RNAi Trigger History Revisited as Alnylam Once Again Gets Tough on IP

Last month, Alnylam lectured  Arrowhead Research that they infringed Alnylam's RNAi trigger IP and added that the use of UNAs would not protect companies using them (Tekmira, Arrowhead Research, Marina Biotech, and Arcturus) either.  So as Alnylam is once again trying to intimidate the competition and their investors by claiming that they control RNAi triggers, it might be worth revisiting some RNAi trigger history.  Doing so suggests that in fact they have been one of the egregious infringers of 3^rd party IP themselves and raises questions as to their own freedom-to-operate and validity of IP.

Sirna and Silence Therapeutics early proponents of modified RNAi triggers

The early RNAi days were marked by the competition for RNAi trigger supremacy between star-studded start-up Alnylam and working-class Sirna Therapeutics which had just averted bankruptcy following failed attempts with ribozymes.  Silence Therapeutics was another company that had ambitions to cornering important RNAi trigger IP and like Sirna had a history in failed attempts with oligonucleotide therapeutics.

Due to their prior experiences in nucleic acid-based drug development, it came natural to Sirna and Silence to apply nucleic acid modifications and soon earned a head-start in creating IP related to the use of modified RNAi triggers.  The belief was that in order to endow RNAi triggers with pharmaceutical properties, they had to be modified.

Sounds familiar? If so, then it is probably because this has become Alnylam’s new mantra, too.  Of course, this comes with a 12-year delay and only after acquiring Sirna’s IP estate and a history of claiming that they want their RNAi triggers to be as ‘natural’, i.e. unmodified, as possible, not due to IP limitations, but because of superior performance and considering safety.  In fact, Alnylam has not only been infringing Baulcombe IP for a short while, but also Merck/Sirna IP for probably as long as they were starting to see decent in vivo knockdown results with their highly modified GalNAc-siRNAs.

Although this clearly shows that Alnylam’s publicly claimed control over RNAi trigger IP has simply been a mirage, to their credit they make efforts in eventually gaining access to IP they are glaringly lacking.  Also, while at some point and for some delivery strategies the notion of minimally modified RNAi triggers had its merits, the emergence of RNAi trigger conjugates has increased the value of RNAi trigger modifications.  One might also criticize companies like Sirna/Merck, Silence, and RXi Pharmaceuticals (one of the first practical adopters of highly modified RNAi triggers and conjugates) for standing still instead of developing their initial technologies to their logical conclusion.

A comeback for AtuRNAi triggers?

Silence Therapeutics left a lot of value on the table by limiting themselves to a modification pattern that involves alternating 2’-O-methyls with a 2’-O-methyl-modified base on one strand opposing an unmodified base on the other like in a zipper.  One reason for this limitation was that during patent prosecution, the attempt by Silence Therapeutics to get patents related to modification patterns in general and not limited to 2’-O-methyls failed.

Interestingly, the RNAi triggers in ARC520 that Alnylam lays claim on involve a modification pattern reminiscent of AtuRNAi, only that it is here 2’-fluoro that is the alternating modification (Wooddell et al. 2013).  Also, if you review Alnylam’s recent patent applications (e.g. WO2014089313), alternating 2’-fluoros seems to be Alnylam’s preferred modification pattern, too.  Could it be that these companies were inspired by AtuRNAi trigger design?   

In any case, AtuRNAi and Silence may hold the key to invalidating some troublesome modified RNAi trigger IP by Alnylam by rendering them obvious.  Even more exciting for Silence, albeit unlikely given that the opportunity may have passed is the prospect that Silence could revive some of the more general RNAi modification pattern claims, thereby affecting the freedom-to-operate by Alnylam (and Arrowhead Research).

And welcome to Amy Shuman, former general counsel of Pfizer, to the Board of Directors of Alnylam.

The Time for the U(nusual)siRNA Strategy Has Come

As Tekmira and Arrowhead Research will unveil their next RNAi Therapeutics development candidates later this year, an interesting question will be whether these will involve one of their RNAi trigger options that some consider to be unencumbered by fundamental IP related to traditional designs (esp. the Baulcombe and Tuschl II IP).  These decisions could have important strategic consequences for the competitive landscape, from targets and indications to Big Pharma involvement.   

Support for freedom-to-operate claim

One of these designs is the usiRNA from Marina Biotech.  These comprise at least one ‘unlocked’ nucleic acid monomer (UNA) in the double-stranded RNA molecule.  While I have reservations about the scientifically tenuous claim (see here why) that UNAs are not to be grouped with most of the other nucleotide modifications for RNAi use because they lack an intact ribose group, usiRNAs were held to be sufficiently non-obvious and of specific utility that the USPTO issued fairly broad claims in 2012.  Moreover, Marina Biotech once commissioned an external IP lawfirm perform a freedom-to-operate analysis on usiRNA, and (surprise, surprise) came to the conclusion that, indeed, usiRNAs have FTO.

Overcoming target picking limitations

This view seems to be shared also by others in the industry. Notably, Roche RNAi (now part of Arrowhead Research) in 2009 gained access to Marina’s usiRNAs, meroduplex siRNAs, and Dicer-substrate RNAi triggers.  This came as a surprise given that Roche had spent over $300M just two years earlier to gain access to RNAi trigger IP held by Alnylam.  Given that none of the three licensed RNAi trigger forms and related IP poses any FTO threat to traditional Baulcombe-Tuschl designs, the most likely explanation for the move is that it was about allowing the company to escape the target picking limitations under the license from Alnylam.  This included the 31 targets exclusively held by Novartis, some Tekmira exclusive target picks, and some targets pursued by Alnylam that Alnylam exempted from competition.  Whether the last of Alnylam’s Big Pharma licensees, Takeda, might pursue a similar strategy is an interesting question.

Facilitating platform partnerships

When Alnylam and ISIS sued Tekmira for infringing on their RNAi trigger IP by collaborating with Bristol-Myers Squibbs on RNAi delivery, it became a priority for them to have access to or control over non-Alnylam RNAi triggers.  As a consequence, they obtained an exclusive license to Halo-Bio’s multivalent RNAi triggers (more than two strands).  Subsequently, they gained access to Marina’s usiRNAs, including the ability to sublicense.   This now puts them in the position to engage in platform partnerships with Big Pharma companies that do not have access to Alnylam IP.

The same strategy would likely also apply to Arrowhead Research with its various RNAi trigger options that it inherited from Roche, especially if Alnylam provided Roche with only product-specific sublicensing rights, if at all.  As RNAi Therapeutics enjoys a return of pharmaceutical interest, this one-stop-shop option by the two leading delivery companies could be critical to bringing new companies into the space.

And for Alnylam, these developments would not only diminish the royalty it might earn from licensing its IP, they could undermine their own product candidates, including ALN-PCSK9 (hypercholesterolemia) and ALN-AT3 (hemophilia).  Accordingly, the preclinical data strongy suggest that subcutaneous DPCs can do everything that Alnylam’s GalNAcs can do, only much more potently and with less frequent dosing.