The Time for the U(nusual)siRNA Strategy Has Come

As Tekmira and Arrowhead Research will unveil their next RNAi Therapeutics development candidates later this year, an interesting question will be whether these will involve one of their RNAi trigger options that some consider to be unencumbered by fundamental IP related to traditional designs (esp. the Baulcombe and Tuschl II IP).  These decisions could have important strategic consequences for the competitive landscape, from targets and indications to Big Pharma involvement.   

Support for freedom-to-operate claim

One of these designs is the usiRNA from Marina Biotech.  These comprise at least one ‘unlocked’ nucleic acid monomer (UNA) in the double-stranded RNA molecule.  While I have reservations about the scientifically tenuous claim (see here why) that UNAs are not to be grouped with most of the other nucleotide modifications for RNAi use because they lack an intact ribose group, usiRNAs were held to be sufficiently non-obvious and of specific utility that the USPTO issued fairly broad claims in 2012.  Moreover, Marina Biotech once commissioned an external IP lawfirm perform a freedom-to-operate analysis on usiRNA, and (surprise, surprise) came to the conclusion that, indeed, usiRNAs have FTO.

Overcoming target picking limitations

This view seems to be shared also by others in the industry. Notably, Roche RNAi (now part of Arrowhead Research) in 2009 gained access to Marina’s usiRNAs, meroduplex siRNAs, and Dicer-substrate RNAi triggers.  This came as a surprise given that Roche had spent over $300M just two years earlier to gain access to RNAi trigger IP held by Alnylam.  Given that none of the three licensed RNAi trigger forms and related IP poses any FTO threat to traditional Baulcombe-Tuschl designs, the most likely explanation for the move is that it was about allowing the company to escape the target picking limitations under the license from Alnylam.  This included the 31 targets exclusively held by Novartis, some Tekmira exclusive target picks, and some targets pursued by Alnylam that Alnylam exempted from competition.  Whether the last of Alnylam’s Big Pharma licensees, Takeda, might pursue a similar strategy is an interesting question.

Facilitating platform partnerships

When Alnylam and ISIS sued Tekmira for infringing on their RNAi trigger IP by collaborating with Bristol-Myers Squibbs on RNAi delivery, it became a priority for them to have access to or control over non-Alnylam RNAi triggers.  As a consequence, they obtained an exclusive license to Halo-Bio’s multivalent RNAi triggers (more than two strands).  Subsequently, they gained access to Marina’s usiRNAs, including the ability to sublicense.   This now puts them in the position to engage in platform partnerships with Big Pharma companies that do not have access to Alnylam IP.

The same strategy would likely also apply to Arrowhead Research with its various RNAi trigger options that it inherited from Roche, especially if Alnylam provided Roche with only product-specific sublicensing rights, if at all.  As RNAi Therapeutics enjoys a return of pharmaceutical interest, this one-stop-shop option by the two leading delivery companies could be critical to bringing new companies into the space.

And for Alnylam, these developments would not only diminish the royalty it might earn from licensing its IP, they could undermine their own product candidates, including ALN-PCSK9 (hypercholesterolemia) and ALN-AT3 (hemophilia).  Accordingly, the preclinical data strongy suggest that subcutaneous DPCs can do everything that Alnylam’s GalNAcs can do, only much more potently and with less frequent dosing. 


 

Brewed up in Seattle: Tekmira and Halo-Bio Seek to Capitalize on Multi-Targeting Potential of RNAi Therapeutics with Multi-Valent RNAi Triggers

It must have been over either coffee, the fuel of scientific discovery and frequent source of business development inspiration, or beer, a beverage that you may enjoy but not mix with business, that Seattlelites Mark Murray (CEO of Tekmira) and Todd Hauser (CEO/inventor of Halo-Bio) initially came up with the idea of joining forces to revolutionize one of the attractions of RNAi Therapeutics: Multi-Targeting, especially for the treatment of complex diseases, cancer and viral infections (see also previous blog entry on Merck’s hypercholesterolemia efforts; link to press release, here).

The technology to which Tekmira acquired a worldwide exclusive license is referred to by Halo-Bio as multi-valent RNAs (mv-RNAs). It is a molecule that in its basic manifestation consists of three separate double-stranded regions, forming a structure similar to a Mercedes star. The RNAi machinery is thought to use each strand as a guide for the targeting of the same or, more interestingly, separate and independent genes.

Data from this technology is yet to emerge, although I would imagine that Tekmira has carefully evaluated mv-RNAs and various other RNAi trigger options before signing this deal given its increasing hints that it is looking at non-Alnylam RNAi triggers. It has become apparent that RNA interference is a robust naturally occurring process that it can harness various RNA molecules as substrates for efficient gene silencing. Of course, not all of them are created equal. Also worth noting in this context is that efficient RNAi largely depends on the 5’ end of the guide strand so that the 3’ end can function to satisfy complementarity requirements such as those for the formation of mv-RNAs.

Besides potency, additional practical and scientific questions remain to be answered. For example, the use of 3 RNA strands to generate one RNAi trigger may increase cost and quality. On the other hand, for those that follow the Tuschl II patent prosecutions in more detail or have seen the somewhat boring, yet useful study by Roche on the purity of annealed siRNAs, it should have occurred to a number of folks in the industry that strand annealing may not be the only way to generate double-stranded RNAs. Furthermore, even when using three strands (one and two may also be possible), the actual complexity may actually decrease compared to using 3 traditional RNAi triggers with 6 individual strands for targeting the same number of genes. Another question would be whether and which mv-RNAs are loaded directly into the RNAi RISC complex, or whether they require prior processing by other nucleases.

mv-RNAs may also have particular utility in lipo- and polyplex settings, or facilitate formulation of SNALP liposomes, because of their increased negative charge.

Of course, this deal also has to be seen in the context of the Tekmira-Alnylam feud. First of all, it is worth noting that Tekmira stated that mv-RNAs are an attractive alternative for multi-targeting RNAi Therapeutics. It still has the more traditional RNAi trigger options from Alnylam which, not least due to their simplicity, appear preferable over mv-RNAs for single-targeting applications.

The transaction also increases Tekmira's business development freedom from Alnylam. Due to the structural differentiation of mv-RNAs from traditional RNAi triggers, it is possible that certain of Alnylam's exclusive rights to Tekmira technology do not apply. In addition, mv-RNAs may also be sub-licensed independent of Tekmira's delivery technology.

Alnylam faces RNAi trigger uphill battle- even 3’ overhangs not safe

The worth of Alnylam’s RNAi trigger IP has deterioriated raplidly over the last two years and Tekmira may not require Alnylam IP even when using Tuschl siRNAs.

While Alnylam once had a decent shot at coming out as gate-keeping with Kreutzer-Limmer and Tuschl-I, failing in those patent prosecutions yet clinging on to ageing technology has meant that it failed to participate in RNAi trigger innovation, even if not gate-keeping. Anybody still remember Commodore or Atari or holds shares in Nokia and Research in Motion?

[correction 8/26/2011: I have re-read my entry and would like to clarify that Tuschl siRNAs are not 'out-dated' technology; it is more the underlying IP strategy that is failing].

Even as Max Planck, UMass, MIT, and Alnylam have just agreed to re-coordinate their Tuschl patent prosecution in the US, it is clear that the double-patenting issue was not the only issue preventing a strong Tuschl II from issuing. For example, by arguing that 3’ overhangs were implicit in T-I, yet T-I cannot claim this since it failed to recognize it, or by claiming 3' overhangs being obvious over other research on the discovery of Dicer in RNAi, the USPTO may have it both ways: deny a therapeutically useful T-I, yet reject T-II over obviousness involving T-I.

The T-II patents that have issued in the US are not that strong as they involve methods of synthesizing two RNA strands and annealing them to form double-stranded RNAs with 3’ overhangs. It is somewhat surprising that such a annealing method would have been granted a patent, and there are signs that the patent offices are starting to realize this.

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