Federal Circuit Finds Deuterated Analogs Of Small Molecule Drug Obvious

By Raffaella Faraoni and Kunyong Yang –

On August 22, 2023, the Federal Circuit issued a nonprecedential decision holding that claims directed to deuterated analogs of ruxolitinib were unpatentable as obvious.  Sun Pharm. Indus., Inc. v. Incyte Corp., No. 2019-2011, Document No. 117 (Fed. Cir. August 22, 2023) (“Sun”).  The Federal Circuit affirmed a Patent and Trial Appeal Board (“Board”) decision from IPR2017-01256 that held unpatentable all claims of U.S. Patent No. 9,249,149 (“the ’149 patent”).

A deuterated drug is a compound in which one or more of the hydrogen atoms of the drug molecule have been replaced by deuterium, a heavier isotope of hydrogen.  Sun, at *3.  The carbon deuterium bonds are stronger than carbon hydrogen bonds, and can impact the pharmacokinetic properties (absorption, distribution, metabolism, and/or secretion) of a drug.  Id.  The claims of the ’149 patent are related to various deuterated analogs of ruxolitinib, a JAK1/JAK2 inhibitor approved for treatment of patients with intermediate or high-risk myelofibrosis (Jakafi®).  Claim 1 of the ’149 patent recites a compound of a generic formula where various positions can be deuterated.  The IPR focused on three specific deuterated compounds recited by claim 7: an “octo-deuterated” and two “tetra-deuterated” ruxolitinib analogs.  The octo-deuterated analog with a high isotopic purity was named “CTP-543.”  Sun, at *4-5.

The Federal Circuit applied the lead compound analysis in its obviousness determination.  The lead compound analysis is a two-step test in which a person of ordinary skill in the art (“POSA”) must have had: (i) a reason to select a prior art compound as a “lead,” and (ii) a reason to modify the prior art compound with a reasonable expectation of success.  Otsuka Pharm. Co. v. Sandoz Inc., 678 F.3d 1280, 1291–92 (Fed. Cir. 2012).  In this case, there was no dispute that a POSA would have selected ruxolitinib itself as the lead compound.  Sun, at *10.

The Federal Circuit rejected the patent owner, Sun Pharmaceutical Industries, Inc. (“Sun Pharma”)’s arguments that the Board erred in applying the second prong of the test, and concluded that the combination of the prior art of record would have provided a POSA with a motivation to deuterate ruxolitinb at its metabolic hotspots to achieve the potential benefit of improved safety, tolerability, and efficacy, including deuteration specifically on ruxolitinb’s cyclopentyl ring that would lead to the octo-deuterated and tetra-deuterated analogs recited by claim 7 of the ’149 patent.  Sun, at *10-12.

Further, while acknowledging that the “magnitude and nature of the deuterium benefit cannot be predicted a priori,” the Federal Circuit held that there was substantial evidence to conclude that a POSA would have reasonably expected that deuterium modifications would lead to beneficial changes in pharmacokinetic properties.  Sun, at *13.

Finally, Sun Pharma argued that CTP-543 displayed two objective indicia of nonobviousness: unexpected results and long-felt need.  The Federal Circuit disagreed.  First, the Federal Circuit opined that there was substantial evidence on the record to conclude that CTP-543’s results − increased time in the therapeutic window and increased clinical response at a given dose – were “an increase in the same clinical activity observed with ruxolitinib, and therefore represent merely a difference in degree and not in kind” and “did not indicate a marked superiority in these properties.”  Id. at *14.  Finally, the Federal Circuit held that, since the long-felt need is for an “FDA-approved” alopecia areata treatment, CTP-543 had not actually satisfied the long-felt need because it has not been approved by FDA yet.  Id. at *15.

Takeaway:

The decision illustrates certain challenges faced by deuterated drug patents.  Likely these cases are fact specific and patentability should be tied to the particular art and the final drug properties.  Despite being nonprecedential, patentees should keep this decision in mind when seeking to patent deuterated drug analogs to avoid pitfalls.