C. Unexpected PK Profile in Relation to “Therapeutic Window”
From the cross-over study data, Concert calculated that, for AA, a dose of 27 mg ruxolitinib would be needed to have efficacy that is comparable to a 16 mg dose of CTP-543. Contrary to Incyte’s allegation, this comparison is neither artificial nor exaggerated. When efficacy and safety are considered together (as shown by reference to the therapeutic window), the difference between CTP-543 and ruxolitinib is significant.10 As explained, these very different doses are required for the two drugs to maintain exposure levels for the same length of time over the IC50 for IFN-γ, a cytokine implicated in AA. Incyte does not dispute that the two different doses would provide exposure levels above the IC50for IFN-γ for the same length of time.11
Also significant is the increased time CTP-543 spends within the therapeutic window. In the cross-over study, following a single dose of each drug, CTP-543 levels were within the therapeutic window 2.2 hours longer on average than ruxolitinib levels. Incyte argues that the 2.2 hour average difference is clinically irrelevant given that both drugs are to be dosed twice daily,12 which it argues would diminish CTP-543’s benefit in that the PK profile of ruxolitinib would be just as suitable with respect to the therapeutic window. Incyte, however, offers little credible evidence for this argument. Incyte relies on Ex. 1072 (Shi) to support its contention that 15 mg ruxolitinib BID had a steady state Cmin above 50 nM and a steady state Cmax of 649 nM, which is within the Incyte’s complaint that Concert had earlier compared 16 mg CTP-543 to 20 mg ruxolitinib is irrelevant. Concert never claimed that 16 and 20 mg doses were comparable with respect to time over IFN-γ IC50.
12 To be clear, there is no requirement that CTP-543 must be administered twice daily, except in the current Phase 2a clinical trial. Further study may reveal the possibility of reduced dose frequency in light of CTP-543’s more favorable pharmacokinetics therapeutic window, but Incyte’s portrayal of the Shi data is misleading. The mean Cmax reported by Shi is close to the upper limit of the therapeutic window. If there is a normal distribution, half of the population would have a Cmax above that mean value. Furthermore, the Shi study did not include CTP-543. Comparing data across two separate studies with two different drugs is not nearly as reliable as the head-to-head, direct comparison performed by Concert in its cross-over clinical trial.
VI. CTP-543 SATISFIES A LONG-FELT NEED Incyte asserts that there is no long-felt need for an FDA-approved AA
treatment because the “full technical solution of using JAK inhibitors to treat AA” was purportedly taught before the priority date.13 (Reply, 3-4.) Incyte’s Dr. Shapiro based this opinion on a patent application that published just one month before the priority date. However, contradicting ¶25 of his declaration, Dr. Shapiro now concedes that this patent application contains no clinical data demonstrating the use of ruxolitinib in AA. Indeed, he confirmed that the first reports of JAK inhibitor use in AA patients occurred in 2014—well after the 2012 priority date.
13 Incyte’s argument lacks clarity, because it fails to cite any legal authority for its “full technical solution” framework. 14 Dr. Shapiro also did not cite any data from any other in vivo or in vitro testing. Although a commercial solution is not necessary (Reply, 4), Incyte fails to adequately link the prophetic pronouncements in Ex. 1014 with its contention that the “full technical solution” of using JAK inhibitors to treat AA—or of a JAK inhibitor with a safety profile sufficient to achieve FDA approval for AA—was available as of the priority date. Indeed, Dr. Shapiro’s own December 2013 article titled “Current Treatment of Alopecia Areata” nowhere mentions JAK inhibitors as a current treatment, belying their use for AA in 2012.
There remains a long-felt need for an FDA-approved treatment for AA.15None of the three approved JAK inhibitors—ruxolitinib, tofacitinib, and baricitinib—are indicated for AA. And both tofacitinib and baricitinib carry black-box warnings which may limit their use in AA. (noting that serious side effects are of concern in treatment of a chronic, non-fatal condition like AA).
Incyte’s bare allegation that Concert’s reliance “on JAK inhibitor side-effect profile[s] in cancer patients is inapplicable to AA patients” (Reply, 4-5) should be
15 Contrary to Incyte’s contention, Concert never asserted that CTP-543 is currently FDA-approved. As Concert noted, the FDA has granted CTP-543 a “Fast Track” designation, in recognition of its potential to fill the unmet medical need rejected under Rule 42. In any event, its allegation is refuted by its own expert. Although Dr. Shapiro asserts here that the side-effect profile in cancer patients is irrelevant to AA patients, his own AA- related article discusses side effects seen in myelofibrosis patients. He also failed to disclose that AA patients are more likely than healthy people to have anemia. Moreover, the prior art reported that even healthy subjects and patients with other autoimmune diseases—populations that Dr. Shapiro contends are more relevant than myelofibrosis patients—experienced hematological adverse events when administered JAK inhibitors. (neutropenia and thrombocytopenia); Ex. 2012, (dose-dependent neutropenia in short-term study); While Incyte tries to downplay these side effects, as both Dr. MacKay-Wiggan and Dr. Reider stated, drug toxicity is less tolerable in AA than in cancer indications and thus they would be of concern to POSAs.
16 Dr. Shapiro was not even familiar with rates of anemia in AA patients, which is not surprising because he does not check his patients for co-morbidities such as anemia.
VII. CONCERT’S EVIDENCE OF SECONDARY INDICIA IS COMMENSURATE IN SCOPE
Incyte expressly limited its patentability arguments to the three compounds recited in claim 7—one “octa-deuterated ruxolitinib” derivative, and two “tetra- deuterated ruxolitinib” derivatives. (Petition, 8.) In response, Concert focused its POR on those same three compounds.
With regard to the tetra-deuterated derivatives (including those in claims 3, 4, 11, and 12), Concert demonstrated that Incyte’s own unpatentability arguments make no sense as applied to these compounds. In its Reply, Incyte did not even attempt to rebut this showing.
With respect to octa-deuterated ruxolitinib, Concert demonstrated unexpected results for CTP-543, an octa-deuterated compound. Where there is “adequate basis to support the conclusion that other embodiments . . . will behave in the same manner,” evidence of unexpected results is generally considered commensurate in scope with the claims. In re Huai-Hung Kao, 639 F.3d 1057, 1068 (Fed. Cir. 2011); In re Cescon, 474 F.2d 1331, 1334 (C.C.P.A. 1973) (concluding that evidence of correlation with result is sufficient to establish unexpected results even though limited embodiments tested). Here, Incyte concedes that POSAs would have known how degree of deuterium enrichment influences metabolic properties and therefore would have known the correlation between degree of isotopic enrichment and unexpected results. Because the only variation between the proffered evidence and the octa- deuterated compound at issue is the level of deuterium enrichment, a POSA would understand the scope of the unexpected results to be commensurate with the claims. Incyte’s failure to offer any experimental evidence that any embodiments falling within the claims would not demonstrate unexpected results further supports this conclusion.
VIII. CONCLUSION For the foregoing reasons, Incyte has failed to carry its burden of proving unpatentability, and the Board should therefore refuse to cancel the claims.