Sunday, July 22, 2012

MC3 Authorship Discrepancies Increase Suspicions of Cover-Up

Last week was a tumultuous one in RNAi Therapeutics and in the relationship between Alnylam and Tekmira.  

On the positive side, results from the ALN-TTR02 phase I study revealed that highly potent knockdowns for liver-expressed genes are possible in Man.  Although solid knockdowns had been demonstrated before using the same delivery formulation for the hypercholesterolemia-related PCSK9 (ALN-PCS), the latest results demonstrate the most potent and prolonged knockdowns in RNAi Therapeutics history.  Thus, this should be reproducible for most liver-expressed genes as long as highly efficient RNAi triggers are selected, further substantiating the claim that RNAi trigger potency matters.

At the same time, the results once again brought into focus the hard-fought battle for this most valuable RNAi Therapeutics delivery asset: SNALP.  On the celebratory conference call, Alnylam’s management was more aggressive than ever in claiming that this ‘second-generation LNP’ technology was entirely theirs: ‘Proprietary!’  Of course, this makes little sense for the reason alone that the composition and formulation method of these particles clearly identify them as SNALPs which belong to Tekmira.  Just as a reminder, there is an important distinction between an exclusive license and owning something.

Not only does it reveal that Alnylam management is apparently unable to grasp this very basic concept of property rights, well captured by John Maraganore's statement 'you pay for it, you own it', Tekmira alleges that what enabled this improvement in liver gene knockdown potency over the ‘first-generation’ liposomal formulations and which is the basis for Alnylam’s ‘proprietary’ statement, namely the MC3 ionizable lipid, was stolen from them in a covert operation.  This operation apparently happened at the end of a series of actions to not only appropriate valuable SNALP technology on which Alnylam has come to essentially wholly rely upon (despite its recent attempts to claim that it employs four different delivery approaches), but also marginalize, and ultimately destroy Tekmira.

The reason why I strongly believe that Tekmira is not making up these shocking allegations, is not just based on the fact that Alnylam’s PR strategy has been so obviously aimed at wrestling away from Tekmira its reputation as THE liposomal RNAi delivery company (see the promotion of the clinically unfit lipidoids to a point where many observers believe that the clinically employed liposomal technology originated at MIT; Alnylam oligonucleotide chemists prominently listed on liposomal patents; or back-handed compliments in the context of ‘1st-generation’ technology).  No, it is also because all of the evidence and accounts that I have gathered in my investigations were consistent with Alnylam having had little respect for Tekmira and thought their financial might and influence can be used to take full possession of SNALP technology and leave Tekmira in the dust. 

MC3 Origins

Probably the most telling of these acts concerns the origin of the MC3 lipid.  This lipid is an important component in ALN-PCS and ALN-TTR02 which have attracted so much attention recently, and which forms the basis for Alnylam’s ‘proprietary’ claim.  Briefly, Tekmira alleges that former employees of the company were hired by Alnylam (first as consultants, and then as employees at pseudo-independent Alnylam Canada, pardon me, AlCana) and were supposedly struck by genius essentially the moment they had left the company's premises (and apparently finished downloading the files) to come up with MC3, ownerhip of which was duly transferred to Alnylam.

Alnylam claims that MC3 was an ‘independent’ lipid and thus would fall under the scope of the Supplemental Agreement.  Based the above timelines alone, it seems that Alnylam management must have very low expectations for the IQ of the jury that they will be facing in late October.  Moreover, it is obvious that MC3 was part of a series of lipids that these employees had started work on as full Tekmira employees.  Note: although they may have been the rightful inventors of the MC series of lipids and may even hate their former employer for personal reasons, the fact remains that they did so when employed by Tekmira.  Consequently, the lipids and related trade secrets are not theirs.  Moreover, the key insight in the 2010KC2 Nature Biotechnology paper by the same authors (when employed by Tekmira) was that changing the length of the linker between the lipid headgroup and tails had a profound impact on performance.  Hence, developing new lipid scaffolds and then start testing series thereof with variable linker lengths was Tekmira's trade secret until then.  And that, of course, is what got them to discover MC3 (from the recent Jayaraman et al): 'In the second group, the dimethylamino moiety is maintained but the distance between the ester and the amine is varied from one to five methylene units to generate lipids with pKa values ranging from 4.17 to 7.16.'

Too bad for Alnylam that ‘rational’ appears in the title of that key Nature Biotechnology paper (Rational design of cationic lipids for siRNA delivery) as it will be Alnylam’s strategy at the trial to convince the jurors that successful lipid discovery is an extremely unlikely chance event, further hoping that the jurors won’t be able to make the distinction between unpredictability in terms of how many carbon atoms exactly would yield the most useful lipid and unpredictability in terms of which search strategy (Tekmira know-how) would likely yield such a lipid.

It is also curious that the research organizations of Tekmira and Protiva had been kept separate until in late 2008.  Supposedly, Alnylam demanded this as a precondition to blessing the Protiva-Tekmira merger so as to keep Merck from getting their hand on certain Old Tekmira’s technology.  Whether true or not, it likely also had the effect that not only Merck, but also Old Protiva were left in the dark on these trade secrets (although they belonged to the combined company).   This darkness was then allegedly exploited to get MC3 ownerhip transferred to Alnylam and to obtain a broad covenant not to sue from Tekmira that according to Alnylam’s interpretation would also absolve it from IP and trade secret theft.

MC3 Authorship Discrepancies

Over a year ago, when the lawsuit broke, it bothered me that in the MC3 patent application (now issued patent US8158601), the key ex-Tekmira employees which should have been the real inventors behind MC3 according to my logic described above, i.e. Madden, Hope, and Semple, were missing as listed inventors.  M. Hope, importantly, was the senior author of the KC2 Nature Biotech paper, which served as the blueprint for the MC series.  Instead, a slew of Alnylam oligonucleotide chemists are listed as if the synthesis of an extra carbon in the linker group here and there was an inventive contribution. Surely not.

This to me strongly smelled like part of the cover-up.  Read for yourself my speculations at the time:

'But looking at the (published) patent application, all these key people are actually missing as named inventors. I would identify these key scientists as Thomas Madden, Sean Semple, and Michael Hope and it would have been natural for Tekmira to have non-compete arrangements in place for these individuals. Importantly, these are also the senior authors on the KC2 Nature Biotech paper from January 2010, a lipid from which MC3 is derived (see also e.g. slide 28 in August 4, 2010, presentation by Alnylam at the International Liposome Research Days held in…Vancouver).

However, despite of Alnylam’s assertions that it was the fired Tekmira employees now working, for apparently legal purposes, at AlCana (but practically for Alnylam) that invented MC3, the published patent application only lists Alnylam employees (and maybe some consultants) as inventors and Alnylam as the applicant: Akinc, Dorkin, Qin, Cantley, Manoharan,Kallanthottathil, Narayanannair, Jayaraman; and (for US purposes only) Chen, Ansell. (the latter two being the two ex-Tekmira employees, but no mention of AlCana).

You would think that, as the inventors of KC2, the inventive contributions by Madden, Semple, and Hope would have played an important role in MC3, much more so than the number of trained oligonucleotide chemists from Alnylam listed as inventors on the application. Given that the Response admits that Alnylam hired the ex-Tekmira employees that would eventually form AlCana as consultants, it seems highly unlikely that Madden, Semple, and Hope played no role in the MC3 patent application.'

12 days ago then finally appeared the peer-reviewed publication concerning the discovery of MC3 (actually a long time after the 2009 patent application).  I could not believe my eyes when the list of authors indeed revealed Michael Hope as the senior author on the paper (highlighted in red along with Thomas Madden):

Muthusamy Jayaraman,* Steven M. Ansell, Barbara L. Mui, Ying K. Tam, Jianxin Chen, Xinyao Du, David Butler, Laxman Eltepu, Shigeo Matsuda, Jayaprakash K. Narayanannair, Kallanthottathil G. Rajeev, Ismail M. Hafez, Akin Akinc, Martin A. Maier, Mark A. Tracy, Pieter R. Cullis, Thomas D. Madden, Muthiah Manoharan, and Michael J. Hope*

For those unfamiliar with how authors are listed on papers in the biomedical sciences, the last author is the senior author with responsibility for the overall study.

I have only four possible explanations for this:

1)      Sheer stupidity/carelessness on the part of Alnylam and their lawyers- this would not be a first considering the VSP Interference history alone;

2)      This hypothesized cover-up had so many tracks to conceal that some of them would always make it through to the daylight;

3)      For scientists which see their future in the academic sciences, it is publish-or-perish and Michael Hope and Thomas Madden insisted being on the paper for this reason (note that also the academic Pieter Cullis from the University of British Columbia is on the paper, likewise absent on the patent);

4)      Alnylam knows that the evidence is such that the involvement of Hope and Madden will be revealed anyway, and trying to further conceal the fact would make it look even worse.  Now, they may claim that the omission of Madden and Hope was an honest mistake and they may file for a correction of inventorship on the patent (otherwise they risk the patent becoming invalid due to Inequitable Conduct).

Personally, I favor a combination of 1) and 2).  Alnylam and their lawyers have surprised me a number of times already with their carelessness, a carelessness that is possibly born out of arrogance.  This arrogance may very well be its downfall.  There are only three months to go until the trial and it looks like, despite of Alnylam's delay and cost-intensifying tactics, as if the jury will have it!

Next up: Judge in Tekmira-Alnylam case orders no more delays and why I believe Alnylam is a highly attractive short here...


Anonymous said...

Any comments on the progress Tekmira has made in their LNP efforts since the AlCana scientists were fired? It seems like pipeline and scientific progress at TKM has stalled since that unfortunate incident. The only press releases out of TKM these days seem to be about litigation or piggy backing on Alnylam's clinical results.

Dirk Haussecker said...

Well, they have started the Ebola trial this year and they are about to finish the phase I PLK1 cancer study. Beyond that there appears to be work on basic delivery (lipids, aerosolation, lyophilization). Overall, of course, efforts have gone down due to cost constraints as the Alnylam situation has cost them lots in legal fees and not allowed them to close the normal type of biopharm patnerships. Once they get back from Alnylam what they had been deprived of, you should expect to see increased activities.

Anonymous said...

Dirk - given the recent clinical results demonstrating potent target mRNA knockdown in the liver via SNALP, have there been any recent developments in terms of SNALP or other RNAi delivery technologies demonstrating potent knockdown in extra-hepatic tissues (i.e., nonhuman primate and/or clinical data)?

Thanks for your continued insights on what is going on in the field.

Dirk Haussecker said...

Your question is too broad though to answer it in this context. There are a few delivery techs that I consider interesting for gene knockdown in various tissues. Some of those that I consider of clinical or near-clinical maturity I have listed in my recent review on the 'Business of RNAi Therapeutics in 2012'.

Anonymous said...


Because there are no comments regarding the “MC3 lipid paper” and the scientific content of it, here are some personal thoughts:

"Maximizing the Potency of siRNA Lipid..." is far away from being a poor copy of Semple's 2010 "Rational design of cationic Lipids...". No doubt, Semple's paper was a real highlight with respect to lipid chemistry and formulation development. Nevertheless it was pretty narrow focused onto the substructure of molecules from the DLin-K5 series. Just those ketals were tested with different head groups followed by different linker lengths - a linear approach.
In contrast, this new paper shows an impressive and comprehensive MedChem approach towards active cationic lipids - starting from K5-, K6-structures, esters, vic. diols etc.... A closer look reveals that a huge effort was actually done to find active DLin-K5 or DLin-K6 derivatives - finally 5 different K structures were identified (including DLin-K-C2) having ED50 of 0.1. At the same time, two M-series structures having ED50 of 0.03 (one is MC3) are described.
The design of such lipids is still challenging and far away from being straightforward or rational – such a rational design of lipids seems to be just possible with strong limitations, e.g. when starting with a predefined substructure (like K5, K6 or M), in other words it is still essential to synthesize the whole bunch of molecules. In this context it might be worth mentioning that changing the linker length is probably not a real trade secret - it is just a version of: methyl, ethyl, propyl, futile... all chemists know this.
What it means with respect to the effort in synthetic chemistry can be seen in these Alnylam patent applications (these applications are part of the Alnylam-Tekmira-litigation):

PCT/US2009/063927, PCT/US2009/063931, PCT/US2009/063933, PCT/US2010/061058

And indeed, this “MC3 paper” seems to be an excerpt of these applications; almost all compounds/activities are described in these PCTs... probably one reason for the author list...
Anyway, one of the most interesting findings & statements from the paper might be this: "... in vivo hepatic gene silencing is driven by pKa rather than specific head group structure or linker length..." … this seems to be true not only for just one charged lipid but even for the overall pKA of a mixture of charged lipids – nice piece of work.

Dirk Haussecker said...

Thanks V. for your comments. Can you elaborate on two issues though that relate to the timing and therefore whether this work happened/was initiated in Tekmira or not:

1) You say this was a 'comprehensive MedChem approach', yet the MC3 provisional was filed just about half a year after ex-Tekmira people left the company;

2)You state that this approach discovered KC2 amongst others. This indicates that this effort originated (at the very least) at Tekmira as there is no question/controversy around ownership of KC2.

I guess what Alnylam has to come grip with is that even though it always acted as if Old Tekmira was theirs, it just wasn't.

Anonymous said...

Love the blog, but on this one I simply disagree with you. Alnylam's MC3 is not like Tekmira's KC2. KC2 is an acetal which metabolizes to a ketone. MC3is an ester that metabolizes to an alcohol. Their structures, routes of metabolism, shelf-lives, PK, potencies - are all different. Alnylam will have no problem whatsoever defending MC3 as their intellectual property.

Anonymous said...

To anonymous:

it seems to me that you got it wrong - Dirk is not arguing that KC2 and MC3 are almost the same lipids. Indeed, there chemical structures are of course different.
Dirk's argumentation is this - as far as I understood:

(1) Patents
- Alnylam & Tekmira filed joined patent application PCT/US2008/088676 (Dec. 2008), subject: DLin-KC-1-DMA and a structure called DLin-M-DMA (ether structure but somehow similar to MC series)

- Tekmira filed PCT/US2009/060251 (Oct. 2009), subject: DLin-KC-2-DMA and DLin-MC-2-DMA

- Alnylam filed PCT/US2009/063927 (Nov. 2009) and PCT/US2010/038224 (June 2010), subject: DLin-MC-3-DMA and different M- and K-structures

(2) Furthermore
- Step from MC2 to MC3 just one methylene group

- Tekmira filed MC2 first

- Former Tekmira chemists are now working for Alcana

- Alnylam is using SNALP formulation procedure

Dirk's conclusion: the whole MC3 technology incl. formulation belongs more or less to Tekmira.

I am still skeptical.

By Dirk Haussecker. All rights reserved.

Disclaimer: This blog is not intended for distribution to or use by any person or entity who is a citizen or resident of, or located in any locality, state, country or other jurisdiction where such distribution, publication, availability or use would be contrary to law or regulation or which would subject the author or any of his collaborators and contributors to any registration or licensing requirement within such jurisdiction. This blog expresses only my opinions, they may be flawed and are for entertainment purposes only. Opinions expressed are a direct result of information which may or may not be accurate, and I do not assume any responsibility for material errors or to provide updates should circumstances change. Opinions expressed in this blog may have been disseminated before to others. This blog should not be taken as investment, legal or tax advice. The investments referred to herein may not be suitable for you. Investments particularly in the field of RNAi Therapeutics and biotechnology carry a high risk of total loss. You, the reader must make your own investment decisions in consultation with your professional advisors in light of your specific circumstances. I reserve the right to buy, sell, or short any security including those that may or may not be discussed on my blog.