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 ‘1^st-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...