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Alnylam Touts HBV IP amid Competition from Arrowhead, Tekmira

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NEW YORK (GenomeWeb) – Alnylam Pharmaceuticals last week announced its control of a US patent, acquired through its purchase of Merck's RNAi drug assets earlier this year, that it says is a necessary piece of intellectual property for any group looking to develop an siRNA-based treatment for hepatitis B virus infection.

An Alnylam spokesperson said that the disclosure was made for the benefit of investors who might not be aware of the IP. But the timing of Alnylam's announcement — almost six months after the US Patent and Trademark Office actually granted the patent — has prompted speculation that the company may be drawing a line in the sand for Tekmira Pharmaceuticals and Arrowhead Research, both of which have HBV programs underway.

Alnylam revealed that it was adding the disease target to its own pipeline last month.

The patent — No. 8,618,277, entitled, "RNA Interference-mediated Inhibition of Gene Expression using Chemically Modified Short Interfering Nucleic Acid" — specifically claims the use of siRNAs and other small nucleic acid molecules that mediate RNAi against an HBV target.

Assigned to Merck, the patent stemmed from work conducted by that company's Sirna Therapeutics division, which was sold off to Alnylam along with the rest of Merck's RNAi assets in January for $175 million in cash and stock. As part of the transaction, Alnylam picked up a fledgling HBV program that it recently said it had decided to advance to the clinic.

According to Alnylam, its HBV candidate — ALN-HBV — will take advantage of its next-generation conjugate delivery technology, dubbed ESC-GalNAc, which enables subcutaneous drug administration. An investigational new drug application or international equivalent is expected to be filed in late 2015.

With its HBV program official, Alnylam is now in direct competition with Tekmira, whose own HBV program is expected to yield an IND before the end of this year, and Arrowhead, which recently began Phase II testing of an HBV candidate that it acquired from Roche in late 2011.

In last week's announcement, Alnylam stated that it has exclusive rights to the '277 patent and that it believes claims within the IP are "critical for the development of RNAi therapeutics" for HBV infection.

Among these claims, Alnylam added, are ones on anti-HBV siRNAs with strands between 18 and 24 nucleotides in length. Also claimed are sense and antisense strands each comprising 10 or more 2'-deoxy, 2-O-methyl, 2'-fluro, or universal base modified nucleotides; and 10 or more pyrimidines of the sense and/or antisense strand with 2'-deoxy, 2-O-methyl, or 2'-fluoro modifications.

"Such chemical modifications of siRNA are generally required to achieve in vivo potency and durability for RNAi therapeutics," Alnylam stated.

While the '277 patent was granted in December, an Alnylam spokesperson said in an email to Gene Silencing News that the company's announcement about its ownership of the IP was made now because the "internal integration" of the IP estate acquired from Merck has only recently been completed given that the closing of the deal occurred in March.

"Since ALN-HBV is an important program in Alnylam’s pipeline, the company wanted to make sure investors were aware of the new patent," the spokesperson added.

However, it appears that it isn't just Wall Street that has taken notice of the announcement.

Late last week, Arrowhead issued a statement indicating that the company feels it has "broad access to intellectual property required" to develop its HBV drug, known as ARC-520, including IP licensed from Alnylam in 2012.

"Arrowhead does not believe there are additional unlicensed patents directed to RNAi therapeutics targeting the hepatitis B virus that affect its freedom to operate," the company said. "Arrowhead and its legal advisors continually review the patent landscape to ensure freedom to operate and the company believes that development and commercialization of ARC-520 would not infringe patents governing RNAi therapeutics targeting the hepatitis B virus," including the '277 patent.

Indeed, its 2012 arrangement with Alnylam specifically includes IP related to Arrowhead's development of an HBV therapeutic. As part of that deal, Alnylam stands to receive milestones and royalties on Arrowhead's drug, giving it a stake in the success of ARC-520.

Still, the Alnylam spokesperson confirmed that the company has "no plans to license the ['277] patent to third parties."

Tekmira's stance on the situation is less clear. The company has not made any public statements about the IP and did not return requests for comment. Complicating matters is the acrimony between Tekmira and Alnylam, which had once been close partners but saw their relationship sour amid an IP misappropriation lawsuit.

As reported by Gene Silencing News, Tekmira sued Alnylam in 2011 for allegedly stealing trade secrets related to its lipid nanoparticles and using them to develop its own delivery technologies. The companies settled the litigation the next year, with each agreeing to give the other access to certain of their respective technologies and Alnylam paying Tekmira $65 million to buy out a manufacturing contract.

Although Tekmira said at the time that the settlement called for it to receive "non-exclusive licenses to develop and commercialize RNAi therapeutics based on Alnylam's siRNA payload technology," it was not immediately clear whether the '277 patent would be covered by the agreement.

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