Alnylam with Dominant RNAi Trigger IP Estate, but Woppmann not that Critical, Really

At a time when we get inundated with various intellectual property claims regarding RNAi triggers, it may seem difficult to tell the wheat from chaff to the degree that investors are now being routinely told that the IP issue is so complex that it is better left to the experts. Nevertheless, because Alnylam’s press release today about the issuance in the US of a patent from the Woppmann patent series supposedly ‘broadly’ covering RNAi Therapeutics has the potential to add to the confusion, I will still attempt to shed some light on the importance of this patent.

This is how the granted claims were summarized in the press release:

1) a double-stranded RNA (dsRNA) of any length having effectiveness in inhibiting a target gene by RNAi;

2) “overhang” and “blunt-end” design features and certain nucleotide pair motifs; and,

3) a 19-28 nucleotide region of the antisense strand that is complementary to the target gene.

It is therefore useful to look up the actually issued claims, and compare....*

At first glance, assertion 1) would appear to cover essentially all types of double-stranded RNAi triggers. The crux of the matter, however, is in the qualifier ‘having effectiveness’. It is true that the granted siRNA structures indeed describe what should make for effective siRNAs. This, however, does not mean that alternative effective siRNA structures are not possible. It is for example quite easy to design around siRNAs of which the first nucleotide of the overhang (which has to be at least 2 nucleotides) has to be a purine (A or G) and has to include at least a ‘GC’ sequence motif. In the case of a 2 nucleotide overhang (the industry standard), this means that any overhang except for ‘GC’ would get around the patent (GC is one out of at least 16 2-nucleotide combinations of which there are many more if one includes non-standard nucleotides). I am not aware that ‘GC’ have any particular advantage (well, at least the patent examiner could be convinced of that), or at least that it would be difficult to find potent siRNAs with non-GC overhangs.

This restriction almost makes it irrelevant to discuss the merit of claim 2 in the press release. But since a similar claim had created similar confusion when the European Woppmann patent issuance was announced two years ago, it is important to point out that fully blunt ended siRNAs are not covered: in addition to having to fulfill the above overhang rules, the Woppmann siRNA would have to have at least one overhang.

The ‘certain nucleotide motifs’ may allude to the requirement that one end of the covered siRNA must contain either a terminal GC base-pair or at least two of those in the last 4 base-pairs. This actually is very similar to the famous Zamore differential end-stability/ strand selection rule, to which Silence may have a claim, and of real scientific value. But again, given the above restrictions, this is more of an academic point.

Alnylam is considered the 800-pound gorilla when it comes to RNAi trigger IP, and rightly so. In fact, most competitors would give an arm and a leg for such a patent that gives broad freedom to design effective siRNAs. It is therefore difficult to understand why the company characterizes the patent in the press release as if it had broad power to exclude, while the actual claims are much more specific than that. By this, it risks to lose the trust of an already wary investor base, quite confused anyway by the barrage of press releases. Worse than that would be if Woppmann would be considered to substitute for the Tuschl patents should the lawsuit not end in Alnylam’s favor. This is not to say that it is any worse than the PR policies of a number of other competing companies in the space. However, to maintain its leadership position in RNAi Therapeutics, it is important to maintaining the credibility of a company that has suffered recently.

Disclaimer: I am not a trained intellectual property expert, and if somebody has concerns about the validity of my interpretation, he/she is free to raise those in the comments section.

*You can do so yourself by going to the following website: http://portal.uspto.gov/external/portal/pair

After you manage to decipher the password, search for patent application ‘10/560,336’. Then go on the ‘Image File Wrapper’ tab and click on the latest document type ‘claims’. This way you will be able to see the claims that should look very closely or identical to what will be issued.

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.