Silence Therapeutics in RNAi Therapeutics Deal with AstraZeneca

Silence Therapeutics, formerly known as SR Pharma/Atugen, disclosed today the signing of a significant collaboration agreement with AstraZeneca. In addition to initial upfront investments of £7.5M (~$15M), Silence stands to receive up to £200M in future developmental milestone payments plus royalties on any resulting drug sales. For this, AstraZeneca may target up to 5 genes for therapeutic purposes using Silence Therapeutics’ AtuRNAi platform with a focus on respiratory diseases.

The AtuRNAi platform is at the heart of Silence Therapeutics. AtusiRNAs are blunt-ended, double-strand oligos with a particular 2’O-methylation pattern that induce post-transcriptional gene silencing. Silence believes that its AtuRNAi platform sufficiently differentiates it from competing RNAi platforms, most notably Tuschl siRNAs, to be considered proprietary. Indeed, the European Patent Office has been a good ally of the company by granting them a core patent relating to this technology earlier this year and restricting the scope of the competing Kreutzer-Limmer patents before that. This has allowed Silence to attract a number of reputable collaborators even before today’s deal with AstraZeneca.

It will be interesting, however, to see whether the value of the AtuRNAi patents are as significant as is claimed, since the seminal Tuschl II patent series demonstrates the use not only of 3’ overhang siRNAs, but also those without such overhangs. It should be noted that while retaining RNAi activity, blunt-ended siRNAs have been shown to be less potent than 3’ overhang siRNAs. Moreover, Tuschl II, to which Alnylam Pharmaceuticals holds exclusive rights, covers siRNA modifications in general and 2’O-methylations in particular. Only last week, Alnylam has strengthened this position by securing exclusive rights to ISIS’ fundamental nucleic acid modification patents for the use in RNAi Therapeutics.

Indeed, at least one licensee appears to have started to doubt the strength of the AtuRNAi IP position. After it had licensed two AtuRNAi agents from Silence that have entered phase I clinical studies this year, Quark subsequently decided to be covered through Alnylam’s InterfeRx siRNA licensing program as well.

However, unless Alnylam feels threatened in its ability to negotiate high-value collaborations due to secondary RNAi IPs such as the AtuRNAi platform, I do not expect them to resort to legal measures at this point. Today’s deal should be seen as yet another validation for the RNAi Therapeutics platform and the considerable funding stream flowing in should strengthen the whole field. Silence has certainly proven its business savvy, now is the time for them to show that they can also execute on their own cancer focussed clinical programs.

RNAi Therapeutics IP: On the Importance of Being Tuschl

A strong patent position is essential for companies to attract investments for the development of RNAi Therapeutics. Although the number of patents and patent applications surrounding RNAi Therapeutics continues to grow, arguably the two or three key early patents are 1) Fire and Mello describing the discovery and use of long double-stranded RNAs for inducing RNAi-mediated gene knockdown in worms and by extension other organisms, and 2) the Tuschl I and II patent series describing the identification of small 21-23nt small RNAs as the mediators of RNAi (Tuschl I) and the use and properties of synthetic siRNA duplexes for RNAi in human cells (Tuschl II).

While Fire and Mello has been granted in the US and can be licensed by almost anyone that wants it, there is much more controversy surrounding Tuschl I and II. It is undisputed that scientifically Tuschl’s studies describing the use of synthetic siRNAs for RNAi in mammalian cells is what opened up the prospect for RNAi to become the next platform for drug development. Tuschl II which is based on the work by Tuschl, Elbashir, and Lendeckel and owned by the Max-Planck Institute in Germany has been exclusively licensed to Alnylam Pharmaceuticals and has already been granted in the US and some other territories (Tuschl is a scientific co-founder of Alnylam). The patent application was provisionally filed in the US on March 30, 2001, and in Europe on December 1, 2000, and describes in great detail the anatomy of effective synthetic siRNAs.

Meanwhile, much of the work in Tuschl I is focussed on the identification of small RNAs as the mediators of RNAi based on the fact that isolated small RNAs derived from processed double-stranded RNAs in Drosophila cell extracts trigger specific gene knockdown and cleavage of a target message at 21-23nt intervals. Interestingly, most of that work does not mention the fact that these 21-23nt small RNAs should be double-stranded. This conclusion could not be derived from the observation of 21-23nt small RNAs on denaturing polyacrylamide gels, but was deduced through the cloning of these small RNAs which is described in Tuschl II, not I. It is therefore very surprising that, out of the blue, Tuschl I demonstrates the use of synthetic siRNAs with preferably 2-nucleotide overhangs for RNAi in mammalian cells. Subsequent claims then focus on the use of such siRNAs for human therapeutic development. This is rather surprising given that the basis for choosing 2-nucleotide synthetic siRNAs is lacking. It therefore appears as if this example had been appended later so as to make the patent more relevant for human therapeutic use. Otherwise, only fruit fly work, albeit important, would have been described. Given the near-identity of this last claim of Tuschl I with work described in Tuschl II, it is difficult to imagine how Tuschl I could be granted in full in the presence of Tuschl II.

Similarly intriguing is the fact that Tuschl I, which by the way has not issued yet, is co-owned by the Whitehead Institute for Biomedical Research in Cambridge, MA, the MIT, the University of Massachussetts, Worcester, and the Max-Planck Institute. At the same time, from the publication record it is clear that synthetic siRNAs were pioneered by Tuschl, Elbashir, and Lendeckel while at the Max-Planck Institute. Interestingly, the UMass has chosen to co-exlusively license their rights to the patent to Sirna Therapeutics (now a Merck subsidiary), CytRX (now RXi), in addition to Alnylam. Clearly, Merck and RXi would benefit most if Tuschl I would be granted eventually and somewhat limit the dominance that Alnylam currently enjoys in the RNAi patent space. Nevertheless, the fact that Tuschl I, filed on the very same December 1, 2000 date as Tuschl II in Europe, has not issued yet and the sudden appearance of synthetic siRNAs and their use in human cells at the very end of that patent application, raises questions about conflicting interests between the involved parties.

Based on publicly available information, the claims of the Tuschl patent series could therefore be divided as follows: Tuschl I getting credit for identifying 21-23nt small RNAs for mediating RNAi in fruit flies and by extension in other organisms, and Tuschl II for characterising effective siRNAs to be double-stranded with preferably 2-nucleotide 3’ overhangs and the ability of synthetic versions thereof to mediate RNAi in mammalian cells. In such a scenario Tuschl II would carry considerably more weight for the development of RNAi Therapeutics which would in turn reinforce Alnylam’s already leading IP position.

I am aware that parts of my interpretation are based on conjecture and criticisms are welcome (email: dirk_haussecker@yahoo.com). For those interested in the patents themselves, please visit

Tuschl I: http://appft1.uspto.gov/netacgi/nph-Parser?Sect1=PTO2&Sect2=HITOFF&p=1&u=%2Fnetahtml%2FPTO%2Fsearch-bool.html&r=1&f=G&l=50&co1=AND&d=PG01&s1=tuschl.IN.&s2=zamore.IN.&OS=IN/tuschl+AND+IN/zamore&RS=IN/tuschl+AND+IN/zamore

Tuschl II: http://www.google.com/patents?id=BlV6AAAAEBAJ&dq=rna+sequence+specific+mediators+of+rna+interference