By Doug Macron
The inventors of the so-called Tuschl-II patent family allegedly co-opted the RNAi-related discoveries of University of Utah researcher Brenda Bass and incorporated them into the intellectual property without acknowledging her work, according to a lawsuit filed by the institution last week.
The suit names as defendants Alnylam Pharmaceuticals, the Max Planck Institute, the Whitehead Institute for Biomedical Research, the Massachusetts Institute of Technology, and the University of Massachusetts. It seeks to have Bass listed as either the sole or joint inventor on the IP in question. The University of Utah is also asking for royalties on the defendants' use of the IP and other unspecified monetary damages.
The IP at the center of the dispute is a collection of patents and applications named for co-inventor and Alnylam co-founder Thomas Tuschl. They essentially claim siRNAs, 21 to 23 nucleotides in length and with 2- to 3-nucleotide-long 3' overhangs, to target specific mRNA degradation in mammals. A related IP family, known as Tuschl-I, covers the same constructs, but without the overhangs.
Both patent families had been at the center of a lawsuit Alnylam and Max Planck filed against UMass, Whitehead, and MIT in 2009, but that case was settled earlier this month (GSN 3/17/2011). However, in part due to disclosures made during the course of that litigation, the University of Utah has now staked a claim to the Tuschl-II IP.
Bass “conceived the inventions of all the issued claims of Tuschl-II and at least some pending claims of Tuschl-I well before any date asserted by the currently named inventors,” according to the suit. She further “reduced her inventions to practice well before any date asserted” by the inventors of the two IP estates.
Tuschl-I lists as inventors Tuschl, Whitehead's Phillip Zamore and Phillip Sharp, and MIT's David Bartel, all of whom are Alnylam co-founders. Tuschl has since moved on to Rockefeller University, while Sharp now works at MIT and Zamore has a post at the University of Massachusetts Medical School. Tuschl-II's inventors include Tuschl and Max Planck's Sayda Elbashir and Winfried Lendeckel. Elbashir currently works at Alnylam.
According to the suit, Bass was the first to discover the C. elegans gene K12H4.8, which is now known to produce the Dicer enzyme required to cleave long double-stranded RNA into siRNA with 3' overhangs.
“She identified this gene well before the RNA interference phenomenon was demonstrated and discovered it has a dsRNA-binding motif, two RNase III domains, and a helicase domain,” the suit states. She was also the first to discern that the gene plays a role in dsRNA metabolism, findings that were published in 1994.
When Craig Mello and Andy Fire discovered RNAi in 1998, work for which they shared a Nobel Prize, “they were unable to describe the mechanism by which RNAi functioned in a cell,” the lawsuit states. Bass, however, “soon recognized that the K12H4.8 gene she had discovered was likely to be involved in RNAi because of its unique structure, and began to consider its features” through experiments begun in 1999.
In 2000, the university states, she was asked to write a review on an article submitted by Tuschl, Zamore, and others. The paper described the discovery that a Drosophila lysate being used to study RNAi “unexpectedly cleaved the long 500-base-pair dsRNA they were using to effect RNAi into short dsRNA of about 21 [to] 23 nucleotides,” the suit says.
The paper, which appeared in Cell, also “indicated that one could effect RNAi by using the short dsRNA … although details of these experiments were not included,” the lawsuit notes.
Bass “immediately recognized that the protein produced by the K12H4.8 gene had all of the properties necessary for RNAi, and that the resultant short dsRNA fragments would have a 3' overhang,” it states. In her review, she proposed her hypothesis that Dicer's RNase III domains were responsible for cleaving dsRNA into siRNAs with 3' overhangs, identifying the genes that encode Dicer in various organisms, and suggested that introducing siRNAs into cells would silence genes.
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The university alleges in its lawsuit that the Tuschl-I inventors were unaware of how the siRNAs were produced in the Drosophila lysate, nor did they fully understand their structure, citing an e-mail between Tuschl and Zamore written in April 2000.
That same month, at a conference attended by about 40 scientists, including Zamore, Bass presented her conception of Dicer's role in RNAi and the 3' overhangs of siRNAs, the suit alleges. Later that year, at a meeting attended by Tuschl and Elbashir, she presented new findings from her lab establishing that “RNAi factors such as Dicer could be targeted by dsRNA,” further supporting the notion that Dicer is essential for RNAi.
Two months later, “Tuschl's lab submitted a paper … in which Elbashir stated that the most effective siRNAs are those that have 3' overhangs,” the suit states. The paper, which appeared in early 2001 and essentially presents the claims of Tuschl-II, cited Bass' Cell review and work on RNase III.
Since that time, a number of patent applications from Tuschl-I and -II have been submitted, both in the US and abroad, claiming the 3' overhang conception. None includes Bass as an inventor, the University of Utah's suit states.
It also notes that the 3' overhang invention was key to Alnylam and Max Planck's recently settled litigation, and that Alnylam CEO John Maraganore stated during that case that the overhang is the “key, if not the only, patentable invention in … Tuschl-II … and the core technology required by Alnylam ... to consolidate and control RNAi therapeutics.”
Essentially, “the parties in the … litigation were fighting over who has rights to … Bass' invention,” the university charges.
Alnylam said it disagrees with the claims in the suit and will defend itself. The other defendants have made no statements.
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