Thursday, May 3, 2007

The RNAi Patent Landscape

Patents are essential for drug development as they protect the significant investments that have to be made in order to obtain marketing approval from the relevant regulatory agencies. Common estimates put the cost of successfully developing a drug at around $1 billion. A whole technology platform such as RNAi would suffer and be unable to attract sufficient funding if the scientific discoverers and institutions failed to file patents and license them to organisations capable of taking RNAi to the clinic. Luckily, fundamental patents have been filed and have been either exclusively or non-exclusively licensed. What are they?

According to folklore, Fire and Mello, the discoverers of RNAi in worms, had to be “encouraged” by the NIH to spend the time to file a patent for RNAi. This resulted in the Fire and Mello patents that can be non-exclusively licensed by almost whoever wants to for a nominal fee. While their science was impeccable, commercially their patents suffer from the fact that originally the dsRNA inducer length was defined as 25bp and above. Additionally, even if efforts to bring this size down to the relevant 21 and upward size succeed, this will not give licensees automatically the freedom to operate as it does not claim the use as a therapeutic. For this, the Tuschl patent series are essential. These are based on Tuschl’s seminal and non-obvious discovery that small double-stranded RNAs (siRNAs) of 19-23 base-pair length are the mediators of RNAi gene silencing. It appears that Alnylam, of which Tuschl is a co-founder, can claim rights to most of the claims in the series, although the Tuschl I series can be claimed by Alnylam, Sirna Therapeutics (now a Merck subsidiary), and CytRX alike. This is because one of the four academic institutions involved in the licensing of Tuschl I decided to go it alone and license it to CytRX and and Sirna in addition to Alnylam. It seems strange to me that one institution alone can do this without the apparent support of the other parties, but I will leave this to the lawyers. The Kreutzer-Limmer patents, covering double-stranded RNAs for the purpose of gene inhibition, may also turn out to be an important piece of the puzzle and were acquired early on by Alnylam through its acquisition of Ribopharma AG.

There are a number of other pending and granted patents in the RNAi field, including siRNA manufacturing and modification patents that will be important in the actual drug development process. However, I view them as secondary albeit important and meritorious patents when measured on an innovation scale. Efforts are also being made to circumvent the need for prototype siRNAs by using either their biological precursors or even variants such as blunt-ended small double-stranded RNAs (apparently it works!), however their exact merit remains to be evaluated. In this context, I am encouraged by recent Supreme Court decisions that emphasise the importance of innovation and non-obviousness in a patent.

Note: The discussion did not cover DNA-directed RNAi that do not involve synthetic siRNAs.


Disco said...

Could you explain the difference between the RNAi therapeutics technology of Alnylam versus the zinc finger DNA binding proteins (ZFPs) and ZFP transcription factors used by Sangamo (SGMO). I understand that RNAi therapeutics can "silence" protein production. Sangamo claims to be able to "down-regulate" and "up-regulate" protein production. Also I am not sure if Sangamo's technology has similar delivery problems as RNAi? Any insight?

Eric said...

I'm curious to hear your thoughts on where Merck will stand should Tuschl I issue (and what will happen if it does not).

Nascent biotechs are accessing FTO via InterfeRx licenses with Alnylam. Will this pattern change following a ruling on Tuschl I?

Dirk Haussecker said...

Disco- Sangamo's technology is basically a gene therapy, with its promises and risks. Instead of synthetic small RNAs into the cytoplasm, with Zinc Fingers you would not only have to reach the cell, but get into the nucleus with quite larger constructs into the cell. The applications may overlap sometimes, but they won't cannibalise each other too significantly. IMO, RNAi Therapeutics are much closer to clinical reality than Zinc Fingers.

Eric- Even in the best case scenario, Tuschl I only won't give Merck freedom-to-operate, only access to all the fundamental IPs, most of which are exclusive to Alnylam. Tuschl I is essentially work in flies leading up work in human cells described in Tuschl II. Tuschl II is therefore the much stronger patent for the use of RNAi in humans.

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