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As Alnylam Awaits USPTO to Issue Tuschl-2 Patent, Ongoing IP Challenges Could Embolden New Attacks


Alnylam Pharmaceuticals came one step closer to winning issuance of a patent within its Tuschl-2 family this week after the US Patent and Trademark Office issued the company a notice of allowance for the IP.

With the allowance, Alnylam is on track to secure patent protection over an even greater potion of the RNAi field; the company expects the patent to be issued within three months. But ongoing opposition proceedings against other of its RNAi patents overseas, as well as an unrelated patent dispute in the US, raise questions as to whether other players in the RNAi field will let the Tuschl-2 patent stand unchallenged.

The patent application on track for USPTO issuance is entitled "RNA Interference Mediating Small RNA Molecules," No. 20040229266. According to Alnylam, it describes the use of siRNAs, between 19 and 25 nucleotides long, to mediate RNAi, as well as the use of overhangs on the 3' ends of dsRNAs to mediate target RNA cleavage.

Alnylam said that the patent application also covers siRNAs, regardless of their target, with these features that incorporate various chemical modifications including the use of phosphorothioates, 2'-O-methyl, and/or 2'-fluoro modifications.

"When all is told as it relates to the prosecution and issuance of claims of [our] patents, we believe that [Alnylam has] built … the strongest IP position in the RNAi field."

Alnylam has long made IP primacy a key component of its corporate image. The company bills itself on its website as having "a leading IP estate" with "a portfolio of … broad and exclusive rights to fundamental RNAi patents and patent applications required for the development and commercialization of RNAi therapeutics."

At the JPMorgan Healthcare Conference in San Francisco last week, Alnylam President and CEO John Maraganore told the investment community that "when all is told as it relates to the prosecution and issuance of claims of [our] patents, we believe that we have built … the strongest IP position in the RNAi field."

In 2003, Alnylam launched an IP out-licensing program, termed InterfeRx, in areas outside of the company's core focus (see RNAi News, 12/19/2003). Earlier this month, Alnylam said it expects to grant five new licenses to its IP during 2006, bringing to 22 the total number of such deals the company has inked since 2003 (see RNAi News, 1/12/2006).

But despite Alnylam's apparent willingness to make its IP available — albeit for a fee — it is unclear whether its rivals in the RNAi drugs arena will go along or chose instead to call for a re-examination of the patent.

Cultivating an IP Landscape

Once the Tuschl-2 IP is officially cleared by the USPTO, Alnylam will hold one of the few issued US patents directly related to RNAi. The US patent office has previously issued the Carnegie Institute's Fire-Mello patent, which covers the use of dsRNA to trigger RNAi in a model organism, and Benitec's US patent No. 6,573,099, which covers the knocking down of gene expression using DNA that transcribes double-stranded RNA, one strand of which has a sequence complementary to that of the target gene.

The Fire-Mello patent, named for inventors Craig Mello of the University of Massachusetts and Andy Fire of the Carnegie Institution, is available for non-exclusive licensing from its academic owner for a nominal fee and is already in the IP portfolios of numerous companies in both the RNAi therapeutic and reagent fields.

Though Benitec has granted licenses to its '099 patent to several companies, the availability of the patent is not so clear cut and its history may provide some clues as to how rival companies might react to Alnylam's new patent if it is issued.

In April 2004, Benitec filed a patent infringement suit against peer Nucleonics after failing to come to terms on a licensing deal for the '099 patent (see RNAi News, 4/2/2004). Nucleonics fought back both in the courts and at the patent office with some success. In September, the USPTO rejected all of the claims within the '099 patent based on a request for re-examination by Nucleonics (see RNAi News, 9/9/2005). Benitec has said it intends to appeal the ruling, which is still preliminary.

Additional insight may be gleaned from an ongoing patent opposition at the European Patent Office over Alnylam's Kreutzer-Limmer patent, which the company obtained through its acquisition of German RNAi shop Ribopharma.

Granted in 2002, the Kreutzer-Limmer patent — EP 1144623/WO 0044895 — covers "a medicament containing at least one double-stranded oligonucleotide (dsRNA) designed to inhibit the expression of a target gene." In 2003, eight parties — Sirna Therapeutics, Atugen, Aventis Pharma, Janssen Pharmaceutica, AstraZeneca, Isis Pharmaceuticals, Novartis, and Munich-based patent attorney Martin Grund — filed to have the patent invalidated, claiming that the IP does not provide sufficient supporting data.

Isis, Novartis, and Grund have previously withdrawn their opposition to the patent — Isis and Novartis each doing so after forming alliances with Alnylam (see RNAi News, 3/192004 and 9/9/2005). Grund dropped his opposition in May 2003, about two months before Alnylam and Ribopharma merged. Contacted by RNAi News in 2004, Grund declined to comment on his role in the opposition proceedings (see RNAi News, 1/16/2004).

But the other opposition parties continue to move forward to have the Kreutzer-Limmer patent struck down. Meanwhile, Sirna went out on its own in Australia last summer to initiate opposition proceedings against an Australian counterpart of the Kreutzer-Limmer patent (see RNAi News, 8/19/2005), and President and CEO Howard Robin continues to tout his company's IP estate as the strongest in RNAi.

Speaking at the JPMorgan conference last week, Robin noted that one of his company's US patent applications covers siRNAs modified 20 percent or more and is expected to be issued this year. This patent application's claims "have nothing to do with any specific chemistry," he assured conference attendees. "If you chemically modify an siRNA, it's owned by Sirna."

However, Richard Warburg, a partner at the law firm of Foley & Lardner, pointed out that Alnylam's Tuschl-2 patent application is significantly different from the Kreutzer-Limmer patent or the '099 patent.

The Tuschl-2 IP covers "a method for preparing or manufacturing an RNAi [compound] of a certain structure," and, for example, its claims are narrower than the Kreutzer-Limmer patent, he told RNAi News this week. Additionally, the Tuschl-2 IP specifically refers to 3' overhangs on the ends of the siRNA, and not all companies are developing RNAi compounds with this feature.

As for those RNAi firms that might be, Warburg noted that "while there may be requests for re-examination, more people are taking licenses from Alnylam and that may well continue now."

Warburg said that he does not currently represent any of the companies discussed in this article.

Officials from Sanofi-Aventis, Janssen owner Johnson & Johnson, AstraZeneca, Alnylam, and Sirna were not available for comment as of press time.

Atugen CSO Klaus Giese told RNAi News via e-mail this week that since his company's siRNA molecules are blunt ended, "we do not feel that the Tuschl-2 [patent] allowance [changes] any of our views."

Sidebar: Tuschl-1 and Tuschl-2; an IP Family Tree

Alnylam became the sole licensee of the Tuschl-2 intellectual property, which is named for one-time Max-Planck researcher and Alnylam co-founder Thomas Tuschl, after it signed a 2002 deal with the Max-Planck Society's tech-transfer arm, Garching Innovation.

That arrangement gave Alnylam the co-exclusive rights to the IP in exchange for establishing operations in Germany — a condition the company satisfied by acquiring German RNAi firm Ribopharma, which happened to be the other co-exclusive licensee of the Tuschl technology.

Garching also gave Alnylam rights to the Tuschl-1 patent application family — which covers the use of siRNAs, 21 to 23 nucleotides in length, to induce RNAi in mammalian cells — but the Max-Planck Institute jointly owns this IP estate with the Whitehead Institute, MIT, and the University of Massachusetts.

In September 2003, UMass exclusively licensed its rights to the Tuschl-1 family to Sirna Therapeutics.

— Doug Macron ([email protected])

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