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Legal Interference in RNAi

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By Meredith W. Salisbury

 

Much ink has been spilled in the past year about patent legislation based on RNA interference. You name the organization —Dharmacon, Ambion, Benitec, Nucleonics, MIT, not to mention several more — and good odds you can find a lawsuit to match. But is there any interest in all this for scientists who don’t practice IP law in their spare time?

You bet. With these knockdown, drag-out legal battles going on all around, there’s a good chance at least one of these infringement cases bears on a method or reagent you use in your own RNAi research. There are some 2,000 RNAi-related patent applications awaiting verdicts at the US Patent and Trademark Office alone, says Sara Cunningham, CEO of Benitec. (Which begs the question: what aren’t these people trying to patent?) And Bharat Chowrira, chief patent counsel for Sirna Therapeutics, points out that of the issued patents, most are being opposed or even reexamined — meaning a patent office agrees to reconsider the patent’s merits, a temporary process during which that patent can’t be enforced by the company holding it. With that much IP angst, the RNAi landscape looks like a field of landmines.

And the fun is only just beginning. The bulk of the RNAi patents are just starting to issue from patent offices around the world, says Robert Towarnicki, president and CEO of Nucleonics. As that progresses, “in all likelihood we’ll see more litigation,” he says. “There’s a tremendous grab around this technology because of all the excitement around it.”

What does it mean to me?

The problem for scientists, be they in academia or at private-sector companies, is that no one’s quite sure how this lawsuit-happy field translates to basic research. Because so much of the RNA interference process — from reagents to simply how the technique is performed — is claimed in these patents and patent applications, it’s hard to tell what could be considered infringement. Cunningham says that Benitec’s issued patents protect both in vitro and in vivo use of expressed RNAi, but that currently there’s no US patent covering the use of synthetic, double-stranded RNA in vivo. “That’s where all US companies are working right now,” she adds. Because of the Madey v. Duke decision that essentially stripped academia of its long-accepted research exemption from patent infringement, a company such as Benitec could in theory sue academic scientists who are using expressed RNA to accomplish interference. But, as Cunningham points out, most companies would never sue a university researcher for patent infringement except in really egregious cases. Still, scientists should be vigilant, especially as their research gets closer to the commercial world, she cautions: “They need to be careful when they start signing MTAs.”

Towarnicki says that in many technology areas, scientists who buy reagents are paying for an IP license as part of the price of the product. The trouble with RNAi is that it’s common for scientists to make their own reagents, and in doing so “practice RNA interference that would potentially infringe patents that have issued already,” he says. But he adds, “a researcher doing basic research, making no money on it, getting no income from it — there is no damage to speak of,” and therefore no chance of a lawsuit. Of course, that researcher is a rarity — companies could argue that getting a grant based on patent-infringing RNAi research is the same as making money from it, and then the researcher is open to being sued.

Scientists at pharmaceutical companies may have an easier time of it, thanks to the Integra v. Merck decision that came out this year, which afforded what’s called safe harbor — a protection similar to the old academic research exemption, but granted to companies trying to get a drug to the FDA — to a much broader range of discovery and development than was previously practiced. “Any research that is performed that generates data reasonably related to filing an IND is exempt from infringement,” explains Chowrira.

But experts agree that these early indicators do not presage a generation of scientists forced to look over their shoulders every time they silence a gene. The frenzy of lawsuits is typical of a nascent field and will likely dwindle as the technology matures. “I think there’s going to be a lot of patents issuing in the next six months to a year that’s going to clarify the landscape quite a bit,” Chowrira says. “People are going to start paying attention to cross-licensing … or things that make business sense rather than trying to litigate.”

In the meantime, there seems to be consensus that scientists should proceed at will, keeping at least marginally aware of the RNAi patent arena. “There’s going to be battles for the next five, seven, 10 years,” Towarnicki says. “I think researchers ought to be doing research.”

 

Patents at Issue

With a couple of thousand RNAi-related patents awaiting decisions from the USPTO alone, the ones that issue will be considered highly important by the field as a whole. The US in particular has been quite slow about returning verdicts on patent filings; Sara Cunningham at Benitec says she’s still getting requests for information on a patent that was filed four years ago, when the usual patent is processed from start to finish in two to three years, she says. Patent offices that have been faster haven’t necessarily helped the situation. “Australia is notorious for issuing multiple patents with overlapping claims,” Cunningham says, and indeed almost all of the patents issued so far in that country are being opposed or reexamined.

 

Here are just a few patents that have been released:

• Known as the Fire-Mello patent, this was the first US patent issued in the field of RNA interference. US Patent 6,506,559, titled “Genetic inhibition by double-stranded RNA,” covers the process of introducing RNA into a cell to inhibit gene expression. It is owned by the Carnegie Institute of Washington and has been licensed nonexclusively to dozens of organizations. It was issued in January 2003.

• The Benitec patent: This is the other main RNAi patent issued by the US patent office. US Patent 6,573,099 came out in June 2003 and covers “genetic constructs for delaying or repressing the expression of a target gene.” Michael Graham is listed as the inventor.

• The Kreutzer-Limmer patents. These two patents, issued by the European patent office in 2002 and 2005, cover the use of double-stranded RNAs as therapeutics. The siRNAs protected by these patents are 25 or fewer nucleotides long. These patents (EP 1144623 and 1352061) are both owned by Alnylam.

 

Meet the litigants

The first thing Robert Towarnicki of Nucleonics told Genome Technology was, “We have been embroiled in a litigation for about 19 months.” That sentiment of frustration is common to most of the companies that have trudged to court to defend their patents or their turf. Here’s a brief sampling of some of the lawsuits that have taken place in the RNAi field.

 

• At press time, a court allowed Benitec’s motion to dismiss its patent infringement case against Nucleonics. That suit began in April 2004 when Benitec sued Ambion, Nucleonics, and GenScript, charging that those companies were infringing its US-issued patent. GenScript and Ambion licensed the technology to get out of the suit.

 

• Also in 2004, Benitec sued Promega for allegedly failing to make proper royalty payments on a deal through which Promega was handling the sublicensing duties for Benitec’s expressed RNAi technology. Promega and Benitec settled the suit this summer.

 

• In January of this year, MIT sued Dharmacon, claiming that the biotech wasn’t meeting royalty requirements in a licensing deal for siRNA-related IP. In July, a court sent the suit to mediation.

 

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