ANTIBODIES
The uncertain future of antibody claims
Amgen v Sanofi continues the Federal Circuit’s trend of undermining certain antibody claims, explains Benjamin Pelletier of Haynes and Boone.
A long string of decisions from the US Court of Appeals for the Federal Circuit has undermined support for purely functional antibody epitope claims through the written description and enablement requirements of 35 USC §112.
The latest chapter in this series of cases, Amgen v Sanofi, Aventisub, issued in February, appears to place the final nail in the coffin of these highly valuable claims.
In Amgen, the patents in suit (US nos 8,829,165 and 8,859,741) are based on Amgen’s discovery that a protein ligand, called PCSK9, binds to and disables low density lipoprotein (LDL, or “bad cholesterol”) receptors, and that this ligand/receptor interaction can be blocked by antibodies that bind to a specific epitope on PCSK9, thereby helping patients achieve better cholesterol levels.
The specifications of the patents in suit disclose amino acid sequences for over 20 antibodies, one of which (designated as 21B12) is the specific composition marketed as Repatha. The specifications also disclose the 3D structures of 21B12 and another antibody, 31H4, and show how these two antibodies bind to an epitope on PCSK9, resulting in a blockade of the ligand/receptor interaction.
The claims at issue are epitope claims, reciting the function of the antibody, and providing a description of the epitope to which the antibody binds, without reciting structural details of the antibody itself.
The procedural posture of the case is notable in that two separate trials took place at the district court level, both resulting in a jury verdict finding in favour of Amgen, and concluding that the claims were not invalid for lack of written description and enablement.
On appeal of the first trial verdict, the Federal Circuit held that the district court had erred in its evidentiary rulings and jury instructions, and remanded the case for a new trial. After the second trial reached the same verdict, the district court granted Sanofi’s motion of judgment as a matter of law (JMOL), overruling the jury’s decision. On appeal of this result, the Federal Circuit affirmed, and underscored its distain for purely functional epitope claims.
“It’s clear that the court is uncomfortable with the ‘trial and error’ approach to identifying antibodies that fall within the scope of the epitope claims.”
Benjamin Pelletier
Analysis
In its analysis, the Federal Circuit revisited the Wands factors from In re Wands, which is well known as the controlling precedent for evaluating whether practising the claims requires undue experimentation, and also considered several more recent cases—Wyeth & Cordis v Abbott Laboratories; Enzo Life Sciences v Roche Molecular Systems; and Idenix Pharmaceuticals v Gilead Sciences—in which the claims were found to lack enablement due to the disparity between the wide breadth of the claims and the narrow teachings of the specification.
The Federal Circuit’s primary concern seemed to fall on the “substantial amount of time and effort” required to produce the full scope of the antibodies falling within the claim language.
During oral arguments, Judge Hughes asked Sanofi why the number of experiments matters if the experiments themselves and the methods to be used are predictable, or in other words, why it would constitute undue experimentation to screen 1,000,000 antibodies versus 100 antibodies, provided it was simply a matter of running a conventional test to determine whether each antibody candidate has the desired function.
Sanofi’s response was to dodge the question and emphasise the amount of work involved, stating “the roadmap requires the same amount of work as the original work”, and “I can’t think of a better definition of undue experimentation than ‘more work than any scientist would even contemplate doing’”.
Reading (and listening) between the lines, it’s clear that the court is uncomfortable with the “trial and error” approach to identifying antibodies that fall within the scope of the epitope claims, as well as the sheer amount of work that would be required to screen all the “millions” of theoretical antibody candidates.
Although it’s well established that the actual quantity of work required is not supposed to be dispositive of the enablement inquiry, in this case, it clearly was.
Writing for the court, Judge Lourie states: “We do not hold that the effort required to exhaust a genus is dispositive. It is appropriate, however, to look at the amount of effort needed to obtain embodiments outside the scope of the disclosed examples and guidance.
“The 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 (original emphasis).”
Amgen is an unfortunate result for biotech innovators seeking to protect antibody inventions, since it removes from their arsenal one of the most powerful exclusionary weapons—the purely functional epitope claim. In light of the court’s emphasis on reducing trial and error and providing tighter boundaries on the theoretical number of antibodies that would need to be screened to support function-based antibody claims, there are some potential strategies that applicants can adopt.
One approach is to include structural limitations in the claims that serve as proxies for functional activity. For example, during the antibody discovery process, clonotype families are typically generated, wherein the family members share a percentage of CDR sequence identity to one another (eg, 85%).
Due to their common genetic history, antibodies from the same clonotype family typically bind to the same epitope, which allows the 85% identity structural limitation to substitute for a functional limitation, like epitope binding.
”Carefully planning the timing of multiple provisional applications can provide applicants additional time to identify key features of their antibodies and support claims with functional attributes.”
While not a perfect substitute for a traditional epitope claim, this approach helps to reduce the “substantial time and effort” that would be involved in a hypothetical screening process, as well as the theoretical number of candidate antibodies that would fall within the scope of the claim, thereby potentially supporting enablement by moving into territory that the Federal Circuit may be more comfortable with.
Another approach is to delay filing until more antibody species have been identified. Although the US adopted a first-to-file system under the America Invents Act, function-based antibody claims are better supported when many different epitope-binding sequences have been created, and the connection between their structural and functional features has been studied.
This approach can allow structural commonalities to emerge, which may also serve as proxies for epitope binding. In addition, carefully planning the timing of multiple provisional applications can provide applicants additional time to identify key features of their antibodies and support claims with functional attributes.
While many antibody practitioners will be unhappy with the Federal Circuit’s conclusion in Amgen, we are stuck, for the time being, with continuing hostility toward broad “functional” antibody claims, and it remains unclear just how much and what kind of support will be required in a patent application to ensure their validity.
Benjamin Pelletier is a partner at Haynes and Boone. He can be contacted at: benjamin.pelletier@haynesboone.com
Image, from top: Shutterstock / StunningArt, liuwenhua/Lightspring
