Saturday, January 28, 2012

Silence Therapeutics About to Be Issued Broad Blunt RNAi Trigger Patent? An Update.

Note from 28 January, 2012:

On January 3, 2012, the EPO issued an 'Intention to grant'. Unlike suggested in the following blog entry, the claims in the accompanying 'Druckexemplar' are not blocking any more for blunt-ended RNAi triggers. The coverage, however, does include 19bp blunt end RNAi triggers which is certainly a useful structure.

This is the main claim that is likely to be issued. As you can see there have been some last-minute modifications.

The original blog entry from November 26, 2011, follows:

Silence Therapeutics (rightly or wrongly) was once considered by Big Pharma as an attractive RNAi trigger alternative to Alnylam. This was because its early RNAi trigger work (e.g. Czauderna et al. [2003] Nucleic Acids Res. 31: 2705) gave it a shot at broad patent coverage. In particular, if patent oppositions in Europe had not caused the AtuRNAi design to be limited to very narrow modification patterns (blunt dsRNAs with alternating 2’-o-methyl-unmodified residues, with a modified residue facing an unmodified one on the other strand), things may not have turned out as ugly as they did for its shareholders and some of its employees.

The problem with the AtuRNAi design is that it makes it difficult to find potent RNAi triggers. If Silence had succeeded in its goal of obtaining a patent covering a broad range of modification patterns instead of just the one, the increased design flexibility would have made it more likely to find potent RNAi triggers within the constraints of the patent claims and, of course, licensees.

I had noted about a year ago that Silence was pursuing another patent prosecution based on the same subject matter that the AtuRNAi patent was derived from (patent application EP 02017601.2). At first, I interpreted it as a Hail Marry, possibly sign of slight desperation trying to take a second bite from the same apple despite all the odds being that it will go the same way as before. When I looked, however, into the last claim set that Silence submitted during an oral hearing on the patent at the EPO earlier this year, I realized that Silence had actually been pursuing not claims to broaden the modification patterns of the AtuRNAi design, but claims covering essentially any blunt-ended RNAi trigger per se:

"1. A ribonucleic acid mediating RNA interference consisting of a double stranded structure whereby the double-stranded structure comprises a first stretch of contiguous nucleotides and whereby said first stretch is at least partially complementary to a target nucleic acid, the second strand comprises a second stretch of contiguous nucleotides whereby said second stretch is at least partially identical to the target nucleic acid and whereby the first stretch and the second stretch for a cuplex, characterized in that the double-stranded structure is blunt ended on both sides of the double strand and the length of said first strand and the length of said second strand is from about 15 to about 23 bases, 17 to 21 bases or 18 or 19 bases, for use in a method for the treatment of a disease."

Although I once considered such a claim plausible as in the early days when Silence (then Atugen) published its blunt-ended RNAi triggers (e.g. Czauderna et al. [2003] Nucleic Acids Res. 31: 2705) such non-3’overhang RNAi triggers were considered a bit heretical so soon after Tuschl’s work. Heretical means that, if the AtuRNAi triggers were effective, they would fulfill at least the patentability criteria of novelty and non-obviousness. As such claims never seem to materialize, I had thought that the moment for that had passed. Apparently not.

It now seems that such a patent is about to be granted. What the exact claims will be remain an open question as the response of the patent office to the latest claim set is not public. The fact, however, that Silence did not protest and the fact that the title for the patent application was just recently changed from ‘Novel forms of interfering RNA molecules’ to ‘Blunt-ended interfering RNA molecules’, makes me think that an important patent grant is coming down the chimney for Silence this Christmas.

The importance of a broad blunt-end RNAi trigger patent

As I will discuss in more detail in a report titled ‘The Business of RNAi Therapeutics 2012’ that I hope will be published soon, the absence of RNAi trigger IP with gate-keeping potential has greatly reduced the attraction of simple workaround solutions, and I believe that Silence with its AtuRNAi workaround has somewhat suffered from this as well (on the other hand, the threat of Kreutzer-Limmer to its freedom-to-operate has subsided). Not surprisingly, Silence is now advertising itself as a delivery company. With a broad blunt-end RNAi trigger patent in a market such as Europe, however, Silence's RNAi trigger offerings would become more competitive again, not as a workaround, but based on scientific potential. It would thus own a good part of the blunt-ended half of the RNAi triggers there. Together with the Zamore patents, Silence therefore could be considered to have a stronger issued RNAi trigger IP position than you know who.

As the current RNAi Therapeutics clinical dataflow should be re-igniting interest in RNAi Therapeutics in general, such a patent could be worth something again.

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Anonymous said...

Hi Dirk,

What happend to your RNAi portfolio performance you use to post on your website? How are your top picks doing in light of all the good insight re: RNAi making a potential comeback (as you note in the recent article here)?

Anonymous said...

If the patent is granted as you think what can it be worth in todays environment to Silence?And will it trigger concerns in at you know who?

Dirk Haussecker said...

Unlike the Zamore patents, such a blunt-ended patent would not affect the freedom-to-operate of YKW. It would make Silence in general more competitive in RNAi triggers.

RE stocks and RNAi comeback. Except for some stirrings in Silence, nothing much yet. The market does not seem to have much confidence in its ability to assess the importance of datasets like the one this week. We may have to wait until the results show more effects on the business development front before confidence returns- or even more impressive PCSK9 results in the next month or two.

My top pick is obviously Tekmira whose technology is responsible for much of this clinical validation. A $20M market cap with a technology and financial gearing as that company. It may be worth for financial regulators to look into the trading of that stock since Tekmira filed the lawsuit against Alnylam, especially if all stock disclosure rules have been followed (incl. 'related parties').

Anonymous said...

What do you think of Arrowhead Research's position and value proposition post Roche asset acquisition?

Dirk Haussecker said...

The cost of the Roche RNAi asset acquisition will be measured in terms of how they can deal with the dilution pressures arising from the jump in cash demand. Arrowhead's market cap that is also nearly double that of Tekmira's while Tekmira's technology is more advanced.

Anonymous said...

Tekmira being more advanced than Arrowhead's RNAi offerings? I was not aware of this. In what way do you describe Tekmira as being more advanced, given the relevant clinical data and disease type? Thanks.

Giles said...

You seem to be very bullish on Tekmira and its delvery despite the need for immuno-suppressants and reliance on a partner who clearly doesn't like them.Are you suggesting that YKH hae actually been manipulating the hsareprice of Tekmira and if so for what reason?All seems abit far fetched given the low volumes and the overwhelming lack of interest in Tekmira amongst investors.Alnylam looks lost and Maraganore on his last legs,benitec dead as it deserves,leaving Arrowhead and Silence,both of which have a lot to prove.At least the latters got a delivery that works without pretreating.

Anonymous said...

Hi Dirk,

Interesting post from Giles. This brings up a number of potentially interesting questions, as it may relate to specific company views. May I ask what your largest RNAi portfolio holdings are since you use to actively list the companies and performance here on this site? Thanks.

Anonymous said...

I have already heard the expression “potent RNAi trigger” quite frequently. But what does it actually mean? What are the criteria for being a potent / non-potent trigger, especially with regards to RNA?
It seems to me that in vivo data might be difficult to use – there are not that many... So would you rather recommend in vitro data to quantify / compare the potency of RNAi triggers?
So what is a good cell line for the comparison of different RNAi triggers / RNAi chemistries and how many cells should one use? Is there any procedure that describes the amount of serum one should use for the transfection and what about the volume of transfection suspension – it clearly makes a difference when the formulations precipitate / "snowing" onto the cells. The lipid system – one of those classical cationic charged transfection lipids together with a pretty fusogenic helper lipid or one of those in vivo lipid systems which are more stable and do not precipitate that fast? Of course – for comparison one should also decide whether PEGylation might be useful or not and everyone who is working on a bench knows that the ratio between lipid and oligo makes a huge difference. And how do we interpret cell tox? So what does i.e. a IC50=100 pM mean?
Once again: what do they mean with “potent RNAi triggers” and is there anyone who has ever seen such a scientific controlled comparison. Are there actually same targets in different chemistries and would company A want to compare their target with company B’s target? The point is: there is no comparison at all and now one needs a comparison! And one is quite clear when you compare different formulations: there is almost now correlation between in vitro and in vivo.
Being focused just onto the RNA is somehow obsolete; one should talk about the potency of an in vivo delivery system and its therapeutic window…

Dirk Haussecker said...

I agree with you that the efficiency of the delivery system also matters. Potencies of RNAi triggers can be easily compared by using the same delivery, of course. I know that RNAi trigger chemistry can be tied to a delivery strategies, but in most cases valid in vitro comparisons can be performed. There is also data that show that (at least) when the in vivo delivery is efficient, such as with SNALP to the liver, in vitro potencies largely translate to in vivo potencies.

Giles- do you know what the importance is of the transient immunosuppression that Alnylam applies currently before SNALP administration? Such pre-treatments to my knowledge are not uncommon (e.g. also seen with MAbs and small molecules, esp. in oncology). It is not ideal, but possibly a precautionary measure following the ApoB trial. We'll have to see whether this remains in place.

Further validation that SNALP is the leading systemic delivery technology today: The FDA approved Tekmira's Ebola IND. This makes it No. 6. To put Arrowhead's pre-clinical DPCs in the same category or even ahead of SNALP seems a bit unfair in that light. Silence also has only 1 AtuPLEX-enabled program in the clinic. Ironically, even if competitors have this anti-SNALP attitude, they are also benefiting from the SNALP success story. I don't even want to think where we'd be without it.

Anonymous said...

Thanks, Dirk. I was not referring to the pre-clinical DPC technology (delivery system acquired via Roche assets), but to the late stage P1 (b) via the Rondel cyclodextrin delivery system at Calando (Arrowhead's subsidiary). What is your comparative view of this system, versus Tekmira? And versus the newly acquired DPC assets they have?

Dirk Haussecker said...

RONDEL...I believe the time has passed for this system. I expect Arrowhead to fully focus internal delivery work on DPCs.

Anonymous said...

Rondel. Appreciate feedback-quite helpful. It seems from Arrowhead's most recent conference call that they had possibly made mention that the DPC technology may be "ripe" for partnering at current? This seemed a bit contrary to similar company comments at the end of 2010 that goal posts had moved to get meaningful partnerships done (i.e pharma wants more later stage data...assume late p1/p2). If Rondel's time has passed, any reason the company would be doing a P1-b for more discreet data as to its therapeutic window; assume cyclodextrin system is much different than DPC, so why bother? Thanks for the insights.

Anonymous said...

Curious about your reply, Dirk, and the recent Roche news. Why would Roche entrust these assets to Arrowhead, if there was competition for DPC and IP? Would they not want the most capable steward of them, so as to unlock future value? Seems if Rondel has no potential value (i.e your comments that the system's time has possibly passed), would the utility of the science (and company know how) there really position the company as the most leading edge steward for these assets? Seems the cash burn has gone way up post asset acquisition with the most mature (partner friendly clinical asset) being Calando. Maybe I'm missing something. Thanks.

Anonymous said...

Seems maybe Alnylam has some competition. I wonder how they will respond, given their Roche IP that has been bought? Interesting times for RNAi.

Anonymous said...

Hello Mr. Haussecker-could please elaborate on why the time has possibly passed for the RONDEL delivery transport technology? I seem to remember a white paper you authored regarding its significance and Journal data not more than about eighteen months ago? Curious on getting an update on changes for better, or worse, since then regarding systemic delivery to solid tumor sites. Much thanks.

Dirk Haussecker said...

For those interested in more detailed comments on RONDEL and Arrowhead, I would encourage you to search my site using 'RONDEL' as a keyword. This should provide plenty of explanation already for what I have expressed here. If you are still puzzled or are interested in a more in-depth discussion, you can also commission such a review.

Anonymous said...

benitec dead as it deserves - clearly researched about as long as it takes to check the share price.

new york times runs article today on potential cure programmes for HIV - two of the 4 research groups are using benitec's ddRNAi in this

yet this highly significant breakthrough clinical work is not nearly important to benitec say as their chronic pain programme they are rumoured to be joining in with Chinese and Stanford Uni with.

Hard to imagine Pfizer not following this closely given their continued work with TT-033/034, pain being their one of their core platforms,snd china's importance to their future plans, and obviously critical need for a jump on the rest of the field in a new class of therapeutics.

Anonymous said...

Hi Dirk,

I took the time to look at your past Rondel commentary, as you had encouraged us (your audience) to do. It did not seem to me that your view for the past 1.5 yrs (and very recently with the Arrowhead/Roche asset acquisition blog) was that this delivery system's time has passed. Actually, quite the contrary, in my opinion. Would it be helpful to you to have me re-post specific cites? Glad to do this, if it will save you time to have to remember/research what you wrote. Thanks.

By the way, is it customary to have one's posts deleted here on your site. I did read your disclaimer and know your site is "for entertainment purposes only...and your commentary may be based on flaws and inaccurate information etc...", as you concede. If nothing else, hopefully this forum can continue to welcome and encourage thoughtful debate. Keep up the good work and insights.

Dirk Haussecker said...

'The time has passed comment'- I encourage you to read my comments RE the clinical data on CALAA-01 that emerged after the Nature publication.

"is it customary to have one's posts deleted here on your site."

I have never deleted a comment that was related to the topic of RNAi Therapeutics. The only comments that I have deleted in the past were the occasional spam message that advertises supplements etc. I have also noted comments to disappear, but I assume that this by the original poster, not me or somebody else.

Gene genie said...

Giles, I wonder why you consider Benitec dead as it deserves, are you anti shRNA or a long suffering shareholder, City of Hope , Callimune , Gradalis , all are successfully moving Benitecs Ip through clinical testing , reagent sales are extensive if only a minor source of revenue, the Hep C data was strong if primate only , and the in-house programs are progessing abait too slowly . I think your announce of shRNA' s demise premature at best and rather foolish at worst,.j

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