Benitec/CSIRO Win Major Patent Battle in US

One of the sadder stories in RNAi Therapeutics history is the many years lost in the commercial development of drugs based on DNA-directed RNAi (ddRNAi) as the space had become embroiled in litigation instead of investing in the science. In a sign that this chapter may be behind us and that ddRNAi Therapeutics can now look forward to a time where the significant medical potential of the technology can be realized, the USPTO Board of Patent Appeals and Interferences (BPAI) just reversed an earlier (2008) decision to revoke the previously issued and fundamental Graham patent that is controlled by Benitec and CSIRO. This had followed a re-exam prompted by their archrival Nucleonics Inc, now bankrupt and buried on the corporate graveyard underneath its legal bills.

Benitec shares went up 50% on the news.

The Graham patent as issued first in 2003 broadly covered the use of double-stranded DNA capable of driving the expression of double-stranded RNAs (dsRNA) for sequence-specific gene silencing in animal cells. The compositions included the expression of sense and antisense RNAs from either separate promoters or in the form of a self-complementary hairpin RNA from a shared promoter. Because the latter construction (single promoter) is the commercially more valuable claim, it will be the focus of my following discussion.

The previous re-examiner had rejected these claims as obvious in light of the famous Fire and Mello studies where the Nobel Laureates (btw, watch out for announcements next week- microRNAs this time?) applied dsRNA (not dsDNA) directly to animal cells and showed that it is in fact dsRNA and not antisense that is by far the more potent trigger for gene silencing. In a mixture of valid scientific speculation and boilerplate legal language, the Fire-Mello patent also contemplated dsRNA generated by transcription in animal cells as well as self-complementary RNAs as variations of the dsRNA RNAi trigger theme. The patent, however, does not provide examples that these methods in fact would work.

Specifically, this examiner argued that the claim in Graham covering the one promoter with the two identical gene copies in inverted orientation and separated by a ‘stuffer’ (i.e. driving the expression of hairpin RNAs) was obvious over Fire in light of antisense literature that described the use of hairpin structures at the end of antisense molecules so as to stabilize them from exonucleolytic degradation. The examiner therefore concluded that it would have been obvious to modify the Fire dsRNAs with hairpins to similarly stabilize them from degradation.

The new examiner, however, concluded that this is not so. In fact, since Fire-Mello already specifically stated that dsRNAs are naturally stable, more stable than antisense, changing this stable structure with things like hairpins would only have risked adversely affecting the stability of the dsRNA. That is, Fire-Mello in fact taught away from such modifications. Moreover, the dsRNA portion of the hairpin elements generated by the antisense stabilization technique would not have had the capacity for being silencing triggers themselves, whereas in Fire-Mello the dsRNA was the silencing trigger. Indeed, in order for the antisense to work efficiently, the target mRNA would first have to displace and disrupt the protective hairpin at the end. Thus, the hairpins in Graham and the antisense literatures served entirely different functions (Graham: efficient production of dsRNA; antisense: stabilization), and to draw such parallels was inappropriate.

In short, the USPTO found that RNAi is Not Antisense and reversed its earlier decision. As a result, when it comes to RNAi Therapeutics, the two fundamental patents are now Fire-Mello for the application of dsRNA to the target cells, and Graham for ddRNAi approaches.

Given the importance of the US market for the pharmaceutical industry, this decision has a number of implications for the RNAi IP landscape. First, of course, is that ddRNAi Therapeutics would likely require a license to Graham for their commercialization until ~2018 (priority date for Graham: 1998). Currently, there are two ddRNAi candidates in phase I clinical development, one for HIV by Benitec itself, and one for the treatment of cancer by US-based Gradalis; another one is a ddRNAi development candidate for HCV that originated with Benitec and is now with Tacere/Pfizer and appears close to the clinic. Considering the time it takes from discovery to the commercialization of new drug candidates and the so-called ‘research exception’, the demand for Graham as a gate-keeping ddRNAi therapeutic patent may therefore be somewhat limited.

Of more immediate financial benefit to Benitec could be the research and reagent market where there are a number of companies that have been selling ddRNAi vectors and transgenic RNAi mice and have yet to obtain a license from Benitec/CSIRO. Because of the complexities of the Benitec-CSIRO-Sigma relationship, we probably have to wait to hear more from the company about the anticipated financial impact here.

An even larger financial windfall would probably occur if CSIRO can get their ddRNAi patent issued for the plant field- despite Fire-Mello. It is CSIRO's dedication and attention to detail that was a major force in achieving the Herculean feat of turning around Graham.The financial windfall is due to the fact that, unlike therapeutics, ddRNAi plants are already a commercial reality and growing.

It is of note here that an interference proceeding against the Fire-Mello patent has been initiated by CSIRO and might even result in invalidating Fire-Mello altogether. In interference proceedings the aim is to determine the priority of patents (here Waterhouse vs Fire) that compete for coverage of the same subject matter, or at least subject matter that the USPTO holds to be the same. I indeed believe that there is a good chance that ddRNAi for plants will be found to have been conceived before Fire-Mello was. It is also possible that, in the end, Fire-Mello and Waterhouse will find a way to peacefully co-exist.

In the end, it is a relief that the USPTO did not lose sight of major themes in RNAi science and did not get lost in technical minutiae. It therefore also bodes well for should the time come that the Crooke antisense patents are moved to the frontlines of the patent battles. But wouldn’t it be great to wait next time until real drugs have been developed before fighting over the spoils?

PS: It seems like there have been major developments on another prominent RNAi patent front, the Tuschl Litigation. As reported on the RNAi Litigation blog, it appears as if UMass is becoming increasingly isolated, and any attempt to rescue the therapeutic value of Tuschl-I is getting less likely by the day.

The Confusing World of AtuRNAi, Stealth siRNAs and mdRNAs (Part I)

“Next-generation” RNAi is all the rage in the world of the ambitious RNAi start-up. The definition (note that everything is allowed under the guise of the satire): “An RNAi-inducing molecule derived from the classical Tuschl siRNA design, however with a magical pattern of modifications and variations in the exact length of the RNA duplex, sometimes an NA duplex, with overhang or not. As important as the chemistry that may sound impressively inventive to the lay (investing) public is that a proper name is chosen to further accentuate its apparent uniqueness. This is intended to suggest freedom-to-operate with the ultimate aim of attracting investments from people hoping the company will eventually catch up to the market cap of Alnylam (why would you invest in any of their direct rivals otherwise?).”

Considering that it has become commonplace to hear CEOs talk about their RNAi being so unique and advanced that they are now operating in parallel universes, the staid Tuschl siRNA must have really lost its relevance for the development of RNAi Therapeutics. While I think that some select siRNA derivatives given names such as StealthTM RNAi or Dicer-substrate definitely warrant further investigation, as it is yet unclear how well they will perform relative to the simple, but fundamental siRNA design, what I would like to do is to cut through the marketing fog and provide a brief overview of the types of RNAi inducers currently being used at the bench or in the clinic and how I think they relate to each other in terms of IP. In this post I will lay the foundation by giving a summary account of the history of RNAi as a tool, including some of the fundamental patents (and applications), before dissecting some of the Next-generation siRNA designs in a follow-up posting.

Studies on RNAi-related gene silencing really started in the early 90’s in plants with the observation of co-suppression whereby genes that share sequence similarity inhibited each others’ expression. Usually, this was triggered by the inappropriate processing of one of the gene products, typically from an introduced designer gene that is recognized as aberrant and therefore as a threat by the plant RNAi surveillance system. While the mechanism by which this occurs is a scientifically very interesting question, it cannot be used for gene silencing in humans and therefore has little or no relevance to RNAi Therapeutics IP. Parallel work on gene silencing in worms by Fire and Mello, of course, discovered that it was long double-stranded RNA (dsRNA) that was central to inducing RNAi and patents were filed covering dsRNAs longer than 25 base-pairs for gene silencing. This patent can be licensed non-exclusively by almost anybody that wants it, and despite it being based on work in worms and the long dsRNA nature in the stated claims, it is nevertheless considered to be a license that you should add to your IP portfolio anyway, I guess just because it has proven so fundamental to the understanding of RNAi in general and nobody would want to argue that. I also think this highlights the fact that real fundamental scientific insight will be credited by the patent courts even if the exact length of the duplex or modification pattern was not spelt out in the claims letter by letter.

Shortly after Fire and Mello published their research, Kreutzer and Limmer from the University of Bayreuth in Germany reasoned that short dsRNAs may have similar gene silencing effects in mammalian cells. This prediction, as we know, turned out to be true and now forms the basis of the Kreutzer-Limmer patents claiming short dsRNA of around 15-49 base-pairs for the induction of gene silencing in mammalian cells, although the exact length is the subject of patent challenges, including Merck’s opposition in Europe. This early work was considered important enough by Alnylam for them to acquire Ribopharma AG, the company founded on the Kreutzer-Limmer patents. Although I consider Tuschl’s subsequent work to be quite a bit more fundamental to the use of RNAi in mammals, Alnylam understood that it was important to remove any uncertainty as to the dominance of their RNAi IP position given the relative timing and overlapping content of Kreutzer-Limmer and Tuschl.

Around the same time, Hamilton and Baulcombe discovered that small RNAs were generated during plant RNAi. While they were prescient in predicting that these may mediate RNAi, they did not formally prove it and the structure of the siRNA that was detected in those experiments remained unknown. A world away, in Australia, DNA-directed hairpin vectors for reliably inducing RNAi were being described by Waterhouse and colleagues from the CSIRO. Based on the utility and impact of these vectors on plant research, the patents derived from these studies should give the CSIRO a strong position in the agricultural uses of RNAi. In many ways, the commercial development of plant RNAi is more progressed than therapeutic RNAi as traits can now be altered relatively quickly without having to resort to lengthy breeding and selection. I guess the most important question will be how uniform these knockdown phenotypes will be across a field of crops. The CSIRO patents also form partly the basis for Benitec’s claims to the therapeutic uses of DNA-directed hairpin RNAs. The Graham patents form the other pillar of Benitec’s contested patent estate describing the use of DNA cassettes driving the expression of various forms of dsRNAs, although I find these patents to be quite theoretical in nature and wonder whether most of the described non-Pol III expression cassettes would actually work for gene silencing in most mammalian cell types (to be continued…).


Two noteworthy developments last week that I would briefly like to comment on:

1) ISIS released further phase II data for their ApoB-targeting antisense compound mipomersen. The 200mg/week dose reduced by about half the level of bad cholesterol in patients already on stable statin therapy. This looks quite impressive and if no safety issues come up in the larger phase III trials, then this has the potential to become a blockbuster. I’ve been quite critical about mipomersen in the past, particularly due concerns about fatty liver which many scientists in the field would have expected to observe following ApoB knockdown. Safety data for the 200mg dose, based on liver enzyme measurements, however do not indicate this to be a problem. Ultimately, the proof is in the pudding and I would be happy to ultimately have to admit to have been wrong on this issue. ISIS explains the absence of fatty liver due to transcriptional compensatory changes in fat metabolism. Overall, these data augur well for the development of all RNA-targeting platform technologies, including RNAi Therapeutics, as it suggests that minor off-targeting should be well tolerated in many cases.

2) Pfizer announced the acquisition of Coley Pharmaceuticals for almost triple of Coley’s market cap before the offer. Coley Pharmaceuticals is an oligonucleotide therapeutics company that exploits the immunostimulatory properties of oligonucleotides for applications such as boosting vaccines or in the fight against cancer. Actually, I’ve been quite impressed by their OTS presentation in Berlin, particularly their vaccine program. This comes only days after a blog this month where I asked the question when Pfizer will make its big move in RNAi Therapeutics (11 Nov 07 Blog: “When Will Pfizer Finally Make its Big Move in RNAi Therapeutics?”). It is notable that Coley is a Massachussetts company and I would like to think that the proximity to Alnylam will not be an impediment to Pfizer’s new biotech initiative that also appears to more and more focus on oligonucleotide therapeutics. With the new oligo expertise in-house (note that Alnylam does not have another subsidiary to throw into the next deal) and plans to add more staff to a research facility in Cambridge (the headquarters of Alnylam) in addition to a possible biotech incubator near Boston, the plot thickens.