Spray your way to non-obviousness: Patents directed to intranasal delivery of migraine drugs not obvious where prior art would have resulted in reduced efficacy
| July 11, 2018
Impax Laboratories, Inc. v. Lannett Holdings, Inc.
June 28, 2018
Before Lourie, Dyk, and Taranto. Opinion by Lourie.
Summary
This case involved a “close” question of obviousness that was ultimately decided in no small part by the perceived relative credibility of the parties’ experts. The Federal Circuit deferred to the district court’s preference for the patent owner’s expert, and consequently, the district court’s determination that, where the efficacy of a drug’s active ingredient depended not on itself, but on its more potent metabolite, a person of ordinary skill in the art would not have found it obvious to pursue a proposed combination of the prior art that would reduce the metabolite’s production.
Details
AstraZeneca AB (“AstraZeneca”) owns U.S. Patent Nos. 6,750,237 (the “237 patent”) and 7,220,767 (the “767 patent”). The patents related to drugs for treating migraine, with zolmitriptan being the active ingredient. AstraZeneca granted Impax Laboratories, Inc. (“Impax”) an exclusive license to the 237 and 767 patents, in order to develop and supply Zomig®, the brand name migraine medicine covered by the patents.
When Lannett Holdings, Inc. (“Lannett”) attempted to secure approval for a generic version of Zomig®, Impax and AstraZeneca sued Lannett for infringement. In response, Lanette challenged the validity of the patents.
The patent claims at issue were directed to a “pharmaceutical formulation”, and were generally similar to the claim reproduced below:
A pharmaceutical formulation suitable for intranasal administration which comprises zolmitriptan and a pharmaceutically acceptable carrier wherein the pH of the formulation is in the range 4.5 to 5.5.
The feature at the center of this case was the claimed formulation’s suitability for “intranasal administration”.
Lannett’s invalidity challenge relied primarily on U.S. Patent No. 6,326,401 to Chauveau et al. (and the French counterpart FR2773489) (“Chauveau”). Chauveau disclosed a pharmaceutical formulation containing an active ingredient and a glyceride compound (namely, capryl caproyl macrogol glyceride). The glyceride compound facilitates the delivery and absorption of the active ingredient in the body.
Of note is Chauveau’s explicit disclosure that its formulation is for “administration by the oro-mucosal, in particular nasal, route” (see, e.g., Chauveau, 2:5-16). Chauveau also explicitly disclosed various active ingredients that could be incorporated into the formulation, including “in particular, an anti-migraine active substance, such as a triptan, or one of sumatriptan or zolmitriptan” (Chauveau, 3:12-14). However, no working examples of Chauveau contained zolmitriptan.
Lannett argued that, in combination with other prior art allegedly teaching other claim limitations, Chauveau’s teachings on nasal administration of zolmitriptan would have rendered the 237 and 767 patent claims obvious.
Impax, on the other hand, presented an expert who testified that zolmitriptan by itself was not known in the art to be effective in providing relief from migraine symptoms. Rather, as Impax’s expert opined, the therapeutic effects of zolmitriptan relied significantly on a metabolite generated during metabolism of zolmitriptan in the liver. Oral delivery of zolmitriptan provided a more direct route to liver, whereas nasal delivery followed a more circuitous route through the bloodstream. Impax thus argued that it would have been “absolutely counterintuitive” to use zolmitriptan in a nasal formulation, when it would have been far more potent as an oral formulation.
The district court, and on appeal, the Federal Circuit, found Impax’s case to be the stronger one.
The district court credited Impax’s expert testimony and found that, first, “a skilled artisan would have expected delayed or lower therapeutic effectiveness from zolmitriptan if administered nasally”, so that a person of ordinary skill in the art would have been “dissuaded” from pursuing a nasal formulation of zolmitriptan. The Federal Circuit agreed that the state of the art was such that the person skilled in the art would have been “taught away” from nasal formulations of zolmitriptan.
Second, the district court found, and the Federal Circuit agreed, that Chauveau “as a whole” was not about nasal delivery of zolmitriptan. Zolmitriptan was “mentioned once, with no further mention in an example or claim”. As such, Chauveau did not suggest that zolmitriptan by itself was efficacious, and would not have provided the person skilled in the art with any reasonable expectation of success in obtaining therapeutically effective nasal formulations of zolmitriptan.
Lannett argued that triptans, as a class of compounds that included zolmitriptan, were specifically designed to provide migraine relief, so that some therapeutic effects would necessarily be expected. This, in turn, would preclude a finding of “teaching away”. The Federal Circuit took care of this argument easily enough—“Lannett’s contentions are without any evidentiary support beyond its attorney arguments concerning factual issues.”
Thus, the Federal Circuit readily upheld the non-obviousness of the 237 and 767 patent claims.
The Federal Circuit’s parting words in the decision suggested that the question of obviousness would have been a toss-up but for Impax’s expert:
Ultimately, we agree that this case was close. But, we defer to the district court in its fact findings, including what Chauveau discloses and the state of the prior art as a whole. And we are especially persuaded by the testimony of [Impax’s] expert…on which the district court relied, who opined that it would have been “absolutely counterintuitive” to make an intranasal formulation of zolmitriptan, given that its activity primarily came from its metabolite…We therefore conclude that the district court did not commit reversible error in its nonobviousness conclusion.
This decision is an interesting one, because the district court’s analysis, and also that of the Federal Circuit, touches on arguments that may not be commonly used in prosecution.
For one thing, in the Federal Circuit’s decision, a finding of “teaching away” is apparently not limited to explicit criticism, discrediting, or discouragement in the prior art. Rather, there may be “teaching away” if the state of the art, including the accepted wisdom of those skilled in the art, at the relevant time would have “dissuaded” a skilled artisan from the claimed invention. See, e.g., In re Hedges, 783 F.2d 1038, 228 USPQ 685 (Fed. Cir. 1986) (cited in the MPEP for the proposition that the totality of the prior art must be considered, and proceeding contrary to accepted wisdom in the art is evidence of nonobviousness).
Further, the Federal Circuit did not seem troubled by the district court’s finding that the prior art “taught away” from the claimed invention simply because zolmitriptan would have been an inferior option as compared to its metabolite. However, “a known or obvious composition does not become patentable simply because it has been described as somewhat inferior to some other product for the same use.” In re Gurley, 27 F.3d 551, 554 (Fed. Cir. 1994).
The decision also raises questions as to what constitutes “reasonable” expectation of success. In this case, nasal formulations of zolmitriptan did not carry a reasonable expectation of success, apparently because such formulations were not expected to be as therapeutically effective as the metabolite. Was it not enough that zolmitriptan would have provided some level of therapeutic effects?
Takeaway
For the purpose of proving or disproving the existence of any reasonable expectation of success, it may be important to define what “success” means.
There is the option of supporting a “teaching away” argument with the accepted wisdom of those skilled in the art. Such technical wisdom should be presented in declarations, lest they be dismissed as mere attorney arguments. However, during prosecution at the USPTO, Examiners would probably not be persuaded by a “teaching away” argument that is unsupported by some explicit criticism in the cited prior art.
