Silence Therapeutics About to Be Issued Broad Blunt RNAi Trigger Patent? An Update.

Note from 28 January, 2012:

On January 3, 2012, the EPO issued an 'Intention to grant'. Unlike suggested in the following blog entry, the claims in the accompanying 'Druckexemplar' are not blocking any more for blunt-ended RNAi triggers. The coverage, however, does include 19bp blunt end RNAi triggers which is certainly a useful structure.

This is the main claim that is likely to be issued. As you can see there have been some last-minute modifications.

The original blog entry from November 26, 2011, follows:

Silence Therapeutics (rightly or wrongly) was once considered by Big Pharma as an attractive RNAi trigger alternative to Alnylam. This was because its early RNAi trigger work (e.g. Czauderna et al. [2003] Nucleic Acids Res. 31: 2705) gave it a shot at broad patent coverage. In particular, if patent oppositions in Europe had not caused the AtuRNAi design to be limited to very narrow modification patterns (blunt dsRNAs with alternating 2’-o-methyl-unmodified residues, with a modified residue facing an unmodified one on the other strand), things may not have turned out as ugly as they did for its shareholders and some of its employees.

The problem with the AtuRNAi design is that it makes it difficult to find potent RNAi triggers. If Silence had succeeded in its goal of obtaining a patent covering a broad range of modification patterns instead of just the one, the increased design flexibility would have made it more likely to find potent RNAi triggers within the constraints of the patent claims and, of course, licensees.

I had noted about a year ago that Silence was pursuing another patent prosecution based on the same subject matter that the AtuRNAi patent was derived from (patent application EP 02017601.2). At first, I interpreted it as a Hail Marry, possibly sign of slight desperation trying to take a second bite from the same apple despite all the odds being that it will go the same way as before. When I looked, however, into the last claim set that Silence submitted during an oral hearing on the patent at the EPO earlier this year, I realized that Silence had actually been pursuing not claims to broaden the modification patterns of the AtuRNAi design, but claims covering essentially any blunt-ended RNAi trigger per se:

"1. A ribonucleic acid mediating RNA interference consisting of a double stranded structure whereby the double-stranded structure comprises a first stretch of contiguous nucleotides and whereby said first stretch is at least partially complementary to a target nucleic acid, the second strand comprises a second stretch of contiguous nucleotides whereby said second stretch is at least partially identical to the target nucleic acid and whereby the first stretch and the second stretch for a cuplex, characterized in that the double-stranded structure is blunt ended on both sides of the double strand and the length of said first strand and the length of said second strand is from about 15 to about 23 bases, 17 to 21 bases or 18 or 19 bases, for use in a method for the treatment of a disease."

Although I once considered such a claim plausible as in the early days when Silence (then Atugen) published its blunt-ended RNAi triggers (e.g. Czauderna et al. [2003] Nucleic Acids Res. 31: 2705) such non-3’overhang RNAi triggers were considered a bit heretical so soon after Tuschl’s work. Heretical means that, if the AtuRNAi triggers were effective, they would fulfill at least the patentability criteria of novelty and non-obviousness. As such claims never seem to materialize, I had thought that the moment for that had passed. Apparently not.

It now seems that such a patent is about to be granted. What the exact claims will be remain an open question as the response of the patent office to the latest claim set is not public. The fact, however, that Silence did not protest and the fact that the title for the patent application was just recently changed from ‘Novel forms of interfering RNA molecules’ to ‘Blunt-ended interfering RNA molecules’, makes me think that an important patent grant is coming down the chimney for Silence this Christmas.

The importance of a broad blunt-end RNAi trigger patent

As I will discuss in more detail in a report titled ‘The Business of RNAi Therapeutics 2012’ that I hope will be published soon, the absence of RNAi trigger IP with gate-keeping potential has greatly reduced the attraction of simple workaround solutions, and I believe that Silence with its AtuRNAi workaround has somewhat suffered from this as well (on the other hand, the threat of Kreutzer-Limmer to its freedom-to-operate has subsided). Not surprisingly, Silence is now advertising itself as a delivery company. With a broad blunt-end RNAi trigger patent in a market such as Europe, however, Silence's RNAi trigger offerings would become more competitive again, not as a workaround, but based on scientific potential. It would thus own a good part of the blunt-ended half of the RNAi triggers there. Together with the Zamore patents, Silence therefore could be considered to have a stronger issued RNAi trigger IP position than you know who.

As the current RNAi Therapeutics clinical dataflow should be re-igniting interest in RNAi Therapeutics in general, such a patent could be worth something again.

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