Wednesday, September 12, 2012

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!


Dirk Haussecker said...

I was asked by Anonymous to leave the following comment regarding Benitec's freedom-to-operate in light of the Baulcombe patents (apparently he/she experienced problems with the robot control on the blog):

'The Baulcombe patent 8,263,569 acknowledges the Graham patent 6,573,099 as prior art and therefore the issuing of this new patent should not impact ddrnai or BLT in any negative way.

Indeed, if the new patent is licensed for human treatments BLT should be entitled to some small amount of revenue.'

My response: the fact that the Baulcombe may reference Benitec patents would not remove the fact that the Baulcombe claims 'could' cover shRNAs and therefore would require a license. Just like the Baulcombe patents would not provide you with FTO if you wanted to use 3' overhangs as claimed by Tuschl II. The more patents, the more complicated the licensing becomes.

Anonymous said...

Depending on licensing and royalty is not a good way to run a long lasting business and to attract investors. I agree with Dirk on the licensing complexity in RNAi area and there is no dominant patent. Cross licensing, peace on earth and focus on developing useful products may be a better strategy for corporations in the field.

Anonymous said...

I agree that BLT "could" require a licence but in order to enforce the licence wouldn't Baulcombe require a licence from BLT for the use of the patent which led to Baulcombe's discovery?

Dirk Haussecker said...

Hamilton/Baulcombe's discovery was independent of the work underlying Benitec's IP. It could just mean companies have to obtain at least 2 separate licenses to obtain freedom-to-operate. This would mean that Benitec is not the sole arbiter on who can do (most forms of) ddRNAi or not.

Anonymous said...

IP sure is a complicated area. If Alnylam require a Baulcombe licence for human treatments and Baulcombe requires Graham patents will this be a breach of Alnylam's cross-licensing agreement with Benitec? The cross-licensing agreement allows Alnylam to develop five 'pre-agreed' targets that depend on the Graham patent estate. By licencing Baulcombe will Alnylam try circumvent any further obligation to BLT?

Anonymous said...

Probably not.

I looked at one of the baulcombe patent prosecutions and noticed a non final rejection whereby PBL cancelled quite a lot of claims. The examiner held firm they were not novel in view of Graham and Waterhouse

Anonymous said...

On the same token, during re-examination of Graham patent and subsequent issuance of related patents, examiners also held ground on specifics of Graham claims. There are potential loopholes as well.

Anonymous said...

Really? - strange then that all claims were rewarded
by the Board of Appeals judges. Very much a summary
dismissal of the examiner arguments which couldn't
tell siRNA from shRNA (I'm not kidding - go look at it on

Anonymous said...

Really, have you looked at the C1 ex parte version?

Anonymous said...

the only version that matters is the BPAI's final decision. Re-instatement of all claims. Everything prior to that doesn't matter. Even if that meant the examiner had it wrong for 5 years.
Unjust given the time it put ddRNAi progress on hold but that's just the way the system is.

all interesting stuff, but we all know the real value for the likes of Alnylam and Benitec now is shifting toward the clinical programmes, their associated patents and eventually their commercialistion.

Anonymous said...

Patents by themselves aren't valued very much. Before this news, with Benitec the dominant ddrnai patent holder, its market cap was a whopping $15 million. No movement in valuation after the news either. Value will be built for Benitec shareholders when their drug candidates start moving through the approval process.

Mr Squiggle said...

"Patents by themselves aren't valued very much". I guess there are exceptions though. The CSIRO's wireless LAN patent comes to mind and the David vs. Goliath battle between Ric Richardson (inventor of Unilock) and Microsoft. Both patents will reap @ $1 billion without the inventors themselves having products in commercialization. There are only so many billion dollar settlements necessary for the wider business community to realise the implications of using others IP without citing them as prior art, taking a licence or paying royalties. The biggest challenge for biotech is the 20 year timeframe.

Anonymous said...

"Hamilton/Baulcombe's discovery was independent of the work underlying Benitec's IP. It could just mean companies have to obtain at least 2 separate licenses to obtain freedom-to-operate. This would mean that Benitec is not the sole arbiter on who can do (most forms of) ddRNAi or not."

Gradalis in their recently awarded patent "ShRNA molecules and methods of use thereof" US Patent 8,252,526 cite neither Graham or Baulcombe. It would seem to me that until there are commercial products in the marketplace and some of these patents have been tested in the courts, there will be uncertainty about what "freedom-to-operate" really means.

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