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.