Much at stake in University of Utah's RNA interference lawsuit
More than a decade ago, University of Utah biochemist Brenda Bass made vital discoveries about manipulating RNA, the material that translates genetic code into proteins.
At conferences, during informal gatherings and in published papers, she talked about her insights with other leading RNA researchers, a type of sharing that can be crucial for scientific progress.
But in a landmark federal lawsuit, the U. is alleging scientists led by Thomas Tuschl at Germany's Max Planck Society, a nonprofit for research, exploited Bass' intellectual generosity.
Without crediting her, Planck and three other research institutions obtained a family of lucrative patents on a process for triggering RNA interference, or "silencing" genes in ways that could interrupt disease processes and inspire new medicines, according to court filings.
"It's a new paradigm for drug development," said John Leavitt, a molecular biologist who works as an analyst for the Connecticut research firm Nerac, which has been tracking long-running litigation arising from these patents.
"It makes every gene in a cell a target. With the advent of this technology, every gene is druggable."
The case highlights how federally funded research can lead to tug-of-wars between universities when it leads to bankable inventions. Before Utah's involvement, the institutions that own the patents fought in court for two years.
At issue are two families of patents, referred to as Tuschl I and Tuschl II. The first is jointly owned, based on work by Tuschl and others affiliated with the Whitehead Institute for Biomedical Research, an independent center at the Massachusetts Institute of Technology. One of the researchers moved to University of Massachusetts, which wound up with a stake in the patents.
The second set was obtained by Planck, and both sets were licensed to Alnylam Pharmaceuticals, a drug-discovery company Tuschl and his colleagues founded in 2002.
The U.'s suit targets the Tuschl II patents, arguing the defendants have profited from technological advances on RNA interference, or RNAi, that would not have been possible without help from Bass.
Last month in Boston, U.S. District Judge Patti Saris refused to dismiss the U.'s suit, paving the way for lawyers to depose Bass which could lead toward settlement or a costly trial.
Neither Tuschl, now at Rockefeller University in New York City, nor Bass would comment, citing the litigation. But court filings and transcripts offer a window into their roles in RNAi and the legal battle.
The discoveries • RNAi, which garnered a 2006 Nobel prize for its discoverers, Andrew Fire and Craig Mello, is useful to medicine as a method for preventing cells from making particular proteins.
The Tuschl I and II patents, awarded in 2006, seek to harness RNAi to develop cures for diseases linked to the overproduction of those proteins, including many degenerative disorders. One of the first breakthroughs is expected to come in the treatment of macular degeneration, an age-related deterioration of vision.
RNA, which stands for ribonucleic acid, normally comes in single strands, unlike the double-stranded form that DNA usually takes inside cells.
In the late 1990s, Whitehead researchers, who hold MIT faculty appointments, learned that small lengths of RNA could be cleaved together and then used to disrupt RNA transcription in test tubes, but they weren't sure why. That led to the Tuschl I patents.
Then, at Max Planck in 2000, Tuschl and colleagues discovered that double-stranded RNA triggers interference in mammals without killing cells, and that it can be synthesized.
"This invention is ground-breaking, in large part because it opens the door for using RNAi technology as a human therapeutic agent," Tuschl wrote in a declaration.
Around the same time, Bass conceived the idea that double-stranded RNA, with overhangs at the so-called 3-prime ends of the strands, could trigger interference. She published this insight in an April 2000 review of Tuschl's published work and also described it at two conferences, according to the U.'s suit.
She also discussed it with Tuschl at a conference dinner.
In his declaration, however, Tuschl claims he and his Max Planck colleagues figured out 3-prime overhangs the basis for the Tuschl II patents on their own.
Their method for triggering RNA interference in mammalian cells could produce billions in royalties, observers say.
The patent dispute • The Planck society and other institutions agreed to pool the Tuschl I and II patents and license them to Alnylam in 2006.
But Alnylam sued Whitehead, MIT and UMass where the former Whitehead researcher was then working three years later. The Whitehead Institute had allowed the researcher's interest in the intellectual property rights to be assigned to UMass, which then licensed its stake to a company later acquired by Merck.
UMass and Whitehead argued Alnylam did not have the sole right to control the technology contending that the U.'s Bass, not Tuschl, may be the key inventor.
Lawyers interviewed Bass and sought to take her testimony under oath which the U. officials claim was the first time they realized they might have a claim to the disputed patents.
But before Bass was deposed, the case settled in March 2011, with each of the four institutions getting a piece of the pie. The technology remains under Alynlam's control as the holder of an exclusive license for exploring new therapies.
The U.'s claim • The U. sued Alnylam, MIT, Whitehead, UMass and the Planck society within days of the settlement, demanding that Bass be listed as a co-inventor or sole inventor on the Tuschl II patents and the U. listed as an owner.
Under patent law, those who collaborate on research that results in a technological breakthrough are supposed to share the patent and the financial rewards that flow from it.
The U.'s lawyers say Bass and Tuschl collaborated in that they were working toward the same end of characterizing the molecules that mediate RNA and often consulted one another at various meetings.
Defense lawyers ridiculed the U.'s case, saying its arguments are a "mockery" of the collaboration requirement, wrote attorney Thomas Maffei in a motion to dismiss the case.
"All scientists studying RNAi could be said to be working to this same end," he wrote. Nor should reading another scientist's published research count as collaboration.
Maffei continued: "If Utah's slippery standard for collaboration were the law, it would have a chilling effect on the free exchange of ideas among academic researchers at scientific meetings."
The judge rules • But in a May 30 hearing, Judge Saris countered that ruling against Utah might be the more chilling move.
"It would mean that people would be afraid to have those dinner conversations. That would hurt science because they'd be afraid, if they shared their exciting insights and their lab [experiments], they'd lose all," Saris told Maffei's colleague, attorney David Grindler.
"[Bass] would have clammed right up because she would be afraid that if she shared what happened in her lab, that he could then use it to get the patent and she'd lose out completely."
Grindler replied that Bass would have a simple remedy: File a patent application.
"We wouldn't be here today, your Honor, if Dr. Bass had done what any other inventor does if they want a patent," said Grindler, a partner with the Los Angeles firm Irell & Manella.
Saris, who also presided over Alnylam's earlier lawsuit, was troubled that Utah only decided to pursue a claim long after the defendants had gone to great effort to secure, license and defend the Tuschl patents.
"It's a little hard to then say that she doesn't have to go through the bother of getting a patent; she just says, 'Move on over. It's mine,' " Saris said.
U. lawyers said the university did not realize the Tuschl patents could be based on Bass' discoveries until the original litigants sought to take her deposition in 2009.
Still, the university is not seeking to invalidate the patents, nor does it contend the named inventors acted in bad faith, even though it is seeking triple damages against Planck.
"They may well be acting under poor advice," attorney Mark Carlson told the judge. "They may be naive."
On June 11, Saris refused to dismiss Utah's case. While her ruling could move the case to trial, the judge made it clear she wants the parties to settle the dispute, citing the massive legal costs.
Meanwhile, Alnylam, which went public in 2008, has reaped millions sublicensing the Tuschl patents to other pharmaceutical companies.
Even a sliver of that action could greatly boost the revenue the U. generates off intellectual property licensing fees, which fluctuate between $15 million and $34 million most years. Bass would be entitled to at least 25 percent of the U.'s stream should it win a stake in the Tuschl patents.
From the labs to the community
The Bayh-Dole Act of 1980 encourages universities to patent technologies developed through federally funded research on their campuses. The law's intent is to give schools and their faculty financial incentives to get their inventions into the marketplace, where they can improve life and promote economic development. But as can be seen in recent lawsuits involving the University of Utah, the patenting of these innovations can get messy.
The scientists behind the debate
The two scientists at the center of the University of Utah's lawsuit over patented RNA inference technologies are among the world's top RNA researchers.
Both have been Howard Hughes Medical Institute investigators and specialize in double-stranded RNA (ribonucleic acid).
Brenda Bass •
Brenda Bass joined the U. faculty in 1989 in the School of Medicine's biochemistry department, with an adjunct appointment in human genetics. Her lab investigates the biological functions of RNA and the proteins that bind to it to mediate those functions. In 1993, she co-founded the RNA Society, which is devoted to the sharing of experimental results and emerging concepts in RNA research.
Thomas Tuschl •
Thomas Tuschl, 46, is a German-born biochemist who heads the Laboratory for RNA Molecular Biology at Rockefeller University in New York City. He is a co-founder of Cambridge-based Alynlam Pharmaceuticals, where he remains a shareholder and serves on the scientific advisory board. His work has garnered numerous international honors, such Ernst Jung Prize for Medicine.
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