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 3rd 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.
