ISIS Files Aggressive Lawsuit against Santaris

It is not a big secret that antisense therapeutics companies ISIS and Santaris are fierce competitors. Today, ISIS filed an unusual, because rather aggressive lawsuit against Santaris Pharma that alleges the Danish company to be selling to the industry technology that is covered by at least two of ISIS’ literally thousands of patents. Because ISIS considers itself the gate-keeper of oligonucleotide therapeutics, and because some of the business development in RNAi Therapeutics has probably occurred under the mantle of the Research Exemption, a ruling in favor of ISIS Pharmaceuticals could have wide ramifications, actually well beyond oligonucleotide therapeutics.

Under the Research Exemption doctrine, the result of Merck vs Integra, it is generally assumed that patented technologies can be used for research purposes quite broadly as long as product, in this case drugs, are not marketed. Without this safe harbor, much of the preclinical pharmaceutical research and academic research would be a legal nightmare.

Nevertheless, ISIS believes this standard does not apply here, because Santaris in a way is selling ISIS technology as part of its platform partnerships. These include relationships with Pfizer, Enzon, GSK, and Shire. Moreover, it probably irks ISIS that Santaris has been rather successful in its business development efforts, and even had the guts to hire a former top ISIS executive, Art Levin, to set up a business development branch in ISIS’ backyard San Diego.

My impression is that Santaris’ LNA-based antisense compounds are more potent than ISIS’ generation 2.0 2’-MOE phosphorothioate gapmers, and this is why Santaris is likely to be the more attractive company to partner from a technical point-of-view. ISIS apparently has realized this as well as it is following Santaris' example in developing conformationally constrained (‘locked’) nucleic acid chemistries (expect Santaris to counter-sue ISIS on that). Anti-miR122 for the treatment of HCV infection is one example where Santaris’ data have been more promising than Regulus’ using ISIS chemistries. Ironically, GSK dumped Santaris’ stronger science on HCV in favor of Regulus for what had to be concerns about IP (I believe though that it was miR-122-specific IP, not antisense platform-related IP that was responsible for GSK’s move).

I don’t want to speculate whether Santaris in fact makes use of technology covered by ISIS patents or not. It is, however, a case worth watching for the entire pharmaceutical industry. Closer to home, it illustrates how aggressive, and so far successful ISIS is in using its sheer number of patents in ‘extorting’ concessions from other oligonucleotide therapeutics companies. Wherever you look, ISIS is getting a piece of the pie. I have been studying ISIS’ patents with regard to RNAi Therapeutics, and cannot really find anything of value there, except maybe if you are interested in using the 2’-fluoro modification which is useful, but dispensable. Still, ISIS was able to extract surprising concessions from Alnylam when Alnylam IPO’d a few years ago and has even called Alnylam a ‘satellite company’ without much public protest by Alnylam. Same story with the multi-million $ that Alnylam gave ISIS for the ill-fated single-strand RNAi collaboration. It goes to show that when it comes to public perceptions and business development, quantity and brand recognition often still trump quality and due diligence.

Post-scriptum (9 October, 2011): On October 7, Exiqon and Santaris on October 7, 2011, settled their legal differences that resulted from Santaris suing Exiqon for selling LNA-based reagents that were used for the development of drugs incorporating LNAs,,,and thus would not fall under the Research Exemption- an ironic twist of fate. In the settlement, Exiqon paid Santaris a minimal amount. It is difficult to conclude from this anything about the outcome of the ISIS-Santaris litigation.

On the Importance of Semple-Wheeler

The Semple-Wheeler (S-W) patents can be considered essential intellectual property (IP) for those liposomal siRNA formulations currently in development that have shown clinical promise. Because Alnylam obtained significant control over Semple-Wheeler (S-W) through a license from Tekmira, this patent estate has been important to Alnylam in controlling access to Tekmira’s SNALP delivery technology and, equally important, keeping Tekmira close to its chest.

Today, I will provide a brief re-cap of S-W and explain why its strategic importance is rapidly waning as patent expiration dates draw close.

What Semple-Wheeler Covers

Most critically, S-W cover LNPs comprising

a) ionizable lipids (e.g. DLinDMA, MC3), a modified lipid that prevents particle aggregation (e.g. PEG-lipid) in addition to the nucleic acid cargo (e.g. siRNA; Semple US6858225); and/or

b) a cationic lipid, a non-cationic lipid, a PEG-lipid conjugate in addition to the nucleic acid (i.e. the chemistry of a SNALP liposome; Wheeler US6815432).

While, until S-W has been tested in court, there will always been some uncertainty as to the real scope of the claims, e.g. in light of such newfangled terms like ‘lipidoids’ or other classes of lipids that may not have been covered by the examples in the specification, such strategies would seem to stand on weak scientific grounds.

Ownership and Control over Semple-Wheeler

Originally, Old Tekmira had an exclusive license to S-W from the University of British Columbia (UBC). Realizing the importance of liposomal delivery for the first wave of value creation in systemic RNAi Therapeutics, Alnylam obtained exclusive rights to Tekmira’s exclusive rights to S-W in January 2007. By this, Old Tekmira’s ability to further monetize this patent estate became greatly limited, and, in the absence of other significant RNAi assets at that time (i.e. lack of Protiva IP, know-how, and trade secrets), was widely regarded as a de facto satellite company of Alnylam.

Fair enough- not only did Alnylam pay $8M in upfront for these rights and is on the hook for milestones and royalties, Old Tekmira was in turn granted RNAi trigger IP and the use of S-W for the selected targets. Interestingly, the latter has been brought into question by Alnylam by stating in their recent Response to Tekmira’s Amended Complaint that Tekmira actually does not have rights to S-W and that Alnylam had given Tekmira such notice:

‘23. Consistent with this pattern, Tekmira has failed to adequately disclose the limitations of its licenses to investors. Despite the clear terms of the license agreements and notice from Alnylam that it lacked licenses to the Semple & Wheeler patent series and Isis patents, Tekmira made representation to the contrary in its public filings with the SEC and in other documents provided to investors.’

It is unclear on what grounds Alnylam makes these claims. Does it claim that Tekmira apparently was never granted such rights, or does it simply mean that Alnylam considers the lawsuit brought by Tekmira as grounds for terminating these rights? In any case, the irony is not lost as it is Tekmira through which Alnylam gained access to S-W and it is for Tekmira to terminate Alnylam's rights if at all.

Strategic Importance of Semple-Wheeler in Light of Upcoming Patent Expirations

In biotechnology, patent infringement typically only becomes ground for lawsuits either when drugs/devices allegedly covered by such claims are about to be commercialized or as generics want to muscle their way onto the markets before the expiration of patents covering an innovator drug. Because of the so called Research Exemption, it is very difficult to enforce patent rights before any commercialization of related drugs, i.e. during the period that patented technologies are being used for drug development pre-commercialization.

Certain licensing and collaboration agreements may be considered to fall between the Research Exemption and the commercialization of drugs, as they may involve technologies covered by 3^rd party patents, even if these patents can be assumed to have expired by the time drugs are ready to be commercialized. In other words, the LCAs may be interpreted as a way of commercializing patents. Although such actions are less common, emotions are running high, so Alnylam may use S-W as pre-text for throwing a wrench into any significant LCA that Tekmira may strike. Old Tekmira e.g. once sued Protiva for allegedly licensing S-W to Merck, and one can only speculate to what extent Alnylam instructed Old Tekmira to do so.

The reason though why such actions are unusual is that chances of enforcing such patent rights are slim if the parties involved in an LCA word their agreement appropriately (e.g. by simply excluding the appearance, implicitly or explicitly, that the partner gains rights to S-W; performing work in countries where S-W is not in force etc etc). As such, Tekmira has substantial freedom to strike deals as long as SNALP-based drugs are not being commercialized before the expiration of the fundamental S-W patents…which should be around 2015-7:

Semple US6858225 (ionizable LNPs):

Date of patent: Feb 22, 20005

Filing date: June 29, 2001

Priority date: May 14, 1997 (claims priority to No. 08/856474)

Approximate term of patent: Feb 22, 2005- May 14, 2017

Wheeler US6815432 (SNALP chemistry):

Date of patent: Nov 9, 2004

Filing date: Feb 24, 2003

Priority date: June 7, 1995 (claims priority to No. 08/5981501; note that although this is just before the famous June 1995 cut-off date, because the patent application of ‘432 was filed after that date, patent terms are according to the new regime)

Approximate term of patent: Nov 9, 2004- June 7, 2015

Tekmira business development prospects

Two factors largely controlled by Alnylam have long held back Tekmira’s full business development potential. In addition to granting Alnylam exclusive rights to S-W, it was particularly Alnylam’s RNAi trigger gate-keeper claim that tied SNALP technology to Alnylam.

Until the expiration of S-W, only those companies with access to S-W (Tekmira, Alnylam, Roche, Takeda, and supposedly Novartis) could commercialize SNALP-based drugs until 2017. Because Tekmira has 8 target picks for which it can use S-W, Tekmira is able to offer an acquirer or product-specific co-development partner more than enough access to S-W until then. 6 years is not a long time in drug development, about the time it would take from initiation of phase I to approval if all goes smoothly. The ~2017 expiration of S-W therefore means that its strategic importance for the development of SNALP-based RNAi Therapeutics is waning rapidly. 2007-8 was a different story.

In this light, a gate-keeping position of Alnylam in RNAi triggers, based on the Tuschl and Kreutzer-Limmer patents would be the real rate-limiting factor, as the terms for these patents may last into 2021-2. However, the RNAi trigger landscape has changed significantly over the last 2-3 years as the importance of Kreutzer-Limmer is rapidly diminishing in Europe and is nowhere to be seen in the US, Tuschl I turns out to be of no relevance for therapeutic applications, and even the validity of Tuschl II is now being questioned. Even if T-II can survive the Utah challenge, as it covers only certain RNAi triggers with certain 3’ overhangs, it is not the type of gate-keeping IP that KL or T-I may have become with a bit of luck.

Consequently, with the strategic importance of S-W waning and access to RNAi triggers ceasing to be a limiting factor, Tekmira’s business development is almost entirely out of Alnylam’s control. If, as a result of the litigation, Alnylam lost all rights to Tekmira’s technology (certainly a plausible outcome if it comes to a trial*), the attraction of partnering with or acquiring Tekmira would increase even more.

* As I am writing this, Alnylam has just filed a $150M shelf registration with the SEC. This typically happens in anticipation of selling stock to the public. The timing of this shelf registration is unusual though, because Alnylam has over $300M in cash/cash equivalents, meaning that with the current and anticipated burn, it should not have a need for raising funds any time soon- under normal circumstances. Given my assessment of the strength of Tekmira’s case and the existential risk to Alnylam’s business, it would not surprise me if Alnylam’s lawyers are advising the company to settle the case. A $150M capital raise may be in the right range to allow for Alnylam to survive and remain an independent company.

A hostile takeover attempt as an alternative explanation? On paper, this would probably make most sense for Alnylam, but I don’t think so.

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.

Has mdRNA Found a Way around Alnylam’s RNAi Trigger IP Wall?

mdRNA has to be The RNAi Therapeutics corporate success story of 2009. At the brink of bankruptcy at this time of last year after problems with their former nasal delivery business sent the company into a breathtaking tailspin, the new management, critically made up of former Sirna Therapeutics executives, was able to save the company by quickly cashing in on some non-core assets, attracting upfront payments of about $12M in two non-exclusive RNAi Therapeutics deals with RNAi heavy-weights Novartis and Roche, and an opportunistic financing shortly after final approval of a partnered legacy generic (calcitonin-salmon nasal spray for osteoporosis) caused an irrational spike in mdRNA’s share price. Although I perceive mdRNA’s lack of RNAi Therapeutics publications as a clear weakness, also in light of its history of later unsubstantiated scientific claims, these developments are signs that not only is the management apparently well connected, but that the company has been able to establish a quite decent RNAi Therapeutics drug development platform and with IP that cannot be dismissed out of hand. Since the Novartis deal on delivery involved not only IP, but also the transfer of liposomal formulation know-how, but the Roche deal on RNAi triggers appears to be an IP-only deal, I have looked more into mdRNA’s claim of having freedom-to operate with its ‘proprietary’ RNAi trigger designs. Out of fairness, I should add here that a lot of this change had been set in motion with the old management.

It has become a popular game in the RNAi Therapeutics industry to design ways around Alnylam’s dominant RNAi trigger patent portfolio. While corporate strategy is the driving force behind these supposedly proprietary designs, given that intellectual property is not always guided by the spirit of science and since new trigger designs might have unexpected beneficial properties for certain applications, it is prudent to pay attention when Roche is willing to pay mdRNA non-refundable $5.0M for a non-exclusive license to mdRNA’s RNAi trigger IP claims after having just paid more than $300M for much less of Alnylam’s RNAi trigger IP. Of course, one might also view this deal, which was also largely free of downstream obligations, as a move by Roche to cover all their bases- just in case.

At the time of that deal, mdRNA had three RNAi trigger designs in its stable: certain rights to City of Hope’s Dicer substrates, the three-stranded meroduplex siRNA design after which mdRNA takes its name, and unlocked nucleic-acid-modified siRNAs (usiRNAs). Subsequent to that deal it emerged from regulatory filings that, perhaps because Dicerna appears to own most of the Dicer-substrate IP, that mdRNA has dropped Dicer substrates from their portfolio. Furthermore, since Dicerna would probably have been quite happy to make a deal with Roche, it would appear that Dicer-substrates, although part of the deal, was not the main motivation for Roche. This leaves us with meroduplexes and usiRNAs.

If you assembled five PhDs in molecular biology for a weekend, presented them with the main claims of Tuschl I and II, and asked them to come up with RNAi trigger design-arounds, in principle the result may have looked similar to what mdRNA arrived at. That the various designs should also likely to be functional biologically, at least to a certain degree, is a testament to the robustness of the RNAi pathway when it comes to relatively short double-stranded RNAs, a realization that has only sunk in subsequent to the Tuschl publications, but that was already heralded by the findings of Kreutzer and Limmer.

Both Tuschl I and II essentially claim double-stranded RNAs of 21-23 (T-I) or 18-24 (T-II) (contiguous?) NUCLEOTIDES in length. Besides size and overhangs which had been the main theater of the RNAi trigger IP war thus far, one might argue that an RNAi trigger that does contains a number of NON-nucleotides or in which the dsRNA is made up of three, and not two strands, does not literally violate the Tuschl claims.

I have long been puzzled why mdRNA would think that using unlocked nucleic acids (UNA) per se would be the solution, as I considered UNA just another nucleotide-modification alternative in the armamentarium of the siRNA synthetic chemist: UNAs are simply nucleic acids in which the C2-C3 bond has been disrupted (that is apparently also the process by which they are generated). But when the company’s CEO Michael French at the BMO Capital Markets Focus on Healthcare Conference made a point that it is the fact that UNAs supposedly are not nucleotides is indeed what underlies mdRNA’s interest in UNAs. A quick, non-representative survey among scientists that I know, however, was consistent with my initial assumption that UNAs clearly have to be considered ‘nucleotides’ as they look and behave like such. Moreover, there are numerous quotes by the inventor of UNA, Jesper Wengel of Denmark, and by the Danish company RiboTask from which mdRNA has exclusively licensed the UNAs for therapeutic applications that UNAs are modified nucleotides. The question therefore appears to boil down to whether potential partners first and then the patent offices can be convinced of that a ‘nucleotide’ that does not contain an intact ribose or deoxyribose strictly is a nucleotide no more. Although I am skeptical that any one nucleotide modification is sufficient to get around the Tuschl patents, I could imagine that the possibility alone of their literal interpretation could motivate others to come up with similar non-nucleotide siRNAs.

Aside from the IP considerations of usiRNAs, it is premature to judge the scientific value of this modification over others. The fact that ‘unlocking’ a nucleotide is a quite distinct modification should allow it to endow an siRNA with unique properties with respect to recognition by the RNAi machinery, target specificity, the potential to be recognized by innate immune receptors etc. What can be said based on the limited publication record (Bramsen et al., 2009: Large-scale screen....; Kenski et al., 2009: Analysis of acyclic nucleoside modifications...), UNAs like many other modifications are best tolerated in the passenger strand and can reduce off-targeting by the passenger-strand, whereas the use in the guide strand is much more position-dependent. Whether its judicious incorporation can indeed largely abrogate innate immune responses and/or allow for a better differentiation of on-target cleavage over microRNA-like off-targeting as claimed, remains to be seen and especially published (also because mdRNA/Nastech has a track record of making similar claims which tend to silently disappear over time). On the other hand, since Sirna Therapeutics (Merck) is evaluating UNA-modified siRNAs (Kenski et al., 2009), despite its access to Tuschl I, may be interpreted as a sign that there may indeed some unique scientific merit to usiRNAs, and mdRNA may derive value from controlling its use for RNA therapeutic applications.

Moving on to 3-stranded siRNAs, the other pillar of mdRNA’s RNAi trigger strategy, from an IP point one has to probably say that this stands a better chance of surviving Tuschl scrutiny with Tuschl II explicitly claiming double-stranded RNAs consisting of two strands. The double-strandedness of Tuschl I, however, could be more broadly interpreted in that a nick should not make a difference in determining the length of a double-stranded region. In this case, it will be interesting to find out how 3-stranded siRNAs with a gap instead of a nick would perform.

When I first heard of the 3-stranded siRNAs in 2006, I thought that this was based on the observations by a number of labs at the time that the passenger strand of the siRNA is cleaved as part of RiSC activation and that the objective of 3-stranded siRNAs thus was to hi-jack the RNAi machinery downstream of the intact siRNA. However, looking at the history of the relevant patents, it appears that this was not the case, but was merely a coincidence. There is, however, an interesting twist to the story. RiboTask, which happens to also be mdRNA’s partner in usiRNas, filed for almost identical patent protection, but with a priority date that appears to be a couple of months ahead of mdRNA’s. In the case of RiboTask, which calls the 3-stranded siRNAs not meroduplexes but small internally segmented interfering RNAs/LNAs (sisiRNA/sisiLNA), I do not want to be as dismissive about their scientific motivation, as they address a major concern of 3-stranded siRNAs related to their potential instability. Since short segments of double-stranded RNAs should be relatively unstable, they demonstrated (Bramsen et al., 2009: Improved silencing properties using small internally segmented interfering RNAs) that it is possible to restore ‘duplex’ stability by modifying it with locked nucleic acids, the mirror-image of UNAs and curiously invented by the same people. Moreover, they show that while heavy modification of both strands renders most siRNAs inactive (with the exception of 2’F and 2’-O-methyl), converting such a modified siRNA into a 3-stranded siRNA often restores at least some of the knockdown activity (also quite interesting from an RNAi mechanism point of view). The ability to heavily modify an siRNA without losing activity may be particularly useful for applications where the siRNA is exposed to nucleolytic degradation such as for conjugate-siRNA approaches. From a scientific perspective, I should also mention that the 3-stranded siRNA design is a way to abolish passenger strand microRNA-type off-targeting, although this is no more a considerable challenge for RNAi Therapeutics. It should also be of interest to evaluate how nicked, and particularly gapped siRNAs are recognized by the various innate immune receptors. The above demonstrations may also help RiboTask and mdRNA in their way through the patent offices, particularly in the US and in light of the mentioned academic research that might have started before RiboTask’s work, and I am curious whether the usiRNA relationship between RiboTask and mdRNA will be extended also to sisiRNAs/meroduplex technology.

Since IP is subject to interpretation and therefore fraught with some uncertainty, it remains to be seen whether mdRNA can achieve certain freedom-to-operate in the RNAi trigger space. Although usiRNAs are the current focus of the company, keeping the meroduplex as an alternative design option open seems prudent. More broadly, RNAi Therapeutics in general can only gain from investments in evaluating new modifications and designs as unforeseen beneficial properties could emerge from this. Until then, however, it is unlikely that any Big Pharma would want to risk their RNAi Therapeutics future entirely on mdRNA’s RNAi triggers. This also explains why mdRNA sees more partnership potential in its RNAi delivery efforts, the currently more pressing need in RNAi Therapeutics and for which the financials should continue to grow. mdRNA urgently needs such a partnership since although the company had just averted bankruptcy, with cash running out over the next 3 months, the struggle to get out of the bankruptcy quicksand has not stopped. Based on management, while a number of early-stage technology evaluations are ongoing, no significant upfront payments from partnerships can be expected until the middle of next year by which time it hopes to have more non-human primate data to satisfy a more discriminating Big Pharma audience. Given the positive developments of the company over the last year and management’s track record, investor interest should be sufficient to support a PIPE within the next 30-45 days so that the company gets a shot at achieving its partnership goal. If one indeed wanted to make the gamble on mdRNA’s management, from an investment perspective, waiting until more is learnt about the terms of the financing may be prudent, unless valuations continue to fall much further.

The Importance of 3’ Overhangs in RNAi Therapeutics

[Note: some of what follows, has already been discussed in the entry ‘On the Importance of Being Tuschl’]

There has been a flurry of activity surrounding the Tuschl patents. It appears that at stake is no less than the Tuschl II patent which claims the use of 3’ overhangs in siRNAs. The uncertainty comes from some of the owners of the Tuschl patent estates prosecuting the Tuschl I patent series such that it uses scientific data underlying the Tuschl II patents. Although I cannot see that 3’ overhangs are explicitly claimed in Tuschl I, the presence of such overhang data in Tuschl I could invalidate the claims in Tuschl II as their prior use would suggest that overhangs were already practiced in the art and/or trigger double-patenting/interference issues.

It has always been a surprise to me that virtually out of nowhere, Tuschl II data, generated at the Max Planck in Gottingen after his time at the MIT, would appear in Tuschl I, which is based on work at the Whitehead/MIT and UMass. The work underlying Tuschl I identified that short siRNAs are generated from longer dsRNAs (in Drosophila extracts) and that the short siRNAs are the likely mediators of RNAi. No mention of overhangs, and no reason to anticipate that overhangs would confer an advantage. The work by Elbashir, Lendeckel, and Tuschl that underlies Tuschl II characterized the siRNAs processed in Drosophila extracts and noted that they contained 3’ overhangs. Synthetic versions of these siRNAs were then found to mediate RNAi in Drosophila extracts and, in the famous Nature paper, human cells. The 3’ overhangs were not just functionally irrelevant consequences of RNase III processing, but found to confer a distinct advantage in RNAi silencing efficacy. This advantage has been borne out in many studies since by labs throughout the world, and the reason seems to be that the overhangs allow for efficient Argonaute loading of the guide strand. For a while, 3’ overhangs appeared to have an additional advantage over blunt-end siRNAs in that they would avoid some of the innate immune responses, although this is an area in which the jury is still out. Another finding that has been borne out by numerous studies is that 19-21 bp lengths work better than smaller or larger siRNAs (not discussing here Dicer-substrates though).

Tuschl I claims double-stranded RNAs of 21 to 23 nucleotides. Note that it says nucleotides, and not base pairs, so in theory it could be dsRNAs that do not have to be blunt ended. But again, at the time of the invention, nobody in the field would have been able to anticipate the presence, let alone an advantage of the overhangs. Tuschl II claims dsRNAs with individual strands of 19-23nt in length, with at least one of the ends having a 3’ overhang.

I do not want to comment here too much on the specifics of the case, and Doug Macron from ‘RNAi News’ has done a great job in following the story- except to say that it is clear that Max Planck (and Alnylam) would never have agreed to such use of Tuschl II data, and even if there had been some procedural issues (e.g. Tuschl ‘swore’ etc, when in reality most academic scientists trust that their patent agents would act in their best interest, and therefore just sign off patent documents that come across their desk/bench) I believe that at some point fiduciary duty has been violated by those hired and paid, also by Max Planck and Alnylam, to prosecute the Tuschl patents.

While I consider it possible that some fancy workarounds of the Alnylam IP estate may give certain freedom-to-operate to some companies, scientifically the sweet spot of siRNAs are those 19-21bp in length with at least one 3’ overhang end and the drug development economics would dictate these to be used and licensed. This area is very well covered by Alnylam through Kreutzer-Limmer, Tuschl I and II, although an unexpected outcome of the Tuschl proceedings could change the picture. On the other hand, one cannot dismiss the possibility that some non-Tuschl-like structure in combination with a certain modification pattern similar to what Silence Therapeutics claims e.g. actually works and is advantageous contrary to expectation, that is non-obvious, and I'd be happy to look at data that systematically demonstrates this.

Alnylam 1500, GSK 800

In what was possibly greeted in investor circles with a slight yawn, GSK and Alnylam announced today that Alnylam would add 1500 issued or pending RNAi Therapeutics-related patents to GSK’s 800 patent filings into an IP pool designed to facilitate the development of drugs for neglected tropical diseases. So what was this all about?

I do not want to dismiss the value of being a good corporate citizen per se or how it may win Alnylam and RNAi Therapeutics some political goodwill when it comes to charting their way through treacherous regulatory waters. I suspect, however, that there was another message hidden in today's press release. What struck me was that the joint press release emphasized the breadth and quality of Alnylam’s patent portfolio, including by juxtaposing Alnylam’s 1500 patents next to GSK’s 800 and the following quite friendly statement by GSK’s relatively new CEO, Andrew Witty (photo):

“We are delighted that Alnylam will join GSK in this important programme by adding their unique RNAi technology [emphasis mine] to the patent pool.”

This indicates to me that Alnylam and GSK are getting along pretty well. Both managements should be familiar with each other following the GSK-Regulus deal for the development of microRNA therapeutics for inflammatory disease (Regulus is the microRNA joint venture of Alnylam and ISIS). A positive experience there with small RNAs may have given GSK extra incentive to join the ranks of Roche, Takeda, Novartis, and Pfizer in considering RNAi Therapeutics as a bona fide remedy, if not cure for Big Pharma’s stuttering innovation machine and oncoming wave of expiring blockbuster. And yes, Merck is also one of them, and it is likely that when they bought Sirna Therapeutics in 2006, it left GSK looking for a new RNAi Therapeutics partner. Just before that in 2006, GSK and Sirna signed a major RNAi alliance for respiratory disease, and since then Merck has not made the impression that it likes to share its mysterious RNAi know-how.

You know where this is going, and regardless of whether an Alnylam-GSK RNAi platform alliance will actually be announced this year or whether this is just another example of my RNAi delusion, it is worth speculating about the scope of such a potential deal of which we expect at least one this year from Alnylam. Similar to the 2007 Roche platform deal, my guess with regards to therapeutic areas would be oncology, respiratory diseases, metabolic diseases and certain liver diseases. Since these are all areas in which significant improvements have been made in siRNA delivery in the last 2 years, the terms may be even more favorable.

And yes, it would be nice for GSK and Alnylam to combine their expertise in malaria drug development and liposomal siRNA delivery to the liver, respectively, to translate promising pre-clinical results by Alnylam and collaborators into a much needed weapon for a disease that disrupts the lives of up to 500 million people a year mostly in impoverished countries. That RNAi is even considered for such purposes is also a sign that the eventual cost of goods for RNAi Therapeutics should be well below that of recombinant proteins, including monoclonal antibodies, which in turn may be more suitable for vaccination approaches.

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.

Do Failed Biomarker Studies Spell Higher Costs for Bellwether Oligonucleotide Therapies?

Two of medicines most popular and accepted biomarkers, LDL-cholesterol for cardiovascular disease and blood-sugar levels for diabetes, have recently come under scrutiny after high-profile studies showed no benefit or even increased health risk despite the lowering of these biomarkers by drug treatment. Since some of oligonucleotide therapeutics’ most advanced early drug candidates are for metabolic diseases and aimed at lowering these two parameters for an accelerated path into the clinic, the issue deserves some further consideration.

The ENHANCE study used an imaging technique to look at changes in the thickness of plaque deposition in the carotid (large artery running through neck) in patients treated with a combination of a statin (Merck’s “Zocor”) and the dietary cholesterol uptake inhibitor ezetimibe (“Zetia” marketed by Merck and Schering-Plough) versus patients treated with the statin alone. After a year of delay in data reporting, the companies admitted that the combination, called Vytorin, did not lead to improvements in plaque thickness with even a trend towards adverse events, despite the fact that LDL-cholesterol was further decreased by the addition of ezetimibe. Combined with Pfizer’s infamous torcetrabip blunder that despite increasing the level of good cholesterol (HDL) the rate of death was actually increased, this shows that particularly with novel drug targets, biomarkers alone will not suffice and expensive outcome studies instead may be necessary to ensure clinical benefit. A similar lesson may be drawn from the results of a recent diabetes study that aimed to aggressively lower the gold standard biomarker in diabetes care, namely blood sugar levels as measured by glycylated hemoglobin.

It will therefore be interesting whether and how this will affect the view the FDA and other regulatory agencies take on drugs such as ISIS’ ApoB100 targeting antisense compound mipomersen or Alnylam’s PCSK9-targeting ALN-PCS01 siRNA. Although there is little doubt that e.g. in the case of mipomersen, similar to Zetia, there is a marked reduction in LDL-cholesterol in humans, because it is aimed at a novel target in LDL metabolism, the FDA may insist on having its therapeutic utility being proven in large outcome studies, except maybe for some patient populations with familial hypercholesterolemia.

These failed biomarker studies are only going to add to the increasingly conservative stance the FDA takes towards drug approval, at a time when drug approval rates are declining despite ballooning drug development expenses. These expenses are also driven in part by regulatory demands for large late-stage clinical registration studies. Clearly, this trend is not compatible with a drug industry from which we expect new medicines addressing unmet medical needs. This is compounded by popular calls for cheaper generic medicines which, while saving the healthcare system dollars in the short term, undermine long-term productivity and innovation. Drug development overall has become a money-losing game for most, and it is not fair pointing out the huge cash reserves of a few Big Pharma, which we know are about to diminish in the near future anyway, without taking into account the many enterprises that never see the light of profitability.

So what could be the solution? It is difficult to argue that savings should come at the detriment of patient safety. In the difficult act of juggling the demands for patient safety, ensuring innovation, drug access, and profitability for the companies, I see fostering innovation, leading to better medicines and more efficient development paths, as probably THE one solution that may satisfy all four demands.

The RNAi Therapeutics platform e.g. opens the prospect of shortening pre-clinical development times which should lead to faster drug approval times and therefore exponentially longer periods of sales exclusivities. Say conventional drug development takes 12 out of the 15 patent years, resulting in 3 years of sales exclusivity, while an RNAi Therapeutic may take on average 9 years to develop, i.e. doubling the time of sales exclusivity. One could therefore even argue that current trends actually amplify the competitive advantages of the RNAi Therapeutics platform. Nevertheless, in the end even RNAi Therapeutics will suffer when innovation fails to be protected, which is why the current temptation for prematurely approving or tolerating unlawful generics should be resisted and fundamental patents enforced. Given the importance of the US for worldwide drug development, I can only hope the candidates running for President understand all of this.