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USPTO to Allow US miRNA Patent to Max Planck; Licensees Alnylam, Isis Tout IP's Importance

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Alnylam Pharmaceuticals and Isis Pharmaceuticals announced last week that the US Patent and Trademark Office has allowed certain claims within a patent application covering microRNAs and miRNA-targeting drugs that the firms exclusively licensed for therapeutic applications.
 
According to the companies, when the USPTO formally grants the claims sometime in the next six months, it may create the first US patent specifically related to the nascent miRNA field (see sidebar).
 
It would also represent a significant addition to both Isis’ and Alnylam’s intellectual property estates: The former aims to apply its expertise in antisense to modulate the small, non-coding RNAs, while the latter hopes to extend its reach beyond its core RNAi focus.
 
Additionally, the IP will provide the companies additional patent protection as they advance an ongoing miRNA collaboration in hepatitis C — apparently their most advanced miRNA effort to date.
 
The patent application, No. 10/490,955, was filed on Sept. 15, 2005, and carries a PCT filing date of Sept. 27, 2002. Assigned to the Max Planck Institute and listing RNAi pioneer Tom Tuschl as its lead inventor, the application is part of the so-called Tuschl-3 patent family, an miRNA IP portfolio Alynlam and Isis co-exclusively licensed in 2004 for therapeutic applications.
 
The diagnostic rights to the IP have been co-exclusively licensed to four companies: Stratagene, Asuragen, Rosetta Genomics, and Exiqon.
 
According to the application’s abstract, in C. elegans, “lin-4 and let-7 encode 22- and 21-nucleotide RNAs, respectively, that function as key regulators of developmental timing. Because the appearance of these short RNAs is regulated during development, they are also referred to as small temporal RNAs.”
 
The abstract notes that “many more” 21- and 22-nucleotide long expressed RNAs — miRNAs — exist in invertebrates and vertebrates, and that “some of these novel RNAs, similar to let-7 stRNA, are also highly conserved. This suggests that sequence-specific post-transcriptional regulatory mechanisms mediated by small RNAs are more general than previously appreciated,” the abstract adds.
 
Although the patent application claims more than 120 novel mammalian miRNAs, as well as the use of molecules to down-regulate the non-coding RNAs, the claims allowed by the USPTO specifically cover miR-122, a highly studied liver-specific miRNA associated with HCV.
 
In 2005, researchers at Stanford University showed in a paper published in Science that miR-122 may be required for HCV replication. The IP surrounding this work was co-exclusively licensed for drug development by Isis and Alnylam that same year.
 
In 2006, Isis published a paper in Cell Metabolism demonstrating that the miRNA could be successfully targeted with an antisense agent. Around the same time, Rockefeller University researcher and Alnylam collaborator Markus Stoffel published data in Nature detailing the use of chemically engineered oligos termed antagomirs to silence miR-122 (see sidebar at the end of this article).
 
Alnylam holds the exclusive rights to antagomirs for therapeutic applications (see RNAi News, 11/3/2005).
 
Last week, Robert Millman, Alnylam’s chief IP counsel, said in a statement that his firm and Isis “have been engaged in consolidating intellectual property in the miRNA field. We believe that, in addition to this first allowed US patent covering isolated miRNAs and molecules that are complementary to the miRNA, several other patents will likely result from the Tuschl-3 patent series because similar claims to each of the over 120 miRNAs are disclosed in the patent application as well as methods of altering the level of the miRNA in a cell."
 
Although these follow-on patents are expected to be issued soon, the USPTO makes its own schedule and it is not clear when such issuances may occur, Isis Senior Vice President of Research Frank Bennett told RNAi News this week.
 
But even if the patent office takes its time with the other claims covered under Tuschl-3, the miR-122 patent will likely prove extremely valuable, not only because it could give Alnylam and Isis a head start in establishing an IP footprint in the miRNA arena, but because miR-122 appears to be the focus of the companies’ most advanced miRNA effort.
 
“Since 2002, [Isis has] had activities trying to find therapeutic opportunities for microRNAs,” Bennett told RNAi News this week. “The most advanced is the program [targeting] miR-122 for hepatitis C virus infection, [on which] we’re closely collaborating with Alnylam.”
 

“Since 2002, [Isis has] had activities trying to find therapeutic opportunities for microRNAs. The most advanced is the program [targeting] miR-122 for hepatitis C virus infection, [on which] we’re closely collaborating with Alnylam.”

While Alnylam officials declined to comment for this article, the company highlights on its website that its alliance with Isis and Stoffel’s efforts to silence miR-122 with antagomirs is central to its miRNA work.
 
According to Bennett, “the main focus [on the miR-122 project] up to this point has been to optimize the chemistry of the microRNA-[targeting] antisense oligo for in vivo delivery.”
 
Although the company has used second-generation antisense oligos to target miRNAs, as published in the Cell Metabolism paper, later on “we found a newer chemical modification that further improves the potency by about eight-fold compared to our second-generation chemistry.
 
“We’re still going through some iterations and optimizing the chemical modifications for inhibiting microRNA activity,” he said, adding that the new modifications also appear to hold potential for siRNAs, though they don’t appear superior to existing modifications for antisense agents. He declined to comment on the specific nature of the modifications, but said that they incorporate “some of our 2’ chemical modifications.”
 
With in vivo work ongoing, the miR-122 program in HCV could be a year or so away from the clinic, Bennett said, but he cautioned that this timeline is only feasible “if resources are available, which is a big if.”
 
Even if Isis and Alnylam had the resources to put the miR-122 effort on the fast track, it is not likely they would due to the uncertainty that still surrounds the biological roles miRNAs play, he noted.
 
“This is a program we want to take our time with [to] understand the roles of microRNAs in normal cellular physiology,” Bennett explained. “So, we want to make sure we’re approaching this judiciously so we don’t run into any unanticipated side effects from isolating microRNAs.”
 
In line with this, Isis is “really focusing on exploiting microRNAs as targets for diseases where either you don’t treat for that long or [ones that have] a high mortality rate, like cancer,” an area being explored under a miRNA drug-development partnership in hepatocellular carcinoma with Rosetta (see RNAi News, 2/23/2006), he added.

 

 
Isis and Alnylam, in ‘Amicable Relationship,’
Won’t Be Antagonized By Antagomir Tech
 
Despite the promise of Alnylam’s antagomirs, which are essentially cholesterol-conjugated single-stranded RNA analogues complementary to a specific miRNA, Isis’ Bennett thinks the new chemically modified antisense oligos his company is evaluating in the miR-122 HCV program may prove superior.
 
“Our data suggest that this new modification performs much better than the cholesterol-conjugated oligos,” he said.
 
But even if antagomirs prove to be the go-to technology, Isis doesn’t expect to be left out of the game on indications with which it has not partnered with Alnylam.
 
“We believe that we have IP that supersedes antagomirs,” Bennett said. “Isis and Alnylam have a relationship where we’ve cross-licensed IP for double-stranded RNA, and that includes cholesterol conjugates, [but] Alnylam does not have rights to [Isis IP related to] single-stranded oligonucleotides. So the cholesterol conjugates they are using, which they call antagomirs, are covered under Isis IP [and] so far we don’t think Alnylam has rights to practice that.”
 
But industry watchers shouldn’t expect a showdown between the long-time partners.
 
“We have a very amicable relationship and anticipate that if the cholesterol conjugate turns out to be the best [technology] … for targeting [miRNAs], we’d work something out,” he said.

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