In its recent review of a district court decision the Federal Circuit characterized as "a thorough opinion," the Federal Circuit affirmed invalidation for obviousness of four claims from four different Orange Book-listed patents in Vanda Pharmaceuticals Inc. v. Teva Pharmaceuticals USA, Inc.
The case arose in ANDA litigation involving Vanda's tasimelteon drug (Hetlioz®) for non-24-hour sleep-wake disorder described in the opinion as a circadian rhythm disorder prevalent amongst blind individuals. Defendants Teva and Apotex filed ANDAs having Paragraph IV certifications that prompted Vanda's assertion of these four claims:
• RE46,604 (Claim 3) (wherein the limitations recited in claims from which the asserted claims depend are set forth in italics):
3. A method of entraining a patient suffering from Non-24 to a 24 hour sleep-wake cycle in which the patient awakens at or near a target wake time following a daily sleep period of approximately 7 to 9 hours, and maintaining said 24 hour sleep-wake cycle said method comprising: treating the patient by orally administering to the patient 20 mg of tasimelteon once daily before a target bedtime, wherein the patient is totally blind and wherein the tasimelteon is administered 0.5 to 1.5 hours before the target bedtime.
• U.S. Patent No. 10,149,829 (Claim 13):
13. A method of treating a patient for a circadian rhythm disorder or for a sleep disorder wherein the patient is being treated with a strong CYP1A2 inhibitor selected from a group consisting of fluvoxamine, ciprofloxacin, and verapamil, the method comprising: (A) discontinuing treatment with the strong CYP1A2 inhibitor and then (B) treating the patient with 20 mg of tasimelteon once daily, that comprises treating the patient for Non-24-Hour Sleep-Wake Disorder.
• U.S. Patent No. 9,730,910 (Claim 4):
4. A method of treating a patient for a circadian rhythm disorder wherein the patient is being treated with rifampicin, the method comprising: (A) discontinuing the rifampicin treatment and then (B) treating the patient with tasimelteon, thereby avoiding the use of tasimelteon in combination with rifampicin and also thereby avoiding reduced exposure to tasimelteon caused by induction of CYP3A4 by rifampicin, [the method] compris[ing] treating the patient for Non-24-Hour Sleep-Wake Disorder, wherein the patient is light perception impaired (LPI) and wherein treating the patient with tasimelteon comprises orally administering to the patient 20 mg of tasimelteon once daily before a target bedtime.
• U.S. Patent No. 10,376,487 (Claim 5):
5. A method of treating a human patient suffering from a circadian rhythm disorder or a sleep disorder that comprises orally administering to the patient an effective dose of tasimelteon without food, wherein the effective dose is 20 mg/d wherein the patient is suffering from a circadian rhythm disorder, and wherein the circadian rhythm disorder is Non-24 Disorder.
Regarding claim 3 of Reissue Patent No. RE46,604, the District Court found this claim to be obvious over two combinations of four references: Hack et al., 2003, "The Effects of Low-Dose 0.5-mg Melatonin on the Free-Running Circadian Rhythms of Blind Subjects," 18 J. Biological Rhythms 420; PCT Publication No. WO 2007/137244; and Lankford, 2011, "Tasimelteon for Insomnia," 20 Expert Op. Investigational Drugs 987; or Hack, the '244 application, and Hardeland, 2009, "Tasimelteon, a Melatonin Agonist for the Treatment of Insomnia and Circadian Rhythm Sleep Disorders," 10 Current Op. Investigational Drugs 691.
The Federal Circuit affirmed, in an opinion by Judge Dyk, joined by Judges Bryson and Prost. Vanda argued on appeal that the District Court erred in considering the Hack reference, which taught using melatonin to entrain circadian rhythms; the Federal Circuit disagreed. While conceding that "tasimelteon and melatonin are not identical," Defendants asserted expert testimony that tasimelteon binds to melatonin receptors and that the Hardeland art taught that tasimelteon could be used to treat patients having circadian rhythm disorders. The panel found no error in the District Court crediting this testimony or the statements in the prior art regarding the similarities between tasimelteon and melatonin. The panel also rejected Vanda's argument that the prior art would provide no reasonable expectation of success in the claimed dose (20mg/d) because the Hardeland and '244 PCT application disclosed a study by Rajaratnam that disclosed that "[t]he most effective doses of tasimelteon were in the range of 20 to 50mg/day," supported by expert testimony), and the Lankford reference disclosed Vanda's own phase III clinical study for entraining blind individuals with 20 mg/d tasimelteon. Finally, the panel held that the District Court was properly unconvinced that the objective indicia of non-obviousness did not rebut Defendants' prima facie obviousness case regarding long-felt need (regarding evidence from a single case) and industry praise (the evidence not being commensurate in scope with what it was being used to support).
Turning to the '487 patent, the panel affirmed the District Court's obviousness determination based on the limitation "without food," which the District Court held would have been an obvious-to-try limitation, citing Section C of KSR Int'l Co. v. Teleflex Inc., 550 U.S. 398, 421 (2007). The panel recognized evidence of there being a "market pressure" to determine the effect of food administration on tasimelteon, which was a consideration for new drugs. There were only two alternatives after all, the opinion states, and they amounted to "two identifiable and predictable options." This situation satisfied the Supreme Court's criteria in KSR and the Federal Circuit affirmed the District Court's reliance thereupon in making its obviousness determination.
The Federal Circuit rejected Vanda's arguments against the District Court's obviousness determination on claim 4 of the '910 patent, the limitation at issue being "(A) discontinuing the rifampicin treatment and then (B) treating the patient with tasimelteon." According to the panel, the District Court properly relied on knowledge in the art that a related drug, ramelteon, had an 80% reduction in blood plasma levels when co-administered with rifampin. Thus it would have been obvious to claim discontinuing rifampicin before treating a patient with tasimelteon, based inter alia on tasimelteon binding to the same receptor as ramelteon in the panel's view. The panel also rejected evidence that a further reference to Vachharajani taught away from the conclusion that an enzyme induced by rifampicin would metabolize tasimelteon because the study did not show the enzyme did not do so after it had been induced by rifampicin as required in the claim. This conjecture, that the enzyme in its rifampicin-induced state would have a different effect than in the uninduced state disclosed by the Vachharajani reference was supported by expert testimony, and the Federal Circuit held that the District Court did not err in relying on this evidence.
Finally, the Court affirmed the District Court's obviousness determination regarding claim 14 of the '829 patent, concerning the limitation "(A) discontinuing treatment with the strong CYP1A2 inhibitor and then (B) treating the patient with . . . tasimelteon." The evidence relied upon by the District Court was found in the Hardeland reference, which taught that "[a]s tasimelteon is metabolized by [CYP1A2] . . . , coadministration of any drug that inhibits [this enzyme] should be regarded with caution," and taught that the blood plasma levels of ramelteon increased 100-fold upon co-administration with a CYP1A2 inhibitor. The panel rejected Vanda's assertion that the prior art did not teach the skilled worker not to administer tasimelteon with a CYP1A2 inhibitor. The opinion rejects this contention as illustrating a misunderstanding regarding the standards for obviousness, specifically that certainty is not required, just a reasonable expectation of success, citing Pfizer, Inc. v. Apotex, Inc., 480 F.3d 1348, 1364 (Fed. Cir. 2007). Using this standard, the opinion states that "a skilled artisan would have expected that taking a CYP1A2 inhibitor with tasimelteon would have negatively impacted the efficacy of tasimelteon and so the two should not be given together," which renders claim 14 of the '847 patent obvious according to the Federal Circuit.
Vanda Pharmaceuticals Inc. v. Teva Pharmaceuticals USA, Inc. (Fed. Cir. 2023)
Nonprecedential disposition
Panel: Circuit Judges Dyk, Bryson, and Prost
Opinion by Circuit Judge Dyk
