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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Recent Alnylam Patents Blur Distinction between Blunt-end dsRNAs and those with 3’ Overhangs

As many of you will be aware, the battle for RNAi IP is heated and particularly centers on whether Alnylam may also dominate over blunt-ended double-stranded RNAs between 22 and 24 base-pairs in length. Longer dsRNAs are covered by Fire and Mello and relatively easily accessible, 21bp and shorter dsRNAs are the domain of Kreutzer-Limmer and exclusive to Alnylam as are dsRNAs up to 25bp with 3’ overhangs (Tuschl II).

Although, even in the absence of applying obviousness criteria, I doubt that if Kreutzer-Limmer ultimately failed to be applied to 22-24bp RNAs, any other patent application would be able to do so based on prior art, this still raises the question whether 22-24bp RNAs will fall into a free-for-all grey zone.

While the seminal Elbashir et al. publication underlying Tuschl II provided compelling evidence that in most cases 3’ overhangs will enhance RNAi gene silencing, at least in tissue culture, recent patent application by Alnylam itself make me rethink the value of blunt-ends, particularly for in vivo applications.

At the end of January, Alnylam issued a press release on the issuance of the Woppmann patents in the UK (UK 2417727). Although I would not, by any stretch of the imagination, consider it to be an umbrella patent of the stature of Tuschl II, it is still a quite curious patent with relatively early 2003-4 priority in that it describes siRNAs with one blunt-end and one 3’ overhang end (often just one nucleotide) to have gene silencing advantages over the classical Tuschl design features (two 3’ overhangs, best if 2 nucleotides long).

I know that the following passage from the PR has caused some confusion among some of the readers of this blog, and admittedly also myself, as without carefully reading the claims of the patent it could be misunderstood as also covering dsRNAs with two blunt-ends, instead of dsRNAs combining the two features in just one molecule: ”The claims cover siRNA molecules of any length that contain "overhang" and "blunt end" design features, including siRNAs containing chemical modifications and certain novel motifs.”

Does this mean that Alnylam is back-tracking here on the value of 3’ overhangs, i.e. Tuschl II, which could have serious repercussions for the whole RNAi Therapeutics IP space and give companies like Silence Therapeutics or RXi some room to breath? The issue therefore is whether the one 1-nucleotide overhang is really that advantageous or just serves as a fig-leaf designed to disguise the value of blunt-end siRNAs. I therefore found the following passage from the description of another recent Alnylam patent application on the targeting of the Huntingtin gene by RNAi (USPTO application no. 11/588,674) of interest:

“In one embodiment, at least one end of the dsRNA has a single-stranded nucleotide overhang of 1 to 4, preferably 1 or 2 nucleotides. dsRNAs having at least one nucleotide overhang have unexpectedly superior inhibitory properties than their blunt-ended counterparts. Moreover, the present inventors have discovered that the presence of only one nucleotide overhang strengthens the interference activity of the dsRNA… dsRNA having only one overhang has proven particularly stable and effective in vivo, as well as in a variety of cells, cell culture mediums, blood, and serum.”

Maybe it should not come as a surprise that with intense research, the design features of RNAi triggers will evolve over time, somewhat reminiscent of what had happened with monoclonal antibodies before and this can only be a blessing for the realization of RNAi Therapeutics. However, from a business point of view, this raises the question what will be considered sufficiently novel or merely an improvement of a fundamental design. Clearly, at a time when many dsRNAs and also single-stranded oligonucleotides are found to be able to accomplish gene silencing via RNAi, the systematic analysis of particularly dsRNAs between ~19-25bp in length with various types of overhangs or no overhangs should be of value here. I’m almost sure this has been done already and is ongoing in other parts of the industry, but it certainly would be nice to see an unbiased publication on that very subject.

Alnylam Granted Expanded Kreutzer-Limmer Patent Series in Germany, Signals Its Intention to Enforce Dominant IP Position

Yesterday, Alnylam announced issuance of the new Kreutzer-Limmer patent series in Germany, covering double-stranded RNAs of 15 to 49 base-pairs for gene silencing in mammals. This is quite significant and Alnylam’s accompanying press release made it clear that this should be understood as a watershed event, sending a stern signal to companies like Silence Therapeutics, RXi, Nastech, Dicerna and others that thought to have identified Kreutzer-Limmer as a potential loop-hole in Alnylam’s IP strategy by employing double-stranded RNAs (dsRNAs) longer than Tuschl’s 19-23 base-pair siRNAs and/or making them blunt-ended to emphasize an apparent difference to the classical Tuschl siRNA that features 3’ overhangs. These patent workaround efforts seemed to bear first fruits last year when the original Kreutzer-Limmer I patent series was restricted by the European Patent Office to covering siRNAs between 15 and 21 base-pairs in length (opposing parties: Sirna [now Merck], AstraZeneca PLC, Atugen [now Silence Therapeutics], Janssen Pharmaceutica N.V., and Sanofi-Aventis).

From a partnering perspective, this seemingly small development could have important implications for striking the next major deal, since which company would feel comfortable paying hundreds of millions of dollars for a technology license that appears to be circumventable.

Kreutzer-Limmer was Alnylam’s first line of defense against such blunt-end siRNAs and siRNA precursors longer than 23 base-pairs (aka Dicer substrates) given that, depending on the explicitly granted range of double-stranded RNA lengths, Kreutzer-Limmer would directly cover such structures. Its short-coming, however, is that in 1999, Kreutzer and Limmer did not understand well how these dsRNAs exactly caused gene silencing, which is what Tuschl II is famous for. While I consider Tuschl II, in addition to the ubiquitous Fire-Mello patent, as the fundamental patent series for therapeutic RNAi, due to its excruciatingly detailed explanation of what it takes to effect efficient RNAi in mammalian cells, it is the early priority date of Kreutzer-Limmer’s invention that makes this patent so potentially valuable and dangerous, and explains why Alnylam saw it necessary to remove any uncertainty and obtain exclusive access to it by acquiring Ribopharma AG in 2003.

I found it curious that a number of companies have chosen to take licenses to Kreutzer-Limmer, but not Tuschl II. While that may be interpreted as reflecting the fundamental importance of Kreutzer-Limmer, it was as if by pursuing this strategy, it is almost made implicit that as soon as the scientifically less detailed Kreutzer-Limmer series were curtailed in scope due to heavy opposition, the field for newly patentable RNAi inducers would be wide open. In this case, Alnylam would probably have argued in a second line of defense that, although not spelt out letter by letter, Tuschl II would also cover Dicer-substrate and other RNAi inducers that obviously function either as siRNA precursors (= pro-drugs) or are derived from it, for example 3-stranded siRNAs (meroduplexes). This argument becomes particularly relevant in the case of a weakened Kreutzer-Limmer as this ironically would directly strengthen Tuschl II. In this way, Alnylam holds all the cards and may play them as they wish.

Silence Therapeutics, in particular, will not be very happy with the outcome in Germany, not only because it and others, myself included (to be explained in my next posting), sees itself as a major force in RNAi in Europe, but also since their blunt-end, modified dsRNA is not only the size of the classical Tuschl siRNA, but with Kreutzer-Limmer any gene silencing dsRNA, modified or unmodified, is covered. Silence Therapeutics’ approach could be likened to first taking an invention (here: Tuschl’s siRNAs), then impair its function (here: by flushing the ends blunt), and finally rescue some of the original function by adding further changes (here: by introducing a pattern of RNA modifications). Certainly original, in its own complicated way.

I should disclose here that I largely agree with Alnylam’s view of their IP position and have invested in this company, but at this time I particularly felt like speaking out on all these confusing claims about proprietary RNAi compositions that threatened to hurt investments in RNAi Therapeutics. The acquisition of Sirna Therapeutics by Merck was certainly triggered in part by Sirna’s IP claims which now appear to be weaker than originally hoped for by the buyer and has escalated into a costly and time-consuming mess for a number of companies. In the same vein, I should also emphasize that I am likewise invested in companies that I have strongly criticized in this and other contexts and that I am therefore not wed to any company’s view of the space. It is in this spirit that I hope that Alnylam does not use their IP position to block the evaluation of RNAi inducers that differ from the classical siRNA design in more than just a modification here or an overhang there. Financial incentives should therefore be created for investments in such start-ups without requiring a $1 billion upfront license fee.

PS: In my next posting, barring further developments, I would like to provide the promised company-by-company overview.


Two additional recent developments that I would like to briefly comment on:

1) The FDA removed the clinical hold on Targeted Genetics’ rheumatoid arthritis AAV gene therapy that had been suspected to have played a role in the unfortunate death of a clinical trial participant. I am relieved by this judgment since there was just no good scientific evidence that the gene therapy caused or was associated with the fatality. AAV vectors are currently probably the most potent method to deliver RNAi in vivo and there are a number of indications where AAV-RNAi may be years ahead of synthetic siRNA strategies, and where the benefits outweigh the real risks of gene therapies. One such indication would be AAV-RNAi for treating Huntington’s Disease, where published and orally presented data so far suggests superiority of the AAV approach compared to siRNAs and that Targeted Genetics should now be in a better position to pursue in collaboration with Sirna Therapeutics/Merck and Bev Davidson’s group in Iowa.

2) At a recent symposium on RNAi and its targeting in Sonoma, California, Ian MacLachlan from Protiva presented more data on the efficacy of SNALP-siRNA delivery in non-human primates. According to the abstract, more than 90% gene silencing of ApoB, with silencing lasting for several weeks, could be achieved by single-dose intravenous administration. These are impressive numbers and the task is now to minimize the toxicities associated with cationic liposomes. I am quite impressed by Protiva’s past work not only on RNAi delivery (in collaboration with Sirna Therapeutics and Alnylam), but also on dissecting the causes for the toxicity, and would expect them to be the first to find a solution for this problem. Unfortunately, the ownership and know-how of SNALP delivery technology is highly contested and I can only urge the involved parties to consider working together on this promising technology. During a recent conference call by Tekmira it was apparent that a lack of suitable scientists caused delays in the development of SNALP technology. I would even venture as far and propose that Alnylam’s delays on their systemic delivery programs have probably cost the company more in terms of reagent, labor, time and market cap than the combined market cap of Tekmira and Protiva.