Zamore Design Rules not Essential, but Highly Desirable and Strategically Important

As Silence Therapeutics is being issued one patent after another from the Zamore siRNA design rule patent families in the US, and possibly also soon in Europe, there has been some confusion about their value, both scientific and strategic. Silence claims that they are highly valuable additions to the RNAi Therapeutics toolbox; Alnylam dismisses them as something they chose to pass on as worthless. This controversy is part of the general debate of how easy it is to work around Alnylam’s historically strong IP position in RNAi triggers at a time that the Tuschl Tussle and a hearing on Tuschl II in Europe in early December are set to provide much-anticipated clarification of the RNAi trigger IP playing field.

As I have detailed before, I personally believe that while one of the Zamore patent families related to enhancing RISC turnover (mismatches between the 3’ end of guide and target mRNA) is quite useful and probably still widely underappreciated, it is the differential end-stability patent family that should be of Alnylam’s concern. Sure, going forward, you can easily get around it by simply not using the covered methods, but ignoring one of the most impactful siRNA design rules would be very much at the considerable expense of the siRNA discovery efficiency. Also, there is a good likelihood that some of the current RNAi clinical candidates have employed these rules and would require licenses at some point. Ask a handful of RNAi molecular biologists and I bet 4 or 5 out of 5 will attest you the importance of the end-stability rules which are quite comprehensively covered by the issued claims. Here is an exemplary main claim:

1. A method of producing a dsRNAi agent having decreased off-target silencing activity, the method comprising:

(a) identifying an off-target silencing activity mediated by a sense strand of a first dsRNAi agent, wherein the first dsRNAi agent directs cleavage by a RISC complex at a phosphodiester bond within a desired target mRNA; and

(b) synthesizing a substituted dsRNAi agent comprising one or more substituted base pairs with respect to the first dsRNAi agent, wherein the substituted dsRNAi agent comprises a sense and an antisense strand, each strand having a 5′ end and a 3′ end, wherein the substituted dsRNAi agent directs cleavage by the RISC complex at the same phosphodiester bond within the desired target mRNA, wherein the one or more substituted base pairs are within about 5 base pairs from the 5′ end of the antisense strand (AS 5′) and the 3′ end of the sense strand (S 3′) and are selected from the group consisting of a mismatched base pair, a wobble base pair, a base pair comprising a rare nucleotide and a base pair comprising a base-modified nucleotide, such that the sense strand of the substituted dsRNAi agent is less effective than the sense strand of the first dsRNAi agent at entering the RISC complex;

You will see that it is a claim on a method detailing specific steps taken to increase the specificity of an siRNA, and in order to enforce it you would probably need to have insight into the development history of individual RNAi Therapeutic candidates. Since I was therefore curious as to how Silence thinks it may enforce such claims, I recently spoke about it to the CEO of Silence Therapeutics, Phil Haworth, on the phone.

Dr. Haworth stated that Silence’s current strategy was to raise awareness of the Zamore patents and have companies decide for themselves whether they ought to get a license to it or not, implying that getting a license now would be cheaper than waiting until products are close to commercialization. He agreed that it may be impossible to prove without doubt that the Zamore rules had been employed without direct insight into the RNAi trigger lead development of the various companies. He added, however, that after Silence Therapeutics and Intradigm merged earlier this year, they found that Silence Therapeutics would indeed have infringed the Zamore design rules. Although only an n=1, this is consistent with the notion that particularly the end-stability rules find wide application in the industry.

I also asked whether we may see composition of matter patents issued covering the end-stability rules, particularly since they may be more straightforward to enforce. For reasons that are not fully clear to me without studying the status of the entire patent family in detail, Dr. Haworth wished to leave this an open question. So it’s possible, I guess, and Silence may want to retain the thunder for any such issuance.

Whatever the case, I feel Silence has a strong case that it is likely that Big Pharma will license some of the Zamore rules on a non-exclusive basis, either broadly for companies interested in RNAi Therapeutics as a platform (Merck, Roche, Novartis probably highest on the list) or on a case-by-case basis.

Alnylam may be in a more tricky situation. Although they would probably also be invited to take a license, such rights are unlikely to come together with rights to sub-license the Zamore rules to Alnylam platform licensees. As such, these potential partners may now feel that even if they pay for a RNAi trigger license from Alnylam, they still would not have all the desirable siRNA design tools at their disposal. Silence, of course, is in a somewhat similar situation, namely that while they can probably work around Alnylam’s RNAi triggers, particularly for blunt-ended dsRNAs 22 base-pairs and longer with some related composition of matter patents to boot ('AtuRNAi'), potential partners may not want to sacrifice on the use of 3’ overhangs that, although dependent on the Tuschl litigation, are likely to be controlled by Alnylam in the future.

Alnylam is arguably in the better position. It could just continue and bury the $20M market cap Silence Therapeutics under patent litigation costs and diverted management attention. One example that struck me here particularly was Alnylam’s opposition to Silence’s PKN3 patent which I feel is built on solid data and given the 20000 or so genes available, Alnylam should have no reason to oppose except to hold up Silence’s efforts with IP costs. On the other hand, as its investors grow impatient about long-promised deals, Alnylam does not have the luxury of there being increased uncertainties not only on its gate-keeping position, but also whether the scope of its freedom-to-operate is scientifically satisfactory. There is, of course, also the distinct possibility that Merck may see Zamore a relatively cheap way to gain leverage over Alnylam and may therefore choose to be Silence’s white knight. With Silence at a $20M market cap and Alnylam having $400M in cash waiting to be invested in RNAi Therapeutics instead of litigation, you’d think Zamore would be a good investment for Alnylam to make.