The legal wrangling over Tuschl patents involves several parties including Alnylam, UMass, Sanofi, Silence Therapeutics, BASF, Max Planck, and the University of Utah. [© frank peters - Fotolia.com]
After the European Patent Office (EPO) ruled on the first of several Tuschl families of patents governing RNAi last month, both sides responded with dueling press releases, each claiming vindication.
Alnylam Pharmaceuticals and the University of Massachusetts (UMass) Medical School trumpeted EPO’s decision as a victory as much for advancement of RNAi drugs toward the market as against co-defendants Sanofi, Silence Therapeutics, and BASF. Laurence Reid, Ph.D., Alnylam’s svp and chief business officer, said that his company has formed over 30 license agreements using the first Tuschl patent family, or the Tuschl I ’726 patent.
But not therapeutics for human use, Silence declared eight days later on March 9, in an unusual public rebuttal. Silence noted that during the hearing, EPO amended the claims in question to exclude human-drug use and limit the claims to double-stranded RNAs between 21 and 23 nucleotides. EPO’s decision, Silence added, would not hinder its plan to develop its lead drug candidate, Atu027, a liposomal RNA therapeutic for systemic cancer indications.
“The patent under review does not impact on the freedom to operate of Silence and does not negatively affect Silence (or its Atu027 product or any of the company’s candidates) in any way,” the company stated. Silence is conducting a Phase I study with Atu027 involving single as well as repeated intravenous administration to patients with advanced solid tumors. The study is expected to be completed in the first half of 2012.
EPO decision notwithstanding, the legal wrangling over the Tuschl patents continues, given a year-old case in the U.S. Behind the legal squabbling is a battle among companies seeking dominance in RNAi-based therapeutics.
Tuschl I Decision in Europe
Tuschl I was vulnerable to IP challenges, according to an RNAi analyst/consultant. Tuschl I was based on research conducted mainly in Drosophila fly lysates and tissue culture cells, Dirk Haussecker, D.Phil., explained to GEN.
“The issue in Tuschl I was that some of the language was ambiguous enough that Alnylam could have used it to sue companies for infringement because they thought it was applied to therapeutics. That’s why companies like Silence and Sanofi and BASF opposed it,” said Dr. Haussecker, an assistant professor at Dongguk University in Seoul.
Dr. Haussecker cited claim 10 of the European T-I patent EP 1309726, “A method of producing knockdown cells, comprising introducing into cells in which a gene is to be knocked down isolated double-stranded RNA from 21 to 23 nucleotides in length and corresponding to a sequence of the gene, that targets the mRNA corresponding to the gene and maintaining the resulting cells under conditions under which RNAi occurs, resulting in degradation of the mRNA of the gene, thereby producing knockdown cells.”
The EPO amended that patent by:
- adding a new clause to claim 5, so that it relates to mediating RNAi and examining gene function “further comprising isolating the double-stranded RNA from 21 to 23 nucleotides in length from the combination of producing knockdown cells and of identifying 21-23 nt RNAs that mediate RNA interference.”
- adding “an in vitro” to claim 15 so it reads: “The present invention also relates to an in vitro method of validating whether a gene product is a target for drug discovery or development.”
“Now it’s quite safe that it probably has no real relevance to therapeutic development, though some claims are still usable for broader RNAi discovery services,” added Dr. Haussecker.
Settling Ownership of Tuschl Families
The RNAi field has become enmeshed in seemingly endless lawsuits. Several have revolved around the Tuschl patent families named after Alnylam founder Thomas Tuschl, Ph.D., and based on discoveries by him and partners while he was at the Max Planck Institute for Biophysical Chemistry.
Tuschl I includes 11 patents and patent applications in the U.S. and seven other nations and the European Patent Convention (EPC) for discoveries at Max Planck, Whitehead Institute for Biomedical Research, Massachusetts Institute of Technology (MIT), and UMass. Those institutions co-own Tuschl I, and Alnylam shares therapeutic rights with Sirna and, to a limited degree, RXi Pharmaceuticals, a company founded by Mello.
Tuschl II is owned by the Tuschl-I co-owners, which have licensed exclusive therapeutic rights to Alnylam. The family includes 23 patents and patent applications in the U.S., 18 other nations, and EPC. Tuschl III pertains to the discovery of more than 120 novel mammalian miRNAs through research performed by Dr. Tuschl while at Max Planck. The society owns Tuschl III, which is co-exclusively licensed by Alnylam and Isis Pharmaceuticals, though Regulus Therapeutics has access to Tuschl III for miRNA therapeutics through license agreements with Max Planck, Alnylam, and Isis.
It took litigation to settle ownership issues and use of Tuschl I and II. In 2009, Alnylam and Max Planck sued MIT, UMass, and Whitehead, alleging that the three misappropriated the use of 3’ overhangs and other siRNA-related inventions from Tuschl II for inclusion in patent applications based on Tuschl I.
In their lawsuit Alnylam and Max Planck contended that if Tuschl II inventions were incorporated into Tuschl I patent applications, Sirna, RXi, and other companies that may sublicense the IP in the future “will unfairly gain access to the Tuschl II property without paying consideration for a license.”
After two years, the first lawsuit was resolved last year, shortly before trial, through a settlement between Alnylam, Max Planck Society, Whitehead Institute, and UMass. MIT, which dropped out of the case, also agreed to terms. The parties agreed that Max Planck should oversee future prosecution of Tuschl I and Tuschl II in the U.S., and continue to lead the prosecution of Tuschl II outside the U.S. UMass received the right to license Tuschl II to Merck subject to permission from Alnylam, which would receive part of the licensing fees, and to prosecute Tuschl I outside the U.S.
Ongoing Case in Utah
Just a week later, another ownership lawsuit arose. The co-owners of Tuschl I and II along with Alnylam were sued by the University of Utah, which alleged that Brenda L. Bass, Ph.D., was wrongfully omitted as the inventor of the 3’ overhang feature of the RNA gene silencing mediators in the Drosophila lysate experiments leading to Tuschl II.
According to Dr. Hassecker, the university’s claim would be hard to pursue, since while Dr. Bass speculated that 3’ overhangs might be involved in the pathway, the Tuschl II inventors demonstrated the utility of the overhangs. As the Tuschl II co-owners noted in a court filing last month, Dr. Bass also speculated that the single-stranded overhang regions would be unstable due to the presence of enzymes known to destroy single-stranded RNA fragments. Additionally, she suggested that the one or two nucleotide-long single-stranded overhangs would be trimmed, leaving blunt-ended dsRNAs of between 21 and 22 nucleotides in length as the actual RNA molecules responsible for RNAi.
“Contrary to Dr. Bass’ speculation, the Tuschl II inventors discovered in subsequent research that dsRNA molecules having 3’ overhangs are especially efficacious mediators of RNAi and conceived the invention of synthesizing dsRNA molecules 19–25 nucleotides long, having 3’ overhangs of one to five nucleotides in length to mediate RNAi in mammalian cells,” the Tuschl II co-owners argued. “As a result, all claims of the Tuschl II patents require “synthesizing” and “combining” strands of RNA to form a dsRNA molecule having at least one 3’ overhang region of one to five nucleotides in length.”
The Utah case also got tangled in another legal argument beyond patent law earlier this year when the university dropped UMass as a co-defendant substituting them with its four top officials. The University of Utah decision came after UMass cited U.S.C. § 1251(a) , which exclusively assigns jurisdiction to the Supreme Court for controversies between two or more states. University of Utah pointed to Ex Parte Young, a 1908 federal case that recognizes suits against state officials seeking prospective action against continuing violations of federal law.
The Tuschl II co-owners countered that UMass, not its officials, was the “substantial party in interest,” that the relief Utah sought was not prospective since it involved a past wrong, and because the Supreme Court resolution remained an alternate enforcement mechanism.
On March 21, the University of Utah submitted a formal rebuttal to a motion to dismiss the case by co-defendants, who have yet to submit formal answers to the complaint. That suggests a long stay in federal court for this case and a long wait before Tuschl patent litigation finally clears the courts.