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Isis Develops Gene Inhibitor, Plans to Use Patent to Make Pharmas Pay

NEW YORK, Oct 20 - Isis Pharmaceuticals has a new tool that it says could greatly enhance genomics-based drug target validation. And big pharma may be forced to buy it.

This tool, an antisense inhibitor, is a synthetic single strand of DNA that blocks a target gene. It works by binding to the transcribed RNA nucleotides, preventing them from encoding proteins.

Like knockout mouse technology, the gene inhibitor helps researchers to understand the gene's function and whether or not the gene is likely to be a successful drug target.

Isis has patented a key feature of the antisense technology, the RNAse H1 enzyme, which degrades the RNA so the antisense inhibitor can bond to it. The Carlsbad, Calif.-based company asserts that most pharmaceutical companies already employ this technology in their drug discovery research.

Isis has begun sending out letters to pharma companies informing them they need a license from Isis to use antisense inhibitors and offering licensing agreements. Currently, Isis says it has partnerships with four companies, Abbott, AstraZeneca, Aventis, and Johnson and Johnson, worth an estimated combined total value of $20 million.

" We believe the next three years will yield very substantial licensing revenue," Stanley Crooke, CEO of Isis told GenomeWeb.  While Isis hopes to gain this revenue through friendly agreements, it is willing to go to war to enforce its patent position. " A lawsuit is just a way of negotiating a license," Crooke said.

Brigid Quinn, spokeswoman for the US Patent and Trademark Office, said that the enforceability of Isis' patent would have to be decided on a case-by-case basis and companies that believe the antisense inhibitor invention is not unique could also ask the office to reexamine the patent.

Meanwhile, Isis has developed inhibitors for 700 different genes and plans to greatly expand this number. " In the next few years, we are going to make an antisense inhibitor to every gene, said Crooke. " We are planning to do 2000 genes per year."

Isis plans to use the antisense inhibitors in its own drug discovery efforts and license them to pharma companies, eventually in the form of a database.

Lexicon Genetics, Crooke said, is Isis' only viable competitor in the gene inhibitor market. Exilisis' model genetics programs with lower life forms are less applicable to humans, and experimental inhibitory proteins developed by Sangamo Biosciences cause some of the same problems as gene therapy when introduce into cells, he said.

But Crooke contended antisense would even wipe out the knockout mouse technology in the next few years. While it is impossible to disable certain genes in mice and still actually produce a living organism, antisense inhibitors, he said, can he be added-either singly or in combinations-to block just about any gene in an existing organism.

Randall B. Riggs, Senior Vice President of Business Development at Lexicon Genetics, disputed this criticism. When a mouse cannot be made due to a knockout, " it's very valid as validation of a target," said Riggs. A knockout mouse that died in utero because it lacked red blood cells has led to the development of Epogen, a dialysis anemia drug now worth four billion in annual sales, he noted.

Antisense inhibitors offer the added advantage of speed, Crooke said. If a company requests an antisense inhibitor, Isis says it can develop it and have it ready to go into animals in as little as a week.

Riggs said that a knockout mouse could take up to a year to develop for a particular gene, although information about the results of hundreds of knockout mouse experiments is already immediately available in Lexicon's OmniBank database.

" I'm sure [Isis'] technology has merits, but you'd want to look at how sublicensees they have and how many deals they have," Riggs said. " These guys in pharma are pretty smart, and we have many, many large pharmaceutical companies using our technology."

 " We have work to do to turn this into a real business," Crooke admitted, but he is confident his growing trove of genes and gene inhibitors will put Isis on the functional genomics map.

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