Written Description a Problem for Biological Drugs

By: David S. Forman, Ph.D.

Half of the ten biggest selling pharmaceuticals are biological drugs based on monoclonal antibodies.  Monoclonal antibodies are made by growing clones of a large number of single antibody-producing cells, and then screening the clones to find cells making antibodies that specifically bind to a desired target molecule, called an “antigen.”  Typically, this screening yields several monoclonal antibodies that have the desired binding characteristics, and one is selected for development into a drug.

Each individual monoclonal antibody is a protein that has a unique chemical structure, and thus can be patented as a chemical compound.  However, a pharmaceutical company that discovers a disease treatable with a monoclonal-antibody-based drug wants to patent not just the specific monoclonal antibody it has developed, but also all other monoclonal antibodies that bind to the same biological target.  Otherwise, competitors could easily design around their patent by developing a different monoclonal antibody that binds to the antigen with the same binding characteristics.

This was the situation in Amgen Inc. v. Sanofi, 872 F.3d 167 (Oct. 3, 2017).  Amgen developed Repatha®, a drug based on a monoclonal antibody that binds to and inhibits a particular protein (PCSK9), leading to a reduction of “bad cholesterol” (LDL-C) in the blood.  Repatha contains a specific monoclonal antibody (21B12) that binds to PCSK9.  But, during their screening of 3000 clones, Amgen found 85 monoclonal antibodies that bind to PCSK9.  To protect their discovery, they tried to patent all monoclonal antibodies that block PCSK9.  USPTO has sometimes allowed patenting monoclonal antibodies by “functional” claims describing their binding characteristics (e.g. where on the PCSK9 protein molecule they bound) and what they did (e.g., block the action of PCSK9).

Sanofi also explored monoclonal antibodies targeting PCSK9, and developed one into a similar drug for lowering LDL-C, Praluent®.  The active ingredient in Praluent is a monoclonal antibody that targets PCSK9, but is different from any of the specific monoclonal antibodies expressly described by Amgen in their patents.

Amgen sued Sanofi for patent infringement.  Sanofi argued as a defense that the Amgen patents are invalid because they lack a written description as required in 35 U.S.C. § 112 of the entire genus of monoclonal antibodies, which includes Sanofi’s antibody.  Section 112 states that “[t]he specification shall contain a written description of the invention . . . in such full, clear, concise, and exact terms as to enable any person skilled in the art to which it pertains . . . to make and use the same” (emphasis added).  To satisfy the statutory requirement of a written description of the invention, it is not enough for the specification to show how to make and use the invention (the “enablement requirement”).  Ariad Pharm., Inc. v. Eli Lilly & Co., 598 F.3d 1336, 1345–48 (Fed. Cir. 2010) (en banc).  An adequate written description must contain enough information about the actual physical or chemical makeup of the claimed products—“a precise definition, such as by structure, formula, chemical name, physical properties, or other properties, of species falling within the genus sufficient to distinguish the genus from other materials.”  Id.  Functional” terminology can do this only “when the art has established a correlation between structure and function.”  Ariad, 598 F.3d at 1350.  Sanofi argued that, in this case, it was insufficient to claim the antibodies based on a detailed description of a “newly characterized antigen” (PCSK9) to which the antibodies bind.  They argued that § 112 requires a “written description of the invention,” not by describing something that is not the invention, i.e., the antigen.  A patent claiming a genus must disclose “a representative number of species falling within the scope of the genus or structural features common to the members of the genus so that one of skill in the art can ‘visualize or recognize’ the members of the genus.”  Id. at 1351.  Thus, if Amgen’s patent does not disclose a representative number of species of monoclonal antibodies binding to PCSK9, then it is invalid.

The court also considered whether information about antibodies discovered after Amgen’s filing date should have been considered by the jury in deciding whether there is a written description, i.e. a representative number of species.  On the one hand, a written description is judged based on the state of the art as of the priority date.  Ariad, 598 F.3d at 1355.  Accordingly, evidence about the state of the art subsequent to the priority date is not relevant to the written description.  Id.  On the other hand, evidence showing that a claimed genus does not disclose a representative number of species may include evidence of species within the claimed genus which are not disclosed by the patent, and evidence of such species (like the Sanofi Praluent antibody) is likely to have been discovered after the priority date.  The Federal Circuit determined that the jury should have been able to receive information about monoclonal antibodies discovered after Amgen’s filing date in order to decide whether Amgen’s claimed genus discloses a representative number of species.  Therefore, the Federal Circuit remanded for a new trial.

This written description issue is extremely important for biological drugs based on monoclonal antibodies.  Some drugs based on monoclonal antibodies are extremely valuable and there are more such drugs in the pipeline.  If the innovators are unable to patent all the monoclonal antibodies that are the basis of their drug discovery because they cannot satisfy the written description requirement of 35 U.S.C. § 112, competitors will be able to design around the innovators’ patents, as Sanofi did, by making a drug with an effective monoclonal antibody that is not expressly described in the innovators’ patents.