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.
Showing posts with label blocking IP position. Show all posts
Showing posts with label blocking IP position. Show all posts
Friday, July 11, 2008
Saturday, February 23, 2008
Recent Alnylam Patents Blur Distinction between Blunt-end dsRNAs and those with 3’ Overhangs
As many of you will be aware, the battle for RNAi IP is heated and particularly centers on whether Alnylam may also dominate over blunt-ended double-stranded RNAs between 22 and 24 base-pairs in length. Longer dsRNAs are covered by Fire and Mello and relatively easily accessible, 21bp and shorter dsRNAs are the domain of Kreutzer-Limmer and exclusive to Alnylam as are dsRNAs up to 25bp with 3’ overhangs (Tuschl II).
Although, even in the absence of applying obviousness criteria, I doubt that if Kreutzer-Limmer ultimately failed to be applied to 22-24bp RNAs, any other patent application would be able to do so based on prior art, this still raises the question whether 22-24bp RNAs will fall into a free-for-all grey zone.
While the seminal Elbashir et al. publication underlying Tuschl II provided compelling evidence that in most cases 3’ overhangs will enhance RNAi gene silencing, at least in tissue culture, recent patent application by Alnylam itself make me rethink the value of blunt-ends, particularly for in vivo applications.
At the end of January, Alnylam issued a press release on the issuance of the Woppmann patents in the UK (UK 2417727). Although I would not, by any stretch of the imagination, consider it to be an umbrella patent of the stature of Tuschl II, it is still a quite curious patent with relatively early 2003-4 priority in that it describes siRNAs with one blunt-end and one 3’ overhang end (often just one nucleotide) to have gene silencing advantages over the classical Tuschl design features (two 3’ overhangs, best if 2 nucleotides long).
I know that the following passage from the PR has caused some confusion among some of the readers of this blog, and admittedly also myself, as without carefully reading the claims of the patent it could be misunderstood as also covering dsRNAs with two blunt-ends, instead of dsRNAs combining the two features in just one molecule: ”The claims cover siRNA molecules of any length that contain "overhang" and "blunt end" design features, including siRNAs containing chemical modifications and certain novel motifs.”
Does this mean that Alnylam is back-tracking here on the value of 3’ overhangs, i.e. Tuschl II, which could have serious repercussions for the whole RNAi Therapeutics IP space and give companies like Silence Therapeutics or RXi some room to breath? The issue therefore is whether the one 1-nucleotide overhang is really that advantageous or just serves as a fig-leaf designed to disguise the value of blunt-end siRNAs. I therefore found the following passage from the description of another recent Alnylam patent application on the targeting of the Huntingtin gene by RNAi (USPTO application no. 11/588,674) of interest:
“In one embodiment, at least one end of the dsRNA has a single-stranded nucleotide overhang of 1 to 4, preferably 1 or 2 nucleotides. dsRNAs having at least one nucleotide overhang have unexpectedly superior inhibitory properties than their blunt-ended counterparts. Moreover, the present inventors have discovered that the presence of only one nucleotide overhang strengthens the interference activity of the dsRNA… dsRNA having only one overhang has proven particularly stable and effective in vivo, as well as in a variety of cells, cell culture mediums, blood, and serum.”
Maybe it should not come as a surprise that with intense research, the design features of RNAi triggers will evolve over time, somewhat reminiscent of what had happened with monoclonal antibodies before and this can only be a blessing for the realization of RNAi Therapeutics. However, from a business point of view, this raises the question what will be considered sufficiently novel or merely an improvement of a fundamental design. Clearly, at a time when many dsRNAs and also single-stranded oligonucleotides are found to be able to accomplish gene silencing via RNAi, the systematic analysis of particularly dsRNAs between ~19-25bp in length with various types of overhangs or no overhangs should be of value here. I’m almost sure this has been done already and is ongoing in other parts of the industry, but it certainly would be nice to see an unbiased publication on that very subject.
Although, even in the absence of applying obviousness criteria, I doubt that if Kreutzer-Limmer ultimately failed to be applied to 22-24bp RNAs, any other patent application would be able to do so based on prior art, this still raises the question whether 22-24bp RNAs will fall into a free-for-all grey zone.
While the seminal Elbashir et al. publication underlying Tuschl II provided compelling evidence that in most cases 3’ overhangs will enhance RNAi gene silencing, at least in tissue culture, recent patent application by Alnylam itself make me rethink the value of blunt-ends, particularly for in vivo applications.
At the end of January, Alnylam issued a press release on the issuance of the Woppmann patents in the UK (UK 2417727). Although I would not, by any stretch of the imagination, consider it to be an umbrella patent of the stature of Tuschl II, it is still a quite curious patent with relatively early 2003-4 priority in that it describes siRNAs with one blunt-end and one 3’ overhang end (often just one nucleotide) to have gene silencing advantages over the classical Tuschl design features (two 3’ overhangs, best if 2 nucleotides long).
I know that the following passage from the PR has caused some confusion among some of the readers of this blog, and admittedly also myself, as without carefully reading the claims of the patent it could be misunderstood as also covering dsRNAs with two blunt-ends, instead of dsRNAs combining the two features in just one molecule: ”The claims cover siRNA molecules of any length that contain "overhang" and "blunt end" design features, including siRNAs containing chemical modifications and certain novel motifs.”
Does this mean that Alnylam is back-tracking here on the value of 3’ overhangs, i.e. Tuschl II, which could have serious repercussions for the whole RNAi Therapeutics IP space and give companies like Silence Therapeutics or RXi some room to breath? The issue therefore is whether the one 1-nucleotide overhang is really that advantageous or just serves as a fig-leaf designed to disguise the value of blunt-end siRNAs. I therefore found the following passage from the description of another recent Alnylam patent application on the targeting of the Huntingtin gene by RNAi (USPTO application no. 11/588,674) of interest:
“In one embodiment, at least one end of the dsRNA has a single-stranded nucleotide overhang of 1 to 4, preferably 1 or 2 nucleotides. dsRNAs having at least one nucleotide overhang have unexpectedly superior inhibitory properties than their blunt-ended counterparts. Moreover, the present inventors have discovered that the presence of only one nucleotide overhang strengthens the interference activity of the dsRNA… dsRNA having only one overhang has proven particularly stable and effective in vivo, as well as in a variety of cells, cell culture mediums, blood, and serum.”
Maybe it should not come as a surprise that with intense research, the design features of RNAi triggers will evolve over time, somewhat reminiscent of what had happened with monoclonal antibodies before and this can only be a blessing for the realization of RNAi Therapeutics. However, from a business point of view, this raises the question what will be considered sufficiently novel or merely an improvement of a fundamental design. Clearly, at a time when many dsRNAs and also single-stranded oligonucleotides are found to be able to accomplish gene silencing via RNAi, the systematic analysis of particularly dsRNAs between ~19-25bp in length with various types of overhangs or no overhangs should be of value here. I’m almost sure this has been done already and is ongoing in other parts of the industry, but it certainly would be nice to see an unbiased publication on that very subject.
Saturday, December 1, 2007
The Confusing World of AtuRNAi, Stealth siRNAs and mdRNAs (III and Final Part): The RNAi Therapeutics Fashion Show
Shortly after Alnylam announced issuance of patent protection for the Kreutzer-Limmer series covering double-stranded RNAs between 15 and 49 base-pairs in Germany this week, the CEO of Silence Therapeutics, Jeffery Vick, shot back at an investor conference presentation reassuring their investors that this development would not affect Silence’s freedom-to-operate, including its all-important ability to close lucrative partnerships based on their proprietary (?) Atu-siRNA technology. Vick’s confidence stems from the observation that the first Kreutzer-Limmer patent had been opposed in Europe before and was consequently reduced to cover dsRNA of 15 to 21 base-pairs in 2006 (see previous Blog entry), and therefore would cover Silence’s blunt, 23 base-pair Atu-siRNAs. He vowed to fight the new patent, which is now likely to be issued throughout Europe in due course, to restrict its scope. My impression is that the patent attorneys will have a feast in the years to come, and just wait until Alnylam sees the time has come to return the favor and go after Silence’s issued patents.
Vick’s views obviously were not echoed by Alnylam’s CEO, John Maraganore, also at an investor presentation, who emphasized that no single patent will give you the right to work on commercializing RNAi Therapeutics. For freedom-to-operate, it takes a whole range of fundamental patents, such as IP covering the use of double-stranded RNAs for gene silencing in humans (Kreutzer-Limmer, Tuschl, Kay), nucleic acid modifications to make them drug-like (Crooke), and even the use of an dsRNAse-mediated mechanism itself (Crooke). It is the view of many, including myself, that it was Alnylam that has understood it very early on to gain exclusive and non-exclusive access to all of the early patents and applications that could even remotely impinge on the use of RNAi in the clinic. What this means is that only Alnylam has a blocking IP estate and that no matter which fundamental (e.g. Fire-Mello) or fringe patents you may have access to, you will still have to pay your dues in one form or another at the Alnylam toll gate. It is worth remembering that at least in the US, a patent does not give you the right to do anything, but the right to block somebody else from using the underlying technology.
So now let’s turn our attention to the RNAi Therapeutics catwalk, looking at the IP and technology strengths and weaknesses of a couple of better known RNAi Therapeutics companies (excluding Big Pharma with RNAi operations):
1) Alnylam Pharmaceuticals: The leader in the translation of the science of RNAi into drugs. Has virtually freedom-to-operate and blocking IP estate, now validated by a number of high-profile partnerships. Ability to gain access to the most promising delivery platforms desirable; IP protection may be sought for knocking down certain genetically validated genes for certain diseases, like they have done for VEGF before. Sorry- “Not-For-Sale”, want to become a top-tier biopharmaceutical themselves.
2) RXi (RNAi subsidiary of CytRx): Has assembled a motley array of patents including access to Tuschl I via UMass and Hannon (both co-exclusive with Alnylam), although many have not issued. These patents may lessen the pain when paying the Alnylam toll. Credible and engaged scientific advisory team including Nobel laureate Craig Mello (UMass) and Greg Hannon (Cold Spring Harbor). Puzzlingly, this company has not made much public progress in moving RNA therapeutics into the clinic. What are they waiting for?
3) Silence Therapeutics: Proven RNAi Therapeutics know-how with already two licensed compounds in the clinic and more to come soon. I am pleased by their progress on siRNA delivery to the vasculature, boding well for their anticipated cancer trials. Their 23 base-pair Atu-RNAi was granted IP protection in Europe and they hope to obtain same in the US soon. This allowed them to close a number of partnerships with Big Pharma, although the upfront payments were not enormous. They are, however, moving on very thin ice if they believe that with this one patent they have freedom-to-operate. It is mostly for their know-how that I believe that they may be one of the next RNAi acquisition targets by Big Pharma. Such a takeover would be “friendly” given Silence’s frequent statements that they would not mind being bought out.
4) Nastech: As RNAi was slowly getting some attention, Nastech quickly assembled a rather large team of experienced nucleic acid scientists that has been busy churning out patent application after patent application with the aim of working around Alnylam’s blocking IP position. Like Silence Therapeutics (and Dicerna) they hope that the scope of Tuschl II and Kreutzer-Limmer will ultimately not cover “long” small interfering RNAs. The ice may be thicker here than for Silence though. Apparently over 150 patent applications, more than Alnylam, according to CEO Steven Quay. Looked up one of their more recent ones on cross-linked peptide-siRNA particles for RNAi delivery. If I understood that one data slide correctly, they only achieved a 15% knockdown (???). Their other applications rather be better in terms of enablement, otherwise I would get the impression that the 150 applications are part of an overblown balloon. Nevertheless, should be considered a takeover candidate for Big Pharma that wants to hit the ground running in RNAi. However, following the P&G disaster, their position in partnership and fund-raising negotiations is quite hurt.
5) Benitec: Australian DNA-directed RNAi company, beaten a hasty retreat from the US after management and dubious patent issues caused them to run out of money. Still, a Benitec-sponsored HIV trial is well and underway at the City of Hope and it can only be hoped that they will remain a force in realizing the promise of DNA-directed RNAi. Only small in-house scientific team, strongly relying on their clinical partners for technology know-how. Major issue is their ability to attract funding when there is a lot of uncertainty surrounding the quality of their IP claims. Nucleonics, which has a phase I DNA-directed RNAi trial for HBV ongoing and is out to raise more funds, considered their arch-rival, but a number of other gene therapy companies, including Targeted Genetics and Introgen, also likely to extend their work in RNAi. DNA-directed RNAi efforts are somewhat less affected by Alnylam’s dominant IP estate, but overlaps exist.
6) Calando (subsidiary of Arrowhead Research Corp.): One of the increasing number of RNAi companies with a focus on delivery, in this case based on cationic cyclodextrin polymers that bind siRNAs for systemic, and potentially targeted delivery. Tox/efficacy data from non-human primate work indicates that this formulation may have promise for cancer applications. Need to license core siRNA patents. Although they may not be a prime acquisition target at this stage, clinical proof-of-concept studies may make them interesting for Big Pharma and Alnylam in 3-5 years.
7) Protiva-Tekmira: Although arch-rivals, I mention them together, because they belong together, both working on cationic liposomal delivery of RNAi. Right now, cationic liposomes are the most advanced systemic RNAi delivery method and both companies consequently had no lack of partnering interest. Unfortunately, IP (Tekmira) and related enabling know-how (Protiva) appear to be split between the companies, and maximal value creation should be achieved through collaboration, rather than wasting their time in the courts. One would hope that both parties realize soon that the whole is so much more valuable than the sum of the parts. If they would face the economic realities they would get back to business and either re-unify or cross-license (I will never get tired of making that plea, in case you have not noticed).
8) Innumerable nanotech delivery efforts, some of which are set to rise to more prominence. One such company is Intradigm that has done some interesting work on RNAi delivery a couple of years ago. Essentially all of them aim to partner their technologies sooner or later. A niche player is Cequent Pharmaceuticals, based on “trans-kingdom RNAi” where orally administered bacteria that express short hairpin RNAs are used to deliver RNAi to the small and large intestine for the treatment of related diseases such as inflammatory bowel disease and cancer. While their Nature Biotech paper showed promise, due to the out-of-the-box nature of this invention and many open mechanistic questions, more data is needed to make me feel at ease with this technology. Nevertheless, the $9M funding round this summer, including the Novartis Option Fund, should be taken as a vote of confidence.
While Alnylam is not-for-sale, many of the other pure play RNAi Therapeutics companies were obviously established and are managed with the intention of being sold off to larger corporations. Sirna Therapeutics was the first one to go and more are likely to follow. Accordingly, John Rossi stated in an interview about the Dicer-substrate start-up Dicerna that this company was basically established with the intention of selling it off to an innovation-starved, RNAi-challenged Big Pharma later on. Consequently, I believe that the RNAi Therapeutics landscape in 20 years will likely largely consist of Alnylam, Alnylam-licensed Big Pharma companies, some of which will have bought in nucleic-acid know-how in the form of small pure-plays biotechs. Those that did not find any suitor will have a difficult time of surviving, and may only survive by hitting the clinical jackpot early on in the game.
Vick’s views obviously were not echoed by Alnylam’s CEO, John Maraganore, also at an investor presentation, who emphasized that no single patent will give you the right to work on commercializing RNAi Therapeutics. For freedom-to-operate, it takes a whole range of fundamental patents, such as IP covering the use of double-stranded RNAs for gene silencing in humans (Kreutzer-Limmer, Tuschl, Kay), nucleic acid modifications to make them drug-like (Crooke), and even the use of an dsRNAse-mediated mechanism itself (Crooke). It is the view of many, including myself, that it was Alnylam that has understood it very early on to gain exclusive and non-exclusive access to all of the early patents and applications that could even remotely impinge on the use of RNAi in the clinic. What this means is that only Alnylam has a blocking IP estate and that no matter which fundamental (e.g. Fire-Mello) or fringe patents you may have access to, you will still have to pay your dues in one form or another at the Alnylam toll gate. It is worth remembering that at least in the US, a patent does not give you the right to do anything, but the right to block somebody else from using the underlying technology.
So now let’s turn our attention to the RNAi Therapeutics catwalk, looking at the IP and technology strengths and weaknesses of a couple of better known RNAi Therapeutics companies (excluding Big Pharma with RNAi operations):
1) Alnylam Pharmaceuticals: The leader in the translation of the science of RNAi into drugs. Has virtually freedom-to-operate and blocking IP estate, now validated by a number of high-profile partnerships. Ability to gain access to the most promising delivery platforms desirable; IP protection may be sought for knocking down certain genetically validated genes for certain diseases, like they have done for VEGF before. Sorry- “Not-For-Sale”, want to become a top-tier biopharmaceutical themselves.
2) RXi (RNAi subsidiary of CytRx): Has assembled a motley array of patents including access to Tuschl I via UMass and Hannon (both co-exclusive with Alnylam), although many have not issued. These patents may lessen the pain when paying the Alnylam toll. Credible and engaged scientific advisory team including Nobel laureate Craig Mello (UMass) and Greg Hannon (Cold Spring Harbor). Puzzlingly, this company has not made much public progress in moving RNA therapeutics into the clinic. What are they waiting for?
3) Silence Therapeutics: Proven RNAi Therapeutics know-how with already two licensed compounds in the clinic and more to come soon. I am pleased by their progress on siRNA delivery to the vasculature, boding well for their anticipated cancer trials. Their 23 base-pair Atu-RNAi was granted IP protection in Europe and they hope to obtain same in the US soon. This allowed them to close a number of partnerships with Big Pharma, although the upfront payments were not enormous. They are, however, moving on very thin ice if they believe that with this one patent they have freedom-to-operate. It is mostly for their know-how that I believe that they may be one of the next RNAi acquisition targets by Big Pharma. Such a takeover would be “friendly” given Silence’s frequent statements that they would not mind being bought out.
4) Nastech: As RNAi was slowly getting some attention, Nastech quickly assembled a rather large team of experienced nucleic acid scientists that has been busy churning out patent application after patent application with the aim of working around Alnylam’s blocking IP position. Like Silence Therapeutics (and Dicerna) they hope that the scope of Tuschl II and Kreutzer-Limmer will ultimately not cover “long” small interfering RNAs. The ice may be thicker here than for Silence though. Apparently over 150 patent applications, more than Alnylam, according to CEO Steven Quay. Looked up one of their more recent ones on cross-linked peptide-siRNA particles for RNAi delivery. If I understood that one data slide correctly, they only achieved a 15% knockdown (???). Their other applications rather be better in terms of enablement, otherwise I would get the impression that the 150 applications are part of an overblown balloon. Nevertheless, should be considered a takeover candidate for Big Pharma that wants to hit the ground running in RNAi. However, following the P&G disaster, their position in partnership and fund-raising negotiations is quite hurt.
5) Benitec: Australian DNA-directed RNAi company, beaten a hasty retreat from the US after management and dubious patent issues caused them to run out of money. Still, a Benitec-sponsored HIV trial is well and underway at the City of Hope and it can only be hoped that they will remain a force in realizing the promise of DNA-directed RNAi. Only small in-house scientific team, strongly relying on their clinical partners for technology know-how. Major issue is their ability to attract funding when there is a lot of uncertainty surrounding the quality of their IP claims. Nucleonics, which has a phase I DNA-directed RNAi trial for HBV ongoing and is out to raise more funds, considered their arch-rival, but a number of other gene therapy companies, including Targeted Genetics and Introgen, also likely to extend their work in RNAi. DNA-directed RNAi efforts are somewhat less affected by Alnylam’s dominant IP estate, but overlaps exist.
6) Calando (subsidiary of Arrowhead Research Corp.): One of the increasing number of RNAi companies with a focus on delivery, in this case based on cationic cyclodextrin polymers that bind siRNAs for systemic, and potentially targeted delivery. Tox/efficacy data from non-human primate work indicates that this formulation may have promise for cancer applications. Need to license core siRNA patents. Although they may not be a prime acquisition target at this stage, clinical proof-of-concept studies may make them interesting for Big Pharma and Alnylam in 3-5 years.
7) Protiva-Tekmira: Although arch-rivals, I mention them together, because they belong together, both working on cationic liposomal delivery of RNAi. Right now, cationic liposomes are the most advanced systemic RNAi delivery method and both companies consequently had no lack of partnering interest. Unfortunately, IP (Tekmira) and related enabling know-how (Protiva) appear to be split between the companies, and maximal value creation should be achieved through collaboration, rather than wasting their time in the courts. One would hope that both parties realize soon that the whole is so much more valuable than the sum of the parts. If they would face the economic realities they would get back to business and either re-unify or cross-license (I will never get tired of making that plea, in case you have not noticed).
8) Innumerable nanotech delivery efforts, some of which are set to rise to more prominence. One such company is Intradigm that has done some interesting work on RNAi delivery a couple of years ago. Essentially all of them aim to partner their technologies sooner or later. A niche player is Cequent Pharmaceuticals, based on “trans-kingdom RNAi” where orally administered bacteria that express short hairpin RNAs are used to deliver RNAi to the small and large intestine for the treatment of related diseases such as inflammatory bowel disease and cancer. While their Nature Biotech paper showed promise, due to the out-of-the-box nature of this invention and many open mechanistic questions, more data is needed to make me feel at ease with this technology. Nevertheless, the $9M funding round this summer, including the Novartis Option Fund, should be taken as a vote of confidence.
While Alnylam is not-for-sale, many of the other pure play RNAi Therapeutics companies were obviously established and are managed with the intention of being sold off to larger corporations. Sirna Therapeutics was the first one to go and more are likely to follow. Accordingly, John Rossi stated in an interview about the Dicer-substrate start-up Dicerna that this company was basically established with the intention of selling it off to an innovation-starved, RNAi-challenged Big Pharma later on. Consequently, I believe that the RNAi Therapeutics landscape in 20 years will likely largely consist of Alnylam, Alnylam-licensed Big Pharma companies, some of which will have bought in nucleic-acid know-how in the form of small pure-plays biotechs. Those that did not find any suitor will have a difficult time of surviving, and may only survive by hitting the clinical jackpot early on in the game.
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