The challenge in obtaining broad antibody genus claims in the US

Are the days of securing broad antibody genus claims in your United States patent over? Well, that all depends on how they are claimed. Recent findings of the US Federal Circuit in Amgen v Sanofi^[1] (Amgen), suggest that so-called “epitope mapping claims”, that is, where the genus claim functionally claims any structurally undefined monoclonal antibody (mAb) that binds to an antigenic epitope, might well be found lacking written description. That of itself it not entirely inconsistent with recent US jurisprudence, however the issue considered in Amgen was whether evidence of a later filed and later developed product could be used to invalidate the claims of an earlier filed patent for lack of written description.

Background

Amgen markets a product called Repatha® (evolocumab) for lowering low-density lipoprotein (LDL). Repatha is a blocking mAb which binds to PCSK9 and thus inhibits its ability to bind to and destroy low density lipoprotein receptor (LDL-R) which extracts LDL from the blood.

The two US patents (US 8,829,165 and US 8,859,741) covering the product contained broad mAb genus claims to the PCSK9 epitope. A representative claim is shown below:

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……….of SEQ ID NO:3, and wherein the monoclonal antibody blocks binding of PCSK9 to LDL-R.

Written Description

The United States Patent and Trademark Office (USPTO) requires that for written description to be satisfied, a patent specification must convey that the patentee had possession of the invention as of the filing date. Possession of the invention requires that either:

1. A representative number of species falling within the scope of the genus are disclosed; or

2. Structural features common to the members of the genus are disclosed (i.e. sequence) so that one of ordinary skill in the art can visualise and recognise the members of the genus.

Although Amgen had screened over 3000 clones, they only disclosed the structure of two, albeit structurally distinct antibodies. Sanofi marketed a competing product, (alirocumab) developed after the priority date of Amgen’s patent, Praluent® (alirocumab) and which also bound PCSK9 thus having the same activity as Amgen’s disclosed antibodies. Although the structure of the Sanofi antibody was different, it was still encompassed by Amgen’s broad genus claims. However, Sanofi sought to rely on its antibody to challenge the validity of Amgen’s patents based on written description for not having disclosed enough representative antibodies across the entire genus to show possession of the invention.

Amgen argued that since written description is judged at filing, post-priority evidence might be relevant only if it illuminated the state of the art at the filing date and since Sanofi’s antibody did not exist until after the priority date, it was not state of the art and could not illuminate it. However, the Federal Circuit held that, although entry of post-priority date evidence is not allowed to show the state of the art at the time of filing, such evidence may be introduced for the purpose of showing that a patent failed to disclose a representative number of species.

So what constitutes a representative number of species?

Unfortunately, there are no hard and fast rules. Amgen has been remanded to the District Court for a new trial on the question of written description, and the post-priority evidence of Sanofi’s antibody will be considered at the trial. Nevertheless, it does raise the question of whether written description will ever be met for functional antibody genus claims since one can never be certain whether there are enough representative antibodies disclosed in the patent specification to cover the genus. If evidence used in a written description challenge is expanded to include post-filing evidence then it seems possible that broad, functionally defined antibody genus claims could be vulnerable to challenge for lack of written description. We may then see a shift to the inclusion of more structural features in the claims thus narrowing the scope of the claims to a subset of the broader genus.

It is also worth considering the earlier decision of Abbvie v Janssen^[2] (Abbvie) in which the Federal Circuit also dealt with what constituted a representative number of species in the context of antibody claims as discussed below.

Abbvie was granted US patents to human IL-12 binding antibodies. By way of example, one of those patents contained a broad genus claim to any neutralising isolated human antibody that binds to human IL-12 and dissociates from human IL-12 with a k_off rate constant of 1 x 10²s^-1 or less, as determined by surface plasmon resonance.

Abbvie had described hundreds of antibodies that met the claimed function, however although the described antibodies had different amino acid sequences in the complementary determining regions (CDRs), they shared 90% or more sequence similarity in the variable regions and over two hundred of the antibodies differed from the lead antibody by only one amino acid. Additionally, all had VH3 type heavy chains and lambda light chains.

A competing product, Stelara was held to be encompassed by Abbvie’s broad genus claim however the evidence showed that Stelara was structurally distinct from the antibodies described and claimed in Abbvie’s patent. Because the two hundred plus antibodies described by Abbvie did not reflect the structural diversity of the claimed genus, the broad genus claim was found to lack written description.

Although Stelara was developed later, this case did not address the issue of post-priority evidence but rather what constituted a representative number of species.

Thus, the upshot appears to be quality rather than quantity. The patentee will likely need to disclose a sufficient number (which may well depend on the target) of diverse, structurally distinct antibodies to have any reasonable likelihood of securing broad, functionally defined genus claims.