Wednesday, August 20, 2014

Alnylam Once Again Clutches at IP Straws to Support Valuation Gap (with correction)

(21Aug14) Yesterday, I mistakenly stated that Alnylam wrongfully concluded that Dicerna was infringing on a newly issued Tuschl patent.  Following comments in the comment section below, it came to my attention that indeed there was a claim that I missed, claim 81 (and some contingent claims), that covers RNAi triggers of 25 base-pairs as follows:

81. An isolated double-stranded RNA molecule, comprising:

(i) a sense strand and an antisense strand that form a double-stranded region of up to 25 
base pairs, said sense strand having an identity in the double-stranded region of at least 85 
percent to a target RNA molecule; and

(ii) at least one strand having a single-stranded 3’-overhang, wherein said 3’-overhang 
has been stabilized against degradation; and

(iii) at least one nucleotide analogue, 

wherein said RNA molecule is capable of target-specific RNA interference. 

Note that Dicerna's RNAi triggers make use of the 2'-O-methyl modification which sometimes is found in the 3' overhang and can also have stabilizing activity.  Taken together, this claim indeed questions Dicerna's RNAi triggers, and although I would expect vigorous debate around whether 25 base-pairs are covered by the patent's description requirements should it come to a patent litigation, the assumption is that Alnylam's new patent rightfully questions many, if not most of the RNAi triggers used by Dicerna currently.  

Since I'm at it, the new patent also comes awfully close to the asymmetric RNAi trigger designs by RXi Pharmaceuticals and others (asiRNAs).  RXi e.g. uses dsRNA lengths of below 15bp with the guide strand having a long 3' overhang.  I am a bit surprised that Alnylam got just enough extension both below and above their traditional 19-23bp stronghold to start overlapping with some asiRNA and Dicer-substrate designs.

Regardless, I stand by my point that Alnylam has re-invigorated their patent-related press releases in order to explain the valuation gap to its peers in the public markets.  The original blog entry follows here:

This morning, Alnylam greeted the competition with another IP-related press release.  It wrongly claims that a patent it just obtained covers competing technologies.  This suggests that it either lacks an understanding of RNA technology basics or that it is afraid that the market will come to understand that the valuation difference to its peers has no basis in either a commercially more attractive clinical pipeline, a superior patent estate, or simply better technology.

Dicerna’s Dicer-substrate technology not in 14-24bp range

Today’s press release concerns US patent application 13/725262 which is part of the Tuschl patent estate covering certain RNAi triggers with 3’ overhangs.  Although the patent has not finally been published, based on the latest submitted claim set, the RNAi trigger covered by the main claim should comprise the following features:

a)      a dsRNA length of 14-24 base-pair; 
b)      at least 1 3’ overhang;
c)       at least one ‘nucleotide analogue’;
d)      and the dsRNA is non-enzymatically processed.

Clearly, in citing the Rose et al. and another paper by Dicerna (actually their scientific founders from the Rossi lab at the City of Hope) as proof of Dicerna’s infringement, Alnylam hopes that its investor and business development audience does not actually read scientific papers. 

‘Specifically, the newly allowed patent application broadly covers small interfering RNA ("siRNA") molecules of various designs, including so-called "dicer substrate" RNAi triggers (Amarzguioui et al., Nat Protoc.2006;1(2):508-17; Rose et al., Nucleic Acids Res. 2005 Jul 26;33(13):4140-56)…’

Otherwise, it would quickly become apparent that Dicerna’s version of RNAi triggers have a dsRNA length of 25 base-pairs and, well, are enzymatically processed: Dicer substrates!

[Note: in the original entry I mistakenly said Dicerna's triggers were 27 base-pairs; to be precise, they are 25/27 designs with 25 base-pairs and a 2 nucleotide 3' overhang on the guide.]

So as the actual clinical pipelines of Arrowhead Research and Tekmira are about to look more attractive in terms of commercial value (HBV alone), look forward to more Alnylam patent-related press releases to help the market understand why Alnylam has a market cap of $5 Billion and its competition only about 1/10th of that.

PS: the claim that usiRNAs infringe on this and other patents by Alnylam largely depends on the definition of ‘nucleoside analogue’ and ‘modified nucleotides’.

PPS: this patent does not change Alnylam's position as very similar ones related to 3' overhangs have already issued.  However, by slicing and dicing a patent application, it is possible to get issued a set of highly similar patents which, of course, is great fodder for the PR department.


Anonymous said...

DRNA has 25-27mer which is a 25 base pair with a 2-base overhanging on one of the strains. ALNY patent covers 25 base pair and at least one over hanging. I see they are on the collision course.

Anonymous said...

LOL. If you want to talk about hot air, how about hyping the valuation of HBV programs whose biological thesis is still very much up in the air? Heck, if we're assigning value to Tekmira's preclinical HBV program, why not do the same for all of Anylam's 15+ pipeline programs?

Latebloomer said...

Well, ALNY sure seems to be worried about others' HBV programs; otherwise, why all the fuss?


Dirk Haussecker said...

(redfaced) Oh, you are right. It's a 25/27 design, that is 25 base-pairs with a 2 nucleotide 3'overhang on the guide. 25 base-pairs still outside of 14-24bp though.

Anonymous said...

Why do you insist on 14-24 bp? The PR clearly stated up to 25 bp, which should include 25 bp.

"New Patent Broadly Covering RNAi-Mediating Double-Stranded Molecules Comprising Up to 25 Base Pairs"

Anonymous said...

Here's the big question: how does this impact the UNAs used by TKMR, ARWR, Arcturus, and MRNA? How many base pairs do these UNAs have?

Anonymous said...

25 bases are in the claims

Dirk Haussecker said...

'25 bases are in the claims'

You seem to be correct. Looks like claim 81 covers it and does not even call with enzymatic activity:

I may have to retract this blog.

Anonymous said...

Dirk, you're a manipulative idiot.

Anonymous said...

Now DRNA came up with their PR. I don't know who is more desperate.

Anonymous said...

See Marina's press release from Dec 4, 2012 where they get protection for UNA patents.

Anonymous said...

How relevant are the current FTAs under negotiation between the U.S. and Europe and the U.S. and JAPA region to the IP issues of ALNY and others?

Highly relevant IMHO given the international theme of contracting out R&D and trial management.

Perhaps the cause of any holdups in market action lies in these areas. After all the secrecy around them is unheard of.

Anonymous said...

TPP talks underway in Hanoi now.

Expected to conclude positively on the tenth.

Could well see some action around then. Especially since Alibaba has been given a green light. The message is American markets are open for Chinese business.

But difficult to imagine ALNY or ISIS being happy playing bridesmaids in this marriage.

Anonymous said...

How relevant are the current FTAs under negotiation between the U.S. and JAPA region to the IP issues of ALNY and others?

Highly relevant. It is one reason why one particular big wig at said company likes to holiday in NZ rather regularly.

One could even consider the FTA as more of a licencing agreement that encompasses a "whole of relationship" gambit rather than your standard up front and milestones terms and conditions.

If you read InvestorVillage, you'd come away thinking the only two companies in the world that matter are ARWR and TKMR and their fate will be decided on a public release of data.

But whose is the IP they are using?

Anonymous said...

If you believe what the CEO of Benitec puts out in his presentations, TKMR are using their ddRNAi platform.

ARWR could well be using the ssRNAi platform Dirk has described in his blog. The one ALNY has tip-toed around all this time.

Anonymous said...

How do you know this? There are some pretty clever guys and gals on IV. You think you know better than they do?

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