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Novartis, Alcon Join Alnylam in Opposing Silence Patent in Europe


By Doug Macron

Drug makers Novartis and Alcon have joined Alnylam Pharmaceuticals in opposing a European patent held by Silence Therapeutics covering a key RNAi molecule-design technology, according to documents on file with the European Patent Office.

The companies are asking the EPO to revoke the patent because, they say, the intellectual property lacks novelty in light of prior art, among other things.

The patent, EP1633890, is entitled "Methods and Compositions for Enhancing Efficacy and Specificity of RNAi," and claims rules for designing RNAi molecules with improved potency and fewer off-target effects. Part of a patent family informally known as the Zamore IP that also includes a US patent, it is based on the work of University of Massachusetts researcher and Alnylam co-founder Phillip Zamore.

According to Silence, the patent specifically covers methods of enhancing the ability of an antisense strand to act as a guide strand; RNAi agents with enhancing silencing activity; and compositions for siRNAs, as well as pre-microRNAs, shRNAs, and vectors that perform gene silencing.

The patent has been a cornerstone of Silence's IP portfolio, and the company's CEO has stated in the past that it is expected to drive partnerships and licensing deals since other firms are likely incorporating technology covered by the IP into their own RNAi drug candidates (GSN 7/15/2010).

Last year, Alnylam CEO John Maraganore dismissed the Zamore IP as “not worth anything,” but months later the company began opposition proceedings against the '890 patent with the EPO (GSN 11/18/2010).

Now Novartis, which holds the rights to use Alnylam's technology against a variety of undisclosed targets, and Alcon, which has filed dozens of patent applications related to therapeutic RNAi with the US Patent and Trademark Office and inked a drug-discovery deal with Dharmacon in 2005 (GSN 10/21/2005), have followed suit.

According to filings published by the EPO last week, both Novartis and Alcon are opposing Silence's patent for a variety of scientific and procedural reasons, most notably on the grounds that the IP lacks novelty in light of multiple examples of prior art.

For example, the patent's first claim states that the ability of an antisense strand to act as the guide strand mediating RNAi can be enhanced by “lessening the base pair strength between the 5' end of the antisense strand and the 3' end of the sense strand of the duplex, as compared to the base pair strength between the 3' end of the antisense strand and the 5' end of the sense strand.”

Novartis stated that this claim is not novel because “prior art had already observed an increase in RNAi efficiency when reducing the G:C content at the 5' end of the antisense strand. Moreover, many prior art RNAi duplexes had inherently achieved the claimed balance of G:C content.”

Additionally, Novartis charged that claims within Silence's patent are “insufficiently disclosed because the required functional result does not automatically arise after making the specified structural modifications.

“Several documents show that weaker base pairing at the 5' end of the antisense strand often leads to lower RNAi efficacy,” it added, and while “some of the claimed duplexes may provide the required result … the patent provides no guidance towards success and instead leaves the skilled person with a trial-and-error approach.”

Alcon takes a similar approach with its opposition.

It stated that certain of the '890 patent's claims — such as decreasing the tendency of an siRNA to silence an unintended target by boosting the “base pair strength between the 5' end of the sense strand and the 3' end of the antisense strand relative to the base pair strength between the 3' end of the sense strand and the 5' end of the antisense strand” — had already been anticipated by an Alnylam patent on file with the World Intellectual Property Organization.

That patent, WO 2004/080406 A2, was published after the '890 patent was filed, but it claims the priorities of 15 provisional US applications, nine of which were filed before the earliest priority date of the Zamore patent, Alcon noted.

The '890 patent was filed in February 2004, and lists June 2003 as the earliest priority date of associated filings.

In addition to this WIPO patent, both Novartis and Alcon cite a variety of peer-reviewed papers as examples of prior art.

Alcon also argued that the '890 patent “does not disclose the invention in a manner sufficiently clear and complete for it to be carried out by the skilled person.”

Echoing Novartis' sentiment regarding the guidance the '890 patent gives those skilled in the art, the company said that some of the “alleged superior properties” claimed by the IP “are not necessarily obtained when making the structural modifications taught by the patent.

“It would therefore be an undue burden for the skilled person to test all possible structural variants of the claimed siRNA constructs to identify those actually having improved selectivity and efficacy,” Alcon said.

And when it comes to claims related to increasing base pair strength, the patent does not indicate how to make such a determination, the company stated in its opposition. “The skilled person is left with the question, 'Which estimation or calculation should be used to determine the base pair strength?' Different methods will result in different results.”

Officials from Silence declined to comment on the opposition proceedings, but confirmed that there are four re-examinations of US Zamore IP, requested anonymously, ongoing within the US Patent and Trademark Office.

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