In a case putting the validity of millions of existing antibody claims at risk, the Federal Circuit decided last month that such claims must expressly enable the full scope of the claimed antibodies by their structure, in Amgen Inc. v. Sanofi. While not terribly unusual in its recitation of the principle, in practice antibody structural complexity, and the ability to change amino acid identity to escape infringement without changing the functional properties of the changed antibody, increases the potential for such claims to provide significantly more restricted patent protection for most antibodies.
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®. The claims of the patents-in-suit defined antibodies falling within their scope with reference to the amino acid sequences of the target, PCSK9, and not the antibodies themselves. 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 low density lipoprotein receptor (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 found that certain claims of the patents-in-suit were not invalid for lack of enablement, but the district court granted Sanofi’s motion for judgment as a matter of law contrary to the verdict, which was the basis for this appeal.
The Federal Circuit affirmed, because "[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." 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."
The Court cited several recent cases where enablement was the dispositive issue (Wyeth & Cordis Corp. v. Abbott Laboratories, Enzo Life Sciences, Inc. v. Roche Molecular Systems, Inc., and Idenix Pharmaceuticals LLC v. Gilead Sciences Inc.), in which the Court had decided there was a lack of enablement 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 provided a synthesis of this analysis regarding satisfaction of the enablement requirement arising from these cases, saying:
"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."
The opinion referenced the unpredictability of the antibody arts as a relevant (and supportive) factor in favor of invalidity, and that the amount of guidance provided by the patent specification was deficient 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." 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 were 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.
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. 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 based on structure 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.
Kevin Noonan is a partner with the law firm McDonnell Boehnen Hulbert & Berghoff LLP and represents biotechnology and pharmaceutical companies on a myriad of issues. A former molecular biologist, he is also the founding author of the Patent Docs weblog, http://patentdocs.typepad.com/.
NOTE: This is the last of these columns I will write for DDN. It has been a pleasure to do so, and I hope readers have felt they benefitted from reading them. Thanks to DDN for giving me the opportunity.