RNAi Therapeutics Readying for Tuschl Tussle

Investors have been rightfully wondering what it is exactly that has been stalling large RNAi Therapeutics platform deals? Is it because of the macroeconomic uncertainties, looming healthcare reform in the US, Big Pharma deals that first need to be digested, or is it simply that the air has come out of RNAi Therapeutics and Big Pharma/Biotech (BPP), after a first wave of enthusiasm, have become more cautious about their investments in the space? I agree that all of this may play a role for why for example Alnylam was unable to meet their 2009 guidance for at least two more significant deals. Nevertheless, investments in RNAi Therapeutics have always have to do with the long-term vision that while risky, RNAi could be a transformative technology for drug development and it would be even riskier not to participate in it. BPP does not want to repeat the mistake it has made 2-3 decades ago when it left recombinant proteins and monoclonal antibodies largely to what were then small biotech companies.

Enter the Tuschl patents that are at the center of a trial set for next month between the Max Planck (along with Alnylam) and the Whitehead Institute, and that could prove transformative for RNAi trigger IP and future deal flow.

To my mind, and more importantly that of the scientific community at large, it was the work by Thomas Tuschl, then working with co-discoverers Sayda Elbashir and Winfried Lendeckel at the Max Planck Institutes in Germany, that was critical for the adoption of RNAi for gene silencing in human cells. In this work (one of the most cited scientific articles of the last decade), he found that short synthetic 19-24bp dsRNA, preferably with 3’ overhangs, efficiently induced RNAi knockdown in mammalian cells. These oligonucleotides form the basis of the Tuschl II patent series, solely owned by Max Planck and exclusively licensed to Alnylam for therapeutic use, that the Whitehead and UMass now want to cannibalize for their own benefit and that I consider together with ‘Fire-Mello’ (almost anybody can get access to these) as the most fundamental RNAi trigger IP.

Of course, the discovery of siRNAs was not made out of thin air. Work in fly cell extracts on the processing of large silencing dsRNAs of the type described by Fire and Mello in worms, showed that small RNAs of 21-23 nucleotides were generated during RNAi and that these appeared to guide target mRNA destruction (Genes and Development and Cell). These at the time of the filing thought to be single-stranded RNAs form the basis for the Tuschl I patent series (co-inventors Thomas Tuschl, Phil Zamore, Davide Bartel and Phil Sharp; jointly owned by Max Planck, the Whitehead, UMass, and MIT). The double-stranded nature and 3’ overhang of these, however, was not immediately apparent, and was the ingenious insight by the inventors of Tuschl II.

Here is the original main claim from the US Tuschl I application:

“1. Isolated RNA of from about 21 to about 23 nucleotides that mediates RNA interference of an mRNA to which it corresponds.”

Clearly, and consistent with the literature, no evidence for a dsRNA trigger. And somewhere down the line, you can find a much narrower claim encompassing 21-23nucleotide RNAs isolated following a what essentially is a fly extract treatment step- certainly not very strong and RNAi Therapeutic-relevant claim language to say the least:

“9. A method of producing RNA of from about 21 to about 23 nucleotides in length comprising:

(a) combining double-stranded RNA with a soluble extract that mediates RNA interference, thereby producing a combination; and

(b) maintaining the combination of a) under conditions in which the double-stranded RNA is processed to RNA of from about 21 to about 23 nucleotides in length.”

Billions of US dollars have changed hands based on the interpretation of the scope of the Tuschl patent series. Sirna Therapeutics, which along with Alnylam and RXi Pharmaceuticals has access to Tuschl I, long maintained that Tuschl I encompassed the use of RNAi in humans since human RNAi data was contained as one example in the Tuschl I patent application, rendering Tuschl II-type siRNAs implicit in the ’21 to about 23 nucleotides’ RNA. According to this interpretation, Tuschl I would have enormous scope and in fact supersede Tuschl II. Merck bought this argument along with Sirna Therapeutics in 2006 for $1.1B!

You would think that before spending that type of money, Merck did their homework on Sirna’s fundamental IP position. If they did, then they were probably not too concerned about the fact that the short synthetic siRNA interpretation of Tuschl I critically rests on an inventive example in the patent application provided by scientists that are not on the Tuschl I patent. Even a person untrained in IP as myself will know that including inventive work by people not named as inventors is enough to invalidate a patent. It is this that I also believe is the hard fact to what it may boild down to in the end in the middle of all the hearsay of the case. I expect that the inventors of Tuschl I themselves would strongly and unanimously support Max Planck. Remember they are scientists and have no reason to risk their reputations by reaping the financial gains from inventions made by fellow scientists.

The manner in which the human siRNA example appeared in the Tuschl I application is equally startling and had long puzzled me. Tuschl I essentially talks extensively about the fly extract experiments, and then suddenly at the very end the human RNAi data are presented. Note also that the fly work and the Tuschl siRNA work were published in two separate papers by distinct research groups, and that the RNAi field is very much aware of the inventive step by Tuschl and co-workers that paved the way for RNAi in humans.

It is therefore not surprising that as a result Tuschl I has run into a host of problems during its prosecution in both Europe and the US and (after Merck-Sirna and Alnylam-Roche) has gradually been whittled down to an extent that it could almost be considered irrelevant for RNAi Therapeutics. Illustrating this point is the fact that the main claim of Tuschl I as recently issued in Europe essentially corresponds to claim 9 cited above (‘small- RNA-derived-from-fly-extract claim’). No wonder that RXi Pharmaceuticals and Merck, both Tuschl I made no mention of it, while ironically Alnylam which does not have an exclusive Tuschl I license, chose to announce it. I found quite curious given that a broader Tuschl I interpretation, if granted, should have started celebrations in Worcester and San Francisco Mission Bay and freed largely them from the pressures imposed by Alnylam IP. However, not a word.

Meanwhile back in the US where Tuschl I had also fought a battle of retreat, the patent office has additionally raised concerns about the overlapping nature of Tuschl I and Tuschl II, essentially based on the inclusion of the human RNAi data in Tuschl I. Since Tuschl I predates Tuschl II, the decision to adopt such a broad claim language would render Tuschl II invalid, something that would also be a huge blow to Alnylam.

Instead of dropping the human RNAi data and make life much easier for everybody, the Whitehead, which is prosecuting Tuschl I on their own behalf and that of UMass, MIT, and (!) Max Planck, started to vigorously embraced the data and in fact make them the main data on which the ‘amended’ main claim rest now almost entirely (see below). This also revives hopes at RXi and Merck/Sirna that Tuschl I is actually worth something. In fact, if adopted in this way, it would be THE gate-keeping patent for human RNAi Therapeutics. Here are the proposed amendments (in bold) to the main claim of Tuschl I proposed by the Whitehead:

"1.-16. (Canceled)

17. (Currently amended) A method of mediating RNA interference of mRNA of a gene in a cell organism comprising:

introducing double-stranded RNA interference of mRNA of a gene in a cell or organism comprising:

(a) Introducing double-stranded RNA of from about 21 nucleotides to about 23 nucleotides in length, wherein the double-stranded RNAs is in the form of two separate strands which are not covalently linked and has sequence correspondence to the mRNA which targets the mRNA of the gene for degradation into the cell or organism; and wherein the double-stranded RNA mediates RNA interference by directing cleavage of the mRNA to which it corresponds, wherein cleavage is directed within the region of sequence correspondence with the double-stranded RNA;

(b) Maintaining the cell or organism produced in (a) under conditions under which degradation of the mRNA occurs, thereby mediating RNA interference of the mRNA of the gene in the cell or organism."

The trial next month essentially centers on whether Whitehead, which is prosecuting Tuschl I, has acted in good faith when it included the mammalian RNAi data in Tuschl I, which really belong to Tuschl II, and by doing so has violated its fiduciary duty viz a viz Max Planck and if Tuschl I was then issued in such a broad form would irreparably harm the interests of both Max Planck and Alnylam as it would essentially kill Tuschl II. The outcome should determine who will be in charge of prosecuting the Tuschl I series and whether the human RNAi data can be included or not.

In my next post, I will detail my predictions on the outcome of the trial and lay out how the new RNAi trigger IP landscape will look like after the dust has settled. This, of course, has profound implications on the business development dynamics of RNAi Therapeutics. It will be important.

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Disclaimer: The above are my own interpretations of the case, based on publicly available documents from the USPTO and court sites, interviews, and press releases. Accuracy cannot be guaranteed as I may have overlooked critical elements of the case, and am neither trained in intellectual property nor contract law.