ISIS Pharmaceuticals Next-Gen cET Technology on Shaky Grounds

As I was listening to a presentation by ISIS satellite company Regulus Therapeutics at the Future Leaders in the Biotech Industry Conference last week, I noticed that the fight between ISIS/Regulus and Santaris over intellectual property has increased in bitterness. On the same day, Santaris announced that the USPTO had rebuffed the second patent challenge concerning its conformationally constrained nucleotide technology (LNA).  As ISIS and Regulus have decided on making the LNA-derived cET technology their next-generation antisense technology, the increased aggression (including an ongoing gapmer patent infringement suit brought by ISIS against Santaris) may indicate that also ISIS sees cET technology on shaky IP grounds.

Thanks for the Validation!

Even during the hard-fought Tekmira vs Alnylam battle, the participants largely refrained from making direct snarky comments.  This, however, cannot be said of last week’s presentation by Regulus, when it sarcastically thanked Santaris for being years ahead in their miR-122 HCV program and doing all the clinical validation- for them.  The comment obviously refers to the fact that Stanford University had licensed the seminal Sarnow patent related to miR-122 inhibition for HCV therapy to Regulus, not Santaris.  It is also what made GSK dump Santaris and partner with Regulus on the program instead.  I would agree that Regulus has a strong case in this matter, but the unmitigated sarcasm was remarkable.

Is it all about cET?

When ISISfirst reported on their next-generation (gen 2.5 that is) nucleotide modification, it (cET) was explicitly derived from LNAs.  The rationale was that although LNA is the most potent antisense technology around, it suffered from poor safety (as supported by the premature termination of the PCSK9 and ApoB programs by Santaris).  Consequently, additional moieties were incorporated into the bridge that fixes the conformation of the backbone ribose in place.  As a result, the high affinity of the parent LNA was retained, but the safety issues were apparently overcome.

As a LNA-derived technology, the obvious question is whether Santaris, which controls fundamental LNA patents, has IP rights in cET.  Given the importance of cET to ISIS Pharmaceuticals and Regulus such uncertainty is intolerable.  Hence, it would make sense for ISIS and Regulus to attack Santaris and its LNA patents, which is exactly what ISIS has been doing.  Two such pre-emptive strikes, however, have failed according to last week's news.  And as a pre-emptive reminder on my part, a patent only gives you the right to exclude, not freedom-to-operate.

The gapmer patent infringement suit against Santaris may thus be viewed as an effort to get Santaris to the negotiating table.  The miR-122 situation, albeit unrelated to the LNA issue, would be further ammunition to ISIS and Regulus in that effort.

Expect the confrontation to get heatier still, as Santaris should strike back as the overall strategy by ISIS Pharmaceuticals, which is continuing to closeone deal after the other, seems to be working despite the lost patent re-examination battles last week, and is taking away the financial oxygen from Santaris.

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