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Patents, Patents, Patents

|Includes:Benitec Biopharma Ltd (BNIKF)

I have previously referred to Benitec's patent estate as being arguably as impressive as that of ISIS ($ISIS) and Alnylam ($ALNY). ISIS patents are predominantly in antisense technology and Alnylam has leveraged siRNA patents it has licensed from others, while developing patents of its own. Benitec's patents are in DNA Directed RNA Interference (ddRNAi) which expresses shRNA. This is a "platform" patent portfolio which, like Alnylam, it has licensed from another party while developing patents of its own. In the case of ddRNAi, this party is Australia's Commonwealth Scientific and Industrial Research Organisation (CSIRO).

The CSIRO discovered this RNAi pathway in plants at about the same time that Fire and Mello were discovering it in animals. In view of this fundamental patent position I thought that it would be worthwhile representing the CSIRO view of their position on the subject. To do this I have quoted below directly from the CSIRO's website:

"In the 1990s, a small industry-focused research team at CSIRO Plant Industry in Canberra, led by Peter Waterhouse, was investigating how potatoes and cereals could be protected against viruses. One half of the team, which included Michael Graham, Neil Smith, and Geoff Ellacott, were working on potatoes. The other half, Ming-Bo Wang, David Abbott and Limin Wu, were working on barley and rice. During this research, they discovered something spectacular - how to activate one of the most fundamental gene control pathways in plants. The pathway, which is now referred to as RNA interference (RNAi), is guided by double-stranded RNA and works by degrading target single stranded RNAs.

While the CSIRO teams, were making their discovery in plants, a similar breakthrough was being made in the genetic model nematode (Caenorhabditis elegans) by the US researchers Andrew Fire and Craig Mello. Together these discoveries have led to the development of gene silencing technologies that have revolutionised the way in which genes and developmental control in plants and animals are studied, and the generation of numerous biotechnology applications. The CSIRO technologies use 'hairpin' RNA to induce and guide gene silencing and this approach has formed the basis for more than 100 patent applications and the production of gene silencing plasmid vectors that have been adopted by over 3 500 public or private-funded research laboratories around the world."


"These studies revealed that both plants and animals recognise double-stranded RNA or hairpin RNA as foreign, break it up and use the broken-up pieces as a guide to attack any RNA in the cell with the same gene sequence. By artificially introducing double-stranded RNA or hairpin RNA into plants, the two teams were in effect tricking a cell into believing that the messenger RNA of the gene they wanted to silence was foreign and dangerous and therefore needed to be destroyed.

In their paper in Nature, Fire et al. comment that they did not yet know the mechanism of RNA-mediated interference in C. elegans but offered some observations that add to the debate about possible targets and mechanisms.

First, dsRNA segments corresponding to various intron and promoter sequences did not produce detectable interference. Although consistent with interference at a post-transcriptional level, these experiments do not rule out interference at the level of the gene.

Second, they found that injection of dsRNA produced a pronounced decrease or elimination of the endogenous mRNA transcript.

Third, dsRNA-mediated interference showed a surprising ability to cross cellular boundaries. Injection of dsRNA into the body cavity of the head or tail of C.elegans produced a specific and robust interference with gene expression in the progeny brood and dsRNA injected into the body cavity or gonad of young adults also produced gene-specific interference in somatic tissues of the injected animal.

The Canberra group in their paper in PNAS - described by Nobel Laureate, Phillip Sharp as 'The purest demonstration that dsRNA mediates gene silencing in plants', (Sharp PA, Genes Dev, 1999,13: 139-410) - postulated a model for how RNA interference was occurring. The cornerstone of their model was that gene silencing is induced by dsRNA and that this is mediated by an RNA-dependent RNA polymerase, present in the cytoplasm, that requires a dsRNA template. This specificity for a dsRNA template is the key to producing sequence-specific degradation. The dsRNA is formed by hybridisation of complementary transgene mRNAs or complementary regions of the same transcript. The dsRNA-dependent RNA polymerase produces complementary RNA (cRNA) to which degradative RNase molecules are attached. These cRNA-RNase molecules hybridise to the endogene mRNA or viral RNA and cleave the single-stranded RNA adjacent to the hybrid. The cleaved single-stranded RNAs are further degraded by other host RNase enzymes. If the transgene is derived from a viral sequence, this will provide sequence-specific cleavage of viral genomic and subgenomic RNAs, thus preventing viral infection. If the transgene is derived from one of the plants own genes (endogene), this will lead to cleavage and degradation of the endogene mRNA and consequent loss of function."


"The discovery that double-stranded RNA can be used by the plant cell to degrade viral and plant RNAs led to the development of a series of technologies by CSIRO based on hairpin RNA-induced gene silencing. Their hairpin RNA constructs for gene silencing and their construct design principles, including the use of intron spacers and high throughput recombinase cloning, are now widely adopted for gene silencing in plants and animals and form the basis of the AGRIKOLA, European Framework 5 project aimed at silencing every gene in the Arabidopsis genome.

The gene silencing technology is supported by more than 100 patent applications and has been adopted by over 3 500 public or private-funded research laboratories around the world. It has become a powerful tool in investigating gene functions and in improving agronomical traits in plants.

These technologies can be used to stop the expression of any plant or virus gene by destroying their RNA message that directs protein production in a cell. Selective silencing of a specific gene, such as a gene for a particular colour in flowers or a specific fatty acid in oils, can result in altered traits in the plant. Such selective gene silencing, using the CSIRO-developed technologies, has been successfully applied to producing plants that are resistant to viruses and insects, produce healthy foods and therapeutic antibodies, or exhibit highly valuable commercial traits."

The CSIRO team went on to prove that this ddRNAi pathway could be used to silence genes in mammals.

Benitec has the exclusive and irrevocable licence for the application of this hairpin technology in humans.

It should be noted that Dr Michael Graham, referred to above, is now the Chief Scientist for Benitec. He has several patents in this field awarded to him and continues to work on the company's pipeline of treatments.

Benitec's patents can be found at

The CSIRO's full statement can be found at

Disclosure: I am long BNIKF, .

Stocks: BNIKF