Tuesday, December 13, 2011

Mr. Anonymous Thwarted in Zamore US Patent Re-exam

Silence Therapeutics reported that a number of valuable RNAi trigger patents related to the Zamore Design Rules that were issued last year in the US were upheld following a re-examination request by an anonymous 3rd party. Even stronger claims related to the same Zamore patent series have been issued in Europe, and unsurprisingly Alnylam, but also Novartis and Alcon are opposing them with the outcome to be decided (EP 1633890 B1). However, given the importance of both the US and Europe in the commercialization of innovative drugs, having a patent position in one jurisdiction alone can be considered a valuable strategic asset already.

The Zamore Design Rule patents are owned by the University of Massachusetts and exclusively licensed to Silence Therapeutics for medical uses. As described in more detail in other blog entries before (here and here), they cover methods of promoting the incorporation of the desired guide strand into the RISC gene silencing complex as well as of enhancing RISC turnover resulting in more effective and selective RNAi knockdown.

Especially the patent covering guide strand selectivity methods (‘thermodynamic end-stability rule’; US 7,750,144) is widely recognized in the art for greatly increasing the likelihood of finding efficacious RNAi triggers and is incorporated in essentially all bioinformatic sequence pre-selection algorithms. It has to be said though that the claims do not cover the entire spectrum of approaches of achieving differential end-stability. They do, however, cover chemical and structural approaches that have been reported by a few companies such as Marina Biotech and Sirna/Merck before. Moreover, because the coverage involves modified nucleotides, there will be the concern that even if such modifications were applied for other purposes (e.g. stability or immune abrogation), they may fall under the patents. Consequently, a company with a promising late-stage candidate may want to take a license instead of taking a chance in an infringement lawsuit.

This makes it the second time within a week (see PKN3 opposition by Alnylam) that important patents by Silence Therapeutics were upheld essentially unchanged following challenges. Alnylam’s management once laughed off the value of the Zamore patents in a conference call following their issuance last year. They obviously considered them serious enough to oppose them in Europe and Alnylam is certainly the most likely identity behind Mr. Anonymous (have your say by participating in the survey on the right). Less likely, but not entirely out of the question would be a Big Pharma company like Novartis which is considering taking a license to the Zamore patents, but first wanted to kick the tires before it did so (patents that have been unsuccessfully challenged are considered stronger).

With all these patent successes, and at least one more likely to come, Silence Therapeutics need to monetize their assets in the form of non-dilutive funding.

Hemophilia Gene Therapy Success Bodes well for ddRNAi Therapeutics

Following years of public scorn and derision, including by Alnylam which in 2006 waved off ddRNAi Therapeutics and gene therapy as ‘dangerous’, gene therapy is back with a vengeance. This week, a consortium of researchers reported in the New England Journal of Medicine that an self-complementary AAV8-delivered Factor IX transgene was able to significantly correct hemophilia B in a small clinical trial.

4 out of the 6 patients treated were able to largely discontinue the standard frequent (often 2-3 times a week) and expensive use of prophylactic recombinant FactorIX protein therapy which accounts for estimated healthcare costs north of $20M a lifetime. This means that even in the limited duration of the trial (6-16 months of follow-up), the low cost of the gene therapy ($30k cost of goods for a treatment that is expected to last many years if not a lifetime) meant that this therapy is already saving money (and improving quality of life). If the results can be confirmed in a larger trial and the side-effects, including transient liver enzyme elevations can be controlled with similar efficiency as in this small one, approval may not be that far away.

The hemophilia results also bode well for ddRNAi Therapeutics. First of all, the study has validated the safety and efficacy of delivering the highly promising AAV vector family by peripheral vein infusion to the liver. This represents progress over a previous hemophilia gene therapy study which employed considerably more invasive direct hepatic infusion. In particular, it is likely that, should the ddRNAi collaboration by Tacere/Pfizer for HepC continue, it would involve not only the same vector family (AAV) and target organ (liver), but also the same serotype (AAV8) and self-complementary genome strategy as employed in this hemophilia trial.

18 comments:

Giles said...

I assume we have to believe it was Alnylam in both cases.Are there any opportunities for Silence to find a non dilutive source of funding in the next few months and if so from whom and what sort of deal would you expect?If nothing happens will this put Silence into Alnylam's grasp or perhaps will they have to dally again with Tekmira in some type of same sex alliance?

Anonymous said...

Is it Alnylam (another Mr Anonymous) challenging Benitec's patent in the UK as well? Seeems likely, they are trying to bully any RNAi company they can. Let's hope they spend tons of legal fees and continue to lose every time! Then we can stop this legal silliness that holds back the whole sector, hopfully dissuade any further legal delays, each company earning fair licensing fees for their rightfully owned patents, and just get on and progress the science to revolutionise medicine and help humanity!

Anonymous said...

I find it outrageous that these cowards are allowed to remain an anoymous third party. If a company feels they have to hide their identity in order to challenge a patent, one can only assume that acts of corporate sabotage are at play. What is to stop them from objecting all of the patents in all jurisdictions just to bury the competition under a mountain of legal bills, preventing them from advancing the research? What utter scum!!!

Dirk Haussecker said...

Exactly my feelings. If somebody has an issue with your (intellectual) property rights, then that person/entity should be required to say that without hiding behind the mask of anonymity. There is a clear pattern here and the strategy behind it is becoming obvious.

Anonymous said...

i don't get why Alnylam bought up Nucleonics IP if they thought ddRNAi was dangerous. The words and actions seem to be in contradiction to each other. Also raises the question of fidicuary duty to ALNY shareholders.

Dirk Haussecker said...

Well, Alnylam justifies the Nucleonics IP purchase in that it also strengthens their synthetic siRNA Therapeutics IP position with 'fundamental' patents...fundamental patents that they had been lacking before, but never mentioned as they claimed freedom-to-operate. I agree, this does not make sense one way or another, except as a way to fill up their IP warchest in case somebody else, e.g. from the ddRNAi side, wants to rival Alnylam in RNAi Therapeutics.

Do you have an idea of why 'anonymous' is targeting the Benitec patents particularly in the UK? The opposition in a relatively small market such as the UK does not make too much sense, unless 'anonymous' has good reasons to believe that it could undermine specific business interest of the opposed party (e.g. a deal with a British biotech such as Oxford Biomedica).

Dirk Haussecker said...

Giles- only with regard to Zamore: Novartis, Merck, Takeda...probably in that order. Also of note, Novartis completed their target picks under Alnylam after the Zamore patents were issued in US and Europe (Novartis has RNAi research presumably not only in Cambridge/Boston, but also Basel). Alnylam has also been accounting for Novartis revenues after the Zamore patents were issued. Applying the ISIS line of reasoning in light of their Santaris lawsuit, the question is whether Alnylam infringed Zamore as they have been evaluating (=selling) siRNA triggers for Novartis.

Anonymous said...

Real reason in my mind for the UK opposition
is same one for the US re- exam in the early 2000's:
To run interference with a potential competitor to
RNAi funding. The US reexam worked for a good few
years, and the UK query still manages to sow seeds
of doubt in the market, despite UK being a small jurisdiction.

Anonymous said...

Well. Looks like Alny or one of the big pharmas in the game has employed military strategist; using anonymous to probe and assess before all out assault? Some people viewing business as a war game rather than peaceful co-existence. Self-defense vs aggressor.

Dirk Haussecker said...

I also think that Alnylam has gotten a bit carried away with their almost war-like strategic approach to the drug development business (I call it Alnylam's quest for 'RNAi World Domination'). While off-putting to many, some of their supporters still believe that this is just business as usual.

Mr Squiggle said...

Maybe Benitec should be sending out some warning letters of their own for infringing activities, considering Gradalis have three Phase II clinical trials in the works. Don't they need to obtain a licence from Benitec for their bi-shRNA FANG cancer vaccine, or are they just hoping that they will let it slide due to lack of funds to waste on more legal fees?

Anonymous said...

Mate the patent 099 is gona expire very soon so whats the point hey.Your seening things upside down mate.

Anonymous said...

well 7 years actually, and a prima facie case for an extension beyond 2020 given the BPAI judges written ruling.

but extension aside, do you seriously think any company would hold back say 2 years of commercialisation of a drug just to avoid a licence fee?

a false economy really

Anonymous said...

hey It aint just me you now there is a whole list of companies no longer just doing research put going into and are in clinic, they have already sailed past the merck vs integra rulling. So what are they waiting for if they know they are on a good thing why not draw out the contracts now. Unless Benitec have plans to welcome them all under it's umbrella to form the beast which will rival, ALNY for supremacy.Benitec is not to be fucked with...By now everybody is well aware of the fact, We have the nuts. Benitec can afford legal action through csiro.Its all the other companies who cant and will not dare take on Benitec" if you cant beat them join them". ADUB.

Anonymous said...

idont mean to sound like a mad scientist. but answer me this why doesnt Benitec share price rocket when an annoucement is made public concerning Pfizer relations.This is where the money is my friend, the details are in the Tacere/Benitec agreement.They might only own 5% of Tacere but i can tell i have a gut feeling they own a hell of a lot when it comes to Milestones and royalties. It would not suprise me if Benitec own 95% of the milestones and royalties.Due to the undisclosed nature of the business.

Anonymous said...

why "does" is what it should read ...late night sorry> If anything ALNY is scared.We are coming for the kill mate!!!

Anonymous said...

Isnt Benitec the one with that well known honest persona nd non share price ramper Ian Ross at the helm?

Anonymous said...

Peace on earth. Ho Ho Ho. I guess Santa lives at North Pole and having trouble deliver presents down to the needies close to the other side of the round ball.

By Dirk Haussecker. All rights reserved.

Disclaimer: This blog is not intended for distribution to or use by any person or entity who is a citizen or resident of, or located in any locality, state, country or other jurisdiction where such distribution, publication, availability or use would be contrary to law or regulation or which would subject the author or any of his collaborators and contributors to any registration or licensing requirement within such jurisdiction. This blog expresses only my opinions, they may be flawed and are for entertainment purposes only. Opinions expressed are a direct result of information which may or may not be accurate, and I do not assume any responsibility for material errors or to provide updates should circumstances change. Opinions expressed in this blog may have been disseminated before to others. This blog should not be taken as investment, legal or tax advice. The investments referred to herein may not be suitable for you. Investments particularly in the field of RNAi Therapeutics and biotechnology carry a high risk of total loss. You, the reader must make your own investment decisions in consultation with your professional advisors in light of your specific circumstances. I reserve the right to buy, sell, or short any security including those that may or may not be discussed on my blog.