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RNAi Roundup: Benitec Gets First US Patent for ddRNAi, Plans to Enter US Market; CombiMatrix Launches siRNA Antiviral Program

NEW YORK, June 6 - A significant - if often ignored - pair of patents has issued in the field of RNA interference this week.


Benitec, of Queensland,Australia, has been awarded US Patent 6,573,099, "Genetic constructs for delaying or repressing the expression of a target gene, and correspondingUKpatent, 2253282, "Genetic constructs for delaying or repressing the expression of a target gene."


These patents cover Benitec's DNA-based technology, ddRNAi, for triggering RNA interference in human and other cells, and are similar to ones already issued in Australia,Singapore, andSouth Africa.


The USpatent, issued June 3, "is the first patent ever which has been awarded [to include] a claim for triggering RNA interference in human cells," said John McKinley, chairman and CEO of Benitec. (TheUKpatent issued the following day.)

The company's ability to show that ddRNAi can work in human cells "distinguishes us from the siRNA companies," according to McKinley, "because they have never been able to show that [RNA interference] can work in mammalian cells."

In fact, Tom Tuschl, Phillip Zamore, Phil Sharp, and David Bartel, claim in a recent US patent application that their double stranded RNA, processed to 21-23 nucleotide segments, act as sequence-specific mediators of RNA degradation in mammalian cells. However, in the patent application (20020086356, published last July 4) they demonstrate this technique in a Drosophila in vitro system, not a mammalian system.


But Tuschl and colleagues demonstrated in a 2001 Nature paper that 21-nucleotide siRNA duplexes suppress gene expression in mammalian cells, including human embryonic kidney and HeLa cells (Nature 2001 May 24;411(6836):494-8.) The next year, McCaffrey et al. showed that siRNAs could be transfected into adult mouse livers and could suppress gene expression of a co-injected luciferase expression plasmid (Nature 2002 Jul 4;418(6893):38-9.


Still, the only other US patent granted in the RNA interference arena is the Adyy Fire and Craig Mello patent, issued in January, which demonstrates how basic dsRNA (not siRNA) can silence genes. The claims in this patent (No. 6,506,559)apply to RNA interference in both animals and plants, but Fire and Mello were only able to demonstrate RNAi-induced gene silencing in nematodes, not human cells.


While many in the life sciences community were well aware of the Fire and Mello patent applications long before the patent was granted, McKinley said this was not the case for Benitec's application, since it was not published for a long time. "It has suddenly come to the surface," he noted. "We have obviously take the world somewhat by storm."


Louis Myers, a patent lawyer at Fish & Richardsion who represents Tuschl's siRNA therapeutics company LNylam, said he thought the Benitec patent was limited in its impact on the RNAi industry because of its narrow language. "You have to have two copies of the gene, and it has to have a particular relationship to the promoter," he explained. Because of this, the patent does not include, "by a long shot, industry-dominating claims," he said.


But even Myers (who admits he's not objective due to his interests in LNylam), said the issuance of the patents was "a positive sign" for the RNA interference industry. "It's a recognition of the patent office that this science is very real."


Indeed, now that its foundational patents have issued in key markets, Benitec is planning to get real with its business plans for ddRNAi and related technologies, according to McKinley. 


McKinley sees the key advantage of Benitec's technology in its claimed ability to silence genes permanently or transiently, whereas siRNA can only silence genes transiently, he claims.


The company is planning to license out the technology on a non-exclusive basis in a number of different areas, including research on target validation, but will retain the rights to the development of human therapeutics using ddRNAi for the time being. Benitec will then either explore therapeutic applications of this technology, along with numerous viral vectors it has already developed, in house, or in collaboration with a strategic partner "who can take it forward," McKinley said.


In the next six months, Benitec is planning to open a US office, although executives have not yet decided where. The company also has filings 12 jurisdictions for patents similar to the issued ones, and has filed applications for high-througphut and in vitro mechanisms of technology.



Another development in the siRNA therapeutic arena this week was Combimatrix's announcement that had launched a drug discovery program in which it is using its semiconductor microarrays to rapidly synthesize pools of siRNAs for various viral pathogens.


The company is planning to synthesize siRNA compounds that target HIV, West Nile Virus, HPV, Kaposi's sarcoma, smallpox, influenza A and B, Hepatitis C, and Leishmania RNA virus. It will then use its bioinformatics platform to test the initial efficacy of its siRNAs for silencing genes in these viral diseases.


"Our initial focus is on virus, since their genomes are small and there are few good antivirals on the market, said CombiMatrix CEO Amit Kumar in a statement.   The small viral genomes enable us to target all of the genes of the virus at once, thus making it more likely that effective inhibition of the virus is achieved, even if the virus rapidly mutates."


This initiative follows on CombiMatrix's use of its microarrays in SARS work. The company used its semiconductor arrays, which consist of a three-dimensional layer of porous material in which DNA, RNA, peptides, or other small molecules can be synthesizedor immobilized within discrete test sites, to synthesize siRNAs against the SARS coronavirus.   The company's proprietary software directed sequence synthesis one base at a time, using individually controlled electrodes on the surface of the semiconductor. After synthesis, the company sent the siRNAs off to the US Army lab SAMRID for testing against SARS.


CombiMatrix, of Squolamie, Wash., is a subsidiary of Acacia Research.

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