Silence Therapeutics’ press release following the initiation of the Glover patent opposition hearings has to be counted as yet another example of the company’s series of misleading and factually flawed public statements.
Claiming that “the Glover patents was arguably Alnylam’s broadest patent” may be true in the sense that the patent claimed a lot, essentially double-stranded RNAs for gene silencing in mammals, but it is far from true, as Silence would want you to believe, that it represented Alnylam’s most important (RNAi trigger) patent. As Michael King from Rodman & Renshaw rightly noted in a report on the Xconomy blog, these are Tuschl II, followed by Crooke and Kreutzer-Limmer. Actually, when you would use the search function on my blog, yesterday may have been the first mention of the Glover patent. That’s how important I have considered this patent to be.
If I had been part in the early planning stages of Alnylam, a company that had been built around Tuschl II, Glover would have been a worry due to its early date and broad claims. But it is clear that Glover did not solve the non-specific interferon response issue that had critically impeded the broad application of RNAi in man, and claiming such based on studies in exceptional model systems such as oocytes and pre-implantation embryos may be overly ambitious. Still, a good patent to have control over and a weakening of Glover after the appeals have been heard, would only strengthen Tuschl II.
Another salient example of Silence’s overly zealous PR machine is the Quark issue. I’ve always found it amusing to come across Silence Therapeutics’ lengthy press releases that typically follow any pipeline and business development progress by their PR-wise much more conservative partner Quark Biotech, making it appear as if these achievements were almost entirely to the credit of Silence Therapeutics. Not surprisingly, according to a report in February this year by David P. Hamilton on the VentureBeat Blog, this appears to be a mis-representation and Quark is not very happy with this situation. I would not be surprised if Alnylam's COO Barry Greene, on his recent visit to Israel, had not visited Quark's operations there to see if the relationship between the two companies could be strengthened.
And finally, whether it’s liposomes or lipoplexes, hey, we are also working with some kind of a fat globule and if Merck says they are safe then we want to be part of it. And who really cares and understands the difference anyway?
I understand that PR is a very important element of the business strategy particularly of a developmental-stage biotech, but it has to be handled with care and, in a financial world where free and fair reporting is lacking, if careless may cost you the credibility in the eyes of one of your most important constituencies- your investor.
Dirk:
ReplyDeleteBack to the good old times, when I was a postdoc in the US, my fellows and I were actually working hard 12-16 h per day at the bench just for the one ultimate goal to produce results and obtain new scientific insights. By this somebody could claim an expert in his particular field of research. Well, this concept has apparently changed recently, and today’s sixth year postdocs obviously prefer sitting in front of a computer and writing blogs on complicated therapeutic development programs, patent landscapes, commercial issues and business strategies,…..and do experiments in their spare time (? Wow). “Smart-ass consulting” seems to become a major activity rather than critically analyzing and addressing scientific opinions and concepts. I am very amazed that you reveal yourself as an expert on science, business and now even patent issues. Wow, I am very impressed.
Anyway, with regard to your last blog “It’s getting lonely…” (What a wording) you have finally urged me to write this comment. In general, there is no problem with having different opinions about a complex issue, but facts, which are discussed and are mentioned, should be correct.
1. The Glover patent was revoked in his entirety by the Opposition Division of the European Patent Office, of course it is a decision, which might be challenged in the future again, but the news is, that the opponents have won this battle.
2. You are mentioning the Kreutzer-Limmer patent “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.”
Kreutzer-Limmer never claimed long double-stranded RNAs ! Originally they claimed 15-49 and no they are down to 15 to 21 nt, a significant narrowing of the original claims- also a decision by the EPA.
3. You mention “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.” This is also an interesting statement but, without reducing the scientific achievements of Tom Tuschl, I hope you and others are aware that the filing of Kreutzer-Limmer is earlier than the Tuschl patent series. The Tuschl II series claim siRNA molecules with overhangs according to the claim 1 (see below).
US Patent No. 7,056,704
Claim 1. A method for preparing a double stranded RNA molecule which mediates the cleavage of an mRNA in a mammalian cell, comprising (a) synthesizing two RNA strands each having a length from 19 25 nucleotides, and (b) combining the synthesized RNA strands under conditions suitable to form a double stranded RNA molecule, wherein said double stranded RNA molecule has a double stranded region of 14 24 nucleotides in length and one or two 3' overhang regions of 1 5 nucleotides in length.
4. “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”
From what I have read in the past in this blog, it’s obvious to everybody that you’ve been admiring and glorifying the efforts of the mentioned company (…even in a situations like this one discussed in the current blog). Therefore, I am surprised that this particular company hasn’t made you an offer to join their PR department…..or maybe the offer to spend a few bucks for funding your 7th and 8th postdoc years? Successful business (…the reason for your admiration?) does not necessarily correlate with scientific excellence!
After following your blog for the past year, I have to recommend that you should get back to the bench and do decent experiments that would help to solve the major obstacles for the development of RNAi therapeutics, instead of blathering absurdities. Perform therapeutic experiments and learn yourself how difficult it is to develop an nucleic acids based drug before judging and commenting on approaches, strategies and even patents: that would clearly have a better impact than blogging!
Someone who is as opinionated as "Anonymous" should not hide behind it. Please post your name and qualifications. (Dr. Nick Ochs, reader and small investor.)
ReplyDeleteJust wanted to say, Dirk, that I appreciate you sharing your insight with us. "Anonymous", the first commentator, clearly has an agenda and an axe to grind (perhaps he works for a company trying to establish themselves in the field?) - but he doesn't speak for me... and I would guess he same could be said for the majority of your readers.
ReplyDeleteThanks again.
Dear Anonymous,
ReplyDeleteThank you for telling me who I am and I sincerely apologize if you as a scientist feel your hard work is being diminished by what I have written here. It is not the science that I criticize, but how it is being grossly misrepresented by the PR strategy of a certain company, definitely not for the purpose of good science and transparency.
Just briefly though, your comment about 6th year post-docs is ridiculous and an insult to all hard-working post-docs, some of which may even choose to stay in that position for various reasons. Success in life is not necessarily measured by the money you earn or the title you carry. Moreover, your assertion here that I am personally in my 6th year is equally absurd, and if you feel I work too little, maybe you would want to contact my PI about your concerns- if you haven’t already done so, of course, in the hope of shutting me down. Some people actually love both science and business and are willing to work hard for both.
But I’m sure there are people out there that wished that I would just be quiet and have financial analysts and PR people without a background in science, not to speak of RNAi itself, shape stakehoders’ opinions on RNAi Therapeutics. I’m glad though that you have now chosen this venue to discuss the issues. It is better than having a PR company regularly contact me with dubious promises.
Kreutzer-Limmer: again, an early patent that’s “dangerous” to anybody working on RNAi Therapeutics for its early filing date and potentially broad coverage. If you had me choose between Kreutzer-Limmer and Tuschl II, scientifically it would be Tuschl II, but as history has shown that good science not always prevails in patent courts and overlapping claims should not co-exist, the purpose of having multiple layers of patent defenses is that once the claims have been narrowed down as part of opposition proceedings and appeals, they should complement each other in the end. The EPO has narrowed down K-L to 15-21 nucleotides, and as you will be well aware, that’s very relevant for RNAi Therapeutics, even more so in light of cost and manufacturing considerations and also innate immune responses such as TLR3 that are more prone to be elicited by longer dsRNAs as well as blunt-ends.
Note, however, there was a divisional patent application that had been granted in Europe (EP1214945) and post the 15-21nt decision of which the claims cover 15-49nt.
To your third point- yes, K-L precedes Tuschl II, and if you ask me, that’s the very reason why Alnylam would have wanted to control it, just in case. And you would also be right to conclude that even if in its final form K-L would not cover dsRNAs over 24 nucleotides due to Fire-Mello, the experiments in K-L, but also Tuschl II represent prior art for so called AtuRNAi and Stealth RNAi designs (length, modification, overhang or not), or at least render them obvious to those in the art. Very difficult to get anybody interested to invest in a technology that is not protected.
I look forward to seeing your progress in the delivery and safety of RNAi Therapeutics, rather than diverting precious research time and money to issues that do not need as much attention. It’s also a better way to create value for your shareholders.
Dirk.
Dirk, you need to add "anonymous asshole comment" filter on your blog page!
ReplyDeleteCritical comments on issues that foster debate make this blog all the more interesting but this comment was just insulting and betrays frustration of whoever wrote it. People posting this should at least have the courage to sign themselves.
Thanks for this great blog and rest assured that the time and effort you put into this is appreciated and admired by most.
Martin
I'll take Dirk's commentary over a financial ANALyst's any day of the week.
ReplyDeleteHi Dirk
ReplyDeleteFor what its worth, I think you generally do a first class job at ensuring you can be as objective as possible.
Great article as always. I suppose that Alnylam has also been guilty of misleading PR - for example, previously making out that its IP covered all blunt ended molecules
I'd be interested to hear your thoughts on why some of the opponents bothered to challenge the Glover patent, while also claiming freedom to operate?
Silence therapeutics has for example, stated that it had freedom to operate under the Glover patent. However, they have opposed it. In some ways, should the various companies not actually want the surrounding IP to be strong to ensure that their own IP is less likely to be circumvented?
Lastly, I've not yet fully reviewed the June 08 non-final rejection on Tuschl I. If you have yourself reviewed it, it would be good to hear your thoughts. Furthermore, if granted, do you see it having a significant bearing on companies such as Silence?
Keep up the good work.
GS
Good point, Anonymous!!
ReplyDeleteJimmy
Just to build on my earlier comment...
ReplyDeleteMy thinking is that Silence should want any IP relating to 25 nucleotide sequences to be strong, since this would block others from bypassing their own patents?
I am learning a lot from reading this blog. Perhaps I am learning too much; the comment by mister angry anonymous is a hint that you are talking too much. So keep at it!
ReplyDeleteP.S.: What is the percentage of bull shit overall in biotech? I would say around 80%. (Conservative figure.)
GS,
ReplyDeleteThank you for your questions.
“I suppose that Alnylam has also been guilty of misleading PR - for example, previously making out that its IP covered all blunt ended molecules”
There are various reasons for making this claim. Of the 3 first demonstrations of RNAi in mammalian cells (Kreutzer-Limmer, Glover, Tuschl), note that Alnylam has exclusive access to all of them. In the underlying research, and as explicitly described in Kreutzer-Limmer and Tuschl II, blunt-end dsRNAs were demonstrated to function in RNAi, albeit generally at lesser efficiencies. My reasoning why Tuschl II only describes blunt-end, but does not claim them is that they would be in conflict with Kreuzter-Limmer. I would be surprised if among the 3 patents, blunt-end dsRNAs would not be covered after all is said and done. Even assuming that they won’t be covered, the patents would constitute prior art for all subsequent blunt-end dsRNAs with all its commercial consequences for RNAi Trigger competitors. But again, if in the current patent system it is not possible to protect blunt-end dsRNAs when you have exclusive access to all the seminal work demonstrating it, then the future of biotech is doomed- with all its consequences for health and the economy.
“I'd be interested to hear your thoughts on why some of the opponents bothered to challenge the Glover patent, while also claiming freedom to operate?”
and
“Silence therapeutics has for example, stated that it had freedom to operate under the Glover patent. However, they have opposed it. In some ways, should the various companies not actually want the surrounding IP to be strong to ensure that their own IP is less likely to be circumvented?”
There are certainly a number of conflicting claims out there in the patent space. To make an RNAi Therapeutic, it takes more than just one patent (structure, mechanism, delivery, target, indication), so the claim of freedom-to-operate would have to be specified also with regard to specific targets and indications. Even when the “freedom-to-operate” claim refers to the RNAi trigger chemistry only, arguably the most valuable piece of the puzzle, this would also require a comprehensive patent strategy. Patent challenges often rightly narrow down claims that were initially overly optimistic, and my feeling is that Glover was indeed too ambitious in generally claiming RNAi for mammalian cells. An eventually narrowed down patent with claims pertaining to oocytes and pre-implantation embryos and possibly “Dicer-substrate RNAi” in mammalian cells, may be stronger and create more clarity for the RNAi Therapeutics patent space.
“Lastly, I've not yet fully reviewed the June 08 non-final rejection on Tuschl I. If you have yourself reviewed it, it would be good to hear your thoughts. Furthermore, if granted, do you see it having a significant bearing on companies such as Silence?”
Thanks for letting us know about this development. Could you please post the link for that? I’ve noted before that Tuschl I does not describe the structure of an siRNA, and surprisingly claims at the very end RNAi in mammals based on an experiment that appeared to be out of place and really should have been part of Tuschl II. IMO, it is Tuschl II that makes life hard for all the other early mammalian RNAi patents. For more of my views on Tuschl I and II, you could use the search function in this blog.
I’m fairly new to the patent prosecution process, and as pointed out above I am not a patent expert, but the non-final rejection letter appears to address two issues: 1) (‘detailed action’) there appear to be a number of Tuschl I applications in the patent aether causing problems with overlapping/conflicting claims- this should be a minor hurdle, but may become interesting as to who is considered the patent assignee. Depending on whether one of the other Tuschl I’s get issued, the rejection will be upheld or not; 2) (in the ‘response to arguments’ section) Tuschl I claims (single-stranded!) ~21-23 nucleotide small RNAs derived from dsRNase processing. The patent examiner holds that a Crooke patent would already cover such dsRNase-derived oligo matter and their subsequent use in biochemical experiments. That’s quite interesting as it would suggest that the way the RNAi triggers were obtained in Tuschl I (dsRNase derived) and Tuschl II (synthetised) could become quite important differentiator for the patentability of such RNAi triggers.
ReplyDelete"But again, if in the current patent system it is not possible to protect blunt-end dsRNAs when you have exclusive access to all the seminal work demonstrating it, then the future of biotech is doomed- with all its consequences for health and the economy."
ReplyDeletei suggest you have a look at the 47p non final response from the examiner in the re-exam of the Graham patent if you want a snapshot of state of the art of patent system. It's quite an eye opener with significant referencing of antisense prior art.
USPTO Pairs website, application No. 90/007,247
Hi Dirk,
ReplyDeleteJust dropping by to reply to some of your comments. I'll try to put together something better later. In terms of the prior art, yes, Alnylam's patents mention blunt ends. However, SLN's hope is that this art showed blunt ends to be inadequate. As such, it is only their invention of blunt ends AND modifications, alternating across the whole strand, that allowed blunt ends to work. It will be interesting to see a) whether they can get this past the US examiner b) whether Tuschl I will eventually be issued in a form that removes SLN's supposed freedom to operate!
GS- Tuschl has already shown that blunt-ends work- just less efficiently than overhang siRNAs. So unless Silence can show that their siRNAs with modifications in the center of the double-stranded RNA and with their exact pattern dramatically improve gene silencing (which btw I doubt very much), I don’t think that this has any chance of being considered sufficiently novel.
ReplyDeleteNeither Tuschl I nor II were deemed prior art for Silence's EU patent. Conversely though, the US examiner does state Tuschl as being prior art (10/633,630). It will be interesting to see how the examiner responds to Silence's reply (expected any day), since if the USPTO agrees that '630 should be allowed despite Tuschl's work, the implications would perhaps be that Tuschl must then be scaled back to exclude blunt ends with modifications - essentially positioning Silence's AtuRNAi as an alternative to getting an Alnylam license?
ReplyDeleteRe Tuschl I in Europe:
ReplyDeleteAn unknown party has filed the following observations to EP1309726
stating:
1) not enough detail on other features such as ends and modifications
2) extrapolated from drosophilia to mammals
3) suggestions that overhanging ends should be introduced to the claims as spec suggests these are needed
I get the impression that this is Silence? Will be interesting to see the examiner's next reply?...
& lastly...
ReplyDeleteAlnylam didnt quote Tuschl I or II in their opposition of Silence's EU patent.
I'd read from that that a) they didnt feel it does sufficiently anticipate Silence's claims b) they dont want to expose their key patents to an attack, even if the risk is low (see Benitec vs. Nucleonics) c) they feel they have sufficient evidence from other sources with which to challenge it.
I'd suspect c) ?
Hi Dirk
ReplyDelete“I suppose that Alnylam has also been guilty of misleading PR - for example, previously making out that its IP covered all blunt ended molecules”
>>There are various reasons for making this claim
Sorry, with that, I was referring to the Wopmann (?) press release.
[apologies for so many comments!]
GS- I agree that the Woppmann release was a bit confusing. And since we are talking about Woppmann already, I also agree with you that sending the Woppmanns et al into the patent battle is about keeping the Queen (Tuschl II) safe until she is needed. As we are learning, the patent courts have totally lost their ability to differentiate between inventions that provide real solutions and those that are me-too workarounds. It's all about semantics by people with little appreciation for the underlying science and Alnylam is only playing the game it has to play in such an environment. I am waiting for the day when the intolerability of the current patent system just becomes too much and there will be sweeping changes.
ReplyDeleteI'd think it was more a case of keeping the Queen safe to protect their business, rather than because its a more potent attacker?
ReplyDeleteThe USPTO has allowed SLN's claims (as has the EU), so it stands therefore that none of Alynlam's patents are prior art.
I'll admit that I dont know the exact origins of Silence's work, but if overly broad patents such as Glover were allowed through, it sould stifle invention. I dont think it would do anyone any good if Alnylam had a total monopoly? Alnylam is doing incredibly well as it is and there is more than enough room for a number of players.
"I'll admit that I dont know the exact origins of Silence's work, but if overly broad patents such as Glover were allowed through, it sould stifle invention. I dont think it would do anyone any good if Alnylam had a total monopoly? Alnylam is doing incredibly well as it is and there is more than enough room for a number of players."
ReplyDeleteIs this innovation: Take a technology that works; disassemble it such that it does not work (nevermind that Tuschl has shown that blunt ends still work, just not as good as overhanged siRNAs; aka as prior art), and then contrive modifications such that they apparently make the old technology functional again? Creative, yes, but not innovative, and AtuRNAis were definitely not a solution to a problem. It's not that the world was biting their nails for AtuRNAis to be "invented" to make use of RNAi.
The patent examiner apparently also does not understand well the origins of Tuschl's work or "AtuRNAi" and puts them on the same level. I have little doubt that Tuschl will get a Nobel Prize once the first RNAi Therapeutics has reached the market, and it will show everybody how broken the patent system is and an insult to true inventors.
Yes, Alnylam is doing well, but taking this as an excuse to say that innovation shouldn't be protected is not a good argument. It's also good to remember that being granted a patent does not protect you from infringement claims.