The European Patent Office said last week that it has upheld an amended version of Alnylam Pharmaceuticals' Kreutzer-Limmer patent, putting to rest a dispute over the validity of the patent begun in 2003.
While Alnylam hailed the EPO's decision as a victory, other players in the RNAi therapeutics space questioned the usefulness of the amended claims upheld by the patent office.
"The outcome of the European opposition proceedings … is a positive step forward in Alnylam's strategic consolidation of intellectual property needed for advancement of RNAi therapeutics as products," John Maraganore, president and CEO of Alnylam, said in a statement. The ruling "adds strength to an intellectual property estate for RNAi therapeutics that contains well over 150 patents issued in major markets."
According to Sirna Therapeutics, however, the narrowing of the patent's claims puts "substantial limitations on the commercial utility" of the intellectual property.
"We contended from the very beginning that the Kreutzer-Limmer patent would not stand up to scientific and legal scrutiny and that its true commercial and scientific value in the field of RNA medicines has been miscast and misunderstood," Howard Robin, president and CEO of Sirna, said in a statement.
"We contended from the very beginning that the Kreutzer-Limmer patent would not stand up to scientific and legal scrutiny and that its true commercial and scientific value in the field of RNA medicines has been miscast and misunderstood."
The Kreutzer-Limmer patent — EP1144623 — was developed by the founders of the German RNAi company Ribopharma, which Alnylam acquired in July 2003. It covers "a medicament containing at least one double-stranded oligonucleotide designed to inhibit the expression of a target gene … [wherein] at least one strand of the dsRNA is at least in part complementary to the target gene."
Opposition proceedings against the patent were launched in May 2003 by eight parties: Sirna Therapeutics, Atugen (now a subsidiary of SR Pharma), Aventis Pharma (now Sanofi-Aventis), Janssen Pharmaceutica, AstraZeneca, Isis Pharmaceuticals, Novartis, and Munich-based patent attorney Martin Grund.
Grund, whom a Sirna lawyer had told RNAi News was believed to be acting on behalf of Alnylam (see RNAi News, 1/16/2004), withdrew his opposition in advance of Alnylam's acquisition of Ribopharma. Isis and Novartis later pulled out of the opposition effort — in March 2004 and November 2005, respectively — after forming partnerships with Alnylam (see RNAi News, 3/19/2004 and 9/9/2005).
The other companies opposing the patent moved forward, however, and by late 2004 Alnylam had issued to the EPO its objections to the opposition, as well as several amendments to the patent's claims (see RNAi News, 1/14/2005). Alnylam's changes, it appears, were sufficient to keep the patent in effect, but may have also hamstrung the IP.
"As originally granted, the claims of [the Kreutzer-Limmer] patent covered siRNAs with up to 25 nucleotides complementary to a target gene," and were obtained through a process that was later deemed inapplicable by the EPO, according to Alnylam. "In consequence, the claims were amended to cover siRNAs with a shorter length and other required features."
Specifically, Alnylam added, the amended claims of the patent cover "methods, medicaments, and uses of siRNAs with a region of complementarity to a target gene between 15 and 21 nucleotides in length; a region of complementarity to a target gene between 15 and 21 nucleotides in length; and a double-stranded structure that is stabilized by a chemical linkage of the single strands, such as and including standard modifications used for stabilization."
Robert Millman, Alnylam's chief intellectual property counsel, said in a statement that "the amended claims granted through the oral opposition proceedings cover features of siRNAs that are critical for RNAi therapeutics."
But Bharat Chowrira, Sirna's vice president of legal affairs and chief patent counsel, said in a statement that the new claims of the patent "are now limited to chemical structures that in our experience are obsolete and essentially ineffective as viable RNAi-based therapeutics. We believe, therefore, that this patent has no impact on our current or future programs.
"Perhaps more importantly, [the patent] does not provide any meaningful intellectual property protection in the field of RNAi-based therapeutics," Chowrira added. Officials from Sirna did not return requests for further comment.
"There's quite a bit of controversy as to how important the Kreutzer-Limmer patent is," and the amendment of the patent's claims only raises the uncertainty.
Sirna's sentiments were echoed by SR Pharma, the parent of the only other pure-play RNAi firm opposing the Kreutzer-Limmer patent. Iain Ross, executive chairman of SR Pharma, said in an e-mail to RNAi News, that his company is "pleased that the EPO has restricted the claims of the … patent," further validating Atugen's freedom to operate.
An Alnylam spokeswoman said that the company was not providing additional comment on the EPO decision to the media.
To ThinkEquity analyst Andrew McDonald, who covers Alnylam, the EPO ruling provides little clarity to the murky RNAi IP landscape.
"It's early days in terms of resolving the IP issue and it has yet to be decided which patents are the fundamental patents," he told RNAi News this week. "There's quite a bit of controversy as to how important the Kreutzer-Limmer patent is," and the amendment of the patent's claims only raises the level of uncertainty.
The true importance of the various RNAi patents and patent applications, including Kreutzer-Limmer, isn't likely to be known until a drug candidate nears market approval, McDonald said. Further, "until you've got a therapeutic with demonstrated clinical activity, this IP isn't terribly valuable."
"We can talk about the potential all we want to, and in biotech we often do," he said. But lacking any tangible clinical evidence that an RNAi drug is effective, "I look at this IP thing almost as a diversion to draw attention away from where there would be true value.
"Ultimately for Alnylam, Sirna, or any company in biotech, their value is going to be driven by the discounted earnings from their products and not the number of patents, the potential, or the promises," McDonald said.