Amgen Inc. v. Sanofi (Fed. Cir. 2021)

By Kevin E. Noonan --

A little less than four years ago, the Federal Circuit rendered a decision in Amgen Inc. v. Sanofi that brought clarity to how the Court (and U.S. Patent and Trademark Office) should apply the written description requirement in 35 U.S.C. § 112(a) to properly circumscribe the scope of claims to monoclonal antibodies.  Earlier this month, on an appeal from remand, the Court took aim at the enablement requirement for antibody claims, with similar, scope-limiting results.

The case arose when Amgen sued Sanofi and Regeneron over sales of Praluent® (alirocumab), which allegedly competes with Amgen's Repatha™ (evolocumab); Amgen's asserted patents, U.S. Patent Nos. 8,829,165 ("'165 patent") and 8,859,741 ("'741 patent"), claim a genus of antibodies that encompass Praluent®.  As background, blood plasma contains low-density lipoproteins that bind cholesterol and are associated with atherosclerotic plaque formation.  Liver cells express receptors for LDL (LDL-R) wherein binding thereto reduces the amount of LDL cholesterol in blood and reduces the risk of plaque formation and cardiovascular disease.  PCSK9 (proprotein convertase subtilisin kexin type 9) is a molecule that binds to and causes liver cell LDL-R to be destroyed, thus reducing the capacity and effectiveness of the liver cell's ability to reduce serum LDL-cholesterol.  The antibodies at issue in this suit bind to PCSK9 and prevent PCSK9 from binding to LDL-R, preventing their destruction and resulting in lower serum cholesterol.

The following claims were recited in the opinion as being relevant to the issues before the Court:

Claims of 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 LDL[-]R.

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%.

Claims of the '165 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.

It is important to note that, while reciting the structure of the residues on PCSK9 (the antigen) that are bound by the claimed antibody, the claim does not recite any structural limitations of the antibody.  The only antibody characteristics recited as limitation are functional, i.e., the ability to bind (and not even specifically bind) to at least one of the recited PCSK9 residues and block PCSK9's interaction with the LDL-R.

Evidence at the first trial showed that Amgen had produced a plurality of anti-PCSK9 antibodies and screened them for the ability to inhibit PCSK9 binding to LDL-R.  This screening was done using a "trial and error" process that reduced 3,000 human monoclonal antibodies down to 85 antibodies that "blocked interaction between the PCSK9 . . . and the LDLR [at] greater than 90%," of which the specification illustrated the three-dimensional binding arrangement for two (one of which became the Repatha™ antibody) by x-ray crystallography.  The specification of the Amgen patents in suit disclose amino acid sequence information for twenty-two human anti-PCSK9 antibodies able to compete for PCSK9 binding with these two more fully characterized antibodies.  Regeneron's patents (not at issue here) recited antibody-specific amino acid sequences for its claimed anti-PCSK9 antibodies.

The jury in the earlier case found Amgen's patents not to be invalid.  The District Court had excluded evidence relating to written description and enablement based on Praluent® and other post-priority-date antibodies (i.e., that were produced after Amgen's earliest priority date).  The District Court, relying on Noelle v. Lederman as precedent, instructed the jury that an applicant can be entitled to claim scope encompassing generically described antibodies (as was the case for Amgen's claims) provided that the applicant provided a full characterized, novel antigen.

The Federal Circuit reversed in part, affirmed in part, vacated in part, and remanded, in an opinion by Chief Judge Prost, joined by Judges Taranto and Hughes.  With regard to the written description question, the Court vacated and remanded, on the grounds that the District Court had instructed the jury based on the Court's pre-Ariad Noelle v. Lederman precedent, which was inconsistent with the Court's later en banc decision in Ariad v. Eli Lilly & Co.  The Court also found it to be error for the District Court to have excluded evidence regarding enablement, related to the "lengthy and potentially undue experimentation" Amgen needed to employ to arrive at its antibodies that fell within the scope of the claims of the '165 and '741 patents.  The Federal Circuit ordered a new trial for the District Court to consider post-priority-date evidence for the purposes of both enablement.  The District Court remanded for a new trial on written description as well, based on the jury instruction and evidentiary errors.

On remand, the jury found that claim 7 of the '741 patent and claims 19 and 29 of the '165 patent were not invalid.  The District Court granted Sanofi's motion for JMOL with regard to enablement for these claims but denied JMOL on written description.  This appeal followed.

In the instant appeal, the Federal Circuit affirmed in an opinion by Judge Lourie, joined by Chief Judge Prost and Judge Hughes.  The panel grasps the nettle of the question before it immediately, stating that "[t]he claimed antibodies are defined by their function: binding to a combinations of sites (residues) on the PCSK9 protein, in a range from one residue to all of them; and blocking the PCSK9/LDLR interaction."  This aspect of the issue before the Court was just as important and dispositive for the enablement question as it has become for the question of written description, under the reasoning set forth in this opinion.  The panel reverted (as it must) to its decision in In re Wands (and its famous "Wands factors"), the dispositive factor in the Court's decision being the amount of experimentation required to encompass the full scope of the claims at issue.  Albeit being a question of law, enablement depends particularly on the facts from which conclusions of law are based.  The opinion is sensitive to the requirement for patenting that the specification enable practice of the claimed invention throughout its full scope, and with the Wands rubrics that the scope of the claims can determine the extent of experimentation required and whether such experimentation is undue.  The opinion then focused on claims 19 and 29 of the '165 patent and claim 7 of the '741 patent in rendering its decision.

Amgen's arguments were grounded in the disclosure in the specification regarding the type of experimentation required and the guidance provided therein on the extent of such experimentation, while Defendants argued that the scope of these claims encompassed "millions of antibody candidates," that antibody production was unpredictable, and that the specification lacked sufficient guidance because, inter alia, "practicing the full scope of the claims requires substantial trial and error."  Defendants emphasized not the antibodies Amgen had actually made but "the number of candidates that must be made and tested to determine whether they satisfy the claimed function."

Calling In re Wands the Court's "go to" precedent, the opinion states that while itself a monoclonal antibody case, "Wands did not proclaim that all broad claims to antibodies are necessarily enabled" because "[f]acts control."  Here, the panel considered the facts (and the findings of invalidity) in more recent cases, including Wyeth & Cordis Corp. v. Abbott Laboratories, Enzo Life Sciences, Inc. v. Roche Molecular Systems, Inc., and Idenix Pharmaceuticals LLC v. Gilead Sciences Inc.  In all these cases, of course, the Federal Circuit found that the claims were not enabled, due to the broad scope of embodiments the claims in these cases encompassed and the amount of undue experimentation required to satisfy the enablement requirement throughout its full scope.  The panel set forth its synthesis of the Federal Circuit's analysis regarding satisfaction of the enablement requirement arising from these cases:

What emerges from our case law is that the enablement inquiry for claims that include functional requirements can be particularly focused on the breadth of those requirements, especially where predictability and guidance fall short.  In particular, it is important to consider the quantity of experimentation that would be required to make and use, not only the limited number of embodiments that the patent discloses, but also the full scope of the claim.

And citing a footnote in McRO, Inc. v. Bandai Namco Games Am. Inc.:

In cases involving claims that state certain structural requirements and also require performance of some function (e.g., efficacy for a certain purpose), we have explained that undue experimentation can include undue experimentation in identifying, from among the many concretely identified compounds that meet the structural requirements, the compounds that satisfy the functional requirement [emphasis added].

This precedent was controlling here:  "[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."  As applied to Amgen's claims, the panel recognized each of them to be "a composition claim defined, not by structure but by meeting functional limitations."  This outcome is consistent with Wands, according to the opinion, because the "functional breadth" of these claims is "indisputably broad" and "the claims are far broader in functional diversity than the disclosed examples."  Taking a real property analogy from AbbVie Deutschland GmbH & Co. v. Janssen Biotech, Inc., the opinion states that "[i]f the genus is analogized to a plot of land, the disclosed species and guidance 'only abide in a corner of the genus.'"  The opinion also referenced the unpredictability of the antibody arts as a relevant (and supportive) Wands factor in favor of invalidity.  And the quantum of guidance factor from Wands was also deficient, according to the opinion, because "any reasonable factfinder would conclude 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."

Importantly, the panel cabined its decision by stating that while the "substantial amount of time and effort" required to produce the scope of antibodies claimed here is undue, "[w]e do not hold that the effort required to exhaust a genus is dispositive" (emphasis in opinion).  The Court struck a balance:  "[t]he functional limitations here are broad, the disclosed examples and guidance are narrow, and no reasonable jury could conclude under these facts that anything but 'substantial time and effort' would be required to reach the full scope of claimed embodiments."  But the facts here (which distinguish this decision from Wands) are that "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."  Under these facts, the substantialness of such time and effort was sufficient to be considered undue experimentation by the Court.

While providing yet another fact-bound basis for invalidating (or limiting the scope of) claims to biotechnological inventions, it is unlikely to have been a coincidence that the opinion is authored by Judge Lourie, the architect of the Court's emphasis on structure in applying the written description requirement to biotechnology claims.  As the Judge emphasized in his seminal Regents of the University of California v. Eli Lilly case:

Thus, an applicant complies with the written description requirement "by describing the invention, with all its claimed limitations, not that which makes it obvious," and by using "such descriptive means as words, structures, figures, diagrams, formulas, etc., that set forth the claimed invention," citing Lockwood v. American Airlines, Inc. (Fed. Cir. 1997).

An adequate written description of a DNA, such as the cDNA of the recombinant plasmids and microorganisms of the '525 patent, "requires a precise definition, such as by structure, formula, chemical name, or physical properties," not a mere wish or plan for obtaining the claimed chemical invention.  Fiers v. Revel (Fed.Cir.1993).  Accordingly, "an adequate written description of a DNA requires more than a mere statement that it is part of the invention and reference to a potential method for isolating it;  what is required is a description of the DNA itself."  Id.

A written description of an invention involving a chemical genus, like a description of a chemical species, "requires a precise definition, such as by structure, formula, [or] chemical name," of the claimed subject matter sufficient to distinguish it from other materials.  Fiers;  In re Smythe ("In other cases, particularly but not necessarily, chemical cases, where there is unpredictability in performance of certain species or subcombinations other than those specifically enumerated, one skilled in the art may be found not to have been placed in possession of a genus․").

This precedent is thus well grounded in the Federal Circuit's concern that a patentee must satisfy the quid pro quo of the patent grant, so that the specification supports its claims throughout their entire scope, whether on enablement or written description grounds.  It has been a bane for the biotechnology industry that the courts (and to a lesser extent, Congress) have played "catchup" in determining the proper application of these standards to biotechnology inventions, resulting in claims either invalidated under such changing standards or failing to encompass the activities of accused infringers.  But this decision provides a consistent standard ("structure, structure, structure," as recited by former Chief Judge Rader on several occasions) and one that can be applied with consistency even though the resulting scope may prove insufficient to provide enough support to justify the costs of commercialization.  Which will be a bane on everyone.

Amgen Inc. v. Sanofi (Fed. Cir. 2021)
Panel: Chief Judge Prost and Circuit Judges Lourie and Hughes
Opinion by Circuit Judge Lourie

Comments

[Paul F Morgan]

Another, prior, Fed. Cir. decision on 112 non-description for a broad pharmaceutical patent claim: University of Rochester versus G.D. Searle & Co., Case No. 03-1304.

[Kevin E. Noonan]

Yes, but that case predates both Noelle, Ariad, and of course all the recent enablement cases. The Court is certainly constraining scope, particularly in antibody claims.

[Derek W.]

Is it really true though that companies will be dissuaded from developing new biologics because they can’t get a patent essentially owning the mechanism of action? Most biologics (as well as small molecules) do have within class competition, and it doesn’t seem to be compressing returns—eg Humira has plenty of competition among anti-TNF alpha therapeutics.

Usually, I would imagine 1) the other company essentially co-invented a similar drug, which means they had to show efficacy and safety to the FDA, or 2) they are a biosimilar maker, in which case the sponsor gets 12 years of exclusivity; plus, most biosimilars are structurally very like the reference product, so broad genus claims are unnecessary.

[Kevin E Noonan]

Biosimilars are an interesting case, because almost all the litigation has been on patents other than the original molecule patent (due to timing of when the biosimilars pathway became available compared with original FDA approval date and expiration date of the molecule patents). This is one of the reasons Humira (and the other half dozen biologics) have many biosimilar competitors.

The issue isn't owning mechanism of action; it is the impossibility of enabling (legally but not scientifically) production of every amino acid sequence variant and then having competitors piggyback over an innovator's discovery that an antibody to antigen X can be used therapeutically.

Biosimilars are less of a problem due to the 12 year exclusivity FDA approval of the reference product gives the innovator. It will be interesting to see if the biosimilar route is used by competitors for easier regulatory approval or if competitors will use the BLA route for their own 12-year exclusivity.

Thanks for the comment.