from John (I’ve been following this story since the beginning of 2010)
The Tuschl II priority application describing the invention of siRNA for therapeutic gene silencing assigned to Max-Planck Institute was filed in the European Patent Office patent application number ‘325 to establish a priority date of the December 1, 2000. This filing date indicates that Thomas Tuschl and his two colleagues, Elbashir and Lendeckel, invented siRNA before that date. The Tuschl I (a second patent family) priority date was March 30, 2000. The Tuschl I interfering RNA invention assigned to Max-Planck, Whitehead Institute, MIT, and UMass described siRNA vaguely in comparison with the Tuschl II invention which described dsRNA molecules of precise size with the required 3’-overhanging nucleotides. Max-Planck agreed to allow one Tuschl II experiment to be placed in the specification of a Tuschl I application. It was because of negligent management of the Tuschl I invention assignment in early 2000 by the Whitehead Institute that Philip Zamore, one of the four Tuschl I inventors, managed to assign his rights to the invention to the University of Massachusetts (UMass) in April 2000. On the record in court, this mistake led Judge Saris to call the Whitehead Technology Licensing office staff “airheads” in dismissing the assignment issue because, at the time of the initiation of the lawsuit by Max-Planck and Alnylam Pharmaceuticals in 2009, the statutes of limitation had expired on this assignment issue.
The size of the siRNA molecule is important for “best mode” practice of the art of therapeutic gene silencing. Large double-stranded RNA molecules will activate innate immune mechanisms such as the induction of Interferon which will diminish therapeutic potential whereas small siRNA molecules by-pass this adverse side effect.
In 2001 Whitehead Institute requested and received approval from Max-Planck to incorporate aspects of the Tuschl II filings into the specifications of the Tuschl I filings, but not as amended claims. Apparently an understanding (outlined in a 2001 document and an Information Disclosure Statement submitted to the USPTO in 2005) was struck that the rights to the Tuschl II invention would be owned exclusively by Max-Planck. In 2005, according to the complaint filed by Max-Planck and Alnylam in federal district court on July 2, 2009, Whitehead began a secret “scheme” to obtain those Tuschl II rights, essentially by incorporating important features of the Tuschl II invention into the claims of the Tuschl I filings. Alnylam Pharmaceuticals which had been founded by the fourTuschl I inventors – Tuschl, Zamore, Sharp, and Bartel – was supposed to have exclusive rights to Tuschl I (and Tuschl II), but UMass licensed its rights to Tuschl I to Sirna Therapeutics, a direct competitor of Alnylam, in 2003. After acquiring this license Sirna Therapeutics purported licensing of Tuschl II because of the Tuschl II features inappropriately placed in Tuschl I applications. An exhibit regarding this Sirna license (from UMass), “List of Patent Rights,” identified the earlier Tuschl II ’325 priority application as the priority document of the Tuschl I patent family. In 2008, Max-Planck and Alnylam Pharmaceuticals accused Whitehead, MIT, and UMass of taking affirmative steps to effectively gain title to the Tuschl II invention and destroy the property interests of Max-Planck Society and Alnylam in those inventions. Thus, in June 2009 Max-Planck and Alnylam sued Whitehead, MIT, and UMass to win back control of both Tuschl I and Tuschl II in licensing for therapeutic uses of siRNA.
Thomas Tuschl had moved from the Whitehead Institute to Max-Planck in 1999 and teamed up with Sayda Elbashir and Winfried Lendeckel. From late 1999 to the fall of 2000, these three inventors determined that the optimal structure of exogenous interfering RNA in mammalian cells was a 21-23 nucleotide dsRNA with one or two nucleotides at each 3’-strand end unpaired (3’-overhangs) which they synthesized de novo. This is the essence of the Tuschl II invention. These three inventors published this discovery on January 15, 2001 (Elbashir et al) that was submitted for publication on October 25, 2000, and in this paper the authors coined the term “siRNA” for “short interfering RNA.” The authors described 21-23 nucleotide synthetic dsRNAs with 3′-overhangs and demonstrated efficient gene silencing in a drosophila cell lysate and later for the first time in human cells four months later in Nature (Elbashir et al) without further processing of the siRNA molecule.
Here are the authors of the Nature paper (about 10,000 reference citations to date) published on May 25, 2001, left to right: Klaus Weber, Jens Harborth, Thomas Tuschl, Winfried Lendeckel, Sayda Elbashir, and Abdulla Yalcin in the lab at Max-Planck in Goettingen.
Merck bought Sirna Therapeutics for $1.2 billion in 2006 purportedly believing (wink, wink) that it had access to the Tuschl II invention. The lawsuit filed in June 2009 was settled in March 2011 with conditions favoring the Plaintiffs, Max-Planck and Alnylam. In return Merck was given several options to pursue siRNA therapeutics. This competitive situation was ultimately resolved when Merck shut down its RNA interference program and Alnylam was allowed to purchase all of Sirna Therapeutics RNA interference IP from Merck in an amicable agreement.
UUtah Sues Max-Planck, Alnylam, Whitehead, MIT, and UMass Claiming Inventorship of siRNA for Therapeutic Gene Silencing
In the week after settlement of the lawsuit described above in March 2011, UUtah sued all the Plaintiffs and defendants of this first case. UUtah alleged that Professor Brenda Bass invented the Tuschl II subject matter before the defendants’ inventors. UUtah alleged that the defendants “misappropriated” her invention stating that the Tuschl II named inventors (Tuschl, Elbashir, and Lendeckel) intentionally claimed Dr. Bass’s invention as their own. The defendants responded that Dr. Tuschl never discussed any joint research endeavors, or even plans for joint research endeavors, at scientific meetings at Cold Spring Harbor Laboratory and in Upsala Sweden which both he and Dr. Bass attended; and in fact, Dr. Bass and Dr. Tuschl never engaged in any such joint research. By contrast, UUtah alleged that Dr. Bass communicated her alleged conception of the Tuschl II invention to Dr. Tuschl in presentations in both meetings.
Dr. Bass had identified a gene “K12H4.8” in C. elegans (a nematode) that was known to produce an enzyme of a type known as “RNase III” colloquially known as “Dicer”. Unlike the Tuschl II inventors, Dr. Bass knew that Dicer cleaved dsRNA into 21-23 nucleotide pieces. As early as 1993, Dr. Bass understood that Dicer cleaved longer strands of dsRNA into short dsRNA causing staggered cuts that leave 3’ overhangs of about two nucleotides in length well before the RNAi phenomenon (gene silencing) was demonstrated. When RNA interference (RNAi) was first reported in 1998, the discoverers (Nobelists Andrew Fire at Stanford and Craig Mellow at UMass) were unable to describe the mechanism by which it functioned in a cell. When she learned of the RNAi discovery, however, Dr. Bass recognized that Dicer was likely to be involved. In 1998, she began developing experiments to test this conception that was ultimately carried out in her laboratory beginning in 1999. These successful experiments, completed in May 2000, reduced to practice Dr. Bass’s conception that Dicer was responsible for catalyzing RNAi; therefore, she concluded that short interfering dsRNA of about 21-23 nucleotides in length with 3’ overhangs were the mediators of RNAi in living organisms, and these short dsRNAs could be used to accomplish RNAi as a treatment for disease. This, later statement was not actually made in Dr. Bass’ insightful April 28, 2000 mini-review in Cell time.
The Tuschl I patents presented an experiment that indicated that the short fragments were less active than larger dsRNA leaving open the discovery of the best mode for siRNA activity. The Tuschl I paper published on March 31, 2000, suggested that one could affect RNAi by using the short dsRNAs but this paper makes no mention of 3’ overhangs or the length of the overhangs. About that time Dr. Tuschl and the other authors admitted in email communications that they did not know how the short 21-23 nucleotide dsRNAs were produced in the drosophila lysate, and that they did not know the structure of the short dsRNA fragments. Upon reading a pre-publication version of this paper in early March (published on March 31, 2000), Dr. Bass recognized that the K12H4.8 gene she had identified had all the properties necessary for RNAi, and that the resulting short dsRNA fragments would have the 3’ overhang. On March 21, 2000, she began drafting her mini-review, titled “Double-Stranded RNA as a Template for Gene Silencing.” Her draft included information about the Dicer enzyme that cleaves dsRNA into short 21-23 nucleotide dsRNAs with 3’ overhangs.
It has never been clear to me that Dr. Bass ever reduced to practice short siRNA-mediated gene silencing although public speculation can be a problem in prior art. She knew very well what the end-product of an RNase III reaction was, but not what the active best-mode structure of siRNA was for achieving therapeutic intracellular RNA interference. In addition, there was the first-time demonstration in the May 2001 Nature paper that synthetic siRNA worked in human cells using Weber’s and Harroth’s elegant (though non-inventive) indirect immunofluorescence assay (Klaus’ contribution of this assay was communicated to me directly with the added note that they repeated the assay over and over again because he was astonished that gene silencing actually worked in living human cells). It seems to me that if Dr. Bass’ description in 2000 was persuasive and enabling, either Dr. Zamore or Dr. Tuschl or someone else who read her paper or heard her talks would have reduced the invention to practice within a month. Klaus Weber mentioned this later in a videotaped interview of him and Thomas Tuschl. In support of this concern there is that pesky patent Figure 12 in the Tuschl I application that indicated that short RNAi duplexes were far less effective in RNAi than the larger duplexes.
Where the UUtah Case Stands Now
This is Moakley Federal Courthouse in Boston where the case is being litigated. If UUtah and Dr. Bass win this case you can imagine that hundreds of millions in royalties might be claimed (royalties previously earned by the four University assignees). Although this UUtah case was initiated in March of 2011, proceedings have been delayed by multiple amended complaints and jurisdiction appeals. On February 4, 2015, the court reconvened to hear arguments for and against release of 18 “banker boxes” containing 20,000 pages of hard-copy documents to the Defense. UUtah believes that these documents are not responsive to the Defense’s requests for evidence and are not relevant to this case. In making their argument the Defense stated “That’s a small amount of documents – and the burden in producing them – is nothing compared to the hundreds of millions of dollars that they’re seeking in this case.” Apparently the Plaintiff lawyers have reviewed each of these documents. These documents include lab notebooks, descriptions of experimental protocols, recording of ideas for experiments, and possibly commentary about the Tuschl inventions mostly written down after the filing dates of the Tuschl patents in 2000 up to March 22, 2011. Early in the first case UUtah learned that the Defense had revealed a theory that Dr. Bass was the actual inventor of siRNA-mediated gene silencing and proposed a deposition of Dr. Bass.
The Defense would like to focus on whether Dr. Bass ever did any experiments with short siRNAs of the type produced by Dicer cleavage or described in the Tuschl II invention. The Tuschl II patents now number 12 issued patents and over 500 claims. The Defense points out that most, if not all, of Dr. Bass’ experimental research on gene silencing was with large dsRNAs of about 500 base pairs in the nematode model. The Defense asks the question “why did she wait for 10 years before she came forward as the purported inventor?”… and she never filed a patent on her concept of the invention – e.g. preparation and use of siRNAs. The Defense wants to know how Dr. Bass was characterizing the discovery of therapeutic siRNA right up to the filing of its lawsuit.
The Plaintiff’s lawyers insist that they have produced all documents relevant to “short double-stranded RNA molecules”. They pointed out that the reason Dr. Bass did most of her research with long double stranded RNA molecules which in theory become Dicer substrates was because her research was conducted in C. elegans which lacked the innate immune response of mammalian cells. The Plaintiffs further pointed to Bass’ 2000 mini-review that described the action of Dicer to produce the active siRNA entities. UUtah’s lawyers assert that the description of siRNA in the mini-review entitles Dr. Bass to become an inventor. The Defense was offered an opportunity to visit UUtah and review the 20,000 pages of documents on December 2nd, but the Defense elected not to take this opportunity asserting that the Plaintiff had already pre-determined that these documents were irrelevant based on their own criteria and therefore would not turn them over.
At the end of this hearing the Defense revealed that Dr. Bass was to be deposed the following Friday (February 7th) . We shall see how this case proceeds.