Dicerna Licenses Baulcombe Patents

Today, the technology licensing arm of The Sainsbury Laboratory and the John Innes Center in the UK (PBL) granted a non-exclusive license to Dicer-substrate company Dicerna for the therapeutic use of the recently emerged fundamental RNAi trigger IP, the Baulcombe patent family.  It follows a similar, non-exclusive license granted last year to Alnylam and confirms the importance of this patent family, especially for companies conducting research and business in the US where patents from this family have issued.

Although the terms, not just the financial ones, but also those regarding sublicensing rights were not disclosed, I would think that the payments are more than token amounts and that certain sublicensing rights are covered.  Notably, Dicerna has an important relationship with Japanese Pharma Kyowa Hakko from which it announced in January that it would receive a $5M milestone payment.  This could be construed to have infringed the patents at issue and provided the final motivation for the license.    

Given that the first therapeutic license was given to Alnylam which focuses on 20-23mer RNAi triggers and the second one to Dicerna which works on 26-29mers, it is interesting to speculate whether PBL aims to increase the attractiveness (and cost) of the non-exclusive license by providing exclusivities regarding specific RNAi trigger structures.  This question is an important one for companies like Silence Therapeutics as they might be shut out from the 20-30 base-pair range should this be the case.

Coming Up: TKM-PLK1 phase I data presentation by Tekmira at AACR. 

Tuschl Patents Stage Remarkable Comeback in US

[please note the changes below after I discovered that I missed the last claim amendments, as correctly pointed out by a commenter]

Alnylam announced today that the US patent office had issued 3 Notices of Allowance in recent weeks pertaining to the Tuschl patent estate.  Before your eyes glace over, read on, it's actually one of the few important patent news.  

The granted composition-of-matter claims cover very broadly 19-25bp RNAi triggers, independent of structure.  This is a stark departure from the trend that had materialized in the Tuschl patent applications where Tuschl I seemed to get relegated to treating diseases of fly lysates and Tuschl II suffering from double-patenting issues over Tuschl I.

Claim 1 of allowed patent application 12/537602:

1. Isolated double-stranded RNA molecule, wherein each RNA strand has a length from 19-25 nucleotides, wherein said RNA molecule is capable of target-specific nucleic acid modifications.

1.  An isolated double-stranded RNA molecule, which is a non-enzymatically processed RNA molecule, wherein: (i) each RNA strand independently consists of 19-25 nucleotides in length, and (ii) at least one RNA strand forms a single-stranded 3'-overhang from 1 to 5 nucleotides, wherein said RNA molecule is capable of target-specific RNA interference.

The reason why such a comeback was possible can be traced back to the settlement over the Tuschl patents 'with Merck' in early 2011.  This allowed the Tuschl I and II prosecutions to be aligned such that the double-patenting issue for the 3' overhang claim could be overcome such that the broadness of the Tuschl I RNAi triggers could be rescued into the valuable human therapeutic uses. 

Among those without RNAi trigger licenses from Alnylam, Silence Therapeutics (and its partners, especially Quark) should be hit particularly hard by the latest development: 19bp RNAi triggers are no place to hide any more.   

There are thus two monsters of RNAi trigger patents that consequently co-exist in the commercially very important US market: Baulcombe for almost all types of therapeutically useful double-strand RNA lengths (20-24/30bp; see here) and Tuschl for the desirable 3' overhang feature of RNAi triggers.  It is unclear to me how two patents can essentially claim the same.  Either the patent office is aware of this and is satisfied with ultra-fine semantics distinguishing the two, or this is an issue worth reconsidering.

Another indication that the last word might not have been spoken may be the multiple requests by Alnylam (i.e. their law firm) to expunge certain materials that were rendered during the Tuschl patent prosecutions (possibly relating to timing and nature of the claimed invention), but are deemed trade secrets by Alnylam (can’t help but smile, here). Has Utah taken notes in time?

Fundamental Baulcombe RNAi Patents Extend Reach

I just got notice of the September issuances of two additional US patents (US 8258285 and US 8263569) belonging to the Baulcombe IP estate.  As previously reported, a first patent (US 8097710) from this series was issued earlier this year and represented a mini-shock to the RNAi Therapeutics IP landscape as it sat smack on the sweet-spot of the prototypical Tuschl-type siRNAs: siRNAs with guide/passenger strands of 20-24 nucleotides in length.  Consequently, Alnylam obtained a non-exclusive license to ‘710 shortly thereafter.

‘569 extends coverage over Dicer-substrate RNAi triggers

The claims of the two newly issued patents extend the coverage of the Baulcombe patent estate in 2 important ways.  Firstly, the ‘569 patent is almost identical to the original ‘710 methods patent.  This time, however, the lengths of the guide/passenger strands can be up to 30 nucleotides in length (20-30 instead of 20-24).  This means that companies working with Dicer-substrates like Dicerna may want to take a license from PBL.  Similarly, the ~25bp dsRNAs previously reported on by RXi and Silence/Intradigm, which curiously did not function as Dicer-substrates, would also fall under this new patent.  The saving grace: like ’710, ‘569 is a methods patent.  Methods patents are often easier to work around.

‘285 is a solid composition-of-matter patent

Having said that, the new ‘285 patent essentially turns the ‘710 20-24nt methods patent into a composition-of-matter one.  There is one important exception though: 20mers have to be unmodified, leaving, de facto (because clinical synthetic RNAi triggers are modified), open important asymmetric designs like the 19/21 and 20/22 designs which have been reported to be even more efficacious in many cases than the classical Tuschl 21/21 design.  Nevertheless, the ‘710 and ‘285 together could pose significant headaches for those trying to find holes with traditional RNAi triggers designs. 

Another interesting question is whether Alnylam will have to seek an additional license to ‘285, as in the press release on the Baulcombe license, only the ‘710 was noted as the subject of the license.  My sense is that ‘285 will be included and that as a result PBL will get a slightly increased participation.

[Update September 17, 2012: in an email, PBL confirmed that the new patents are part of their non-exclusive agreement with Alnylam.]

Classical ddRNAi also impacted?

All 3 patents share claims directed towards DNA-directed RNAi (ddRNAi).  It is therefore possible that they will impact the freedom-to-operate of Benitec which practices short hairpin RNAs from which short RNAs are generated by enzymatic processing in the cell.  Accordingly, an important question will be whether the DNA-directed guide and passenger strands covered by the Baulcombe claims would have to be directly generated by the described vector or can also be provided for in the form of a shRNA-type precursor.  I would guess 'probably', because in the Hamilton et al. work, the small RNAs that were seen and form the basis of the claims were also only indirectly generated. 

In summary, the Baulcombe patents have, quite unexpectedly (because based on plant work), emerged as the strongest RNAi trigger IP estate.  Stronger than Kreutzer-Limmer and stronger than Tuschl I.  In many ways, very deservedly so.  The main limitation is though that they are rapidly ageing.   


Addendum: I reviewed some of the prosecution history of the Baulcombe patents and it seems that for '285 to be granted it had to overcome a 'Crooke' patent (in this case US 6,107,094).  I've always found it a travesty that the Crookes often get cited during RNAi trigger patent prosecutions- although they have no scientific relationship to the biological RNAi process.  It is thus pleasing to see that the Examiner in this case saw the light that a double-stranded RNA that directly inhibits an enzyme (i.e. a PROTEIN) does not represent prior art for a dsRNA that targets an mRNA.  Duh!

PBL Grants Alnylam Non-Exclusive License to RNAi Trigger IP, Increasing Alnylam Partnering Prospects

The fact that Alnylam has started to advertise itself as a product- and not platform-based company can be partly attributed to the the loss of its once strong position in RNAi Trigger intellectual property.  After it became clear that the company not only forfeited its gate-keeping potential (see Kreutzer-Limmer and Tuschl patent prosecutions), it got even worse when other IP, most notably the Baulcombe US patent issued earlier this year interfered with that company’s freedom-to-operate in RNAi triggers, once its core value proposition.  This also meant that prospects for product partnering deals that have been promised by the company to happen this year were quite low. 

Today’s announcement that the IP commercialization arm of various British plant research organization, Plant Bioscience Ltd (PBL), is granting Alnylam a worldwide, non-exclusive license to the Baulcombe IP thus removes some of the overhang.  This IP, and the US patent in particular, covers much of the size range for which Alnylam’s exclusively held core Tuschl II overhang IP is useful for, including all of the RNAi triggers in Alnylam’s development pipeline (for a more detailed background on the IP, see here).  Of course, it does not remove the overhang that Tekmira owns the delivery technology on which Alnylam’s most valuable pipeline assets rely on…

It is notable that PBL granted Alnylam solely a non-exclusive license.  This is because the licensing organizations of academic institutions generally prefer to provide exclusive licenses to drug developers with gate-keeping IP positions as this arguably increases the value of the IP versus a scenario in which critical IP is divided between competing companies.  This could thus be consistent with PBL considering Alnylam’s IP estate as non-gatekeeping- as I do.  

Today’s development is positive in two ways.  For one, it acknowledges the scientific contributions of the plant community in the discovery of RNAi.  It also indicates that Alnylam is becoming more realistic about its own IP position and will take additional licenses to IP even if it does not control them outright.  Having said that, I do not consider it likely that it will likewise seek RNAi trigger IP licenses from competing companies such as Silence Therapeutics (e.g. Zamore) unless it can do so after a bankruptcy, or even that Alnylam’s management and BoD will abandon personal pride and brinkmanship in light of Tekmira.

Brief comment on Facebook IPO 'outrage'

Just as I find it incredulous that a newspaper like the New York Times poses the (really rhetorical) question of whether insider trading is part of the fabric of Wall Street (if they don't even know what  has been going on in their backyard for decades, why does the NY Times get so much acclaim?), I find it unbelievable (well not really as it is about gaining business advantage and popular votes) that the story about the potentially illegal sharing of insights between the research and investment banking arms of financial institutions such as Morgan Stanley is getting so much attention.  It's been happening in biotech all along.  What is ironic, without violating the Chinese Wall, it seems almost impossible for biotech companies these days to raise capital.  

Alnylam Squares Off with Dicerna

Dicer-substrate RNAi triggers are often seen as a (probably cheaper) alternative to Tuschl siRNAs. Initially, based on a small sample size, it was even claimed that Dicer-substrates had superior potencies and prolonged durations of knockdown. Of course, Alnylam, considering Tuschl siRNAs to be its property, has recognized this and regards Dicer-substrates along with its corporate champion, Dicerna, a competitive threat. Although Alnylam has long claimed that Tuschl siRNAs are preferable over Dicer-substrates for various reasons, until now it has largely been Dicerna’s word against Alnylam’s word.

This has changed with a publication by Alnylam in the journal RNA which provides a comprehensive, and I believe fair comparison between the two structures (Foster et al 2012). Comparing large numbers of RNAi triggers both in vitro and in KC2-SNALP animal studies, the study shows that Tuschl siRNAs and Dicer-substrates are essentially equivalent in terms of potency and the duration of knockdown. However, when these structures are compared in terms of innate immune stimulation, Tuschl siRNAs had a very slight edge when unmodified sequences were tested. Of course, it is well recognized that chemical modifications are required and very effective at abrogating these immune responses. When these were applied, the potencies of Dicer-substrates were more likely to suffer than those of Tuschl siRNAs, and in a few cases innate immune stimulation was not entirely abrogated. The former can be explained by the additional requirement for the Dicer processing step which can be affected by chemical modification.

Overall, this means that it may take a little bit more effort to identify a suitable Dicer-substrate clinical development candidates, and there could be an increased risk in encountering unforeseen innate immune stimulations in humans. On the other hand, the study also suggests that for some genes it may be possible to find more potent RNAi triggers with Dicer-substrates, so that in an ideal world one would keep an open mind. I should also add that, not discussed in this paper, there are also other considerations which may favor one structure over the other.

Unfortunately, we are not living in an ideal RNAi Therapeutics world, but one in which patent trolls and IP freeloaders abound. The timing of the comparison study is particularly ironic since the freedom-to-operate of US-based Alnylam is very much in doubt, thus increasing the attractiveness of Dicerna's offering. This is because of the recent issuance of the Baulcombe patent in the US which has put essentially all the Tuschl siRNA structures, bar one, in a straitjacket. Until Baulcombe is sorted out, all buy-out and partnering efforts will be on hold, and if Merck gets exclusive rights to that patent...then Alnylam may well be toast.

Issued Baulcombe Patents Fundamental to Mainstream RNAi Therapeutics in USA

Yesterday, UK-based Plant Biosciences Limited (PBL) announced that it was awarded a fundamental RNAi patent in the US. The patents can be considered necessary for commercializing RNAi in the US as long as both strands of the RNAi trigger are between 20-24 nucleotides in length.

Claim 1 of US patent 8,097,710:

1. A method of silencing a gene in cells by post-transcriptional gene silencing (PTGS) which method comprises introducing into said cells a composition that contains short RNA molecules (SRMs),

which SRMs are isolated short sense RNA molecules (SSRMs) and isolated short antisense RNA molecules (SARMs) at the same abundance;

wherein said SARMs are complementary to a region of a target RNA transcribed from a gene which is silenced when said short RNA molecules are present in cells containing said gene and said SSRMs correspond to said target RNA; and

wherein the SSRMs and SARMs consist of 20, 21, 22, 23 or 24 nucleotides,

whereby said gene is silenced.

The patent issuance is a testament to the seminal contributions the plant RNAi community have made to the field. In fact, there was considerable unhappiness that the Nobel Prize committee did not recognize this when it awarded the RNAi-related Prize to Fire and Mello. Baulcombe, it was felt, should have been added as a 3^rd recipient.

The issued patent is based on work by Hamilton and Baulcombe from the Sainsbury Laboratory in Norwich, UK, who found that small RNAs were generated during post-transcriptional gene silencing (PTGS), that is RNAi in plants (Hamilton and Baulcombe SCIENCE 1999). It was then instantly realized, also in light of the fact that a previously discovered microRNA (in C. elegans) was in that size range, that small silencing RNAs are likely the universal (i.e. plants and animals) mediators of RNAi.

I can say the above pretty confidently from my own experience as my exposure to RNAi began in 2000 (before the Tuschl II publication) in- you guessed it- a plant laboratory in the UK (Edinburgh University). There I was an undergrad designing plant RNAi expression vectors and it was pretty obvious then that small RNAs are involved in microRNA and RNAi silencing, two phenomena which had been linked genetically through work in a diverse set of organisms: slime mold, C. elegans, Arabidopsis, fruit flies and the likes. The only remaining uncertainty at that time was whether RNAi would also exist in humans, although I can well remember a speculation in my ‘RNA World’ elective class by David Tollervey that he more or less was certain that RNAi would be shown to exist in humans (not sure whether this was based on scientific intuition or rumors in the scientific community).

(My other claim to getting close to RNAi fame is that David Baulcombe, now Sir David Baulcombe, was my D.Phil. examiner regarding my graduate work on Dicer biology in humans)

I can well imagine that this uncertainty was an issue as PBL argued its case for an all-organism-encompassing patent, but it now seems that it prevailed.

Note on Alnylam patent infringement suit

The timing of the patent issuance, of course, is a bit ironic since the biggest violator of this patent as of January 17 is Alnylam which, as you will know, has just sued Tekmira for patent infringement. It is also of note that since Alnylam has cited an RNAi-unrelated patent by ISIS (US 7,695,902) in the suit, Alnylam has officially revealed itself as a patent troll. Benitec may want to take note since Alnylam acquired the Nucleonics patents which I suspect was done to provide similar cannon fodder for the courts in future litigations.

Also, since Alnylam only threw patents licensed from other companies into the fray, it is a lesson to any company about the perils of licensing IP to Alnylam: Alnylam is more likely than not to first expose such licensed patents before it will expose their own (note: a patent infringement suit such as this one predicts that the patents will be challenged by the alleged infringer and thus stands to be revoked or cut back in scope).

My Keystone meeting was great, and I also learned of interesting work by Alnylam. But I can tell you that coming home from a long trip and the first thing I see is that Alnylam is looking hard to come up with reasons to bury Tekmira under legal costs has quickly eroded any of that goodwill. Somebody needs to stop the insanity, and it's not going to be Alnylam's legal advisers which are making a fortune out of this.