Thursday, September 30, 2010

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.

46 comments:

biochemyst said...

Dirk, great review of ddRNAi IP estate and background. This is an area that receives little attention and not many know the story. One area of question is the length of patent for the Benitec ddRNAi patent. Since this has a priority date of 1998, does this mean they only get 17 years of protection (through 2015) or have the new USPTO rules of 20 years' of protection been back applied to such patents?

Anonymous said...

Thanks Dirk - comprehensive update on the ddRNAi story

Do you have any thoughts as to how the cross licencing with ALNY's InterfRx options would likely be played out - from both ALNY and Benitec's side?

(Biochemist - patents filed post June 8, 1995 get 20 years protection i believe)

Dirk Haussecker said...

Anon- From Alnylam's side probably not much impact, but that could change if Fire and Mello got revoked on the Interference filed by CSIRO.

If the Benitec-CSIRO contract stipulates that therapeutic monies go to Benitec, even if CSIRO was the original filer of a patent (ie Waterhouse), such a scenario, of course, would also greatly benefit Benitec.

Anonymous said...

Do you now regret removing Benitec from your RNAi portfolio?

Dirk Haussecker said...

Yes, I would not have removed Benitec from the portfolio had I expected the decision to go in the company's favor. On the other hand, RXII (the stock that I replaced Benitec with) has performed even somewhat better since that decision (from 1.75 to 2.83 for RXII vs 2.4c to 3.6c for BLT.AX), albeit probably with a bit of good luck.

Jerry said...

Silence Therapeutics, as listed on the London Exchange, has silently doubled during the month of Sept on no news that I can find.
What rumors and theories are circulating?

Anonymous said...

I notice that over the last 3 years almost all research is now focussed on shRNA , yet almost all the biotec companies save Benitec has persisted with si RNA a dead technology it appears on the research side anyway. Interestingly Benitec's programs HIV, HepC, Hep B ,Cancer seem to have made more progress than all the other companies put together , in spite of having less than 1% of the combined resources spent. Benitec CSIRO deal means that if the Waterhouse interference prevails on Fire and Mello it will own the entire RNAi space for therapeutics in humans leaving Sirna and Alnylam and the rest patentless.
Benitec now owns the only RNAi patent estate that has successfully survived a global interference , reexamination to be reissued everywhere now even in the US. All the companies that have done Si RNA deals wont they need to hedge there bets on targets by getting an shRNA license? How long until Pfizer or Merck wakes up and bids for Benitec, the Australian minnow that owns the RNA patent estate that actually works? Alnylam is dead in the water maybe Benitec is what it needs to get a return on all that cash they have been burning- or maybe not ? Dirk , your the expert what are the companies saying?

Anonymous said...

Hey dirk after reading your blog on the out come of the bpai decision for benitec i couldnt help notice you sounding a bit sour.You at first said you removed benitec from you r portfolio cus it wasnt going to be directly effected by novartis decion, yet now you say you removed benitec from your portfolio cus you expected the uspto to affirm the examiners decision.When, how soon will you put benitec back in your portfolio.

Anonymous said...

Hi Dirk,

Just wondering your thoughts on the new intractible pain therapeutic programme benitec have announced with their ddRNAi. It has a couple of interesting aspects - not a typical 'disease' target, and potential fast track - depending on FDA deliberations. I recall you mentioning before ddRNAi may be well suited to neuro applications.

Dirk Haussecker said...

I'm not familiar with the specific targets they are going after, but yes, it looks like an appropriate area for ddRNAi Rx. It is also my understanding that the market/demand for managing pain in diseases such as cancers is considerable.

Anonymous said...

thanks Dirk.

here's hoping it's a super fast tracked program - the RNAi space in general will get its own, much needed, shot in the arm from the first RNAi commercial therapy

Anonymous said...

Dirk, excellent review of the IP, I like many thought Benitec and the CSIRO were dead in the water, now scanning google I am shocked by the extent of reagent companies in the shRNA space and the huge number of research papers claiming success in vitro with the approach. I agree with the examiners that SIRNA does teach a short hairpin ddRNA approach but what about the other way around? If Tuscle goes and Fire loses to the CSIRO on priority , what companies can I safely own , the space seems very dangerous , if I like shRNA in the lab can I extrapolate to the clinic ? What are the risks here? What companies can I buy to get exposure to the space other than Sigma Aldridge or Benitec ( which I worry about as you dont own it)? Is Nucleonics going to list?

Anonymous said...

Soryy - I agree with the examiners that SIRNA does NOT teach shrna , but what about the other way around?

Anonymous said...

WOW 2 weeks ago Benitec looked dead now reading your blogs on the reexamination result and the Waterhouse interference of Fire it looks like it maybe the only safe long in the space. Am I missing something here? Or should I be buying an Australian penny stock with my ears pinned back?

Anonymous said...

Only safe long in the space? LOL. Sounds like you've already got yourself a ton of Benitec stock.

Dirk Haussecker said...

Definitely agree that the picture has changed considerably for the better for Benitec. I also believe that CSIRO has a strong case that they invented RNAi first. I have some strong views, however, about how a platform ddRNAi therapeutics company ought to be developed, so I will watch Benitec closely to see whether they are moving in that direction. There is a lot happening at Benitec, and I guess we should have more clarity on their strategy in a few months' time.

Anonymous said...

Microsoft <=> Apple
ALNY <=> Benitec
??

Anonymous said...

Hello Dirk, your work on this blog is greatly appreciated, having read your last comment on benitec, i couldnt help wonder how a platform ddRNAi therapeutics company in your point of veiw should be developed. Thanks

Dirk Haussecker said...

That's a loaded question. In any case, a strong research base would be part of it. The trick, of course, is where to focus on. I don't think it would have to be overly expensive. The science is there, just the people in power have to decide. The sad thing is that years and precious funding have been wasted and some patients just don't have the time to wait any more.

RNAi believer said...

Dirk , do you think there will be some merger activity in the RNAi space? Do you think the CSIRO/ Benitec patent success will prompt a move especially given how small Benitec's market cap is? Alnylam bought the rump of Nucleonics - does this mean they are interested in diversfying into the shRNA space? Their IP is in the Tuscl tussle - would Benitecs IP and the human therapeutics of Waterhouse be complimentary ? What do you think about delivery vs platform companies? Who are the main delivery players and who are the main platform vehicles? Do you think there will be activity within the respective spaces or across to produce vertically integrated companies ? There has been surprisingly little corporate activity I wonder if the recent patent results will change this. For big pharma a little money could go a long way at the moment!

Anonymous said...

Dirk, with Benitecs expanded IP portfolio and expanding R&D program do they need more experts on the team? Ever thought of working in Australia?

Dirk Haussecker said...

RNAi Believer...all good questions. Interesting for you to mention Alnylam along Big Pharma in missing out on inexpensive RNAi investment opportunities. Herd behavior will probably cause many of these companies to pay higher prices for the same assets later.

Anonymous...sure, I would always look closely at an opportunity that would allow me to build a ddRNAi Therapeutics research engine. That decision, however, is for others to make. Also, having too big a product-specific pipeline at this stage of the game already may be difficult to reconcile with building that platform. It's a difficult equation for companies like Benitec to solve (taking into account patent life, cash balance etc).

Anonymous said...

ShRNA transgenic animals must number in the millions I dont see much on unwanted side effects , except when massive doses have overwhelmed the cellular machinery , seems to indicate it is a very safe process. I agree it is very sad that the shRNA therapeutic space is so chronically underfunded , amazing what has been achieved on so little funding , with patents dying that could be cured not just treated I pray that big pharma will but some resources behind this amazing technology . Thank God for your work Dirk , the lone voice in the wilderness condencing and promoting a forum for this scientific breakthrough. I thank you for your heroic efforts and pray that it does not go unnoticed or rewarded.

Anonymous said...

Hello Dirk.

I couldnt help notice rumours floating about in an Australian stock forum, on how Alny might appeal the Bpai decision over the 099 patent given their interest through the purchase of Nuecleonics IP. Whats your take on this. Thanks

Dirk Haussecker said...

It wouldn't be appropriate for me to comment on such a rumor, but as a general rule, as Tuschl and 099 have shown, be very careful when starting lawsuits that involve IP important to you.

Anonymous said...

Dirk, with regard to the HIV stem trial being done by CoH/Benitec, in its final form this would be a 'one shot' treatment. Given the current HAART is approx $18k per annum per patient, would you see such a one shot treatment likely to get the backing needed from Big Pharma to be realised?

Dirk Haussecker said...

I wouldn't expect a one-shot ddRNAi therapeutics to be priced too cheaply- at least initially. The companies have to recoup also their investments, while bringing added benefits to patients. Accordingly, Big Pharma's interest in gene therapeutics seems to be increasing again, often as part of their orphan disease strategies.

Anonymous said...

Dirk,

The paper in the link below lists ddRNAi's potential for brain disorders. I recall you've noted such potential before. Do you know if anyone is getting close to clinic yet for any of these, or is it still early days?

best regards.

http://www.springerlink.com/content/50578458t620g3p6/fulltext.pdf

Dirk Haussecker said...

No ddRNAi candidates for CNS disorders yet in clinical trials, certainly pre-clinical research going on (e.g. Huntington's). However, it seems to be more of an investment rather than scientific issue as I see the technologies pretty much ready for the clinic. Remember, there are numerous gene therapy trials ongoing for CNS disorders already. 'Just' plug in the right ddRNAi cassette.

Mr Squiggle said...

Interesting that after all this time, the third party just gave up. Suggests it was just an attempt at corporate sabotage after all, and legally done with the help of third-party anonymity.

"Sydney June 25, 2012. Benitec Biopharma today announced that the challenge to the validity of the UK Graham patent GB 2353282 is over, following the withdrawal of the Application for Revocation of the patent by the applicant, and the acceptance of the amended claims by the United Kingdom Intellectual Property Office (UKIPO)."

http://imagesignal.comsec.com.au/docserver/01308166.pdf?fileid=01308166&datedir=20120625&edt=MjAxMi0wNi0yNisxMToyNzo1MysxMjArMCtjb21zZWMrcmVkaXJlY3QrL2ltYWdlc2lnbmFsL2Vycm9ycGFnZXMvUERGVGltZW91dC5odG1sKy9pbWFnZXNpZ25hbC9lcnJvcnBhZ2VzL3BkZmRlbGF5ZWQuanNw

Anonymous said...

"Interesting that after all this time, the third party just gave up."

I suspect that the third party didn't just give up. The amendment that the CSIRO was allowed to make to the patent made it absolutely clear that the third party had no chance of winning. It will be interesting to see if the CSIRO make the same change in other jurisdictions. It will also be interesting to see if any company crawls out of the woodwork to ask for a licence from Benitec.

Anonymous said...

Tacere's paper on non human primate HCV study using shRNA cassette via AAV8 now published.

http://www.nature.com/mt/journal/vaop/ncurrent/full/mt2012119a.html

Tacere plan clinical trial in 2013, sans Pfizer.

Anonymous said...

Pfizer might want back in to this programme before too long:

http://www.forbes.com/sites/edsilverman/2012/06/29/why-a-change-in-a-bristol-myers-hepatitis-c-trial-has-big-implications/

Anonymous said...

Ha. It wont be neither the first, nor the last time they double back on themselves. They'll need people that understand RNAi again though!

Anonymous said...

Genable have taken ddRNAi licence for their
RP (ocular) treatment. Benitec in discussions for
further licensing with others.

Anonymous said...

Just another shRNA collaboration announced. Becoming clear why ddRNAi IP was involved in so many patent oppositions and court battles.

http://www.marketwatch.com/story/baylor-college-of-medicine-and-gradalis-enter-collaboration-agreement-to-utilize-gradalis-bifunctional-shrna-platform-in-translational-medicine-research-2012-07-11

Anonymous said...

I just saw Benitec (and their work to bring their HCV candidate to clinic) brought up recently in relation to the attention Arrowhead's ARC520 has gotten of late.

See, for example, an Benitec analyst's update from August 12, 2013:

http://www.benitec.com/documents/13%2008%2012%20Lodge%20Partners%20Update.pdf

Benitec apparently sees itself soon to be in direct competition with Arrowhead (among others). And they claim to have a better basic technology for treating HBV via their use of ddRNAi, although first using it on HCV.

On their webpage, they don't seem to take into account the kind of safety and potency that Arrowhead's DPC delivery system has demonstrated so far.

Their webpage seems to be looking back on the past difficulties of siRNAi delivery, noting that their solution is far safer and more potent.

I can see Arrowhead's DPC delivery system putting that part of things to rest (pending clinical trial results).

But what about ddRNAi vs. siRNAi therapeutic approaches (in the event that the delivery system for siRNAi is well resolved), which is what is fundamentally different about the approaches of Benitec vs. Arrowhead?

I would guess that a big part of it depends on what you have been highlighting in your blogs about ARC520 – the extent to which a high knockdown of HBsAg actually does serve to reactivate the immune response in chronic HBV patients.

If that does indeed take place, I guess the question would then be how long does it take to occur?

If that idea does solidly prove to be the case via Arrowhead's upcoming trials, ARC520's duration would then be paramount - how many doses of ARC520 would it take before the immune system within a chronic HBV patient typically takes over?

If it takes several doses over a fairly long period of time (say, 6 months or more), and Benitec's product can do the same thing, starting even further upstream in the process, with only one dose that could last approx 180 days or more (what they project on their website), that would be Benitec's key competitive advantage, yes?

(I don't think they would have an advantage over ARC520 in safety or potency due to the apparent effectiveness - so far - of the DPC delivery system.)

What are your current thoughts on Benitec, especially compared to Arrowhead's ARC520 (and Arrowhead’s overall plans for siRNAi/DPC going forward)?

Or perhaps the broader question is... whether or not Benitec can successfully bring ddRNAi therapeutics forward (likely some company can at some point if it is truly viable), how do you think Arrowhead (with its DPC platform for delivering siRNAi therapeutics) will hold up to competing companies using ddRNAi technology? in the short-run? in the long-run?

Latebloomer said...

After a bit of further consideration, my guess is that there will be room for both siRNAi therapy and ddRNAi therapy within the overall RNAi space, especially if a very safe and effective delivery system for siRNAi (or more than one) can be proven out in the clinic, and particularly if ARC520 can not only show with HBV that high knockdown of HBsAg does indeed favor a comeback of the immune system, but also with relatively few doses over a fairly short amount of time, for example, within 6 months.

For one thing, if much the same result occurs for both within a 6 month period of time, some patients might prefer a therapeutic that remains only temporarily in the body vs one that may remain more or less permanently. The sense that "there is no turning back" with a more "permanent therapeutic addition" may come into play.

Cost could also play a part in it. The upfront costs for a single dose could be considerably higher than the costs for a therapy that is spread out over a few doses. And if the end result is the same, that of the immune system reviving enough to take over within 6 months or so (and if safety issues for both are resolved), then a few more doses, with lower upfront costs, could still win the day.

And perhaps there are other strengths and weaknesses of both kinds of therapies in biomedical terms since their approaches to RNAi are fundamentally different?

Anyway, I'm beginning to see a complementary place for both siRNAi and ddRNAi, that there's a good chance one wouldn't completely supercede the other, as some have suggested, in the event that both become well developed through clinical trials.

(I've now invested in Arrowhead and am considering *also* investing in Benitec.)

I'd be curious about your thoughts, Dirk.

Linda

Anonymous said...

Dirk H., I thougth ddRNAi was buried 2006 as a viable drug, with the killing of 23+ mice by Dirk Grimm. I know that Kay and Grimm blamed "dose makes the toxicity" whereas Maraganore and Zamore pointed to "gene therapy = ddRNAi = no longer state of the art". As you worked that time door to door with Grimm in Kays Group, would be really interested about your thougths.

Dirk Haussecker said...

Once you have an equivalent anti-viral cure with a non-gene therapy option that requires only a few months or even years of dosing, it will be hard to justify a gene therapy.

Dirk Haussecker said...

Kay/Maraganore...I don't think I need to reiterate my thoughts on ddRNAi. They can be found on this blog in extenso.

Regarding Maraganore, did you notice he is newly on the Board of gene therapy Co Bluebird Bio. When he made those comments about ddRNAi=gene therapy being 'dead'...I better stop right here.

Anonymous said...

Interestingly, the majority of RAC members in their review of Benitec's TT-034 (webcast live) were enthusiastic toward the this gene therapy trial for HCV. They saw it as definitely needed.

Maybe they are thinking of the % of HCV patients for whom the non gene therapy treatments will ultimately fail.

Anonymous said...

Once you have diagnosis from the doctor of HCV infection and he says "Not to worry, I have a one-shot gene-therapy that can fix that, without side-effects, and prevent you becoming reinfected", it is pretty hard to justify prescribing a treatment that takes months or even years.

Different stokes for different folks I guess.

Latebloomer said...

To the commenter just above this comment, I think you're writing about a couple of different things... The possibility that one therapy may take only one dose, while the other may take a series of doses to maintain... that's something that would be likely.  That's one thing.  

But that's a separate issue from the question of whether each therapy, from the start, is effective as far as knockdown and is safe.  I agree with you that I certainly wouldn't want to wait for months or years for a therapy I was taking to start to work against what the virus was producing.

(The following assumes all goes well for both therapies all the way through clinical trials.)

While it's being administered, ARC520 wouldn't be doing anything less than the other as far as the actual therapy is concerned.  Both would be, if all bears out through clinical trials, providing the highest ever knockdown of all aspects of HBV expression, with much the same timing and potency... since both work ultimately through siRNAi, one therapy directly administering a synthetic siRNAi to the cell, and the other therapy indirectly producing siRNA via DNA in the nucleus.

I think Dirk was saying that if there actually is a non-gene based HBV therapy that could address the issues of safety and high knockdown, then that would be preferable to a gene-based therapy, even if it took ongoing doses to maintain for a while.

Further, the hope is that it wouldn't be too long (say, within 6 months) before the immune system itself could take over, with no more therapy needed.  (The gene-based therapy would be in place and active more or less permanently, regardless.)

There was a time when it didn't look like synthetic siRNAi could accomplish that overall high knockdown, and when the safety of it was highly questionable in attempting to do so.  And so, it wasn't really an option.  Benitec's website still states that to be the case with synthetic siRNAi.  I could imagine that the potential for ddRNAi in that context might have been particularly attractive.  

But things have changed for synthetic siRNA's potential from what ARC520 has shown so far.  There now does look to be a very potent and very safe non-gene based HBV therapy, something that we'll find out for sure regarding humans via current and upcoming clinical trials for ARC520.

Further, it might be that the immune system does indeed take over relatively soon once therapy has begun so that ARC520 can cease from being administered; we'll find out about that soon enough too.

Linda

Anonymous said...

Dirk H, I´m not making things up, here´s the link:http://www.nytimes.com/2006/05/25/science/25rna.html?_r=0

and here the relevant excerpt out of it:

"These data really represent the fundamental limitations of gene therapy, not of RNAi," John Maraganore, chief executive of Alnylam Pharmaceuticals, said of the report in Nature.

I reassesed the two (probably not too divergent) explanations Grimm/Kay vs. Maraganore/zamore and here´s the more precise question to you:

How can dose be controlled with ddRNAi?

Anonymous said...

Benitec's share price has gone from 28c to 61.5c in less than 2 months. Anyone care to speculate why?

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