A Very Obvious Method of Generating Tuschl-type siRNAs

John Leavitt over at the RNAi Litigation blog just posted ‘Alnylam’s’ defense against the accusation of the University of Utah that Utah had been deprived of ownership over the 3’ overhang feature of the Tuschl-type siRNAs. Setting aside the underlying merits of the case, the Motion to Dismiss the Second Amended Complaint by the University of Utah highlights one thorny issue with the granted Tuschl II (T-II) patents in the US, namely that they, so far, do not claim the 3’ overhangs themselves, but a method of generating 3’ overhang siRNAs. This method stipulates, in a first step, the synthesis of the individual strands, and then, in a second step, hybridizing (‘combining’) them to form the 3’ overhung siRNAs. The motion by the Defense consequently argues that Utah is missing the point in its suit by alleging ownership over the 3’ overhang feature, but not the method of generating 3’ overhung siRNAs subject of the US patents.

This to me is a) misleading since the Tuschl II IP estate to which Utah lays claim includes the European T-II patent which expressly claims the overhangs and Alnylam/Max Planck are obviously hoping to get similar composition of matter claims issued in the US, and b) the issued US T-II could only be considered novel by the USPTO based on the novelty and utility of the composition of matter that results from this method, i.e. 3’ overhang siRNAs for inducing gene silencing.

That the USPTO issued these claims in the first place is quite puzzling. Synthesizing and combining small RNAs is the most obvious method of generating 3’ overhung siRNAs. I would argue that even the average highschool student can come up with this method after a basic lesson on nucleic acid structure, not to speak of the ‘person having ordinary skill in the art’ which is considered the standard for obviousness. Unless I have missed an important exception in US patent law, similar to the Swiss-style claim construction in Europe to which the US T-II claims are reminiscent of, the US T-II claims seem very tenuous to me and probably should not have been granted.

It is amazing that both Plaintiffs and Defense are spending all this energy (=time and legal fees) skirting around the main issues (namely that Tuschl was probably motivated to test the 3' overhang feature based on Bass' speculations, and that Bass cannot be named a (co-)inventor since there was not even a semi-formal collaboration between Bass and Tuschl and Utah never bothered to file a patent). The answer by Utah to this motion is predictable, and so it will go on and on...

Alnylam Now Sued by University of Utah Over 3’ Overhang Inventorship

Not a day goes by without a lawsuit involving Alnylam. This time it would seem unjustly so.

The company disclosed in a regulatory filing today that the University of Utah (‘Utah’) is suing the owners of the valuable Tuschl II (T-II) patent estate (Max Planck, the Whitehead Institute, MIT, and UMass) along with licensee Alnylam (but not Merck) for wrongfully omitting Utah scientist Brenda Bass as the inventor of the 3’ overhang feature central to that patent family. While the demands of the plaintiff, i.e. naming Dr. Bass as the sole or at least joint inventor plus damages, are unlikely to be met, it is a reminder that the validity of the T-II invention has yet to be confirmed in the US and that Alnylam’s aggressive bid to control the world of RNAi Therapeutics may have triggered a backlash gathering steam.

In the Complaint, Utah basically asserts that Dr. Bass first conceived of the 3’ overhang feature of the small RNA gene silencing mediators that Tuschl and colleagues saw in their elegant Drosophila lysate experiments. The plaintiffs cite as evidence a review on the Tuschl work that she began writing on March 21, 2000 and which incorporates a highly speculative model featuring small 3’ overhang siRNAs as the intermediates and likely mediators of RNAi. On April 11, 2000 she then presented her ideas at a conference at which Zamore, a co-inventor of T-I and claimed by some to be a co-inventor of T-II also, was present. More such presentations and communications as is normal in academia took place and which allegedly involved other inventors named on T-II.

The Complaint further alleges that the named T-II inventors improperly used that information to file on December 1, 2000, the first T-II priority document with the European patent office- but without naming her and therefore depriving the University of Utah of the economic benefit of T-II, arguably Alnylam’s crown jewels.

I find it very hard to believe that Utah’s request of Max Planck naming Dr. Bass as an inventor on the T-II patent application will go anywhere. First, she speculated that 3’ overhangs might be involved in the pathway, but it was only the presently named T-II inventors that actually demonstrated the utility of such overhangs. More importantly, however, if Dr. Bass and Utah really believed the 3’ overhang feature had economic value, they should have filed for their own patent application before publishing the review. Since this has not happened, the review became a public disclosure and a free-for-all. According to the description in the Complaint, there never existed a ‘real’ collaboration between Dr. Bass and the Tuschl inventors so that including her as an inventor would be wrong in my opinion.

But then again, because of her disclosure, whether she were to be included or not, it would be an invalid patent due to her own prior art if the review held up as such.

I would have expected the Bass issue to come up as part of the US T-II examination back-and-forth anyway, but not to the extent that it would have real threatening power. It is, however, highly unusual that Utah would challenge the inventorship of T-II already at this stage, in the same court that heard the Tuschl litigation, as inventorship questions are normally dealt with during patent prosecution or after a potential grant. The timing is even more so unfortunate for Alnylam, as they have to now deal with two lawsuits simultaneously, lawsuits that are challenging the two most important elements of Alnylam’s RNAi world domination strategy: SNALP delivery and T-II.

My humble advice: Deal with the Tekmira issue first, i.e. acquire Tekmira as Alnylam should have done all along, then focus on clinical progress. The Utah issue will then feel less of a nuisance and distraction.

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.

It’s Getting Lonely as Silence and Merck Attempt to Climb Alnylam’s Many RNAi Trigger Patent Walls

Today, Alnylam announced the completion of initial oral opposition proceedings concerning the Glover patent EP1230375 for the use of double-stranded RNA to inhibit gene expression in mammalian cells, one of the many RNAi trigger patents and patent applications Alnylam either owns or has (often exlusively) licensed access to and which are based on pioneering RNAi research in mammalian cells thus shoring up the company’s gate-keeper position in the therapeutic application of RNAi.

Such opposition proceedings are common in Europe, particularly for patents deemed valuable enough to have the potential to restrict the freedom-to-operate of other parties. One familiar example that has been the subject to similar proceedings in Europe is Kreutzer-Limmer, yet another of Alnylam’s RNAi trigger patents backing up its crown jewel Tuschl II which is currently successfully sailing through the global patent systems.

Most of you reading this blog will be well aware that while Fire and Mello’s seminal discovery shed light on double-stranded RNAs as the trigger of RNAi, subsequently found to be true throughout almost all eukaryotic life, its application to human cells was not immediately apparent as the long double-stranded RNAs used are well known to induce non-specific innate immune responses in most mammalian cell types, therefore making long double-stranded RNAs not useful for the vast majority of conceivable RNAi Therapeutics. It was therefore the breakthrough discovery by Tuschl and colleagues that opened up RNAi for widely applicable human use by showing that structurally defined short double-stranded RNAs, siRNAs, derived from the processing of long double-stranded RNAs can induce gene-specific gene silencing in essentially all mammalian cells without the induction of the non-specific responses.

One exception to the non-specific response to long double-stranded RNAs are oocytes and pre-implantation embryos, and indeed in the wake of Fire-Mello work underlying the Glover patent and published by Florence Wianny and Magdalena Zernicka-Goetz from Cambridge University (UK) in 2000 demonstrated that long double-stranded RNAs could be used for specific gene silencing in these cell types. While a highly exciting finding for reproductive biology, including potential uses for RNAi-enhanced ES cell therapeutics, it is clear that its impact for the wide development of RNAi Therapeutics is far more limited than Tuschl II. It is probably one of the patents that Alnylam would want to control to make sure that it was not construed to precede Tuschl II and forms part of a well thought-through patent strategy, but that it does not critically rely upon. Of course, because Glover, similar to Kreutzer-Limmer, also claims long double-stranded RNAs and would therefore also impinge on Dicer-substrates etc., it is particularly susceptible to attack by companies whose sole existence depends on having varied the size of the double-stranded RNA or having engineered a “proprietary” modification or pattern thereof into double-stranded RNAs.

From the title you might think that I am a blind Alnylam supporter (and, yes, I do own Alnylam shares, but, no, I am not paid by the company to write this), but note that I refer to RNAi trigger IP, that is the molecules themselves that induce RNAi silencing in mammalian cells by synthetic double-stranded RNAs. This does not mean that there is enough potential for big and small alike to create valuable enabling IP around these siRNAs (delivery, safety, and gene target-specific), also to gain some leverage with regards to Alnylam. It is interesting to speculate that the subject of another announcement today, namely the creation of Boston-based “Enlight Biosciences”, a technology incubator jointly sponsored by Pfizer, Merck, and Eli Lilly, of which one of the stated goals is the development of RNAi delivery methods all the while trying “…to find the next RNAi,” according to the Xconomist blog. A tall order, particularly the latter.

In the ideal world of free market capitalism, resources would flow to where problems need to be solved, in the case of RNAi delivery and safety, not into the coffers of lawyers- they get their share anyway in each and every deal sealed or not sealed even without patent litigation. It therefore certainly makes sense that rather than engaging in costly and futile battles with a strong company, more and more large biotech and pharma companies have opted to join a strong Alnylam in its quest to develop RNAi Therapeutics.

After Novartis, ISIS, Janssen/Johnson&Johnson, and Quark have withdrawn their opposition to Kreutzer-Limmer and Glover, it is now essentially Sirna Therapeutics/Merck and Silence Therapeutics with some of their partners that remain the only opposing parties. Meanwhile Alnylam, confident of their freedom-to-operate and overall strong IP position, continues to watch the early legal wranglings in the field, while focusing on the real issues at hand. As Nucleonics and Benitec would tell you, it’s probably wiser to handle patent violations by exacting appropriate royalties once products near the market, not now. Shares in Silence Therapeutics closed at 23.75p today on the London Stock Exchange, down almost another 10% and off more than 80% its high of last year.

My strong opinion is founded on having looked at the totality of the high quality science underlying Alnylam’s fundamental patent estate, and I would consider it a travesty of the patent system if as a result of a gap in the understanding of the science of RNAi by judges or patent attorneys, the commercial value of the IP would be eroded, with serious consequences for the therapeutic exploitation of RNAi. Such a weakening of the patent system would not only hurt Alnylam, but the entire drug industry which will only survive if truly deserving innovation can be protected. So far, this has not happened to RNAi, and I believe the outcome of these proceedings and future Alnylam deal flow will substantiate this.

Big Pharma would therefore do well not to attempt to kill the goose that lays the golden RNAi eggs for them.