Tuesday, October 26, 2010

(Very) Broad Zamore End-Stability Patent Issued in Europe

Last week, Silence Therapeutics announced that the European Patent Office has granted a patent from the Zamore RNAi trigger design IP estate (EP 1633890 B1). This follows the issuance of related patents over the summer in the US. This IP is assigned to the University of Massachusetts and exclusively licensed to Silence Therapeutics.

What is newsworthy in this latest patent issuance is that very broad claims were allowed which would almost require a company with RNAi Therapeutics platform ambitions to take a license. As I have discussed here before, Zamore made the highly influential finding that it is both the absolute and relative base-pairing strength (relative to the base-pairing strength on the other end of an siRNA duplex) at the 5’ end of the guide strand that determines its RNAi effector complex (RISC) incorporation as well as discourages passenger strand incorporation. Accordingly, the rules have implications for both efficacy and specificity of RNAi gene silencing. It has to be assumed that the end-stability rule figures in one form or another into the siRNA design algorithms used by companies as part of the siRNA screening process, and it should also be an important guiding principle in optimizing an initial candidate siRNA.

A strong patent, of course, does not necessarily follow such fundamental biological insights. In this instance, it could well turn out to be the case. The US claims cover methods focussed on the reduction of off-targeting effect, including first assessing the off-targeting of a first siRNA, and then changing it according to the end-stability rules. As the recent Merck paper illustrates, companies in the field undertake such modification-RISC incorporation studies. Since a given siRNA structure can theoretically be arrived at via a number of different routes, such methods papers are more difficult to enforce. In addition, the direct value of the US claims may somewhat affected as they emphasized the reduction of off-targeting aspect of the design rules rather than the enhanced efficacy aspect which might be considered the more attractive feature of the invention.

What is therefore different in the European patent issuance is that not only does it emphasize the efficacy aspect, but it also importantly includes very broad composition of matter claims relating to the structure of an siRNA. It should be very straight forward to enforce these.

The breadth of the claims is striking: siRNAs with small features already that lessen the base pairing at the 5’ end of a guide RNA are covered in these claims. This can be a mismatched base pair, relatively widely employed for example at the very 5’ end of the guide RNA, or a single nucleotide modification. One of the methods claims even covers siRNAs solely characterized by having fewer G:C base-pairs at the guide strand 5’ end compared to the 3’ end. I would expect many if not most siRNAs to fall into that bucket.

In a phone conversation last night with Phil Haworth, the CEO of Silence Therapeutics said that Silence Therapeutics are naturally excited of having been granted these broad claims. When asked, he added that similar efficacy and composition of matter claims derived from the original Zamore patent application are also being considered in the US (note: due to a restriction requirement, the off-target reduction elements of the invention were initially pursued in the US and the efficacy aspects put on the back-burner). I also agree with him that given the strength of the claims and because this is a European patent prosecution, competing RNAi Therapeutics companies can be expected to challenge the validity of the patent. This should also be a good indicator whether Alnylam really meant what it said when it stated that it saw nothing of value in the Zamore siRNA design IP estate.

Given the importance of the siRNA end-stability rules and broad-ening claims, will we therefore see Silence Therapeutics soon swim in cash? Here, Phil Haworth was a bit more cautious and said that Silence’s RNAi trigger IP estate would be just one element in the discussions they are having right now with pharmaceutical companies.

As you will be aware, Silence Therapeutics has been ‘approached’ by a company a few weeks ago, an approach that could lead to an offer, and Dr. Haworth confirmed that these discussions were still ongoing. Without going into any more details, he also said that they are conducting a number of platform partnership talks in parallel and that the ‘approach’ and platform conversations would be separate discussions.

Phil Haworth did not disagree when I speculated on the potential strategic value of the Zamore end-stability IP to particularly Merck, given the one billion dollar+ Merck spent on Sirna Therapeutics for access to the 3’ overhang IP which it now stands to lose (see coverage on the 'RNAi Litigation Blog'). He emphasized, however, that the company does not spent much time speculating internally what other companies might be scheming and instead focus their limited resources on building strong science and IP. In the end, the value of the Zamore siRNA design rules will be closely tied to advancements in the delivery of RNAi triggers and in that regard they are pleased with the continued dose escalation of Silence’s first clinical candidate Atu-027 (6th of planned 11 dose cohorts ongoing).

9 comments:

Anonymous said...

Any thoughts to what cross-licensing (ALNY-SLN or others, incl MRK) might look like, as opposed to an IP litigation scenario?
Thanks

Anonymous said...

Thanks, most interesting and much appreciated insight. Has your list of companies behind the approach changed at all?

Anonymous said...

Was the Zamore group the first to use these features in the design of siRNA? Given the breadth of the claims, what are the chances the patent survives prior art challenges?

Dirk Haussecker said...

Cross-licensing...agree that in general it would make sense for the industry to preserve the value of IP based on the fundamental technology breakthroughs and for now at leat focus on clinical progress. However, I expect challenges if for no other reason but that the claims are so broad (deservedly so if you consider the science behind it).

List of companies behind approach...has not changed at all. Novartis and Pfizer still top it.

Yes, Zamore was the first to use these design features AND being able to predict with a high degree of confidence what was going to happen with regard to RISC incorporation. Sure, others had used siRNAs satisfying the Zamore design rule features before, but unwittingly so. This, however, does not affect patentability. Questions like this were part of the patent prosecution.

Trewqrewq said...

Do you have any opinion of Silence Th as an investment. When I see penny stocks, I get wary.

Dirk Haussecker said...

Trew- You are right in that there are many risks in investing in a microcap like Silence Therapeutics, liquidity being one of them. The overall investment climate for early-stage biotechs does not help either as Silence needs to raise capital if it has to go it alone. But then again, if the situation changes for the better, some of these companies could represent interesting investment opportunities.

Anonymous said...

US Zamore are going into re-exam...

http://www.uspto.gov/web/offices/com/sol/og/2010/week45/TOC.htm


7,459,547, Reexam. C.N. 90/011,125, Requested Date: Jul. 30, 2010,
Cl. 536/024, Title: METHODS AND COMPOSITIONS FOR CONTROLLING EFFICACY OF RNA
SILENCING, Inventor: Phillip D. Zamore et al., Owners of Record: University
of Massachusetts, Boston, MA, Attorney or Agent: Lahive & Cockfield, LLP.,
Boston, MA, Ex. Gp.: 3991, Requester: Karen E. Flick, Law Offices of Karen E.
Flick, El Granada, CA

7,732,593, Reexam. C.N. 90/011,129, Requested Date: Aug. 2, 2010,
Cl. 536/024, Title: METHODS AND COMPOSITIONS FOR CONTROLLING EFFICACY OF RNA
SILENCING, Inventor: Phillip D. Zamore et al., Owners of Record: University
of Massachusetts, Boston, MA, Attorney or Agent: Lahive & Cockfield, LLP.,
Boston, MA, Ex. Gp.: 3991, Requester: Karen E. Flick, Law Offices of Karen E.
Flick, El Granada, CA

Dirk Haussecker said...

Mmhh...I expected opposition in Europe, not so much in the US, but it indicates that somebody is not very happy and considers the patents 'a problem'. Do you know who requested the re-exam?

Anonymous said...

A company called Oligoengine was selling a Si2 Silencing Duplex with what they called a 3' G:C clamp and a 5' modified passenger strand in 2002. It even had a 3' passenger/5' guide mismatch in the ordering software art. For the most part, this was freely offered to all academics in the field internationally.

By Dirk Haussecker. All rights reserved.

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