Wednesday, April 7, 2010

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.

7 comments:

Anonymous said...

Hi Dirk

I am an attorney, however, I do not do intellectual property.

Having read the actual claims, I agree with your analysis, although I am, of course, not qualified to comment how easy/difficult it is to work around the specific sequences in the claims.

It is disappointing (and worrisome) to see Alnylam adopt spin tactics reminiscent of some of its competitors.

Best

Martin

Anonymous said...

Hi Dirk,

Got any thoughts on Baulcombe patent being extended to cover siRNA in mammals? (ref Nature flyer below)

Regards,
Mike

RNAi patent jolt
- Nature Biotechnology 28(4):300 (2010)
The US Patent and Trademark Office has issued a patent for detection of RNA-mediated gene silencing to Sir David Baulcombe, University of Cambridge, and Andrew Hamilton, University of Glasgow, over a decade after their gene silencing findings in plants were first reported (Science 286, 950–952, 1999). "The new patent has implications beyond plants," says Jan Chojecki, CEO of Plant Bioscience Limited (PBL), of Norwich, the tech transfer company that owns the patents.

Anonymous said...

Dirk

Thanks for your excellent ongoing analysis of RNAi therapeutics. Yours is the first blog I check every morning.

In today's webcast from RXII, it was stated that their technology does not lie under the purview of the Tuschels since their technology only involves 14 or fewer nucleotides. The presenter also claimed complete freedom in the space.

Could you provide an analysis of these claims?

Thanks

Dirk Haussecker said...

Baulcombe and Hamilton patent...Unfortunately, the Nature Biotech article does not mention which patent application has just issued, but the main claim of the equivalent plant-specific patent (see below) states that(a) a small RNA has to be detected, and then (b) this has to be correlated with silencing of a target gene. If only (a), then I would have said that microRNA Dx companies could have been affected by the patent, but since also (b) is required, I would think that the overall impact on small RNA IP should be fairly limited even for the small RNA Dx space. This is because patents for research tools, even if they contribute to making a drug, de facto are not enforced.

1. A method of detecting the silencing of a target gene in a plant, wherein said silencing is initiated by introduction of an exogenous nucleic acid, which method comprises the steps of:

Main claim from the plant-specific small RNA detection patent:
(i) obtaining a sample of material from said plant,
(ii) producing a nucleic acid extract from said sample,
(iii) analyzing said extract such as to determine the presence or absence of short RNA molecules which are 21-25 nucleotides in length (SRMs) in said extract,
(iv) characterizing any SRMs which are present in said extract such as to determine sequence identity or similarity with said target gene, and
(v) correlating the presence of said SRMs having sequence identity or similarity with said target gene in the extract with the occurrence of gene silencing in said plant.

Dirk Haussecker said...

RXi's <15bp RNAi trigger IP.

I agree, the Tuschls do not cover double-stranded RNAs below 15bp, and it is reasonable to assume that RXi would have generated or obtained for reasonable terms freedom-to-operate in this space. The question, of course, how easy it is to find potent siRNAs in this areas since RNAi potency is known to generally decrease 'dramatically' once you go below 17bp. On the other hand, for some siRNA-conjugates, short size should help in delivery.

Anonymous said...

Dirk, great blog. Really appreciate the obvious time and effort you put in to this.

Your attention seems to be taken with SNALP for systemic delivery but I am curious to know what your opinion is on the RXi self delivering siRNA.

A cursory search of your blog using keyword RXi doesn't reveal much.

I am curious whether or not you have an informed opinion on this and if you would be so kind as to perhaps rate the two against each other.

TIA.

Dirk Haussecker said...

Hi,

I commented on sd-rxRNAs a few times, as much as possible based on the limited disclosure of the technology. What we know is that the RXi sd-rxRNAs have a size of 14bp and less. I further speculate that it is an siRNA conjugate with most likely a lipophilic group, but would not exclude transducing peptides etc.

The efficacy data that I have seen from the presentations are not that exciting to me. Lots of imaging stuff, but to be honest, not too much conclusion about functionality can be drawn from that because they don't show cytoplasmic localization and some of the signals appear to be cellular autofluorescence at that. I hope we'll see more controls on that issue in the future.

Sure, siRNA conjugates could become important for the field and I look forward to seeing progress here that will eventually get us to the clinic. RXi, however, is only one of the players here.

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