Can Coherus invalidate Amgen’s Enbrel® patents?
Amgen’s Enbrel® blockbuster faces encroaching biosimilar competition from Sandoz and Coherus Biosciences. Sandoz has already filed its aBLA with FDA for its biosimilar, which spawned a patent litigation lawsuit from Amgen. The case was commenced in February 2016, and is scheduled to go to trial in April 2018, which is only a few months away.
The case seems ripe for a settlement, and settlement windows typically open before trial. Yet, in parallel with that lawsuit, Coherus Biosciences has filed petitions for inter partes review against Amgen’s two protein patents covering Enbrel®, the ‘182 patent and the ‘522 patent. The institution decisions are due before the trial: March 15, 2018 for the ‘182 IPR, and March 13, 2018 for the ‘522 IPR. If the IPRs are instituted, that could shift the dynamics, and push the parties to agree on an entry date.
Amgen’s protein patents covering Enbrel® are potentially lethal, given that they do not technically expire until at least 2028. Given that the patents cover Enbrel®’s protein itself (entanercept), both Sandoz and any other biosimilar will likely find it difficult to design around them and avoid infringement. Accordingly, Sandoz will likely focus its defenses on invalidating the patents. Sandoz can pursue a number of avenues to do so, which we have previously written about before, including lack of written description and double patenting. The most direct route, however, would be to show that the patents are anticipated or obvious in view of the prior art, i.e., they are not novel. So what is the obviousness argument?
Entanercept is a fusion protein, which fuses a fragment of the TNF receptor to the human immunoglobin G antibody (IgG). More specifically, entanercept constitutes a soluble fragment of the 75 kilodalton human tissue TNF receptor that is fused to the hinge, CH2-CH3 region of the heavy chain of IgG. The purported benefits of Enbrel®’s fusion protein is that fusing a receptor with IgG proteins yields increased affinity for the TNF antigen. The TNFr:IgG protein dimerizes, and therefore displays two copies of the receptor, thus increasing affinity. In addition, the half-life of the fusion protein is also purportedly much greater than the TNF receptor alone.
What is Coherus’s invalidity argument? Rather than detailed explanation of the hairy technical and legal concepts, this post attempts to summarize the arguments as simply as possible. (Also, the inventive aspects of ‘182 and ‘522 patents are essentially the same, and Coherus’s arguments against the ‘182 patent apply equally to the ‘522 patent.)
The image below summarizes the invention of the ‘182 patent. This figure is taken from Coherus’s IPR for the ‘182 Patent (IPR2017-02066, Paper 1, p. 2). On the left is the IgG antibody. The antibody resembles the letter Y (but on its side.) The letter Y essentially has three parts, the vertical base and two diagonal portions extending from the top of that vertical base. The point where all three parts meet we will call the “hinge portion.”
As shown above, the invention of the ‘182 patent essentially takes the vertical base of the Y, which is the CH2-CH3 regions of IgG, and fuses it with a fragment of the 75 kiladalton TNF receptor. Prior to the ‘182 patent, it was known that fusion proteins between a protein and IgG could make the protein receptor a more effective inhibitor. Indeed, prior scientists had also previously fused IgG with a TNF receptor fragment. Accordingly, the most important part of the invention is the location that the IgG part fuses with the TNF receptor fragment. In the ‘182 patent, that fusion happens at the hinge region.
Kyle Bass previously filed an IPR against the ‘522 patent. That IPR was not successful. Importantly, Bass failed to convince the PTAB that it would have been obvious to fuse the TNF receptor fragment to the hinge region of the IgG antibody. With that in mind, Coherus’s IPR pays special attention to attempting to anticipate this precise element of the patent.
Coherus principally relies upon three prior art references, Smith, Watson and Zettlmeissl. According to Coherus, Smith taught a fusion protein between IgG and a 75 kiladalton TNF receptor fragment. Yet, the fusion was not at the hinge region of IgG. Watson taught a fusion protein between IgG and a different receptor protein, murine peripheral lymph node homing receptor (“pln HR” or “mHR”). Yet, Watson taught the fusion at the hinge region of IgG was optimal because it “resulted in chimeric molecules that were efficiently synthesized and dimerized.” Zettlmeissl also taught a fusion protein between IgG and a different protein, CD4. Yet, Zettlmeissl also studied fusing CD4 to different locations on IgG, and taught that fusion at the hinge region was purportedly best because “in general poor expression was observed for fusion proteins bearing CH1 domains.”
These references, and their combinations, are summarized below. This figure is also taken from Coherus’s IPR for the ‘182 Patent (IPR2017-02066, Paper 1, p. 3).
Thus, the invalidity argument against Amgen’s Enbrel® patents is fairly straightforward: Smith taught fusing IgG to a TNF receptor fragment. And both Watson and Zettlmeissl taught that, for proteins fused to IgG, fusing at the hinge region of IgG was best. Together, these references, according to Coherus, would have motivated a scientist to fuse a TNF receptor fragment to the hinge region of IgG, which is essentially the inventions behind the ‘182 and ‘522 patents. (A future post will discuss Amgen’s response to these arguments.)