Friday, September 23, 2011

ISIS Files Aggressive Lawsuit against Santaris

It is not a big secret that antisense therapeutics companies ISIS and Santaris are fierce competitors. Today, ISIS filed an unusual, because rather aggressive lawsuit against Santaris Pharma that alleges the Danish company to be selling to the industry technology that is covered by at least two of ISIS’ literally thousands of patents. Because ISIS considers itself the gate-keeper of oligonucleotide therapeutics, and because some of the business development in RNAi Therapeutics has probably occurred under the mantle of the Research Exemption, a ruling in favor of ISIS Pharmaceuticals could have wide ramifications, actually well beyond oligonucleotide therapeutics.

Under the Research Exemption doctrine, the result of Merck vs Integra, it is generally assumed that patented technologies can be used for research purposes quite broadly as long as product, in this case drugs, are not marketed. Without this safe harbor, much of the preclinical pharmaceutical research and academic research would be a legal nightmare.

Nevertheless, ISIS believes this standard does not apply here, because Santaris in a way is selling ISIS technology as part of its platform partnerships. These include relationships with Pfizer, Enzon, GSK, and Shire. Moreover, it probably irks ISIS that Santaris has been rather successful in its business development efforts, and even had the guts to hire a former top ISIS executive, Art Levin, to set up a business development branch in ISIS’ backyard San Diego.

My impression is that Santaris’ LNA-based antisense compounds are more potent than ISIS’ generation 2.0 2’-MOE phosphorothioate gapmers, and this is why Santaris is likely to be the more attractive company to partner from a technical point-of-view. ISIS apparently has realized this as well as it is following Santaris' example in developing conformationally constrained (‘locked’) nucleic acid chemistries (expect Santaris to counter-sue ISIS on that). Anti-miR122 for the treatment of HCV infection is one example where Santaris’ data have been more promising than Regulus’ using ISIS chemistries. Ironically, GSK dumped Santaris’ stronger science on HCV in favor of Regulus for what had to be concerns about IP (I believe though that it was miR-122-specific IP, not antisense platform-related IP that was responsible for GSK’s move).

I don’t want to speculate whether Santaris in fact makes use of technology covered by ISIS patents or not. It is, however, a case worth watching for the entire pharmaceutical industry. Closer to home, it illustrates how aggressive, and so far successful ISIS is in using its sheer number of patents in ‘extorting’ concessions from other oligonucleotide therapeutics companies. Wherever you look, ISIS is getting a piece of the pie. I have been studying ISIS’ patents with regard to RNAi Therapeutics, and cannot really find anything of value there, except maybe if you are interested in using the 2’-fluoro modification which is useful, but dispensable. Still, ISIS was able to extract surprising concessions from Alnylam when Alnylam IPO’d a few years ago and has even called Alnylam a ‘satellite company’ without much public protest by Alnylam. Same story with the multi-million $ that Alnylam gave ISIS for the ill-fated single-strand RNAi collaboration. It goes to show that when it comes to public perceptions and business development, quantity and brand recognition often still trump quality and due diligence.


Post-scriptum (9 October, 2011): On October 7, Exiqon and Santaris on October 7, 2011, settled their legal differences that resulted from Santaris suing Exiqon for selling LNA-based reagents that were used for the development of drugs incorporating LNAs,,,and thus would not fall under the Research Exemption- an ironic twist of fate. In the settlement, Exiqon paid Santaris a minimal amount. It is difficult to conclude from this anything about the outcome of the ISIS-Santaris litigation.


8 comments:

tettrazini said...

Is Santaris licensing patented technology owned by a third party seems to be the core issue. If that is the case it would seem to be a rather broad extension of the Research Exemption Doctrine.

Clearly ISIS is putting the industry on notice that even if the Research Exemption Doctrine is applicable, it still precludes others from commercializing ISIS’ intellectual property.
On what basis would Santaris counter-sue? They could try to invalidate ISIS’ patents regarding conformationally constrained (‘locked’) nucleic acid chemistries, but that is quite a different battle and one ISIS might welcome if they believe their intellectual property in this area is strong.

jetmanbash said...

I really think that your comments are misplaced and several other view points could also apply. It is well known that you are not a fan of ISIS so the most likely negative comment that fits the bill is what is grabbed at. For example, ISIS has had a long-standing program for LNA's and continue to develop that program. Santaris definitely does not have a monopoly on that IP. The toxicity people at ISIS still have reservations about LNA technology. One always needs to remember that in-vitro isn't the same as in-vivo. Also, for you information ISIS let ALNY into Regulus because of two patents that Regulus had that could/would cross into ALNY's IP. Regulus is a luxury for ISIS, it will turn out to be a necessity for ALNY. That dropping of ALNY in the ssRNA venture with ISIS was because ALNY could not figure out how to develop the technology to put it to clinical use. ISIS has sense really increased the potency of those ssRNA compounds to where they may make it into ISIS pipeline. The GSK vote to drop Santaris relates to the success that Regulus has had and the more thoroughly prepared they are in the lab to go forward with their products. Watch and see how the mRNA space plays out. And in regards to Regulus it will be mostly ISIS delivery technology for Regulus that will be used. It was engenius of Dr. Crooke to develop Regulus because ISIS has created organic growth with Regulus expansion and success for ISIS to have more products and revenue come from that. And for your information I witnessed when one of my friends asked the CEO of ALNY who was at an ISIS annual meeting if ALNY was considered a satellite company by him and he said YES and that it was an honor to be associated with ISIS. t

Dirk Haussecker said...

You are right: The first question will be whether the ISIS patents apply to Santaris' chemistries in the first place (and whether Santaris does not have access to them through a license from ISIS). I'm not sure, but ISIS obviously assumes that.

What makes this case interesting is the Research Exemption. You would not believe how much RNAi services are being offered and sold. RNAi is everywhere in preclinical resesarch, including target discovery and validation. There are a number of issued RNAi patents patents as well that may apply (note that it is easier to get patents for tissue culture use than therapeutic applications). I can see the point of ISIS and other patent holders. On the other hand, enforcing all these patents for preclinical research activities is impractical. Academic research, as an example, would grind to a halt. The judges in Merck vs Integra realized this and that's why we have the Exemption. This could be an interesting test to the doctrine.

Santaris counter-suit...Santaris' bread-and-butter are conformationally constrained nucleic acids. I would assume that they built some IP around that, probably the strongest in the industry. I would not be surprised if these included claims that might apply to ISIS' CRN development activities.

Dirk Haussecker said...

Jet...the paper below by ISIS relates to the contention that LNAs have tox issues. I thought that paper was a punch below the belt. ISIS has published similar 'comparison papers' to disparage other oligo technologies (e.g. U1-adaptors), so there is a pattern. In any case, you can as easily find similar tox issues with ISIS' antisense compounds. These are also to a certain degree sequence-specific phenomena. My conclusion is that ISIS feels the heat of Santaris' scientific competition and does what it can to fight it, also by non-scientific means.

"Antisense oligonucleotides containing locked nucleic acid improve potency but cause significant hepatotoxicity in animals.
Swayze EE, Siwkowski AM, Wancewicz EV, Migawa MT, Wyrzykiewicz TK, Hung G, Monia BP, Bennett CF.
Nucleic Acids Res. 2007;35(2):687-700. Epub 2006 Dec 19"

tettrazini said...

If the data in the paper (http://nar.oxfordjournals.org/content/35/2/687.full) is accurate, which I assume you are not questioning, why do you consider it a punch below the belt? Do you feel they are misinterpreting the findings or perhaps displeased that they paid the Open Access publication charges?

tettrazini said...

My last comment/question on the litigation.

I am not a lawyer and may be misstating the issue, but it seems because Santaris is obtaining financial gain by licensing technology dependent on the unlicensed intellectual property of others they have moved beyond the scope and spirit of the Research Exemption. Doesn’t ISIS deserve some of the fruits being reaped by Santaris at ISIS’ expense?

Dirk Haussecker said...

If Santaris' LNA antisense was so toxic as ISIS claims, why is ISIS so concerned about competition from Santaris? It's also not like it has just emerged that Santaris has these LNA-antisense partnerships. Seems like 4-5 years late to sue them now.

Anonymous said...

As it pertains to future competition between these two companies for commercialization partners, future development of 3'-Fluoro Hexitol Nucleic Acid (FHNA) Modified Oligonucleotide chemistries, recently described in the article in press from Egli et al. (which includes Isis & Regulus co-authors), will be interesting to follow.

In single dose and 3 week dosing schedules with mice, the potency of FHNA and Locked Nucleic Acids (LNA) were reported as close to identical (e.g., ED50 = 2.2 mg/kg and 2.1 mg/kg, respectively, in the 3 week study). ALT data for FHNA was encouraging as well. The authors stated that further studies using FHNA in other antisense mechanisms such as siRNA, miRNA and splice modulation will be reported in due course. Hopefully we will also see non-human primate data soon if this chemistry continues to look promising.

The risk that is lurking and inherent in having an entire drug pipeline based on one specific chemistry (e.g., MOE gapmer until recently for Isis or LNA for Santaris) or one delivery modality (fortunately not a consideration in this particular case) is why I was encouraged to at least see the rollout of generation 2.5. Obviously, I’ll be more relieved as the long-term clinical safety profile of generation 2.5 plays out. I also appreciate and am encouraged by the fact that there is a much more extensive clinical safety database for the MOE gapmers than LNAs (I believe this was alluded to in responses to Dirk’s post).

If (and this is still a pretty significant if at this point, but FHNA looks like a promising start) Isis can develop additional medicinal chemistries beyond generation 2.5 with similar, or slightly lower in vivo potency to LNA with an attractive long-term safety profile, then in terms of attracting future investors or commercialization partners committed to investing in antisense technology long-term, regardless of where the two companies stand today, this would just seem to shift the balance tremendously in favor of Isis as the go-to antisense company partner (this statement is based on my understanding Santaris only has one ASO chemistry to bring to the clinic as of today and of course this could change).

Lastly, perhaps I’m overweighting the value that investors and commercial partners would place on an antisense company having 2 to 3 clinically viable ASO chemistries at their disposable versus a company just having one and would encourage anyone to point out factors I’m overlooking. In the same manner that pursuing “undruggable” targets can mitigate risk from small-molecule competition, if Isis has multiple ASO chemistries with sufficient potency and proven safety, that greatly differentiates them from Santaris in terms of further minimizing the risks inherent in drug development (i.e., there should still be a few medicinal chemistry options for Isis with comparable potency/safety to partner if one chemistry had to be taken off the table, whereas everything with Santaris would be riding on LNA).

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