HUMIRA FORMULATION PATENT SURVIVES IPR

Abbvie Biotechnology Ltd.’s (Abbvie) strategy to protect the drug HUMIRA from biosimilars relies on a number of patents that claim the liquid formulation of the drug HUMIRA.  Previously, the Patent Trial and Appeal Board (PTAB ) denied Amgen’s IPR petitions to invalidate two of Abbvie’s liquid formulation patents.  U.S. Patent Nos. 8,916,157 and 8,916,158 in IPR2015-01514 and IPR2015-01517.  Coherus Biosciences Inc. (Coherus) petitioned the PTAB to invalidate a related formulation patent that was not previously litigated, U.S. Patent 9,114,166.  The PTAB has also denied Coherus’ petition (IPR2016-01018).

The Patent (U.S. Patent 9,114,166) challenged by Coherus claims a stable liquid aqueous pharmaceutical formulation:

1. A stable liquid aqueous pharmaceutical formulation comprising: a human anti-human Tumor Necrosis Factor alpha (TNFα) IgG1 antibody at a concentration of 50 mg/ml, wherein the antibody comprises the light chain variable region and the heavy chain variable region of D2E7, and a buffer system; wherein the formulation is isotonic, suitable for single-use subcutaneous injection, and has a pH of 4.0 to 8.0.

Coherus’s (the petitioner) position was that:

Petitioner argues that “the only difference between the formulation components in Example 4 (formula b) [of Relton] and the challenged claims is the presence of a different IgG1 antibody, as opposed to the IgG1 antibody D2E7.” Petitioner then relies on van de Putte for its teaching of D2E7.  Petitioner argues that it was well known that D2E7 effectively treated rheumatoid arthritis when administered as a weekly dose of 20, 40, or 80 mg D2E7 by subcutaneous self-injection. Id. Petitioner further argues that a person of ordinary skill in the art would have had a reason to prepare a stable liquid formulation of D2E7 with a buffer system because liquid formulations were the preferred form of delivering proteins due to the convenience of manufacturing and clinical use.

PTAB’s reasoning for denying the petition was that:

We are not persuaded by this argument and supporting evidence. Petitioner’s argument that Relton’s disclosure of the class of IgG1 antibodies is sufficient guidance for a skilled artisan to prepare a stable, high concentration, liquid formulation of D2E7 is once again belied by the state of the art and Dr. Manning himself. In his book chapter (Chapter 8), Dr. Manning states that “[t]he exquisite sensitivity of protein structure, function, and stability to the primary sequence does not readily lend itself to a generic approach for protein formulation.” He continues, stating “[e]ven for closely related proteins, the relative stability and major pathways for degradation might be quite different.” Dr. Manning’s opinion (from his book) is consistent with Patent Owner’s summary of the state of the art at that time.  For example, Wang explains that, although certain factors have been identified that contribute to the stabilization of proteins, “the structural differences among different proteins are so significant that generalization of universal stabilization strategies has not been successful.”  Accordingly, Wang concludes that “the most formidable challenge in formulating a liquid protein pharmaceutical is to preserve the biological activity of the protein for an acceptable shelf life. Unfortunately, there is no single pathway to follow in formulating such a product. Usually, proteins have to be evaluated on a case-by-case basis.”  Thus, we are not convinced by Petitioner’s argument that Relton’s generic disclosure of IgG1 antibody formulations translates to a reasonable expectation of success in formulating a stable, liquid, high-concentration D2E7 formulation.

Accordingly, we determine that Petitioner has not shown sufficiently that a skilled artisan—without the benefit of hindsight—would have combined van de Putte and Relton to achieve the claimed formulation with a reasonable expectation of success. See Grain Processing Corp. v. Am.- Maize Prods. Co., 840 F.2d 902, 907 (Fed. Cir. 1988) (“Care must be taken to avoid hindsight reconstruction by using ‘the patent in suit as a guide through the maze of prior art references, combining the right references in the right way so as to achieve the result of the claims in suit.’” (quoting Orthopedic Equip. Co. v. United States, 702 F.2d 1005, 1012 (Fed. Cir. 1983))).