Wednesday, July 2, 2014

RNAi Trigger History Revisited as Alnylam Once Again Gets Tough on IP

Last month, Alnylam lectured  Arrowhead Research that they infringed Alnylam's RNAi trigger IP and added that the use of UNAs would not protect companies using them (Tekmira, Arrowhead Research, Marina Biotech, and Arcturus) either.  So as Alnylam is once again trying to intimidate the competition and their investors by claiming that they control RNAi triggers, it might be worth revisiting some RNAi trigger history.  Doing so suggests that in fact they have been one of the egregious infringers of 3rd party IP themselves and raises questions as to their own freedom-to-operate and validity of IP.

Sirna and Silence Therapeutics early proponents of modified RNAi triggers

The early RNAi days were marked by the competition for RNAi trigger supremacy between star-studded start-up Alnylam and working-class Sirna Therapeutics which had just averted bankruptcy following failed attempts with ribozymes.  Silence Therapeutics was another company that had ambitions to cornering important RNAi trigger IP and like Sirna had a history in failed attempts with oligonucleotide therapeutics.

Due to their prior experiences in nucleic acid-based drug development, it came natural to Sirna and Silence to apply nucleic acid modifications and soon earned a head-start in creating IP related to the use of modified RNAi triggers.  The belief was that in order to endow RNAi triggers with pharmaceutical properties, they had to be modified.

Sounds familiar? If so, then it is probably because this has become Alnylam’s new mantra, too.  Of course, this comes with a 12-year delay and only after acquiring Sirna’s IP estate and a history of claiming that they want their RNAi triggers to be as ‘natural’, i.e. unmodified, as possible, not due to IP limitations, but because of superior performance and considering safety.  In fact, Alnylam has not only been infringing Baulcombe IP for a short while, but also Merck/Sirna IP for probably as long as they were starting to see decent in vivo knockdown results with their highly modified GalNAc-siRNAs.

Although this clearly shows that Alnylam’s publicly claimed control over RNAi trigger IP has simply been a mirage, to their credit they make efforts in eventually gaining access to IP they are glaringly lacking.  Also, while at some point and for some delivery strategies the notion of minimally modified RNAi triggers had its merits, the emergence of RNAi trigger conjugates has increased the value of RNAi trigger modifications.  One might also criticize companies like Sirna/Merck, Silence, and RXi Pharmaceuticals (one of the first practical adopters of highly modified RNAi triggers and conjugates) for standing still instead of developing their initial technologies to their logical conclusion.

A comeback for AtuRNAi triggers?

Silence Therapeutics left a lot of value on the table by limiting themselves to a modification pattern that involves alternating 2’-O-methyls with a 2’-O-methyl-modified base on one strand opposing an unmodified base on the other like in a zipper.  One reason for this limitation was that during patent prosecution, the attempt by Silence Therapeutics to get patents related to modification patterns in general and not limited to 2’-O-methyls failed.

Interestingly, the RNAi triggers in ARC520 that Alnylam lays claim on involve a modification pattern reminiscent of AtuRNAi, only that it is here 2’-fluoro that is the alternating modification (Wooddell et al. 2013).  Also, if you review Alnylam’s recent patent applications (e.g. WO2014089313), alternating 2’-fluoros seems to be Alnylam’s preferred modification pattern, too.  Could it be that these companies were inspired by AtuRNAi trigger design?   

In any case, AtuRNAi and Silence may hold the key to invalidating some troublesome modified RNAi trigger IP by Alnylam by rendering them obvious.  Even more exciting for Silence, albeit unlikely given that the opportunity may have passed is the prospect that Silence could revive some of the more general RNAi modification pattern claims, thereby affecting the freedom-to-operate by Alnylam (and Arrowhead Research).

And welcome to Amy Shuman, former general counsel of Pfizer, to the Board of Directors of Alnylam.


experiencedmentor said...

"Amy Shuman, General Counsel" was a rather humorous tongue-in-cheek pat on the back of Alnylam, litigator for the world...oh, and a little research.

Anonymous said...

Look for Pfizer to make a Sanofi type deal with ALNY after they've bought out ISIS.

If Sanofi were happy to pay eighty bucks per share, what are Pfizer going to have to pay?

Get the feeling ALNY's inter-company diplomacy is similar to George W's. You're either with us or agin' us. If you're with us, hand over all you've got for nothing or we'll just take it anyway.

Anonymous said...

OT regarding the TKMR Ebola cock up today. Amidst all the red, it is worth noting that the pre-clinical TKM-HBV program uses a different delivery from the 3rd gen. delivery used for TKM-EBOV.

This may or may not be positive, what it means, though, is that one cannot infer to much (or to be exact nothing more than: "they thought TKM-EBOV would not cause a cytokine response, and look what happened) re a possible cytokine problem concerning the new liver optimized delivery used in TKM-HBV. Wouldn't you agree, Dirk?

Furthermore, I do not (yet) consider the EBOV program a lost cause, as standard HED conversion charts suggest a human dose of 0,16mg/kg would be equal to the 100% protection dose of 0,5mg/kg in NHP's, as well as TKMR's own statements regarding PK/PD data in the May presentation.

Notwithstanding, i think the management screwed up the communication big time!! An appalling choice not disclose the questions raised by the FDA right away, but instead wait for a hold and then disclose the existence of unresolved issues in a very brief and uninformative PR, without a conference call.

However, i feel more confident that the cytokine question will not be an issue for TKM-HBV, as it will most likely require much smaller doses and a less strenuous regime, but MOSTLY because it will utilize a new liver specific LNP formulation, or "liver centric LNP-formulation", which ought to be state of the art. One would also think that the cytokine issues can be solved more easily in a liver specific Tx compared to EBOV, which has to function outside of the liver as well; less moving parts.

Anonymous said...

ALNY to buy ISIS eh?

Could that be the reason why they handed back the ssRNAi stuff? Once they knew they were going to buy them or merge with them it was decided ISIS should develop it.

Makes sense to me.

Should it be so, that must make ssRNAi DA BOMB.

All the TKMR, ARWR, MRNA, BLT of this world are just also rans.

Anonymous said...

BLT to posit data next week on HCV trial.
Would you like cream on your humble pie Dirk?

Anonymous said...

Actually, I don't think that Benitec has agreed to post any data next week. I think all that it has agreed to do is say when the next patient is dosed. This may be next week and it may not. Whenever it is, there is no commitment to release any data as far as I can see.

Hold off on the cream.

Anonymous said...

Patient two can only be dosed if patient one data is deemed safe by independent third party authority. Released or not only one conclusion to be had if patient two is given the go ahead.
Previous pilots at CoH have shown this to be the case.

Anonymous said...

"Released or not only one conclusion to be had if patient two is given the go ahead."

This is true but is quite different from the release of data re safety. The release of data implies that data regarding the first patient is made available for anyone to review. For example, saying that patient one has had no adverse events and so patient two can be dosed is quite different to publishing the results of patient one's biopsy. But I take your point.

I would also caution that as yet only the lowest dose has been given and, even if it is non-toxic in the first patient, this does not guarantee that it will be non-toxic at therapeutic dosing levels

Anonymous said...

Spin off effects will be good for TKMR if BLT gets the go ahead. Even though Dirk is no longer fully invested in TKMR and BLT still does not have a lab.

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