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Executive Summary

Merck is planning to appeal a successful challenge of its Flexeril patent by the generic manufacturer Danbury. In a 92-page opinion dated Aug. 31, Delaware Federal Court determined that Merck's Flexeril (cyclobenzaprine) patent in unenforceable. The opinion is based on a finding of "inequitable conduct" by Merck in that is misrepresented and withheld information from the Patent & Trademark Office (PTO). Judge Murray Schwartz had instructed Merck and patent challenger Danbury "to confer and attempt to agree upon the amount of attorney fees" the court will order to be paid to Danbury. "I conclude Merck's withholding of all information about amitriptyline and misrepresentation with respect to drowsiness [as a Flexeril side effect] was in bad faith and with the intent to mislead" the PTO, Schwartz wrote. "Given the flagrant inequitable conduct by Merck before the PTO, it would be unjust not to award Danbury reasonable attorney fees." A more significant outcome of the challenge is an award to Danbury under the 1984 ANDA/patent law of a six-month exclusivity period as the sole generic competitor for the Flexeril market. Danbury received a prospective ANDA approval last February. Merck's patent was due to expire in 1992. Under a provision to prevent patent holders from employing dilatory tactics, the Waxman/Hatch legislation stipulates that challengers with approved ANDAs may begin marketing 30 months after litigation begins. Therefore, Danbury can market its generic cyclobenzaprine in May 1989, with the risk of losing at the appellate level. The court ruled that Danbury failed to prove that the Flexeril invention was obvious and that Merck's patent is consequently invalid. However, the court ruled that the patent is unenforceable because Merck withheld information about the similarity between cyclobenzaprine and amitriptyline (Merck's Elavil0 and because Merck told PTO that Flexeril did not cause drowsiness. Danbury filed its patent certification, or challenge under the Waxman/Hatch law, when it submitted its ANDA on Oct. 31, 1986. Merck sued Danbury for patent infringement within 45 days, as the law requires, and is therefore the plaintiff in the case. The Flexeril case is the second patent challenge of a Merck product. In July, Merck successfully defended its Moduretic patent from a challenge by Biocraft. In the only other patent certification case decided so far, Vitarine successfully challenged a patent for the Lederle and Mylan product Maxzide last fall ("The Pink Sheet" July 18, T&G-1 and Nov. 9, p. 3). Schwartz wrote that "Danbury has carried its burden" of establishing "by clear and convincing evidence" Merck's "bad faith conduct" in seeking a patent for Flexeril. When Merck filed for the patent in 1971, it had long known but withheld information that cyclobenzaprine is "very similar in chemical structure" to amitriptyline, the opinion states. Both are tricyclic compounds, and the only difference in their chemical structures is that "there is a single carbon-carbon bond in amitriptyline at [one position in the structure] while cyclobenzaprine has a carbon-carbon double bond at the [same] position," the opinion states. Schwartz also said the two products "share similar phramacological properties." The opinion suggests that the similarity between the compounds would have been important to the PTO because amitriptyline, marketed since 1961 for depression, had been known to display muscle relaxant effects. Both drugs were tested in the 1950s in Merck's Mental Health Program. After Elavil was approved "it exhibited significant activity as a muscle relaxant," Schwartz noted. Danbury argued that Flexeril's patent is invalid because its muscle relaxant properties were obvious, given the drug's similarity to Elavil. However, the court determined, "the conclusion that amitriptyline was a known useful muscle relaxant does not lead automatically to the ultimate conclusion that use of cyclobenzaprine as a selective muscle relaxant was obvious." Although Merck should have informed PTO of the similarity, Schwartz said the Flexeril patent is valid because Flexeril's selectivity was not obvious. The court agreed with Merck that cyclobenzaprine is selective insofar as its muscle relaxant effect do not produce ataxia, or adversely affect muscle tone. Danbury tried to argue that the drug is not selective because it causes drowsiness. The court agreed that Flexeril causes drowsiness, but disagreed that that showed the drug was not selective. Schwartz chastised Merck for failing to inform PTO about the drowsiness effect. "The PTO examiner was critically misled by Merck's misrepresentations about selectivity, the very basis for grant of the patent," the judge wrote. "Merck correctly represented [that] cyclobenzaprine was selective in that it reduced hypertonic muscle tone without loss of normal muscle tone. However, Merck repeatedly throughout its submissions assured the PTO examiner that [unlike other tricyclic agents] cyclobenzaprine had no sedative side effects," the opinion states. The court noted that although Merck did not inform the PTO about Flexeril's drowsiness side effect, the company included "all of the information about drowsiness . . . in its submissions to the FDA, resulting in the FDA requirement that the Flexeril package insert [states] that the most frequent effect is drowsiness." Merck's conduct also was "inequitable" in that the company did not inform the PTO about published studies demonstrating amitriptyline's muscle relaxant properties. In fact, Merck initially may have pursued a muscle relaxant indication for cyclobenzaprine rather than amitriptyline precisely because of the published studies. Three Japanese studies published in 1965 and 1966 conclude that three tricyclics -- amitriptyline, imipramine, and desipramine -- act as muscle relaxants. Although Merck argued that the studies were flawed and did not constitute "prior art" that might undermine the newness of the Flexeril invention, a Merck memorandum of Jan. 25, 1967 cites the studies and recommends that the firm's amitriptyline analogs, including cyclobenzaprine, be submitted "to our muscle relaxant screen." Furthermore, minutes of a Merck internal meeting in October 1970 to consider developing amitriptyline and cyclobenzaprine as muscle relaxants state: "It was pointed out that a publication in the Japanese Journal of Pharmacology several years ago, which claimed that amitriptyline has muscle relaxant properties, will probably preclude obtaining use patent on this compound." Schwartz wrote: "Merck has failed to overcome this proof: (a) the information concerning amitriptyline's usefulness as a muscle relaxant, and the knowledge of the drowsiness side effect, comprising both omissions and misrepresentations, was not merely cumulative; (b) relevant personnel at Merck did know of the art omitted; (c) likewise, these persons knew of the high degree of materiality of the omissions and misrepresentations; and (d) the only showing Merck has made on its purported lack of intent to mislead the PTO is unconvincing protestations of subjective good faith."

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