prohibitive and unnecessary disclosure requirements.¹⁷ Their brief centers on the antibody arts and the discovery of the underlying target and connection to the disease, arguing that it is easy to create variations of an antibody after discovering the target and application. Pfizer focuses on the threat to innovation by functional claims to a broad genus without identifiable structural features and argues that the claims here have “enormous breadth,” containing no structural limitations defining any claimed antibody, and the “roadmap” is “an open-ended research plan for identifying any antibodies that work.”¹⁸

Recent Federal Circuit Enablement Precedent

In Wands, the Federal Circuit found that the functionally defined antibodies in the method claims were enabled based on known techniques.¹⁹ Recently, the Federal Circuit has, in some cases, held genus claims to small molecules invalid for failing to meet the enablement requirement. These cases contribute to the current enablement landscape, and the applicability of these cases—Wyeth, Enzo, and Idenix—is at the center of the instant dispute.

In Wyeth & Cordis Corp. v. Abbott Laboratories, the Federal Circuit affirmed summary judgment of invalidity for nonenablement.²⁰ The claims were directed to the use of a genus of rapamycin compounds for treating or preventing restenosis. The specification disclosed only one rapamycin species, sirolimus, that demonstrated the claimed antirestenotic effects.²¹ The court determined that the claims’ scope is broad: the invention is a method for the use of a known compound (sirolimus) and any other compounds that meet the structural and functional requirements.²² The court found there was no genuine dispute that practicing the invention would require more than routine experimentation for two reasons. First, the court found there are “at least tens of thousands” of candidate compounds that could meet the recited functional effects and the specification was silent about how to modify sirolimus to preserve the antirestenotic effects.²³ Second, the court found that a POSA would have to synthesize each candidate compound and screen it, and that having to synthesize and screen each of at least tens of thousands of these candidate compounds in these circumstances constitutes undue experimentation.²⁴

In Enzo Life Sciences, Inc. v. Roche Molecular Systems, Inc., the Federal Circuit also affirmed summary judgment of invalidity for nonenablement.²⁵ The claims were directed to nonradioactive labeling of polynucleotides, where the label is attached at the phosphate position. The court observed that the claims require a particular structure and functionality, i.e., the labeled polynucleotides must be hybridizable and detectable upon hybridization.²⁶ The court then addressed whether the specification enabled creation of a labeled polynucleotide that meets this functional requirement. The court determined that the scope of the claims was broad, as variables such as number or location of the label result in at least “tens of thousands” of possible embodiments, and the specification’s guidance on how these variables would impact the functionality was “sparse.”²⁷ The court found this scope “particularly concerning” because of the evidence presented of unpredictability in the art and Enzo’s expert testimony that each compound would need to be tested to understand the functionality.²⁸ The court found the specification’s working embodiment insufficient for enablement as “undue experimentation would still be required with regard to the many other embodiments of the claims based on the number of possible embodiments and the unpredictability in the art.”²⁹

In Idenix Pharmaceuticals LLC v. Gilead Sciences Inc., the Federal Circuit affirmed a JMOL overturning a jury verdict supporting enablement.³⁰ The claim was directed to a method of treating hepatitis C (HCV) by administering a “β-D-2’-methyl-ribofuranosyl nucleoside” and was construed to encompass any nucleoside meeting the claimed structural limitations and the functional limitation of efficaciously treating HCV.³¹ The court identified the question for appeal as whether a POSA would know which nucleosides would be effective for treating HCV without undue experimentation and concluded as a matter of law that the patent is invalid for lack of enablement.³² The court found that a reasonable jury could have only found that at least “many, many thousands” of nucleosides would meet the structural limitations of the claim, and based on the evidence of the unpredictability in the art, each would need to be screened to understand whether it is effective against HCV.³³ The court further found that although the level of skill in the art is high, the specification did not provide meaningful guidance or working examples sufficient to assist a POSA.³⁴

Enablement Issues for Federal Circuit Consideration

The Amgen v. Sanofi appeal presents some case-specific issues. For instance, it involves a JMOL overturning a jury verdict supporting enablement; thus, the court will review the factual underpinnings of enablement for substantial evidence.³⁵ Amgen argues that the district court created a new enablement test by analyzing the effort of a POSA to discover and make every antibody within the scope of the claims, while Sanofi-Regeneron raise evidentiary issues to send the case back for trial. However, several other issues could impact future cases.

Large vs. Small Molecules

This case involves antibodies. Wyeth, Enzo, and Idenix do not. Both parties, as well as amici, note this distinction. Bristol-Myers Squibb and Merck suggest that a different outcome is justified because “antibodies are harvested, while synthetic organic molecules are built.”³⁶ Pfizer proffers that the logic underpinning the Federal Circuit’s recent holdings applies, i.e., that making modifications to the claimed molecule—whether a synthetic organic compound or an antibody—may have a dramatic effect on its function. Amgen’s position is largely based on analogy to Wands, which Amgen argues is “not merely [the Federal Circuit’s] seminal enablement decision,” but is directly on point because it addresses the same technology.³⁷ Sanofi-Regeneron argue in turn that Amgen “massively overreads Wands,” and that its narrow holding does not dictate any antibody-specific precedent that controls here.³⁸ Whether, and to what extent, the Federal Circuit distinguishes synthetic organic small molecules from antibodies could have important ramifications for patents across the life sciences fields.

Structure of the Unclaimed Antigen

Amgen’s argument that the claim scope is narrow relies on its claim that the “sweet spot” on PCSK9 is small, with only a limited number of antibodies with the structure to bind there. The Federal Circuit is thus presented with an argument as to whether a claim to antibodies by the structural features of the antigen can use functional language to result in a narrowing construction that withstands an enablement challenge. If the court addresses this argument, it could have implications for construction of functional claim language.

Specification Guidance

The district court found there was no dispute that the patent does not teach a POSA how to determine from the antibody’s sequence whether it will bind; thus, it found that a POSA would still have to test a newly generated antibody to understand if it meets the claimed limitations. The district court found that the specification did not improve a POSA’s ability to discover antibodies within the claim scope, but that the “roadmap” is significantly similar to the inventors’ path and thus a POSA would have to do the same amount of work. Amgen argues that the specification picks up where the inventors left off and the rest is routine in the antibody arts. The Federal Circuit’s consideration of this issue could shed light on this Wands factor for antibody claims.

How Many Is Too Many Candidates?

The parties dispute the potential number of candidates that would potentially satisfy the claimed function: Sanofi-Regeneron assert “millions,” while Amgen asserts 400 as the relevant scope. The court therefore may have to deal with the threshold question of the number of candidates in its analysis of enablement, which could have ramifications for genus claims, particularly in the life sciences fields.

Written Description for Genus Claims

Sanofi-Regeneron appealed the denial of JMOL regarding written description. The district court found that the specification discloses a representative set of species, based on the substantial evidence at trial of similarity between both the three-dimensional structures and sequences, as well as the functionality, of the antibodies in the patent and antibodies developed by Sanofi-Regeneron, Merck, and Pfizer, termed the “Competitor Antibodies.”³⁹ The Federal Circuit may therefore face the question of whether the inventors were in possession of the antibodies within the claims’ bounds; thus, this appeal also has the potential to create more written description precedent in the context of genus claims to antibodies. This, too, may have important implications for genus claims.

Takeaways

Amgen v. Sanofi demonstrates the highly factual nature of the enablement analysis, consistent with the Wands factors. In that environment, accused infringers have been making challenges to broad claims under 35 U.S.C. § 112. The Federal Circuit’s decision will likely further elucidate the ability of claims that encompass a broad genus of antibodies with specific functional limitations to withstand an enablement challenge.

The U.S. Supreme Court now also has the chance to weigh in—a petition for writ of certiorari was filed by Idenix in Idenix v. Gilead.⁴⁰ Idenix’s petition presents two relevant questions regarding enablement: (1) whether enablement is a context-specific jury question, and (2) whether § 112 sets forth a single substantive requirement: “a written description of the invention” sufficient “to enable any person skilled in the art . . . to make and use the same.”⁴¹ Gilead’s response is scheduled to be due December 16.

Endnotes

1. U.S. Patent Nos. 8,829,165 and 8,859,741.

2. MagSil Corp. v. Hitachi Glob. Storage Techs., Inc., 687 F.3d 1377, 1380 (Fed. Cir. 2012).

3. Factors considered in assessing the enablement requirement include: (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).

4. Amgen Inc. v. Sanofi, No. 1:14-cv-01317-RGA, D.I. 1050 at 13–24 (D. Del. Aug. 28, 2019).

5. Id. at 13–15.

6. Id. at 16–21.

7. Id. at 21–24.

8. See Brief of Plaintiffs-Appellants, Amgen Inc. v. Sanofi, No. 20-1074, D.I. 55 at 2, 20–23, 39–50 (Fed. Cir. Feb. 21, 2020).

9. Id. at 2; see also id. at 40.

10. See id. at 3, 46–49, 56–60.

11. Id. at 26, 32–37, 51–56.

12. Id. at 60–61.

13. Brief of Defendants-Appellees, Amgen, No. 20-1074, D.I. 76 at 34–41 (Fed. Cir. June 2, 2020).

14. Id.

15. Id. at 28–34.

16. Id. at 24–27, 41–46.

17. Brief of Amici Curiae Bristol-Myers Squibb Co. and Merck Sharp & Dohme Corp. in Support of Plaintiffs-Appellants, Amgen, No. 20-1074, D.I. 67 (Fed. Cir. Mar. 25, 2020).

18. See Brief of Amicus Curiae Pfizer Inc. in Support of Appellees, Amgen, No. 20-1074, D.I. 91 at 6 (Fed. Cir. June 8, 2020).

19. In re Wands, 858 F.2d 731, 740 (Fed. Cir. 1988).

20. 720 F.3d 1380 (Fed. Cir. 2013).

21. See id. at 1382–83.

22. Id. at 1385.

23. Id.

24. Id. at 1385–86.

25. 928 F.3d 1340 (Fed. Cir. 2019).

26. Id. at 1346.

27. Id. at 1346–49.

28. Id.

29. Id. at 1349.

30. 941 F.3d 1149 (Fed. Cir. 2019).

31. Id. at 1156.

32. Id. at 1156–62.

33. Id. at 1162.

34. Id.

35. See id. at 1153–54.

36. Brief of Amici Curiae Bristol-Myers Squibb Co. and Merck Sharp & Dohme Corp. in Support of Plaintiffs-Appellants, supra note 17, at 19–20.

37. Reply Brief for Plaintiffs-Appellants, Amgen, No. 20-1074, D.I. 105 at 5 (Fed. Cir. July 23, 2020).

38. Brief of Defendants-Appellees, supra note 13, at 45.

39. Amgen Inc. v. Sanofi, No. 1:14-cv-01317-RGA, D.I. 1050 at 6–10 (D. Del. Aug. 28, 2019).

40. Idenix Pharms. LLC v. Gilead Scis. Inc., No. 20-380 (U.S. docketed Sept. 24, 2020).

41. See id. at i.