Companies have been exploring the potential to use combinations of various checkpoint inhibitors to enhance the treatment of patients with various cancers. The recent approval by the U.S. Food and Drug Administration of Bristol Myers Squibb’s Opdualag for the treatment of patients with unresectable or metastatic melanoma shows that such combinations offer new avenues for patients suffering from cancer. Opdualag, a fixed-dose combination of the antibodies nivolumab (a programmed death-1 inhibitor) and relatlimab (a lymphocyte activation gene-3 inhibitor) formulated as a single intravenous injection, showed improved results compared to nivolumab monotherapy.
These results are good news from a clinical perspective. They also provide good news from a patent protection perspective because they offer the opportunity to bolster patent protection around the new therapy. In addition to patent protection on the individual antibodies and their uses as therapeutic agents, patents covering the combination as a therapy and its formulation may extend the date for loss of exclusivity. But obtaining such patents may not be straightforward. The prior art disclosure of data from monotherapy of the antibody components of the combination may present barriers to obtaining a patent claim covering the use of the combination therapy for diseases similar to those treated by the monotherapies. Similarly, prior art patents covering the individual antibodies may contain boilerplate disclosures in the specification contemplating a combination use. These earlier data and disclosures could render the combination “obvious,” as was the case in some recent patent challenges to combination therapies that included at least one antibody. See, e.g., Hospira v. Genentech, IPR2017-00731, Paper 120 (P.T.A.B. Oct. 3, 2018), aff’d, Genentech, Inc. v. Iancu, 809 Fed.Appx. 781 (Fed. Cir. Mar. 26, 2020).
To defend against challenges brought on the basis of “obviousness,” companies offering combination products should develop evidence related to secondary considerations of non-obviousness, such as commercial success of the combination product. Such evidence may come from the sales of the combination product. But it is not sufficient to show sale figures; a nexus must exist between the claimed invention and these sales. It may be difficult to show the nexus for combination products because of the existence of patents on the individual antibodies. Patents claiming the individual antibodies may be considered blocking patents that prevent a competitor from making its own combination product. Therefore, it may be difficult to show that the commercial success is attributed to the patent claims to the combination as opposed to patent claims to the individual antibodies. This could derail an argument that a nexus exists between the combination patents and the commercial success, and may reduce the ability of the combination patent claims to extend protection of the combination product. Considering the potential difficulty in establishing a nexus between the sales of the product and the patent claims covering the combination therapy, it is important to gather evidence of other secondary considerations, such as unexpected results. Proving unexpected results also requires showing a nexus between the claims and the results. For patents covering formulations of the combination product, the evidence may be the difficulty in making such a single formulation where the unique nature of each antibody and the antibodies’ respective varied physicochemical and thermodynamic properties give them different stability profiles. For the method-of-treatment patents, such evidence may exist from the clinical trial data if the baseline for the combination was the efficacy of monotherapies of the individual components. The improved results of the combination may establish a nexus as to synergistic effects of the claimed combination in treating patients. As courts look at the totality of the evidence when concerning secondary considerations, it is important to also look for evidence of failure by others, praise from the industry, and a long-felt need to support claims to the combination.
As with many medical treatments—particularly in cancer therapies—combination immunotherapies will likely expand over the upcoming years. It is important that companies investing in these therapies consider ways to position their IP to protect revenue from the combination product to support future research and development.