Will Trillium Therapeutics’ patents protect its CD47 candidate against competitors?
Zachary Silbersher
Trillium Therapeutics ($TRIL) is a clinical stage immune-oncology company that focuses on cancer treatments, and in particular, treatments that inhibit CD47. Trillium is among a group of drug candidates exploring CD47 targeting agents that are attracting investment from Big Pharma. Pfizer recently announced a $25M investment in Trillium. In conjunction with developing its own two CD47-inhibitor candidates, Trillium is also building out its patent portfolio. On February 2, 2021, two additional U.S. patents issued to Trillium, including U.S. Patent Nos. 10,906,954 and 10,907,209. Will Trillium’s patents offer protection against brand competitors or eventual biosimilars?
The body’s immune system uses cells called macrophages to consume viruses, bacteria and even some cancerous cells. This is called phagocytosis. To do so, macrophages need to distinguish between healthy and unhealthy tissue. Healthy tissue typically exhibits high levels of the protein CD47. This helps macrophages know not to destroy, or phagocytose, that tissue. (CD47 is often called the “don’t eat me” signal.) When macrophages encounter healthy tissue exhibiting high levels of CD47, it triggers SIRPα receptors on the macrophage that prevent it from destroying it.
CD47 is overexpressed, however, in certain hematological cancers and solid tumors. These cancers, therefore, circumvent the macrophage by expressing high levels of CD47. By doing so, the macrophage believes that cancerous tissue is, in fact, healthy, and the immune response fails. Trillium’s CD47 candidates therefore inhibit CD47, thereby permitting the macrophage to detect and consume cancer cells. The obstacle to this approach is toxicity. By inhibiting CD47, these inhibitors not only consume cancer cells but are at risk of consuming healthy cells as well. Thus, a main challenge among the diverse group of CD47-antibody candidates is overcoming the toxicity from over-inhibiting CD47.
Numerous drug candidates are exploring CD47 target agents. In at least one respect, the candidates differ with respect to how they heighten CD47-targeting efficacy without exacerbating toxicity risks. For instance, Forty Seven’s magrolimab agent is administered with a priming and maintenance dosing strategy that mitigates anemia, and appears to condition the patient against toxicity risks. (Early CD47 agents caused significant anemia in patients.) Alternately, I-Mab’s candidate, lemzoparlimab, targets “tumor cells while exerting a minimal untoward effect on red blood cells to avoid severe anemia.” (Gilead acquired Forty Seven for $4.9B and AbbVie did a $2B deal with I-Mab.)
Trillium’s biologic candidates work by blocking the CD47 “don’t eat me” signal on certain cancer cells. Trillium’s candidate delivers a decoy receptor (SIRPαFc). The SIRPαFc is a fusion protein. The fusion protein performs two functions. First, it binds to CD47 and neutralizes the “don’t eat me” signal. Second, it delivers a delivers a pro-phagocytic, or “eat me,” signal through the Fc region.
Trillium specifically has two candidates, TTI-621 and TTI-622. The two candidates differ with respect to the strength of their respective “eat me” signal. TTI-621 has a strong a pro-phagocytic (“eat me”) signal, whereas TTI-622 has a moderate “eat me” signal. The two candidates thus represent a tradeoff. TTI-621 increases phagocytosis, and thus may have increased therapeutic efficacy, but has higher toxicity risks, and is thus most likely less well-tolerated. TTI-622, by contrast, is better tolerated, but likely with reduced therapeutic efficacy.
Trillium’s CD47 antibodies candidates are backed up by a small, but growing patent portfolio. (Trillium has several patents, but this blog post only addresses Trillium’s patent protection within the United States for its CD47 inhibitors.) In October 2020, Trillium announced the allowance of two new U.S. patents: U.S. Patent Application Nos. 15/962,540 and 13/320,629. The patents issued on February 2, 2020 as U.S. Patent Nos. 10,906,954 and 10,907,209.
The ‘540 application covers Trillium’s fusion protein for the TTI-622 candidate, specifically comprising the fusion of SIRPα with IgG4 Fc region. Trillium has already patented the fusion protein for the TTI-621 candidate, specifically comprising the fusion of SIRPα with IgG1 Fc region. The patent is U.S. 9,969,789. To the extent these patents cover Trillium’s antibodies themselves, they are unlikely to be infringed by brand competitors that are exploring different CD47 antibodies.
The patents may nevertheless become very important for staving off eventual biosimilar competition in the event Trillium’s drugs are successfully launched. (Prior art challenges to biologic fusion protein patents have been upheld. One example is Amgen, which faced invalidity challenges to its fusion protein patents for Enbrel.) Exactly how important the patents prove to be, however, is likely to be a matter of timing. For instance, the ‘789 patent will expire in approximately 2035. If approved, Trillium is likely to enjoy approximately twelve years of FDA-biologic exclusivity before the patents are required to keep out biosimilars. Thus, depending on when Trillum’s drug candidates are approved, the patents may offer little protection against biosimilars.
The ‘629 application covers a method of using SIRPαFc fusion proteins against CD47+ cancer cells and tumors, including hematologic and solid cancers. This patent is broader than the composition-of-matter patents covering TTI-621 and TTI-622. The patent covers a method for using a fusion protein of SIRPα and the Fc region of IgG to “interrupt signaling between human SIRPα and Fc.” Because it is broader, it is potentially more powerful against competitors developing a CD47 antibody that relies upon a fusion protein.
Interestingly, the ‘629 application required an appeal at the Patent Office before being allowed. That indicates that the Examiner rejected the application as obvious, and Trillium was unable to persuade the Examiner to otherwise allow the application. On appeal, the PTAB agreed with the Examiner that prior art fusion proteins rendered Trillium’s claimed fusion protein prima facie obvious. In other words, Trillium faced some fairly strong prior art that broadly covered similar fusion proteins claimed in their patent. However, the patent was nevertheless allowed based upon unexpected results of Trillium’s protein.
There are two ways to interpret this. On the one hand, it shows that the solution explored by Trillium exists within a relatively crowded art, which increases the likelihood its patents could be invalidated in subsequent litigation. On the other hand, having prevailed on appeal to earn allowance of the application, and done so on the basis of unexpected results, that presumably strengthens the patent’s validity in subsequent litigation. The strength of these patents will eventually hinge on how “unexpected” those purportedly surprising results were.
Trillium has at least four additional pending patent applications, including U.S. Patent Application Publications 2019/0091290 (SIRPαFc plus a macrophage stimulating agent); 2019/0255082 (CD47 blockage drug plus a proteasome inhibitor); 2020/0157179 (CD47 blocage drug and a cell checkpoint inhibitor); and 2019/0269756 (CD47 blockage drug and a histone deacetylase inhibitor).
These patent applications appear to be broader than the composition-of-matter patents specifically covering TTI-621 and TTI-622. If allowed, they may prove effective against competitors developing CD47 targeting agents. That, however, will depend upon the scope of the allowed claims, and how closely they align with the approaches eventually developed by the competitors that make it to market. And even if allowed, the prosecution history for the ’629 application suggests that the patents could very well face invalidity challenges before any competitors agree to pay royalties.