Broad functional limitations in claims “raise the bar for enablement”
| April 13, 2021
Amgen Inc. v. Sanofi
February 11, 2021
Before Prost, Lourie, and Hughes (Opinion by Lourie).
Summary
The Federal Circuit invalidates genus claims with functional limitations for lacking enablement. The Federal Circuit focuses the enablement analysis on the broad scope of structures covered by the claims and the lack of guidance in the specification on how to identify those structures that exhibit the claimed functionalities.
Details
Low-density lipoprotein (LDL) cholesterol is often called the “bad” cholesterol. An elevated LDL level leads to fatty buildups (or plaques) in arteries and contributes to heart disease. LDL receptors remove LDL cholesterol from the bloodstream and regulates the amount of LDL cholesterol in circulation.
The proprotein convertase subtilisin/kexin type 9 (PCSK9) enzyme has for years been an important cholesterol-lowering target. The PCSK9 enzyme degrades LDL receptors and can interfere with the regulation of circulating LDL cholesterol levels. It has been found that loss-of-function mutations in the PCSK9 enzyme lead to higher levels of the LDL receptor, lower circulating LDL cholesterol levels, and protection from heart disease.
U.S. Patent Nos. 8,829,165 and 8,859,741, owned by Amgen Inc., relate to antibodies that bind to and block PCSK9 to inhibit PCSK9-LDL receptor interactions.
The relevant claims in the 165 and 741 are all directed to an antibody, and all define the antibody in terms of two specific functions: first, the antibody “binds to” a combination of amino acid residues on the PCSK9 protein, and second, the antibody “blocks” binding of PCSK9 to LDL receptor.
For example, independent claim 1 of the 165 patent recites:
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.
Independent claim 29 of the 165 patent specifically requires that the antibody blocks the binding of PCSK9 to LDL receptor by at least 80%.
Independent claim 1 of the 741 patent recites:
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.
The 165 and 741 patents share a common written description. The specifications disclose 26 specific antibodies, including their production, screening, and amino acid sequences. For only 2 of those antibodies, the specifications disclose the 3D structures showing the binding of the antibodies to specific PCSK9 residues. The examples test the binding of only 3 antibodies to PCSK9.
Another one of Amgen’s patents, not at issue in this case, claims Repatha®, which is a PCSK9 inhibitor that Amgen currently markets as a prescription injection therapy for treating adults with high cholesterol. Amgen used to sell Repatha® for $14,520, but to stay “competitive” with other drug makers’ PCSK9 inhibitors, Amgen lowered the price tag to $5,850 in 2020. Amgen still made nearly $900 million from Repatha® in 2020.
Repatha® is exemplified in the 165 and 741 patents, but not claimed. And whereas Amgen’s Repatha patent claims the amino acid sequence of the antibody, the 165 and 741 patents at issue in this case do not define the antibodies in terms of their amino acid sequences. Rather, the 165 and 741 patent claims use functional language to recite an entire genus of antibodies that bind to specific amino acid residues on PCSK9 and block PCSK9 from binding to LDL receptors.
The use of functional limitations is central to the Federal Circuit’s affirmance of the district court’s determination that the 165 and 741 patent claims lack enablement.
The Federal Circuit begins with the usual reiteration of the Wands factor for evaluating enablement:
- the quantity of experimentation necessary;
- the amount of direction or guidance presented;
- the presence or absence of working examples;
- the nature of the invention;
- the state of the prior art;
- the relative skill of those in the art;
- the predictability or unpredictability of the art; and
- the breadth of the claims.
The Federal Circuit then compares the facts of the case to several precedents:
- Wyeth & Cordis Corp. v. Abbott Laboratories, 720 F.3d 1380 (Fed. Cir. 2013);
- Enzo Life Sciences, Inc. v. Roche Molecular Systems, Inc., 928 F.3d 1340 (Fed. Cir. 2019); and
- Idenix Pharmaceuticals LLC v. Gilead Sciences Inc., 941 F.3d 1149 (Fed. Cir. 2019).
In each of those precedents, the claims required both a particular structure and functionality. And in each case, the Federal Circuit found that the claims were not enabled, because the large number of embodiments within the scope of the claims and the specification’s lack of guidance on the structure/function correlation would have required undue experimentation to determine which embodiments would exhibit the required functionality.
None of these precedents are favorable to Amgen. The precedents, together with Sanofi’s argument that the binding limitation in Amgen’s claims alone encompasses “millions” of antibodies, effectively focuses the Federal Circuit’s attention on the breadth of Amgen’s patent claims:
While functional claim limitations are not necessarily precluded in claims that meet the enablement requirement, such limitations pose high hurdles in fulfilling the enablement requirements for claims with broad functional language…
Turning to the specific Wands factors, we agree with the district court that the scope of the claims is broad. While in and of itself this does not close the analysis, the district court properly considered that these claims were indisputably broad… However, we are not concerned simply with the number of embodiments but also with their functional breadth. Regardless of the exact number of embodiments, it is clear that the claims are far broader in functional diversity than the disclosed examples. If the genus is analogized to a plot of land, the disclosed species and guidance “only abide in a corner of the genus.” Further, the use of broad functional claim limitations raises the bar for enablement, a bar that the district court found was not met.
Amgen argues that the specifications provide “roadmap” for making the claimed antibodies, but the problem, as the Federal Circuit sees it, is that even after the antibodies are made, identifying those specific antibodies that exhibit the claimed functionalities of binding and blocking PCSK9 is only possible through laborious “trial and error” requiring “substantial time and effort”.
Amgen is not helped by seemingly undisputed expert testimony on the unpredictability of the art. There appears to be agreement between the two sides’ experts that a small modification in an antibody’s sequence can result in big changes in structure and functions. Further, there is evidence that translating an antibody’s amino acid sequence into a known 3D structure is still not possible, so that it is difficult to visualize and evaluate the binding of an antibody to PCSK9. As the Federal Circuit articulates, “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.”
There are some interesting observations.
First, while the patents at issue clearly claim a biotech invention, the Federal Circuit’s decision cites frequently to McRO, Inc. v. Bandai Namco Games Am. Inc., 959 F.3d 1091 (Fed. Cir. 2020)—a computer case—for its discussion on the enablement of a claimed range. However, in McRO, the Federal Circuit did not even address the question of whether the disputed claims were enabled. The Federal Circuit held only that the enablement analysis required first delineating the precise scope of the claimed invention, and having failed to make that delineation, the district court’s summary determination of non-enablement must be vacated.
Second, at first glance, the Federal Circuit appears to have articulated a “heightened” standard of enablement for claims reciting functional limitations. But really, the “heightened” bar seems to be no more than a proposition that the broader the claim, the more guidance the specification may need to provide to satisfy the enablement requirement.
Third, during prosecution of the 165 patent, the Examiner rejected the claims as lacking enablement. However, Amgen overcame the rejection by arguing, without any Rule 132 declarations, that “various antibodies” and “crystal structures” provided in the specification explained how antibodies bound to PCSK9 to achieve the claimed functionalities.
Takeaway
- The use of functional limitations, while desirable for imparting breadth to a claim, remains rife with pitfalls. For certain types of claims, such as claims directed to biologics, functional limitations are almost unavoidable because claiming the invention strictly in structural terms would be unduly narrow. For those claims, details in the specification are especially important.
- Where a claim requires both a particular structure and functionality, the specification should preferably describe some correlation between the structure and the claimed functionality.
- Where a claim recites a broad genus of structures for achieving a specific function, it is important for the specification to exemplify more than one species within that genus. Ideally the specification should also describe structural characteristics common to the species of the genus.
