Antibodies and the Section 112 Written Description Problem After Amgen v. Sanofi
Earlier this month the U.S Supreme Court denied certiorari in Amgen Inc., Amgen Manufacturing Ltd., and Amgen USA, Inc. v. Sanofi, Aventisub LLC, Regeneron Pharmaceuticals, Inc., and Sanofi-Avantis U.S., LLC, a case that asked the Court to review the law related to the written description requirement of 35 USC Section 112. This case arose when Amgen sued Sanofi and Regeneron, alleging that their monoclonal antibody product, Praluent® (alirocumab), infringed Amgen’s patents (U.S. Patent Nos. 8,829,165 and 8,859,741). Amgen owns and commercially markets a competitor product named Repatha® (evolocumab). The Supreme Court’s refusal to review the case means that the Federal Circuit decision (872 F.3d 1367, Fed. Cir. 2017, “Sanofi”) will stand and the standard for obtaining broad protections for therapeutic monoclonal antibodies will continue to be challenging.
In Sanofi, the Federal Circuit ruled on October 5, 2017 that in order to obtain broad patent coverage for a class of antibodies that bind to a particular antigen and perform a particular function, companies must disclose a sufficient number of representative antibodies across the claimed genus or establish a clear relationship between the function of the antibody and the genus of the antibody in their specification. In doing so, the Federal Circuit essentially overturned the "newly characterized antigen" test and raised the bar for protecting antibody inventions by requiring more data when disclosing and claiming antibodies.
In Sanofi, the claims were directed to a monoclonal antibody that bound to one or more of 15 different amino acid residues on the sequence of the target antigen and performed a certain function (e.g., blocked the antigen from binding to its target). Claim 1 of U.S. Patent No. 8,829,165 ("'165 patent") is representative. It recites:
“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.”
To support its claim that antibodies that bound one of the 15 residues or any combination of them were covered by the patent, Amgen disclosed two specific antibodies with binding data and affinity data. These data probably would have been sufficient to support the claims prior to Sanofi. In Sanofi, however, the Federal Circuit ruled that such disclosure was insufficient. The court noted that patent specifications must disclose a “representative number” of species of the genus of claimed antibodies in order satisfy the written description requirement. The Federal Circuit did not, however, provide any guidance as to what a “representative number” of species would be. Therefore, it still remains an open question as to what counts as a representative number of species remains today.
While obtaining protection for antibodies is still possible after the Federal Circuit’s decision in Sanofi, certain types of claims are now more susceptible to attack and possible invalidation. We previously reviewed several different types of patent claims that are available to protect antibody inventions and their relative strengths in the wake of Sanofi. Each of the most common types of antibody claims is discussed again below.
Historically, one of the broadest types of claims a company could obtain in an issued patent directed to an antibody was claims describing the antibody by its function. Functional claims to a genus of antibodies typically recite the functional property of an antibody without reciting any structural or sequence information, for example “an antibody that specifically binds to target Y”. Similarly, functional claims can be in the form of competition claims where “an antibody that competes with antibody X for binding to antigen Y” is covered. While such broad claims can cover nearly any antibody in a group of antibody products that are directed to the same target, such functional claims are becoming increasingly vulnerable in light of Sanofi, as US courts will now require a “representative number” of examples of the genus of claimed antibodies, i.e. a representative number of antibody sequences and associated binding data.
Method of Use/Treatment
Claims directed to the method of use or method of treatment have also proven to be vulnerable as these types of claims have not fared well when challenged in an Inter Partes Review (IPR) at the Patent Trial and Appeal Board (PTAB). These types of claims are by far the most popular target of IPR petitioners. In a study of antibody-related IPR petitions, the IPR petition grant rate on method of treatment claims is 65% (24 petitions granted, 13 denied), but, in all 6 of the Final Written Decisions to date, all instituted claims were held unpatentable. Therefore, it appears that if the PTAB institutes an IPR on a method of treatment antibody claim, those claims are more likely than not to be found unpatentable. One potential reason for why these types of claims are relatively easy to invalidate is because if you knew the antigen and what it does, it would be obvious to develop an antibody against that antigen to treat people. As such, method of use and method of treatment claims are probably the weakest types of claims for protecting antibodies.
On the opposite side are composition claims directed to the chemical structure of the antibody. These types of claims define an antibody by its six complementary determining regions (CDRs), by its two variable regions, or even by its heavy and light chain sequences (both cDNA and peptide sequences). Patent prosecutors keen on obtaining the most protection for clients will attempt to claim sequences by the shortest and fewest number of sequences possible. Often times the amount of sequence data needed to pass examination hurdles will depend on which U.S. Patent and Trademark Office examiner has been assigned to prosecute the application. These types of claims will likely survive invalidation attempts due to their precise definition of the chemical structure of the antibody, leaving little question regarding which antibodies might be encompassed by the claims and which may not be encompassed. However, while antibody sequence claims are a strong type of claim to have, in terms of claim scope they are also the narrowest option, which makes them easier for a competitor to design around.
Besides claiming the antibody itself, a company can claim a pharmaceutical composition or formulation. While these types of claims are theoretically easier to design around because they include the antibody structure, they also appear to be successful in surviving IPR challenges at the PTAB. In fact, the PTAB rarely institutes challenges to composition claims, and when it has, the claims almost always survive. Antibody formulation claims are the second most frequently challenged type of antibody claim behind method of treatment claims, discussed above. However, of the 13 IPRs that have been filed against claims to antibody formulations, three were instituted and 10 were denied. In the three instituted IPRs, all of the claims survived the challenge. Of the IPR petitions that were denied, most were denied because the petitioner failed to establish “a reasonable likelihood that the petitioner would prevail.” It is likely that these types of claims survive challenges because there is high unpredictability in the art since even small changes in antibody formulations can have unexpected effects on protein aggregation, viscosity, and other factors, making it harder to prove that such formulations are predictable and obvious. As such, pharmaceutical formulation patent are important to include when deciding how to protect antibodies.
A final type of claim for protecting an antibody a claim directed to an antibody conjugate. These types of antibody claims describe an antibody with a particular sequence fused to, or conjugated to, a drug. In an IPR challenge to Kadcyla®, an antibody-drug conjugate consisting of the monoclonal antibody trastuzumab, Herceptin®, linked to the cytotoxic agent emtansine, the PTAB ultimately upheld the claims because a person skilled in the art at the time of the invention would have expected Herceptin®-maytansinoid immunoconjugates to be unacceptably toxic. While claims to antibody conjugates may survive obviousness challenges, it is important to remember that they are also relatively narrower tan other antibody claims because they describe both the antibody sequence and a conjugated drug. Such claims will also likely face challenges as to how much data and support is required to be in the specification to broadly claim the antibody conjugate and variants thereof. Nevertheless, these types of claims may be valuable to an antibody patent portfolio.
The recent case law in the antibody space has made it more challenging for companies to obtain broad protections for antibodies, especially in the wake of the Federal Circuit’s Sanofi decision and the Supreme Court’s refusal to review that decision. When patenting antibodies, therefore, it is important to review the antibodies on a case-by-case basis and decide which features to claim based on the amount of data and investment available. A patent portfolio can be more valuable when including many different types of claims directed to the antibody and its uses. However, by including at least some claims narrowly tailored to the data available for the antibody, a company can increase the likelihood that the at least some of these claims will be patentable and reduce the chances that at least these claims will be invalidated.
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