Machiavelli would have blushed. Feeling the heat from both RNAi and
antisense competition for targets in the liver, Alnylam has made it clear in its recent
McSwiggen patent-related press releases that it is determined to wipe out at
least the RNAi competition through patent and contract strategy (see here and here).
Whereas before it used to call out
Tekmira/Marina/Arcturus by claiming that unlocked nucleic acid would fall under
their patent estate, today it added Arrowhead Research to the club of companies
that entered an RNAi trigger licensing contract with Alnylam, but then find
that those contracts were not worth the paper written on: Merck, Tekmira, Arrowhead Research, and others.
In brief, the McSwiggen patents
that Alnylam bought from Merck claims RNAi triggers that satisfy the following
conditions:
1) RNAi
trigger with strands that have a length that fall within the classical range
for siRNAs;
2) At
least 10 or more bases (often pyrimidines) of either or both strands have to be
one of the following modifications: deoxy, 2’F, or 2’0-methyl.
Depending on the patents there
are slight variations as to the strand lengths covered, additional requirements
for phosphorothioate linkages etc.
Given the above limitations, it is strange
that coincident with the acquisition of the McSwiggen patent estate, Alnylam repeatedly
adds in the related press releases that it owns RNAi triggers, including those
modified with acyclic nucleotide analogues (--> usiRNAs). By contrast, it
would appear that replacing any of those modifications with the very unlocked nucleic acid analogue would be a simple way of circumventing McSwiggen without any destabilizing effect on the RNAi trigger.
Isn’t that odd? A company in a position of strength would not
do that. But we all knew that Alnylam
still wishes Tekmira to disappear from the face of the earth, so that’s not
really new.
The real shocker may be to investors
of Arrowhead Research (from Alnylam’s press release):
‘we intend to maximize the
value of this newly issued IP solely through the advancement of ALN-HBV - our
GalNAc-conjugated siRNA targeting the HBV genome for the treatment of HBV
infection’
In other words, Alnylam says that
the HBV target-specific license it gave to Arrowhead just 2 years ago does not
include rights to the newly acquired McSwiggen patent estate. And indeed, ARC520 by Arrowhead infringes the
newly issued patent subject of today’s press release (US 8,618,277). I will just use si-74 (one of the 2 siRNAs in
ARC520) to illustrate why.
chol-siHBV-74 sense: chol-uAuCfuGfuAfgGfcAfuAfaAfuUfgGfuAf(invdT) 23 bases,
chol-siHBV-74
antisense: dTAfcCfaAfuUfuAfuGfcCfuAfcAfgdTsdT 21 bases.
I’ve highlighted the
pyrimidine bases in red. ‘f’ after a symbol stands for 2’-fluoro,
small case is 2’-o-methyl, dT is deoxy-T.
1. ‘277
claims an HBV-targeted RNAi trigger which meets the following requirements:
a)
Each strand 18-24 bases (applies
to si-74);
b)
the sense strand comprises 10or more 2'-deoxy,
2'-0-methyl, 2'-deoxy-2'-fluoro, or universal base modified nucleotides (applies to si-74 where 21 nucleotides are accordingly modified
in si-74 sense);
c)
the antisense strand comprises 10or more
2'-deoxy, 2'-0-methyl, 2'-deoxy-2'-fluoro, or universal base modified nucleotides
(applies to si-74 where 21 nucleotides are accordingly
modified in si-74 antisen);
d)
10 or more pyrimidines (i.e. U or C) of either
strand modified by 2'-deoxy, 2'-0-methyl, 2'-deoxy-2'-fluoro nucleotides (applies to si-74 as each strand has at least 10 of those
modifications).
Genius, by
acquiring the Merck patents in January, Alnylam not only gave the withering
Kreutzer-Limmer patents a new life given that Merck was in some cases the only
party fighting it. No, Alnylam thereby also pulled the chair from underneath Arrowhead given the reliance of that company on ARC520 for its valuation.
Of course, a crumbling valuation of Arrowhead could really help Alnylam as it tries to catch up and develop its own
version of DPCs based on what Merck has been able to copy from Arrowhead. Given that ‘277 will only expire in 2022/3,
just waiting it out may not be an option for Arrowhead.
Sorry, Arrowhead, just because Alnylam
really, really ‘dislike’ Tekmira and is calling you ‘a friend’ does not mean
that you can trust them any more than Tekmira or that you are any more savvy in your drafting
contracts.
