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RNAi Roundup: Reading Between the RNAi IP Battle Lines; PNAS Papers Proliferate; Dharmacon Launches RNAi Tool for SARS Studies

NEW YORK, May 30 - Some two-dozen companies have taken licenses already to the patents held by Carnegie Institution and University of Massachusetts for the RNAi inventions of Andy Fire and Craig Mello - the first RNAi inventions to be awarded USPTO protection. So when BD Biosciences Clontech issued a press release this week to announce that it had jumped on the bandwagon, the statement seemed innocuous. But one loaded line in the release hints at the battle brewing over RNAi intellectual property. Of US Patent 6,506,559, BD stated, "This patent is the first patent to issue on the use of this critical new technology in mammalian systems."


What seasoned RNAi IP observers know is that the long, double-stranded RNAi's described by Fire and Mello in 1998 proved effective at silencing genes in lower organisms, but not in mammals. In the US, it was Tom Tuschl who, several years later, first showed how short interfering RNA duplexes, 21-nucleotides in length, could induce RNA-mediated gene silencing in mammalian cell cultures.


Tuschl's work, the licenses for which are held by MIT, has not yet been awarded a patent. Some debate whether it ever will, and many question the necessity of acquiring a license from MIT to use the technology. Some are arguing that holding a license to the Fire-Mello patent gets a company all the rights it needs to practice RNA interference in any type of organism.


The Fire-Mello patents are being licensed nonexclusively by Carnegie. For an up-front fee of $35,000, annual payments of the same amount, an additional $50,000 upon each of three milestones - one being the issuance of the first patent, which occurred in January this year - and a "reasonable" royalty for "sales of products embodying the invention or produced using the same," anyone can use, make, or sell products incorporating the discoveries.


What BD Biosciences and others argue is that because the first claim of the Fire and Mello patent described RNA interference using double-stranded RNA without defining organism or duplex length, they have prior art over Tuschl's discovery. BD's group leader for molecular biology, Andrew Farmer, who said his company is "bullish" on the Fire and Mello patents, said, "Their first claim is double-stranded RNA, full stop." Placing bets that the Fire and Mello patent overrides Tuschl's, several companies have gone the route of BD Biosciences and decided against purchasing a license to the Tuschl short interfering RNA technology from MIT. Farmer said, "This is an area where people are drawing battle lines."


Since scientists first began conducting RNA interference studies in earnest five years ago, more than 750 papers on the topic have been published. This week saw four more added to the heap. PNAS's May 27 edition includes two separate research papers, one by Stephen Fesik of Abbott Laboratories looking into the specificity of short interfering RNAs, and another by Stanford's Pat Brown looking at RNAi in genomewide expression profiling, as well as a commentary by Andrew Dillin of the Salk Institute. In addition, PNAS Online today will publish "Allele-Specific Silencing of Dominant Disease Genes," by University of Iowa researchers Henry Paulson and Victor Miller.


"Specificity of short interfering RNA determined through gene expression signatures," describes how Fesik and his team in Abbott's global pharmaceutical Research and Development group designed siRNAs against different regions of the same target gene for three different targets and compared their effects on cells using DNA microarrays. The scientists reported that siRNA is highly specific for targeted gene knockdown and said their results establish "siRNA-mediated gene silencing as a reliable approach for large-scale screening of gene function and drug target validation."


In their paper, "Genomewide view of gene silencing by small interfering RNAs," Pat Brown and colleagues show that siRNA-induced silencing of genes with transient or stably expressed mRNA is highly gene-specific and does not produce secondary effects detectable by genomewide expression profiling.


Dillin's "The specifics of small interfering RNA specificity," is a primer on RNA interference, in which he explains the rapidly emerging technology and describes the current state-of-the-art as it is applied to plants, nematodes, and animals. Dillin also explains why he believes the field is not yet ready for siRNA therapy.


Nevertheless, the Paulson paper proposes that one potential therapeutic use for siRNAs is in the silencing of dominantly acting disease genes, especially by selective targeting of mutant alleles. The Iowa researchers demonstrate how allele-specific silencing of disease genes can be achieved when siRNAs are targeted at a linked SNP or directly at the disease mutation. The team was able to silence a mutant gene linked to Machado-Joseph disease, a neurodegenerative condition, as well as a single mutation in the Tau gene that is known to cause dementia, without affecting expression of the normal gene.


They conclude that siRNA "can be engineered to silence disease genes differing by a single nucleotide and highlight a key role for SNPs in extending the utility of siRNA in dominantly inherited disorders."


Dharmacon launched a library of short interfering RNA duplexes targeted against multiple regions of the coronavirus that is believed to cause SARS. The company's SARS siArray Gene Set will enable researchers to study the life cycle and pathogenicity of the virus and to potentially facilitate development of therapeutics and vaccines against SARS. Dharmacon said it used the Toronto SARS sequence to identify 25 regions within the viral genome that carry the genetic information for key viral proteins that will be individually targeted with siRNA duplexes.


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