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Alnylam Outlicenses Ribopharma IP, Opposition in Europe Casts Its Shadow

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ALNYLAM Pharmaceuticals announced this week three separate, non-exclusive licensing deals for an issued European patent directly covering double-stranded RNA-induced gene silencing as a therapeutic, helping the company put an end to talk about its reluctance to outlicense its intellectual property. Meanwhile, the patent is still being opposed by a number of different companies, casting some doubt on its eventual value.

The patent in question is the so-called Kreutzer-Limmer patent — EP 1144623/WO 0044895. It carries priority dates of January and November 1999 and specifically covers “a medicament containing at least one double-stranded oligonucleotide (dsRNA) designed to inhibit the expression of a target gene.” The patent’s abstract notes that in the invention, “at least one strand of the dsRNA is at least in part complimentary to the target gene.”

Under the first deal, Cell Signaling Technology has the right to sell research products that incorporate the patented technology. Under the second deal, Cenix Bioscience has the right to market research services under the Kreutzer patent. Under the third deal, Invitrogen may market research products and services under the patent. In exchange, all three licensees will pay initial and annual fees to Alnylam, as well as royalties on licensed products. Additionally, Alnylam will receive the right to use Cenix’s siRNA design technology with its own therapeutic compounds.

None of the deals includes rights to the patent for therapeutic applications.

The Kreutzer-Limmer patent was invented by Roland Kreutzer and Stephan Limmer, founders of the German RNAi company Ribopharma, and it became part of Alnylam’s IP estate when the two companies merged in July last year. Based on the patent’s early priority dates, it would appear to be an essential piece of IP for anyone looking to work on RNAi-based therapeutics in Europe (the US version of the patent is still pending). However, seven parties — Sirna Therapeutics, Atugen, Aventis Pharma, Janssen Pharmaceutica, AstraZeneca, Isis Pharmaceuticals, and Novartis — have joined together to oppose the Kreutzer patent in Europe, casting some doubt on the IP’s viability.

Incidentally, an eighth party, Munich-based patent attorney Martin Grund, had opposed the Kreutzer-Limmer patent but withdrew his opposition in early May 2003. Dan Boehnen, a partner with the law firm McDonnell, Boehnen, which represents Sirna, told RNAi News that he believes Grund was opposing the patent on behalf of Alnylam itself, but withdrew the opposition when the companies merged.

He stressed that he has no tangible evidence that this is the case, but pointed to the timing of the withdrawal — about two months before the merger was announced — as indicative of Alnylam’s dropping its opposition in lieu of a business deal.

Grund declined to comment on the patent opposition or whether he filed it on anyone’s behalf, although he did note that he withdrew the opposition for “business reasons.” Alnylam CEO John Maraganore told RNAi News that he didn’t know any details about the Grund filings.

The Opposition

The opposition asserts that the patent is not entitled to its priority dates and that it does not provide sufficient supporting data, according to Bharat Chowrira, vice president of legal affairs at Sirna.

“[The patent] is very broad and has very minimum disclosure to support [its] claims,” Chowrira told RNAi News. “All the data they had in 1999 was with long double-stranded RNA” 400 and 500 base pairs in length, he said. “They did not envision using shorter versions of this double-stranded RNA.”

Chowrira said that the opposition alleges that that Kreutzer and Limmer only mentioned short dsRNA in follow-on filings to the patent made in January 2000, and that these specifically described a short dsRNA with a loop at an end — in a sense a short hairpin RNA. “They had some minor data there on one cell culture model system, but we don’t believe it works through an RNAi mechanism,” he said.

The inventors also claim in their filings that an effective short dsRNA must be linked at one end to prevent dissociation between the two strands, which “we know today is not true — you don’t need to have a linker hold the two strands together.”

“[Kreutzer and Limmer] did not really envision the … utility of the whole technology,” Chowrira said. “They were focusing on long double-stranded RNA [and] they were focusing on vector-expressed RNA — they were not really focusing on chemically synthesizing short pieces of double-stranded RNA to mediate RNA interference.”

“The only thing [the patent] has support for is to say [each dsRNA is] less than 25 [nucleotides in length],” Boehnen added. “When you say less than 25, and that goes down to 15, 12, 13, 10, 9, and those don’t work. The only thing they have support for is described in a way that covers embodiments that don’t work.”

Boehnen said that instead of including hard data about short interfering RNAs in their patent application, Kreutzer and Limmer “just made a very minor change with this verbal description [of nucleotide length] without backup examples. As near as we can tell, they hadn’t actually scientifically confirmed what worked or hadn’t worked.”

“What they tried to do is design around [the] Fire and Mello [patent]” to work around prior art, Chowrira added. “Fire and Mello said ‘at least 25 base pairs.’”

Alnylam senior vice president of business development Vincent Miles, who is overseeing the company’s IP outlicensing efforts, told RNAi News that “as a company, we are confident that we will prevail in the opposition proceedings and that the patent will stand.” He declined to comment further.

He also declined to specify whether the agreements with CST, Cenix, and Invitrogen anticipate the possibility that the proceedings will go against Alnylam, but said that “any license agreement that involves patents always includes language that is appropriate for the stages of the patent applications or the granted patents.”

Miles added that the signing of the license agreements are interpreted by Alnylam as “a strong statement about the validity of our patent estate and the Kreutzer-Limmer patent portfolio.”

CST’s vice president of business development Michael Melnick told RNAi News that his company made its own evaluation of the legal situation and “felt Ribopharma had a very strong position and we felt comfortable with making [the] decision [to license].” He noted that CST has also licensed the Fire-Mello patent from the Carnegie Institution.

Nikki Zahl, director of the RNAi business group at Invitrogen, told RNAi News that her company was aware of the opposition proceedings when it made the decision to license the Kreutzer-Limmer patent, but “it is an issued patent … [and] we want to take an appropriate stance that we have the IP necessary to be able to convey to our customers the ability to use the tools and services that we’re developing for RNAi. We just felt that this was important because it’s an issued patent.” She added that Invitrogen has also licensed the Fire-Mello patent.

Cenix CEO and CSO Christophe Echeverri told RNAi News that his company was well-aware of the opposition, but noted that “for us, it’s important to have clear freedom to operate in all areas for which we offer research services … and siRNA technology is central to what we’re currently offering.

“Obviously, we wouldn’t have taken the license if we didn’t think there was a basis to the patent,” he added. “We’re hedging our bets — there’s language in the license to protect us, but we wouldn’t have taken a license in the first place if we didn’t think it would survive.”

It is not clear when the opposition proceedings will conclude, and Chowrira noted that European opposition proceedings are notoriously slow. “We filed the opposition in May 2003, and since there are seven opponents, we’ll probably have the first set of back and forth sometime this year,” with a hearing around late 2004 or early 2005. “It may happen this year — the European Patent Office is trying to expedite all of these proceedings and they’re hiring a lot of new examiners,” he added. “Maybe they’ll speed this up because of the importance of the technology, but we don’t know.”

—DM

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