Follow the Court Proceedings of the Tuschl Tussle

The ‘RNAi Litigation Blog’ is a service by John Leavitt and his colleagues Doug Naab and Scott Lloyd from the technology Research and Advisory firm Nerac that provides a great deal of background information on the Tuschl case and real-time summaries and insights of the court proceedings. As you will remember, this case touches on the ownership of the fundamental Tuschl I and II RNAi trigger patents and of which the outcome could decide what kind of economics Alnylam will be able to extract from its IP and what type of workaround strategies Alnylam’s competition will have to adopt (primers on the Tuschl Tussle and the potential fallout can be found here and here).

The most recent entry on the RNAi Litigation blog was on a hearing held on April 12 about Whitehead’s and UMass’ (the defendants) motion to dismiss the plaintiffs’ (Max Planck and Alnylam) First Amended Complaint. A lot of the hearing seem to have concerned Zamore’s assignment of his rights to the Tuschl I invention to UMass which the plaintiffs strongly feel Whitehead was contractually obligated not to have allowed. After all, it is UMass’ involvement in all of this which makes this case so important because UMass then decided to go it alone and essentially licensed all of the Tuschls most importantly to Sirna Therapeutics (now Merck). This could very well substantially deprive Alnylam of the economic benefits of its, what it believed to be exclusive rights to Tuschl II. To me, it actually seems quite fantastic how UMass believes that the one month that Zamore worked at UMass until the first filing of Tuschl I would now entitle them to the entire Tuschl inventions. Should the plaintiffs prevail in the assignment question alone, then much of the risk to Alnylam’s future business dealings would be taken off the table, unless of course events would escalate in such a way that both the Tuschl patents explode because the USPTO declared the patents invalid because of mishandling of inventorship. The defendants first line of defense is to claim statute of limitations on the assignment question to which the plaintiffs responded that they only became aware of the fact that Whitehead allegedly deceived them in their recent discovery and that they were first damaged in 2007 as Tuschl II ran into problems at the USPTO because of the way Whitehead prosecuted it.

There was an awkward moment in the hearing when the judge asked why Sirna/Merck was not part of the case as it appears that overlooking for a moment the few million in royalties that UMass may enjoy, it is Merck that stands to lose their $1B investment should they end up with a therapeutically useless Tuschl I. It appears, however, that UMass will have to bear the brunt instead because it apparently told Sirna/Merck that they were able to provide access to the inventions described in both the Tuschl patents. Maybe not surprisingly, Merck (‘outside pressures’) also appears to be the reason why attempts to settle this case have failed miserably.

The next important milestone in the case seems to be which counts will eventually be admitted. Unfortunately, it seems as if the judge is not keen at all to delve into the technical details of the case and would rather let the USPTO agonize over it. I am afraid, however, that in order to understand and solve any of the counts at hand, she would eventually have to refresh her high-school biology...

Well, instead of my second-hand account, why not bookmark and visit the 'RNAi Litigation Blog' here directly.

While Alnylam Focuses Suit on Whitehead and UMass, a New Tuschl Loophole Approach Gains Traction

Not a day goes by in RNAi Therapeutics land without hearing the sounds from the RNAi trigger IP battle grounds. Today is no exception…

Wading through the court documents from the Alnylam-Max Planck suit on how the Whitehead prosecuted the Tuschl I (T-I) patent application (aka the 'Tuschl Tussle'), it struck me that while it was Whitehead, their hired patent counsel, and UMass that apparently conceived of the strategy of how to incorporate data from the T-II patent into T-I against the interests of Alnylam and Max Planck, the MIT seemed to merely go along unwittingly. As a result, MIT not only became a victim in that they were deprived of the benefits from the therapeutic agreement they were part of with Max Planck and the Whitehead, which to my knowledge anticipated equal sharing of the profits from therapeutic licenses derived from the combined T-I and T-II estate, but also because they ended up as defendants in the suit.

Perhaps realizing this, Alnylam announced today that it will leave the MIT off the hook in return that they will be bound by any ruling in favor of Alnylam/Max Planck. It could also help drive a wedge between the former co-defendants as the MIT will now feel less fearful about telling their side of the story which could turn out to be quite revelatory. The MIT should have every reason to be unhappy with the Whitehead and the way T-I was handled. The argument that Whitehead, and implicitly, the MIT, aided UMass for political reasons, thereby leaving therapeutic licensing money on the table, never really flew with me since a) institutions just don’t give away money like this, and b) I could never imagine a research institution of the stature of Whitehead as being nationalistic and therefore anti-Max Planck.

While the Tuschl Tussle is going on, there is another Tuschl loophole movement in the field that appears to be gaining some traction. It initially started with mdRNA’s claims that the mere inclusion of a single ‘funny-looking’ nucleotide into an siRNA, unlocked nucleic acids (UNAs), would help it get around the Tuschls. It long cited evidence by outside patent counsel that supposedly supported their belief that they had freedom-to-operate in the RNAi trigger space. The news that Quark Pharmaceuticals had just initiated dosing for their 5^th (!) clinical RNAi program for a neuroprotective agent of the eye, it reminded me of their similar claims about ‘proprietary siRNAs’. To find out about the nature of these claims, I looked up what potentially applicable patent applications they had filed, and came up with the following main claim:

"1. A compound having structure (IX) set forth below:

(IX) 5' (N)x - Z 3' (antisense strand)

3' Z'-(N')y- z" 5' (sense strand) wherein each of N and N' is a ribonucleotide which may be unmodified or modified, or an unconventional moiety; wherein each of (N)x and (N')y is an oligonucleotide in which each consecutive N or N' is joined to the next N or N' by a covalent bond; wherein Z and Z' may be present or absent, but if present is independently 1-5 consecutive nucleotides covalently attached at the 3' terminus of the strand in which it is present; wherein z" may be present or absent, but if present is a capping moiety covalently attached at the 5' terminus of (N')y; wherein x =18 to 27; wherein y =18 to 27; wherein (N)x comprises modified and unmodified ribonucleotides, each modified ribonucleotide having a 2'-O-methyl on its sugar, wherein N at the 3' terminus of (N)x is a modified ribonucleotide, (N)x comprises at least five alternating modified ribonucleotides beginning at the 3' end and at least nine modified ribonucleotides in total and each remaining N is an unmodified ribonucleotide; wherein in (N')y at least one unconventional moiety is present, which unconventional moiety may be an abasic ribose moiety, an abasic deoxyribose moiety, a modified or unmodified deoxyribonucleotide, a mirror nucleotide, and a nucleotide joined to an adjacent nucleotide by a 2 '-5' internucleotide phosphate bond; and wherein the sequence of (N)x is substantially complementary to the sequence of (N')y; and the sequence of (N')y is substantially identical to the sequence of an mRNA encoded by a target gene."

As the red highlight shows, the ‘proprietary’ claim of the Quark siRNAs rests on the sense/passenger strand similarly containing at least one ‘funny-looking’ nucleotide. I was disappointed, however, that the specifications did not explain why this should have any unique advantages. Since in addition to novelty (that's where they will likely try to focus their arguments on), a patent has to also fulfill the demands of non-obviousness and utility, I have my serious doubts that this and the usiRNA patent applications will stand up to closer scrutiny, and if they did get by any patent offices, Alnylam would ultimately challenge them. It suggests, however, that while patent protection for these RNAi triggers is unlikely, a number of players increasingly view this strategy as a way to at least gain independence from the Tuschls. The exact reasoning behind this is mysterious to me, since these modifications should already be explicitly covered by the Tuschls when they refer to 'nucleoside analogues' which usiRNAs are. And even if the Tuschls did not explicitly mention them, it would appear obvious that an siRNA is an siRNA whether it contains a limited number of ‘funny’ nucleotides or not.

As I said, I have yet to hear a convincing argument by the companies what their belief is based on. Just stating that they believe so is not enough to convince investors and potential partners. I am always willing to listen to such arguments.

Clutching at Straws, Whitehead Attempts to Force Unwitting Scientist to Testify

According to recent court filings, the Whitehead is facing stiff opposition in getting a scientist to play a role in their defense in the Tuschl case.

The scientist in question is Brenda Bass from the University of Utah. In April 2000, she speculated in a review article that the small RNAs reported in the scientific publication underlying the Tuschl I patent application had been generated by an RNase III enzyme. Since RNase III enzymes are known to leave 3’ overhangs, the defense wants to use this speculative review article as proof that 3’ overhangs had been common wisdom in the gene silencing field at that time. This is designed to substantiate their claim that small RNAs 3’ overhangs were already implicit in Tuschl-I.

While I take my hat off to her remarkably prescient insights, the relevant remarks were clearly only speculations. Even if those speculations came from a well-respected scientist, most speculations in review articles do not turn out to be true to the same extent and for these reasons such speculations are generally not adopted as gospel in a scientific field, or by ‘those in the art’.

Maybe the Whitehead should start looking in the notebooks of Zamore, Bartel, and Sharp, or any other scientist for that matter, whether, since it was apparently so obvious, they were already in the know about the 3’ overhangs at the time (April 2000). This may be better than trying to annoy another person to become involved in a legal action. It essentially inconveniences her for being an insightful scientist.

If Whitehead is now alarmed that Dr. Bass does not really like to play according to their tune, then they really seem to be clutching at straws and continue to alienate the scientific community in their quest to lay claim on what belongs to the inventors of Tuschl II. And as a technicality, even if (unlikely) the judge could be convinced of this review article to have made 3' overhangs common wisdom, then given the filing dates it is still likely that Tuschl would be able to show that he first conceived of the overhangs before the April 2000 date.

Partly responsible for the alarm could be the fact that Max Planck and Alnylam are seeking, in addition to the permanent injunction, treble damages from the Whitehead and UMass for willfully conspiring to undermine the interests of Max Planck and Alnylam. If the $1.1B price tag for Sirna Therapeutics is any guide, it could get quite expensive. I just cannot get my head around Whitehead's eagerness to side with UMass, who along with their licensees Sirna/Merck and RXi seem to be the only financial beneficiaries should Tuschl I emerge as the fundamental RNAi trigger patent. In fact, Whitehead would even suffer financial harm by doing so, if it is true that Whitehead, MIT, and Max Planck would share equally in the combined Tuschl I-II royalties as per the Therapeutic Agreement. The only reason provided by them and Alnylam/Max Planck seem to be the political damage that siding with Max Planck instead of fellow UMass would entail. Clearly, there must be more to this than meets the eye.

Excerpt from the review:

Does PTGS by dsRNA Involve an RNase III–Like Enzyme?

Although the identity of the RNAi nuclease has not been determined, the characteristics of the short 21–25 nucleotide RNA pieces suggest they were generated by RNase III or a highly related enzyme (see [16] and [1], and references therein). RNase III is the only characterized nuclease known to cleave dsRNA at specific sites to generate dsRNA fragments of discrete sizes. For RNase III to stably bind a dsRNA, it must be at least two helical-turns in length, consistent with the observation that RNAi and transgene-induced silencing yield stable fragments of 22 base pairs. RNase III can produce fragments <22 class="apple-converted-space"> Figure 1, fragments less than 21–23 base pairs would not have been observed in the recent experiments because they would not remain stably bound to the enzyme and thus would be more accessible to degradation by other cellular nucleases.

Given the similarities between the cleavage products of RNase III and the RNAi nuclease, I have incorporated properties of the RNase III enzymes into the model of Figure 1. For example, RNase III makes staggered cuts that leave 3′ overhangs of two base pairs, as shown for the 23-mers of Figure 1. If RNAi involves an RNase III-like enzyme, it might explain why the small RNAs observed by Zamore and Tuschl range from 21–23 nucleotides. The initial cleavage might produce dsRNAs comprised of sense and antisense 23-mers, but the 3′ overhangs would be more accessible to single-strand–specific nucleases present in the extract, and trimmed to 21 and 22 nucleotide pieces. Zamore and Tuschl observe that cleavage of the dsRNA, unlike mRNA cleavage, does not absolutely require ATP. However, dsRNA cleavage is faster in the presence of ATP, and without ATP the pieces are predominantly the longer 23-mers. Certainly this is a clue to the role of ATP in this in vitro reaction, but at present its meaning is unclear.

The RNAi Trigger Marketplace in the Post-Tuschl World

This entry is the second of a 2-part series on the upcoming decision of who will control key intellectual property for therapeutic applications of RNAi. In the first part, I tried to provide an outline of the developments causing ownership of certain data in the Tuschl patent applications to become such an important issue. Here, I will try and delve more into the technical details of the scientific milestones that made RNAi a conceivable new class of human therapeutics, and based on that understanding make an educated guess about the outcome of the Tuschl Tussle and how this could shape the RNAi trigger IP marketplace in the future.

Back to Science.

Could RNAi be used as a therapeutic? That was the sort of topic of wild speculation in the lab where I worked as an undergrad in 2001 on a plant gene silencing project. Hey, Fire and Mello reported this cool stuff in worms 3 years ago and as we can see double-stranded RNAs can trigger the same process so beautifully also in plants thanks to some nice work by the Baulcombe group and another one in Australia. But humans? Well, unfortunately vertebrates seem to represent the exception when it comes to the existence of RNAi. That darn interferon response system...All this would change in a watershed moment when Tuschl and colleagues at the Max Planck reported in Nature the very existence of RNAi in human cells and taught a captivatingly simple technology to induce it there: siRNAs. The story therefore seemed quite simple until then. First it was Fire-Mello, then Tuschl's siRNAs.

Fire-Mello

Fire-Mello coins RNAi. The critical contribution by Fire and Mello in 1998 was their realization that it was in fact double-stranded RNA that was the effective inducer behind a variety of strange gene silencing phenomena in worm genetics and quite likely beyond (e.g. variegated Petunia flower color). While it was not necessarily obvious at the time that this would be applicable to humans as it was still very much doubted that RNAi existed in humans, the deeply influential nature of this eureka moment of the field of gene silencing and the non-exclusive licensing approach taken by the Carnegie Institution, the owner of Fire-Mello, established it as a widely respected patent. Add to this the endorsement by the scientific community as evidenced by the Nobel Prize in Physiology and Medicine this work entailed, there should be little doubt in the mind of patent examiners about the therapeutic relevance of that work. Prohhhhbably a fundamental patent.

Biochemical work in fly cell extracts by the inventors behind Tuschl I (Tuschl, Zamore, Bartel, Sharp) and involving the MIT, the Whitehead, UMass, and Max Planck on the same gene silencing phenomenon in flies aimed at the elucidation of the molecular fate of these long dsRNA RNAi triggers. Their main finding was that during RNAi, long dsRNA gave rise to 21-23 nucleotide small RNAs and that target RNA was cleaved at 21-23 nucleotide intervals also. This strongly indicated that it was the 21-23 nucleotide RNAs that were guiding the destruction of the target RNA. This, however, is different from demonstrating that the 21-23 nucleotide small RNAs are able to trigger RNAi themselves, something one would think would be important for claims to this effect to be considered enabled. To test this hypothesis, they therefore isolated and then reintroduced the 21-23 nucleotide mix of RNAs into fresh fly cell extract and asked whether those were able to induce RNAi gene silencing, too.

What may come as a surprise to a few: the silencing with these purified 21-23nt RNAs was actually quite mediocre, about 50% silencing compared to >>95% silencing with the long dsRNA (Figure 12 of US Tuschl I application). Similarly, when the dsRNA length dependency of RNAi was tested, the shorter the dsRNA, the worse the silencing. Together, these types of findings described in Tuschl I seriously calls into question claims that Tuschl I technically enabled human RNAi. Some may even cite such data as proof to the opposite, namely that this work made it even less likely that short RNAs would be useful RNAi triggers.

What is the explanation for this somewhat surprising finding? In retrospect, it is most likely the fact that when the 21-23nt small RNAs were introduced they were single-stranded and not double-stranded and demonstrates that at that time, the authors did not know about the requirement for double-strandedness also of the small RNA intermediates for triggering RNAi . Consequently, the patent contemplates both single-stranded and double-stranded RNAs as candidate RNAi triggers. Thus, while an important piece of the puzzle of RNAi molecular biology history with ~1600 citations to the underlying Year 2000 paper, it by no means was the catalyst leading to the adoption of RNAi in humans. I would not even be surprised if the authors did test the hypothesis of whether such isolated 21-23nt small RNAs were able to silence genes in humans cells (not very difficult to do) and came up short. It is also worth noting that their discovery of small RNAs during RNAi was not entirely new to gene silencing scientists then, a year after Hamilton and Baulcombe reported such an observation in Science, something that also has not escaped the patent examiner.

Tuschl II

Tuschl II coins ‘siRNA’. The critical insight that, first of all, proved the existence of RNAi in Man and even more importantly in terms of enablement, taught a straightforward method for triggering this process in humans, came from very elegant work led by Tom Tuschl at the Max Planck in Goettingen and forms the basis for Tuschl II.

The spark of ingenuity by the people at Max Planck, not involving those at the MIT, Whitehead, or UMass, was that the small RNAs had to be in double-stranded form to serve as useful triggers of RNAi. To prove this, they generated short dsRNAs, which they coined siRNAs, through chemical synthesis, also a first, and found them to be potent triggers of gene silencing not only in fly lysates, but subsequently also in human cells. The fact that the fly lysate work was reported separately by the Max Planck group and temporally between the Tuschl I 21-23 nucleotide RNA paper and the human RNAi findings, further illustrates the temporal, geographic, and intellectual separation of Tuschl's work in Massachussetts and then as a group leader in Germany.

Importantly, these siRNAs allowed for gene silencing that was specific and independent of the interferon response, again something speculated about, but not clearly proven in Tuschl I. The Tuschl siRNA-template is now used by thousands of laboratories around the world, with an amazing 6000 citations to the underlying paper further illustrating its importance.

In the Max Planck vs Whitehead case, the Whitehead argues that 3’ overhang siRNAs that are at the core of the Tuschl II patent application were already part of Tuschl I. On the surface this is true. This is because for some strange reason and that is the biggest mystery to me in all of this and that I hope the next months will shed some light on, the human siRNA data miraculously appear at the end of the Tuschl I application, as does the term ‘siRNA’ emerge without prior definition. If this data were to remain part of Tuschl I, there is the real possibility that Tuschl II could be declared invalid on a technical basis because of Tuschl I’s priority status (in a temporal sense) and double-patenting laws. Not good for Alnylam!

The two related questions of which the answer will rock the RNAi Therapeutics universe are therefore: a) Has the human siRNA data that in light of the weak activity of the ’21-23 nucleotide RNA’ in fly lysates and very uncertain translation of those results into humans now form the inventive basis for the broad human RNAi claims in Tuschl I, been rightfully included? b) In doing so, has the Whitehead, responsible for prosecuting Tuschl I also on behalf of Max Planck, fulfilled its fiduciary duty towards all its partners?

First of all, as I explained in my previous post, the data critical for the siRNA claims of Tuschl I had been generated by the inventors behind Tuschl II (most importantly, in addition to Tuschl, Elbashir and Lendeckel; both of them also at the Max Planck then), but who are not named as inventors on Tuschl I. On this technical ground already, Tuschl I in its present form is invalid. Beyond that, there appears to be early communication in which Max Planck confirmed with the Whitehead that the human siRNA data were the domain of Tuschl II. So even if Max Planck and the inventors of Tuschl I had been wrongly convinced by the Whitehead and their hired patent attorneys that this should not pose a problem for the approval of both patents, any patent attorney worth his salt should have known this to be a fundamental omission. It would therefore seem to be wise to remedy this deficiency either by including the inventors on the Tuschl I patent or by leaving out the data as stipulated by Max Planck, before the specter of 'malpractice' was raised. And obviously, Whitehead now is clearly not acting on Max Planck’s behalf and this should be sufficient cause to give back Max Planck de facto veto power in Tuschl I by confirming that the Whitehead does not have Max Planck's power of attorney any more.

Because some of these issues are civil ones that are not the domain of the USPTO, it is important to sort them out before it goes back to the patent office and can cause lasting damage to the patents. For the stated reasons, I am quite confident that Max Planck and Alnylam will prevail and regain control of the human RNAi data and some sort of declaratory judgement that the way that data had been used in Tuschl I cannot be construed to contest the validity of Tuschl II in the future.

Before I consider the ramnifications of the two main outcomes of the Tuschl Tussle for the RNAi Therapeutics RNAi trigger IP space, it should be noted that Tuschl II already disclosed the observation that blunt-ended siRNAs can silence, too, just not as efficiently as 3' overhung siRNAs on average. 3' overhangs were therefore taught to be a preferred characteristic of siRNAs when used for mammalian RNAi applications. Hence, with many more reports confirming that RNAi in fact is so robust that all sorts of exogenously introduced small dsRNAs can efficiently induce RNAi in humans, it will become more and more difficult to convince the patent offices of a proprietary nature of not only overhung siRNAs, but also those without overhangs. One exception may be Silence Therapeutics’ blunt ‘Atu-siRNAs’ which because it was a relatively early disclosure Silence/Atugen was able to convince the US and European patent offices of their arguably surprising stability, an important feature for most RNAi Therapeutics approaches.

Outcome 1: Tuschl II becomes dominant, Tuschl I essentially irrelevant

The most likely outcome. This will confirm Alnylam to be the most desirable partner based on RNAi trigger IP alone and leave Merck and RXi Pharmaceuticals empty-handed. Clear freedom-to-operate and exclusivity for the most efficient RNAi trigger that is also highly competitive with regards to other challenges such as innate immune activation. However, since Tuschl II does not claim blunt siRNAs, something I believe should have been done at least initially and maybe wasn’t because of an integrated Tuschl I-II strategy that now clearly has fallen apart, there remains scope for plenty of blunt-ended workarounds in the important 19-24 base-pair range. These workarounds, however, are not very attractive for licensing purposes if they cannot be protected by patents. Again, the exception here is Silence Therapeutics which, assuming that Kreutzer-Limmer's staying power is questionable, would be a beneficiary of such an outcome since it would now free Atu-siRNAs from the Tuschl I threat. There are, however, some significant limitations with Atu-siRNAs, since the scope of the patents is quite narrow in terms of allowed siRNA patterns and chemical modifications. Thus, while Tuschl II will offer a platform that should be applicable to RNAi Therapeutics for many years to come, Atu-siRNAs may not be able to adapt to the evolution in cutting-edge siRNA modification technology and hence its value should decline over time relatively quickly.

The IP position of Dicerna is probably least affected by the Tuschl outcome among the synthetic siRNA Therapeutics companies. There may be some uncertainties with whether and how the Tuschl patents may be applicable to Dicer substrates, but unless there will be a messy outcome in which both Tuschl’s go up in fire (highly unlikely), neither outcome 1 or 2 should change this much.

Under outcome 1, the market would have to balance the luxuries that Tuschl II offers, namely patent protection and overhangs, with the lower price, but added liabilities of the Silence Therapeutics and Dicerna platforms or even non-patented siRNA workaround designs. Last but not least, due to its use of overhangs, mdRNA’s overhung ‘usiRNAs’ would be a loser under this scenario.

Outcome 2: Tuschl I becomes (almost) gate-keeping, supersedes Tuschl II

If Tuschl I were allowed in the US in the form now proposed by Whitehead, then Tuschl II may go up in flames with Tuschl I covering blunt and overhang siRNAs comprising RNA strands of 21-23 nucleotides. Under this, albeit very unlikely scenario, Alnylam would have to share gate-keeper privileges for the most direct route to RNAi Therapeutics with Merck and RXi. Further risking to put pressure on price would be RXi selling such rights for a pittance as well as uncertainty about UMass’s ability and willingness to further grant rights to Tuschl I. Not all would be lost for the rest of the field even under this scenario. Silence Therapeutics, for example, would still be able to operate in the 15-20 base-pair range, with maybe 19 and 20 base-pair offering quite good opportunities of discovering efficacious and non-immunostimulatory siRNAs with acceptable efficiency. Similarly, 19 to 20 base-pair siRNAs may also become the preferred space for other non-patented siRNA designs, though all of this is dependent on what happens to Kreutzer-Limmer. Again, Dicerna would be little affected by all of this, and mdRNA may be well advised to try its luck with ‘usiRNAs’ outside the 21-23 nucleotides range, although I still feel chances are slim that one or two supposedly ‘non-nucleotide’ nucleotides will allow them to call what look and behave like siRNAs by another name.

Where does Big Pharma stand in all of this? Those interested in taking broad platform licenses to RNAi trigger IP can probably be classified into into two categories: 1) those like Pfizer and GSK that have diligently done their homework and will already have made up their minds about what type of RNAi triggers are required, including whether they consider overhangs to be an essential feature or not. Such companies can simply await the outcome of the trial and then choose the most economical option everything else (e.g. access to delivery and other know-how) being equal; 2) those companies that have shied away from heavy investments thus far and would prefer to get started with a pure-play RNAi Therapeutics partner providing patent-protected siRNAs and other basic RNAi capabilities. These companies may be most swayed by the outcome of the Tuschl Tussle, since they may be more relaxed in terms of what they consider acceptable siRNA designs.

Tekmira is a pure-play RNAi Therapeutics company that should be uniquely affected by the outcome, because it does not tout having invented unique siRNA triggers, although it certainly could make up such claims to the same degree that others do in the space, and because of its complex relationship with Alnylam. For one, it may determine whether potential partners consider it to be necessary to access SNALP delivery via Alnylam or whether they can go directly to Tekmira and get the same for probably considerably less. Moreover, in the unlikely case of a Max Planck/Alnylam loss, it may become even more difficult to insist on controlling SNALP delivery for RNAi Therapeutics all the while it is obvious that Alnylam is intent on minimizing the importance of Tekmira for their delivery efforts (the whole issue of what is called a SNALP which clearly differs between Alnylam and Tekmira). If SNALP is old and first-generation where is the harm in letting Tekmira fully exploit this technology by partnering it out ex-ALNY instead of letting it wither on the vine? I guess something ought to be worked out here to the satisfaction of both companies.

After 8 years of spending enormous efforts on confusing the investor world with what is valuable RNAi trigger IP, it looks like everything will come down to basic science. The collective scientific community based on the number of citations a paper gets and how it has recognized critical inventions for example in the form of scientific awards, would have been a much more straight-forward, fairer, and infinitely cheaper way of determining ‘good’ RNAi IP. Who else was better suited to spot critical contributions in technically demanding areas such as RNAi than scientists themselves? One would hope that the judge will concur, also in the interest of what RNAi Therapeutics could do for society.

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. Information provided herein cannot be relied upon for making investment decisions. Investments in RNAi Therapeutics are very risky and not suited for most. Consult with your own professional advisor before doing so.

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.

To read the rest of the story, click here...

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.

RNAi Therapeutics IP: On the Importance of Being Tuschl

A strong patent position is essential for companies to attract investments for the development of RNAi Therapeutics. Although the number of patents and patent applications surrounding RNAi Therapeutics continues to grow, arguably the two or three key early patents are 1) Fire and Mello describing the discovery and use of long double-stranded RNAs for inducing RNAi-mediated gene knockdown in worms and by extension other organisms, and 2) the Tuschl I and II patent series describing the identification of small 21-23nt small RNAs as the mediators of RNAi (Tuschl I) and the use and properties of synthetic siRNA duplexes for RNAi in human cells (Tuschl II).

While Fire and Mello has been granted in the US and can be licensed by almost anyone that wants it, there is much more controversy surrounding Tuschl I and II. It is undisputed that scientifically Tuschl’s studies describing the use of synthetic siRNAs for RNAi in mammalian cells is what opened up the prospect for RNAi to become the next platform for drug development. Tuschl II which is based on the work by Tuschl, Elbashir, and Lendeckel and owned by the Max-Planck Institute in Germany has been exclusively licensed to Alnylam Pharmaceuticals and has already been granted in the US and some other territories (Tuschl is a scientific co-founder of Alnylam). The patent application was provisionally filed in the US on March 30, 2001, and in Europe on December 1, 2000, and describes in great detail the anatomy of effective synthetic siRNAs.

Meanwhile, much of the work in Tuschl I is focussed on the identification of small RNAs as the mediators of RNAi based on the fact that isolated small RNAs derived from processed double-stranded RNAs in Drosophila cell extracts trigger specific gene knockdown and cleavage of a target message at 21-23nt intervals. Interestingly, most of that work does not mention the fact that these 21-23nt small RNAs should be double-stranded. This conclusion could not be derived from the observation of 21-23nt small RNAs on denaturing polyacrylamide gels, but was deduced through the cloning of these small RNAs which is described in Tuschl II, not I. It is therefore very surprising that, out of the blue, Tuschl I demonstrates the use of synthetic siRNAs with preferably 2-nucleotide overhangs for RNAi in mammalian cells. Subsequent claims then focus on the use of such siRNAs for human therapeutic development. This is rather surprising given that the basis for choosing 2-nucleotide synthetic siRNAs is lacking. It therefore appears as if this example had been appended later so as to make the patent more relevant for human therapeutic use. Otherwise, only fruit fly work, albeit important, would have been described. Given the near-identity of this last claim of Tuschl I with work described in Tuschl II, it is difficult to imagine how Tuschl I could be granted in full in the presence of Tuschl II.

Similarly intriguing is the fact that Tuschl I, which by the way has not issued yet, is co-owned by the Whitehead Institute for Biomedical Research in Cambridge, MA, the MIT, the University of Massachussetts, Worcester, and the Max-Planck Institute. At the same time, from the publication record it is clear that synthetic siRNAs were pioneered by Tuschl, Elbashir, and Lendeckel while at the Max-Planck Institute. Interestingly, the UMass has chosen to co-exlusively license their rights to the patent to Sirna Therapeutics (now a Merck subsidiary), CytRX (now RXi), in addition to Alnylam. Clearly, Merck and RXi would benefit most if Tuschl I would be granted eventually and somewhat limit the dominance that Alnylam currently enjoys in the RNAi patent space. Nevertheless, the fact that Tuschl I, filed on the very same December 1, 2000 date as Tuschl II in Europe, has not issued yet and the sudden appearance of synthetic siRNAs and their use in human cells at the very end of that patent application, raises questions about conflicting interests between the involved parties.

Based on publicly available information, the claims of the Tuschl patent series could therefore be divided as follows: Tuschl I getting credit for identifying 21-23nt small RNAs for mediating RNAi in fruit flies and by extension in other organisms, and Tuschl II for characterising effective siRNAs to be double-stranded with preferably 2-nucleotide 3’ overhangs and the ability of synthetic versions thereof to mediate RNAi in mammalian cells. In such a scenario Tuschl II would carry considerably more weight for the development of RNAi Therapeutics which would in turn reinforce Alnylam’s already leading IP position.

I am aware that parts of my interpretation are based on conjecture and criticisms are welcome (email: dirk_haussecker@yahoo.com). For those interested in the patents themselves, please visit

Tuschl I: http://appft1.uspto.gov/netacgi/nph-Parser?Sect1=PTO2&Sect2=HITOFF&p=1&u=%2Fnetahtml%2FPTO%2Fsearch-bool.html&r=1&f=G&l=50&co1=AND&d=PG01&s1=tuschl.IN.&s2=zamore.IN.&OS=IN/tuschl+AND+IN/zamore&RS=IN/tuschl+AND+IN/zamore

Tuschl II: http://www.google.com/patents?id=BlV6AAAAEBAJ&dq=rna+sequence+specific+mediators+of+rna+interference