By Doug Macron
Alnylam Pharmaceuticals last month announced that it had joined the Max Planck Institute to sue the Whitehead Institute for Biomedical Research, the Massachusetts Institute of Technology, and the University of Massachusetts for allegedly misappropriating certain RNAi-related intellectual property.
At the heart of the case are the so-called Tuschl-I and Tuschl-II IP estates. Both generally relate to the use of siRNAs, 21 to 23 nucleotides in length, to target specific mRNA degradation in mammals, although the latter also includes claims related to two-to-three nucleotide-long 3' overhangs.
Alnylam holds exclusive therapeutic rights to Tuschl-II and semi-exclusive rights to Tuschl-I, and the IP represents the keystone of a lucrative portfolio: the company claims to have inked over 30 patent- and patent application-licensing agreements worth about $640 million to date.
As such, there is much at stake in the fight with Whitehead, MIT, and UMass, which are charged in the lawsuit with having misrepresented as their own inventions exclusively owned by Max Planck and licensed to Alnylam. However, the RNAi drugs field has been steadily moving away from the conventional siRNAs covered by Tuschl-I and Tuschl-II toward the use of new, distinct molecules, raising questions about the ultimate value of the IP.
The Tuschl-I IP was invented by Max Planck researcher Tom 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 at the University of Massachusetts Medical School.
According to the complaint filed by Max Planck and Alnylam in the Suffolk County Superior Court in Boston on June 26, Tuschl performed a portion of the work that gave rise to the IP while at Whitehead and a portion at Max Planck, and therefore assigned his interest in the inventions to both institutes.
Sharp and Bartel assigned their interests to Whitehead and MIT, and Zamore transferred his to UMass.
Separately at Max Planck, Tuschl and two other researchers — Sayda Elbashir and Winfried Lendeckel — developed a series of related inventions and technologies that fell under the Tuschl-II IP. All three researchers assigned their interest in this work solely to Max Planck, the suit states.
In 2001, Max Planck, Whitehead, MIT, and UMass signed an agreement essentially making Whitehead responsible for securing patent protection on the inventions covered by Tuschl-I and authorizing MIT to out-license the Tuschl-I and Tuschl-II IP for research purposes, according to the lawsuit.
About two years later, Max Planck, MIT, and Whitehead forged a new deal under which Whitehead would once again take charge of filing patent applications for the Tuschl-I IP, but giving Max Planck the responsibility of granting two non-exclusive licenses to the Tuschl-I and Tuschl-II IP for therapeutic applications. One of those licenses went to Alnylam and the other to German RNAi shop Ribopharma, which Alnylam acquired in 2003 (see RNAi News, 7/7/2003) and later divested to Roche (see RNAi News, 7/20/2007).
Importantly, UMass chose not to enter into this second agreement, instead licensing its ownership interest in the Tuschl-I inventions to Sirna Therapeutics, now a subsidiary of Merck, with the caveat that Sirna would make the IP widely available for sub-licensing (see RNAi News, 9/12/2003).
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UMass' arrangement with Sirna did not preclude a deal the university struck earlier that year giving rights to the Tuschl-I IP in the areas of obesity, type II diabetes, and amyotrophic lateral sclerosis to CytRx. CytRx transferred those rights to spinout RXi Pharmaceuticals (see RNAi News, 1/11/2007).
In their suit, Alnylam and Max Planck allege that the defendants have been "inserting Tuschl-II inventions into the Tuschl-I patent applications … [which] impermissibly broadens the scope of patent protection to embrace the Tuschl-II property that rightfully belongs only to Max Planck.
"If a Tuschl-I patent issues that incorporates the usurped Tuschl-II invention, then UMass' licensees will unfairly gain access to the Tuschl-II property without paying consideration for a license" to the Tuschl-II IP, it adds. "As a result, Alnylam will no longer be able to reap the benefit of its license agreement with Max Planck.
"Hence, Alnylam has a substantial and immediate interest in preventing the defendants' misappropriation of the Tuschl-II inventions as it stands to lose any and all competitive advantage in the marketplace that it otherwise would have if it were the sole company with licensing access to the Tuschl-II inventions for therapeutic purposes," the suit states.
Alnylam and Max Planck claim in their suit that they have "repeatedly informed" Whitehead about the issue and that Whitehead has "failed and affirmatively refused to remove the Tuschl-II inventions from the Tuschl-I patent applications."
As such, Alnylam and Max Planck have asked the court to bar the defendants from "taking any further action in connection with the prosecution of any Tuschl-I patent application.
"An imminent and significant danger exists that [the] defendants will take actions to obtain such a patent, thereafter making it essentially impossible to remove the Tuschl-II inventions from any patent that may issue based upon a Tuschl-I application."
According to Alnylam, only two Tuschl-I patents have been issued, in New Zealand and Australia, although the European Patent Office has indicated that it expects to grant a patent. Tuschl-II patents, meanwhile, have been issued or granted in 33 countries including the US and Japan, the company said.
"It is unfortunate that we needed to take this action, but we are convinced that it is necessary to correct improper and negligent prosecution of the Tuschl-I patent applications," Alnylam CEO John Maraganore said in a statement last month. "We have confidence that the court will recognize the merits of our case, and we will continue to take all appropriate actions needed to ensure the proper prosecution of our intellectual property rights."
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Alnylam and Max Planck said that they will not respond to inquiries regarding the IP dispute since it is now "in active litigation." Representatives from Whitehead and MIT declined to comment.
Jim McNamara, executive director of the office of technology management at the University of Massachusetts Medical School, told RNAi News this week that it is "not clear" what specific aspects of Tuschl-II Alnylam and Max Planck allege have been misappropriated. He declined additional comment.
To date, Alnylam's IP portfolio, anchored by Tuschl-I and Tuschl-II, has been one of the biotechnology field's fattest cash cows. But as the RNAi drugs space matures, companies working with the gene-silencing technology are increasingly finding success with molecules that apparently fall beyond the scope of those patents and applications.
Perhaps the most striking example is RXi Pharmaceuticals, which has access to the Tuschl-I IP in certain indications but had recently shifted its focus onto proprietary, in-house RNAi molecules that the company says are not subject to other groups' IP.
According to RXi, its so-called rxRNAs are of various lengths, including ones less than 15 base pairs long, and can be several times more effective than standard siRNAs. The company has indicated that it expects at least its first drug candidate to be an rxRNA.
Another RNAi shop looking beyond the standard siRNA is Dicerna Pharmaceuticals, a startup that aims to develop dsRNAs about 27 nucleotides long, dubbed Dicer-substrates, as therapeutics. These molecules were developed at the City of Hope and Integrated DNA Technologies, and have been shown to be capable of significant gene knockdown while avoiding interferon responses.
Meanwhile, MDRNA recently handed back its limited access to the Dicer-substrate technology to City of Hope in order to focus its efforts on developing drugs based on its meroduplex and usiRNA technologies. Meroduplexes are siRNAs with a nick or gap in the sense strand; usiRNAs are siRNAs modified with non-nucleotide acyclic monomers known as unlocked nucleobase analogs.