Amgen Inc. v. Sanofi: U.S. Supreme Court Addresses Enablement for Biotechnology Inventions | Harris Beach PLLC
I’m a bit behind and therefore am not part of the slew of commentary that flowed from the Supreme Court’s decision in Amgen Inc. v. Sanofi, 143 S. Ct. 1243, 1248 (2023), addressing Amgen’s claims to “antibodies that (1) bind to specific amino acids on a naturally occurring protein known as PCSK9, and (2) block PCSK9 from impairing the body’s mechanism for removing LDL cholesterol from the bloodstream.” I was a bit disappointed, but not surprised. Upon reflection, the result is tolerable, but I wonder where it leaves biotech genus claims, particularly those related to antibodies. Are patent owners really limited to claiming species (i.e., sequence listings)?
The Supreme Court described both the “primary structure” (amino acid sequence) and “tertiary structure” (three-dimensional shape) of an antibody, and how a particular antibody’s ability to bind to and block an antigen is largely dependent on both its amino acid composition and shape. Antibody science is still unpredictable — scientists cannot always predict even how substitutions of single amino acids will affect the binding and/or blocking function of an antibody. The Supreme Court’s decision leaned highly on unpredictability of the art, although in the oral argument, it also seemed heavily influenced by the sheer number of antibodies that could be encompassed in a single functional claim.
Antibodies that inhibit PCSK9 (a natural protein) from binding to and degrading LDL receptors are a promising method of treating high LDL cholesterol. Several pharmaceutical companies researched antibodies that could bind to a region of PCSK9 known as the “sweet spot,” a sequence of 15 out of PCSK9’s 692 amino acids. Both Amgen and Sanofi had patents directed toward the specific sequence (amino acids) of the products. Amgen’s patented PCSK9 inhibiting drug contacted to the side of the epitope and less than half of the identified residues in the “sweet spot.” Sanofi’s patented PCSK9 inhibiting drug, which had a different amino acid sequence, bound to the middle area of PCSK9, contacting most of the amino acid residues in the “sweet spot.”
Additional Amgen patents were directed to a genus of antibodies that (1) “bind to specific amino acid residues on PCSK9,” and (2) “block PCSK9 from binding to [LDL receptors].” (Amgen Inc. v. Sanofi, 872 F. 3d 1367, 1372 [2d Cir. 2017].) The Supreme Court held that Amgen’s claims were not enabled because the specification failed to enable a person of ordinary skill in the art to make and use the claimed invention. The specification only identified 26 antibodies by their primary structure and 2 of those 26 by their tertiary structure. It also provided a method of screening antibodies by generating candidate antibodies and screening for their binding properties, and a method of conservative substitution, which called for modifying an antibody with a known function by replacing select antibodies in the sequence and then testing the result for its function.
Although there were experts on both sides with opinions on the amount of experimentation required, the Supreme Court found these methods were trial and error and did not provide the requisite certainty. The Supreme Court’s holding boiled down to this statement: “If a patent claims an entire class of processes, machines, manufactures, or compositions of matter, the patent’s specification must enable a person skilled in the art to make and use the entire class. In other words, the specification must enable the full scope of the invention as defined by its claims.” Amgen Inc. v. Sanofi, 143 S. Ct. at 1254.
The Supreme Court explicitly stated it was not changing the law of enablement but applying it in accordance with 150 years of precedent. While Amgen applied the law of enablement to “modern” technology, the case is like those the court had addressed in the past: “Today’s case may involve a new technology, but the legal principle is the same.” Amgen Inc. v. Sanofi, 143 S. Ct. at 1258.
What next?
Having pondered the decision, my first thought is “what about me”? What am I supposed to do now?
Functional claims are (mostly) out: The Supreme Court clearly disapproved of functional claims, particularly in the antibody context, but did not foreclose genus claims, noting that a few examples might support a genus claim if a “general quality” is disclosed that “may reliably enable a person skilled in the art to make and use all of what is claimed, not merely a subset.” Amgen Inc. v. Sanofi, 143 S. Ct. at 1255 Some experimentation is permissible, if it is reasonable.
I would think that the use of “R”, “R1” or “R2” etc. to represent groups in organic molecules would continue to be acceptable, but examiners do sometimes raise a section 112 objection if the number of permissible options generates an overly large genus.
How Would You Support a Valid Functional Claim or a Broad Genus:? In the antibody context, the Supreme Court has stated “scientists understand that changing even one amino acid in the sequence can alter an antibody’s structure and function” Amgen Inc. v. Sanofi, 143 S. Ct. at 1249 and, in the Amicus Brief of Sir Gregory Paul Winter, Nobel Prize-winning molecular biologist, “an antibody scientist is unable to predict the function of an antibody from its sequence.” No. 21-757 at 15 (Feb. 10, 2023) It is therefore difficult to contemplate a “general quality” common to antibody amino acid sequences. There are deep learning methods being developed to predict antibody interactions based on sequence, but these methods are not yet at the stage to assist in patent procurement.
What to Claim Now?: A patent application should include lots of species specified by their amino acid sequence or structure. With respect to antibodies, some attorneys suggest not describing the targeted epitopes because their disclosure likely doesn’t give enough structure to the claims, and would be better maintained as a trade secret. Patent owners should consider reissue if they don’t have a current patent or pending application with sequence claims.
The use of claims with a percentage of sequence identity (90% identity with SEQ ID NO: 1) or conservative substitutions may not be effective. As noted in The Antibody Patent Paradox, such claims will not cover species with similar binding if they have different structures, and may be invalid if many of the species are inoperative or require further screening. 132 Yale L.J. 994, 1054 (Feb. 2023)
Another suggestion has been using means plus function claims, which has been used successfully in certain (non-antibody) applications. Under current case law, an element in a claim may be expressed as a means for performing a function, but is limited to the means described in the specification, and their equivalents. Notably, later-developed equivalents are generally covered. While these types of claims have not been used in the antibody context, they are perhaps worth exploring as covered in The Antibody Patent Paradox, 132 Yale L.J. 994, 1055-1060 (Feb. 2023).
Enforcement: If you have patented only species claims, are you able to enforce the claims against competitors who have attempted to “design around” your sequence? The answer is unclear. In its Brief as Amicus Curiae, the solicitor general suggested the “doctrine of equivalents” may apply in enforcing sequence claims, including against a “competitor who has made ‘unimportant and insubstantial changes and substitutions’” to attempt to avoid the patent. No. 21-757 at 32 (Feb. 10, 2023) (citing Graver Tank & Mfg. Co. v. Linde Air Prods. Co., 339 U.S. 605, 607 (1950). If the patented and allegedly infringing antibodies bind to the target epitope at different residues and have a different sequence, do they achieve the same result “in the same way”? The use of the doctrine of equivalents relating to inventions disclosed by a sequence listing is an area that should be explored.
