Thursday, July 10, 2008

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.


Anonymous said...

Dirk, I am somewhat confused as to how Glover relates to the other fundamental patents, most notably Kreutzer-Limmer.

What does Glover cover that is not covered by Kreutzer-Limmer? Longer siRNAs/dicer substrate such as the ones researched by Silence and Dicerna?


Dirk Haussecker said...

Hi Martin- The coverage of both patents was originally quite broad. What is important is what they actually demonstrated.

Both are early, pre-Tuschl patents showing gene specific gene silencing by double-stranded RNAs in mammalian cells. Kreutzer-Limmer essentially concerns synthetic double-stranded RNAs up to about 50 base-pairs, while Glover used long in vitro transcribed double-stranded RNAs for gene silencing in a certain subset of mammalian cells. While double-strandness is the key here, it was Tuschl that really taught the art of what makes an efficient siRNA.

Anonymous said...

Interesting comments. I see it as having three outcomes really:

1) Alnylam's fundamental patents hold
2) Alnylam IP narrowed to create a 'gap' and freedom for everyone
3) Alnylam IP narrowed to create a 'gap', but which is still covered by SiRNA or Silence's IP.

It would seem that Novartis, J&J and Quark all used their challenges against Alnylam's IP as tools for deal negotiation - and have therefore now dropped the challenges. [It is perhaps notable then that Pfizer is also now challenging ALNY's IP - a deal in progress I'd suspect?...]

So, that leaves Silence and Sirna. I agree totally that these companies would be foolish to create gaps in ALNY's IP, since that could allow anyone to also bypass their own 'too-gates'! as per your golden goose comments. I put this to Silence regarding Glover ie. why bother getting it revoked when they already by that point had freedom to operate around it (it had been cut back I think). Silence didnt seem to get that point though and I would guess that they simply wanted the kudos of beating ALNY?

But, there is another scenario. Silence and Sirna should attack Alnylam's IP to maintain freedom to operate - but stop there to ensure that Big Pharma's wanting to develop RNAi products have to pay someone. As you say, creating a loophole that lets anyone have freedom will not do any of these RNAi companies any good - although I dont see this outcome being at all likely...

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