Orexo AB v. Actavis Elizabeth LLC (Fed. Cir. 2018)
The varying appellate fortunes of patentees regarding the question of obviousness is illustrated nicely in the Federal Circuit decision in Orexo AB v. Actavis Elizabeth LLC handed down earlier this month. The statute, 35 U.S.C. § 103, was intended to tether the question of obviousness to the prior art (and untether it from judicial whim regarding "inventiveness" or "invention" as found in several Supreme Court decisions stating with Hotchkiss (and, to patent law's detriment, resurrected under § 101 by Justice Breyer and in other recent decisions from the Court). Nevertheless, there cannot help to be a subjective aspect to the issue of obviousness, which is illustrated by this decision when placed in contrast, for example, with other recent obviousness determinations by the Federal Circuit (see, for example, "Acorda Therapeutics, Inc. v. Roxane Laboratories, Inc.").
The case arose as litigation over Actavis's Abbreviated New Drug Application (ANDA) over Orexo's Zubsolv® product, which was approved by the FDA for treating opioid dependence. Orexo asserted its Orange Book-listed U.S. Patent No. 8,940,330, where claims 1 and 6 are representative:
1. A tablet composition suitable for sublingual administration comprising:
microparticles of a pharmacologically-effective amount of buprenorphine, or a pharmaceutically-acceptable salt thereof, presented upon the surface of carrier particles,
wherein microparticles of buprenorphine or a pharmaceutically acceptable salt thereof are in contact with particles comprising citric acid,
wherein the buprenorphine or pharmaceutically acceptable salt thereof and the citric acid are not in the same particle;
a pharmacologically-effective amount of naloxone, or a pharmaceutically-acceptable salt thereof;
and a disintegrant selected from the group consisting of croscarmellose sodium, sodium starch glycolate, crosslinked polyvinylpyrrolidone and mixtures thereof.
6. The composition as claimed in claim 1, wherein the particles of citric acid are presented and act as carrier particles.
(wherein the italicized terms are relevant to the Court's determination).
The District Court found the asserted claims of the '330 patent to be obvious, based on prior art disclosure of sublingual formulations of buprenorphine and naloxone in 4:1 concentration ratios known to be effective for treating opioid dependence. Formulations according to the '330 patent provided smaller doses of buprenorphine to be effective and were less subject to abuse (which in the prior art comprised dissolving the formulation and injecting it directly into the bloodstream). There was no dispute between the parties regarding the improved effectiveness of the '330 patent formulations. The opinion states that the evidence presented at trial showed a 66% increase in bioavailability for buprenorphine for tablets containing 29% less of this drug. The District Court's obviousness determination rested on the components recited in the claims being known in the art, and that "although the specific formulation was not shown or suggested in any reference" the claims to the specific formulation were obvious. The District Court also held that evidence provided by Orexo regarding the objective indicia (aka secondary considerations) did not rebut its obviousness determination.
The Federal Circuit reversed, in an opinion by Judge Newman joined by Judges Hughes and Stoll. The prior art disclosed formulations (Suboxone®) comprising buprenorphine, naloxone, citric acid, sodium citrate, and sublingual excipients, made by a "wet granulation" process described as "buprenorphine, citric acid, and sodium citrate are dissolved together and then mixed with excipients." Orexo argued that its claims specify (and the formulations produced thereby showed improved bioavailability due to) microparticles of buprenorphine that are adhered to citric acid carrier particles and that such a formulation, having 66% increased buprenorphine bioavailability were not "suggested or reasonable predictable" from the prior art. This argument was supported by the Examiner's reasons for allowance:
[T]he mere presence of citric acid in the sublingual tablets formulated according to the prior art (e.g. Cairns) is insufficient to achieve the superior pharmacokinetic profile exhibited by the instant invention. Applicant has persuasively demonstrated that the instant tablet exhibits unexpectedly superior sublingual buprenorphine bioavailability due to the ingredients as well as the structural characteristics recited in the instant claims [emphasis in opinion].
Also in the prior art were Suboxone® provided as "orally dissolvable films," which have the disadvantage (according to the opinion) that they cannot be easily removed once applied and limit the dosages that can be achieved (because no more than two films can be applied at one time). In addition to buprenorphine and naloxone in a 4:1 ratio, the films contain citric acid to reduce the pH to 3.0-3.5 in order to provide optimum bioavailability. This form of the drug dosage does not have the improved bioavailability or reduced amount of buprenorphine as provided in the '330 patent formulations.
The District Court also relied on an earlier Orexo published application (which did not mention citric acid as a component) and a European patent, EP 0 324 725, which listed a "large number of water-soluble carrier particles." Neither citric acid carrier particles, sublingual tablets, nor application of these formulations to opioids were mentioned in this reference.
The Federal Circuit opinion characterizes the District Court's error(s) as relying on the prior art for not excluding Orexo's formulation, for example with regard to including citric acid in the formulation (and, sub silentio appearing to consider inherent the bioavailability-improving properties of using citric acid as carrier particles for the buprenorphine microparticles specified in the '330 patent claims). The District Court also discounted Orexo's argument that lowering the pH using citric acid would change the effective concentrations of buprenorphine and naloxone, thus disrupting the 4:1 ratio known to be effective, saying that the ratio itself was an "unclaimed feature" and that this went to whether there would have been a reasonable expectation of success rather than any motivation to combine the prior art. The District Court was persuaded by Actavis's expert's testimony that citric acid "fits the definition of a carrier particle" and would act as one, although the panel notes the cited art did not disclose using citric acid as a carrier.
Regarding the objective indicia, although the District Court acknowledged that "the unexpected result of increased bioavailability provides some support for nonobviousness," the improved bioavailability were "a difference in degree,' not a difference in 'kind.'" The District Court also was unpersuaded by Orexo's evidence regarding teaching away, long-felt need, and copying.
The panel opinion rejected the District Court's analysis as being infected by hindsight and using the '330 patent disclosure as a template for finding the disclosed aspects of the claimed invention in the prior art. The prior art disclosure of using citric acid to lower the pH of buprenorphine/naloxone formulations either disrupted the 4:1 drug ratio or did not increase buprenorphine bioavailability and thus did not support Actavis's argument nor the District Court's persuasion by it. The Federal Circuit also did not find assertion of Orexo's earlier published application to support non-obviousness, insofar as this reference made no mention of including citric acid in any opioid formulation. And the cited EP'725 patent merely recited a "general description of interactive mixtures as pharmaceutical formulations" and did not recite any specific disclosure relating to sublingual tablets, opioid formulations, citric acid as a carrier particle (despite reciting an "extensive list of carrier particles") or anything else relevant to the question of obviousness of the '330 patent claims.
The opinion also cites the undisputed novelty of the claimed formulations, and colloquy during oral argument regarding the conventionality of using citric acid as a carrier:
Actavis Counsel: Your Honor, I will confirm what counsel said before and what we've said in our briefs. There is no piece of prior art that was presented that says citric acid is a carrier particle or should be used as a carrier particle.
Court: If both of those things are really well known, then one would think that if citric acid were routinely or it was obvious to use it as a carrier particle, you could have found some reference that used it. . . . Your expert didn't even testify that he was familiar with this industry and that citric acid was routinely used as a carrier particle in interactive mixtures. He just said it was the right size and it could be used.
Actavis Counsel: Well. You're right Your Honor in terms of your characterization of the record. There was not citric acid used as a carrier particle that was in the record.
The opinion illustrates the District Court's error in accepting as evidence supporting obviousness testimony that, if selected, citric acid as a carrier particle would have been expected to work, citing In re Gordon, 733 F.2d 900, 902 (Fed. Cir. 1984) ("The mere fact that the prior art could be so modified would not have made the modification obvious unless the prior art suggested the desirability of the modification."). A similar error arose regarding the District Court's dismissal of Orexo's argument regarding preserving the 4:1 ratio of buprenorphine to naloxone, the panel stating the error to be the District Court's finding that "there is nothing in the prior art which would have discouraged a person of ordinary skill from following the path set out in the various references" instead of recognizing that "no reference or combination of references proposes the path of the '330 Patent." Put more succinctly the opinion states "[t]he question is not whether the various references separately taught components of the '330 Patent formulation, but whether the prior art suggested the selection and combination achieved by the '330 inventors."
Finally, the opinion turns to the objective indicia, which "guide the analysis of obviousness," citing Leo Pharm. Prods., Ltd. v. Rea, 726 F.3d 1346, 1357–58 (Fed. Cir. 2013). Without expressly stating it, the Court here finds clear error in the District Court's discounting these factors, for example, stating that a 66% increase in buprenorphine bioavailability was "more than a trivial 'degree.'"
Orexo AB v. Actavis Elizabeth LLC (Fed. Cir. 2018)
Panel: Circuit Judges Newman, Hughes, and Stoll
Opinion by Circuit Judge Newman