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Is Novartis’ S1P modulator titration patent a “roadblock” to Celgene’s ozanimod?

Zachary Silbersher

While Bristol Myers ($BMY) proposed acquisition of Celgene’s ($CELG) remains in question by activists questioning Revlimid®’s pending patent cliff, a new patent angle emerges.  A Credit Suisse analyst recently identified a patent owned by Novartis ($NVS) that could purportedly act as a “roadblock” to Celgene’s MS drug ozanimod.  Is this true?

The Novartis patent at issue appears to be U.S. Patent No. 8,492,441.  The patent claims are directed to, inter alia, “a S1P receptor agonist” that is administered first at a “dosage lower than the standard daily dosage” and then “increased, up to the standard daily dosage . . . .”  Accordingly, Novartis has a patent on titrating up the dosage for an S1P modulator.

 Novartis markets Gilenya® (fingolimod), which is a sphingosine-1-phosphate receptor modulator.  The Orange Book currently lists only three patents for Gilenya®.  None of those patents include the ‘441 patent.  Rather they include U.S. Patent No. 5,604,229, which is a compound patent and scheduled to expire later this year, and therefore unlikely act as a roadblock to Celgene’s ozanimod.  The Orange Book also lists U.S. Patent No. 8,324,283, which is a compound patent for an S1P receptor agonist, U.S. Patent 9,187,405, which is a method-of-use patent for treating MS with an S1P receptor modulator, and U.S. Patent No. 9,592,208, which is a formulation patent for an S1P receptor modulator.

Therefore, none of the patents listed in Orange Book for Gilenya cover a titrated dose regimen for an S1P modulator.  Does this prevent Novartis from claiming that Celgene’s ozanimod infringes the ‘441 patent?  No, Novartis is free to assert any patents its owns against Celgene, regardless of whether they are listed in the Orange Book. 

But, if Novartis did not list the ‘441 patent in the Orange Book, that suggests that the patent does not cover Gilenya®.  And in that case, Novartis is likely not practicing the ‘441 patent.  And if it is not practicing the ‘441 patent, then it would be very difficult for Novartis to obtain an injunction against Celgene’s ozanimod through enforcement of the ‘441 patent.  And thus, it’s not really a “roadblock” to Celgene’s MS drug.

One reason that Gilenya may not be covered by the ‘441 patent is because Gilenya®’s label does not indicate titrated dosing.  Another reason that Gilenya may not be covered by the ‘441 patent is because the patent is not as broad as it looks.  During prosecution of the patent, the PTO complained that Novartis’ patent application covered too many inventions.  Novartis therefore elected to restrict the patent to two species of S1P modulators identified as formulas 1a and 1b in the patent.  If Gilgenya® is different from either of these formulas, then the drug is unlikely to be covered by the ‘441 patent.

Even if Novartis cannot enjoin Celgene’s ozanimod from the from the market, Novartis could nonetheless enforce the patent against Celgene.  Its relief would essentially be limited to a reasonable royalty.  But the ‘441 patent does not cover the active ingredient in Celgene’s ozanimod.  Rather, it covers a titration dosage regime.  Accordingly, it is unlikely to be the primary driver of consumer demand.  Thus, the royalty could theoretically be manageable even if Celgene would found to infringe. 

Another aspect that mitigates the threat of the ‘441 patent is that the history of the patent suggests it could be invalid.  The patent covers a method of starting at a lower dose, and then titrating up to a standard dose.  The goal of doing so is reduce negative chronotropic side effects.   

During prosecution of the ‘441 patent, the Patent Office identified prior art that was directed to administering S1P receptor agonists with a “loading dose”—in other words, a dose in excess of the standard dose to rapidly achieve steady state blood levels.  Novartis easily distinguished this prior art from its claims in the ‘441 patent, and the patent was allowed.  Accordingly, it does not appear that the Patent Office conducted an exhaustive prior art search of the ‘441 patent’s invention.

Meanwhile, given that Novartis applied for the ‘441 patent in 2009, it is unlikely that Novartis invented the idea of starting at a lower dose and titrating up to avoid side effects.  In sum, there is reasonable basis to assume that Celgene could invalidate this patent if necessary, thus obviating the risk to its drug.

Overall, there is always a risk that a competitor holds patents that can create a roadblock to any product.  Pharmaceutical companies typically obtain patent coverage that is broader than their own products, and these patents are always lurking in the shadows.  But the devil is in the details.