Abstract
Synopsis
U.S. Patent No. 8,940,330 (“the ’330 Patent”) claims a sublingual tablet formulation comprising naloxone (an opioid antagonist) and buprenorphine (an opioid agonist) that has been approved by the Food and Drug Administration (FDA) for treatment of opioid dependence and is sold under the brand name Zubsolv®. The claims recite that buprenorphine is present in the form of microparticles, and that these microparticles are adhered to the surface of carrier particles of citric acid. In Suboxone®, a prior art sublingual formulation used for the same purpose, on the other hand, the naloxone and buprenorphine are provided as a homogeneous mixture. Clinical trials comparing Zubsolv and Suboxone demonstrated that Zubsolv (the claimed invention) shows a 66% improvement in bioavailability of buprenorphine and that the claimed formulation achieves bioequivalent results using a sublingual tablet containing 29% less buprenorphine than in Suboxone tablets. A district court ruled the ‘330 Patent invalid for obviousness since all the ingredients of the claimed formulation were generally known to the prior art. The Federal Circuit reversed, finding that the prior art does not show or suggest the claimed combination, and does not show or suggest that this combination would achieve enhanced therapeutic effect while being less subject to abuse. Writing for the panel, Judge Newman pointed out that the district court's finding that “a person of ordinary skill in the art would not have excluded citric acid,” is not a teaching or suggestion to use citric acid. She also found that the district court had erred in discounting the enhanced bioavailability in the ’330 Patent's formulation as “a difference in degree, not a difference in kind.” Particularly in the context of this invention, she found the reported 66% improved bioavailability to be “more than a trivial ‘degree.’”
Orexo AB and Orexo US Inc. (collectively “Orexo”) appeal the decision of the United States District Court for the District of Delaware, holding claims 1, 3–6, and 8–10 of U.S. Patent No. 8,940,330 (“the ’330 Patent”) invalid on the ground of obviousness. The ’330 Patent, entitled “Abuse-Resistant Pharmaceutical Composition for the Treatment of Opioid Dependence,” claims a product having the brand name Zubsolv®, approved by the FDA for treatment of opioid dependence.
We reverse the judgment of invalidity of the ’330 Patent, for we conclude that obviousness was not proved by clear and convincing evidence.
Background
A. The ’330 Patent
The ’330 Patent specification explains that opioid-based pharmaceutical products intended for the relief of pain have become a source of addiction, dependency, and abuse. Treatment for opioid addiction includes a protocol called “substitution therapy,” where partial opioid agonists that have higher binding affinities at opioid receptors but produce lowered dependency than full agonists like heroin, can lead to cessation of addiction by relieving the opioid craving. The prior art shows use for this purpose of the partial agonist buprenorphine, administered in sublingual tablets and in oral films.
The ’330 Patent explains that while buprenorphine has less narcotic effect than a full opioid, addicts were known to dissolve the buprenorphine from the substitution therapy tablet, and inject the dissolved buprenorphine intravenously to achieve an enhanced opioid effect. To counteract this abuse, it was known to combine buprenorphine with the opioid antagonist naloxone in substitution therapy.
It was known that formulations containing buprenorphine to naloxone at a ratio of 4:1 provide the therapeutically optimal balance for sublingual treatment. Naloxone has poor transmucosal bioavailability, so that if the mixture is taken in tablet form as directed, the buprenorphine will act as intended to treat opioid dependence with little interference from the naloxone. However, if the tablet is dissolved and injected, the naloxone will antagonize the effects of the buprenorphine, resulting in withdrawal symptoms and thus deterring abuse of the formulation. The 4:1 ratio provides for appropriate pharmacological amounts of naloxone to deter abuse when injected, but does not interfere with buprenorphine when taken in tablet form. However, naloxone's “functional blockade of buprenorphine's action is also only partial and is short-lived in its nature,” and there was a continuing need for improvement in substitution therapy formulations.
The ’330 Patent is for a sublingual tablet formulation that is less subject to abuse. The formulation enhances the agonist effectiveness of buprenorphine, permitting a reduced amount of buprenorphine in the tablet and thus reducing the amount available on dissolving and injecting the product. In this formulation, microparticles of buprenorphine are adhered to the surface of carrier particles of citric acid, and the formulation also contains naloxone in the 4:1 ratio. The ’330 Patent explains that the buprenorphine in the microparticles acts with little interference from the naloxone, but if the tablet is dissolved in water for injection into the bloodstream, the naloxone will also be dissolved and will antagonize buprenorphine's effects.
All parties agree that the product in the ’330 Patent provides improved treatment of opioid dependence, as compared with the prior art. The ’330 Patent specification includes data from clinical trials comparing the related sublingual product Suboxone®. Patent Example 2 shows a 66% improvement in bioavailability of buprenorphine, and Patent Examples 7 and 8 show bioequivalent results for a sublingual tablet containing 29% less buprenorphine than in Suboxone tablets.
Actavis does not dispute the improvement, or its value in treatment of addiction. Rather, Actavis argues that this formulation is obvious based on a combination of references, and that improved function and use are irrelevant if the product is obvious. This theory is flawed, for an unobvious improvement in properties or use is highly relevant to patentability of a new product.
Claims 1 and 6 were deemed 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; 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.
The district court found that all the ingredients in the claims were generally known, and held that although the specific formulation was not shown or suggested in any reference, the new combination would have been obvious to a person of ordinary skill. However, the prior art does not show or suggest the claimed combination, and does not show or suggest that this combination would achieve enhanced therapeutic effect while being less subject to abuse.
B. The prior art
1. Suboxone® and Subutex®
The buprenorphine and naloxone combination in the 4:1 ratio has been used for substitution therapy at least since 2002. The prior art Suboxone sublingual tablets are a homogeneous combination made by mixing the ingredients of buprenorphine, naloxone, citric acid, sodium citrate, and sublingual excipients. Subutex® is the same formulation as Suboxone, but without the naloxone.
Orexo attributes the improvements achieved by the Zubsolv product to the microparticles of buprenorphine adhered to the surface of citric acid carrier particles. Orexo states that the 66% higher bioavailability is not suggested or reasonably predictable from the prior art. We have been directed to no reference to show or suggest otherwise. Orexo stresses the Examiner's statement in allowing the ’330 Patent, that the improvement is due to the ingredients and the structure:
[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.
2. Suboxone® film
U.S. Patent No. 8,475,832 (“the ’832 Patent”) describes an orally dissolvable film that cannot be easily removed once placed inside the mouth. The film contains the buprenorphine/naloxone combination in the 4:1 ratio, and is described as bioequivalent to Suboxone sublingual tablets. The ’832 Patent teaches that optimum bioavailability of buprenorphine and naloxone from the film is achieved at pH 3–3.5, with citric acid included in the film to lower the pH. The district court relied on this presence of citric acid to render obvious the citric acid carrier particles in the Zubsolv formulation.
However, the ’832 Patent does not reduce the amount of buprenorphine needed to provide an effective substitution therapy dose. And the use of film in substitution therapy presents recognized problems, as stated in the ’330 Patent, for the film does not dissolve quickly and a maximum of only two films may be administered simultaneously, producing inadequate dosage as well as problems of compliance and administration.
3. The Orexo Application
Orexo's U.S. Patent Application No. 2010/0129443 (“the ’443 Application”), titled “Non-Abusable Pharmaceutical Composition Comprising Opioids,” was filed on December 3, 2007, published on May 27, 2010, and issued as U.S. Patent No. 8,470,361 on June 25, 2013. It is prior art as of its filing date.
The ’443 Application describes sublingual tablets where smaller particles of opioid agonists are carried on larger particles that include an opioid antagonist. The ’443 Application lists many opioid agonists including buprenorphine, and many antagonists including naloxone. However, citric acid is not mentioned or suggested as the carrier particle.
4. European Patent Application No. EP 0324725
European Patent Application No. EP 0324725 (“the EP ’725 Application”) lists a large number of water-soluble carrier particles, to which smaller particles of a pharmaceutically active substance may be adhered. The EP ’725 Application does not mention sublingual tablets, does not mention opioids as the active substance, and does not mention citric acid as a carrier.
C. The district court decision
The district court held the asserted ’330 Patent claims invalid, ruling that a skilled artisan would obviously have selected these components from the prior art and reformulated them as in the ’330 Patent. The district court stated that the ’443 Application taught that “a person of ordinary skill in the art would have been motivated to reformulate Suboxone tablets as an interactive mixture to improve bioavailability,” that the ’832 Patent for an oral film “expressly taught a person of ordinary skill that the addition of citric acid facilitated an increased level of absorption of buprenorphine despite a lower pH,” and that the EP ’725 Application “described how to make such a mixture using dry mixing.”
In response to Orexo's argument that no reference showed the new formulation in the ’330 Patent, stressing the unexpectedly enhanced bioavailability and its benefits, the district court reasoned that a skilled artisan “would not have excluded citric acid” as a carrier and “would have known how to form an interactive mixture using citric acid.”
Orexo argued that a person of ordinary skill would have been dissuaded from using citric acid in this interactive mixture because Examples 6–8 of the ’832 Patent taught that as the pH is lowered through use of citric acid, the buprenorphine bioavailability increase is accompanied by a compromised naloxone availability such that the 4:1 ratio is lost. The district court described this argument as irrelevant because the 4:1 ratio is an “unclaimed feature” of the ’330 Patent, the court stating “any problems with maintaining the ratio forecast by the ’832 patent goes to the reasonable expectation of success requirement, not to motivation to combine; i.e., this argument is irrelevant in this context.”
Orexo stresses that no reference teaches or suggests using citric acid particles as a carrier for micronized buprenorphine, and that the benefits of this formulation were unexpected. Rejecting this argument, the district court cited the testimony of Actavis' expert that citric acid “fits the definition of a carrier particle” and “therefore it would act as a carrier particle, because it is in the Suboxone tablet.” However, no reference suggests citric acid carrier particles.
The district court also discussed the objective indicia of unobviousness, responding to Orexo's arguments of unexpectedly increased bioavailability, long-felt need for improved treatment of opioid dependence, copying by Actavis, and hindsight. The court stated that “the unexpected result of increased bioavailability provides some support for nonobviousness,” but found that interactive mixtures were generally known to improve bioavailability and that the increase here was a “difference in degree, not a difference in ‘kind.”
Discussion
Standard of review
Obviousness is a question of law, based on the facts of (1) the scope and content of the prior art, (2) the level of ordinary skill in the field, (3) the differences between the claimed invention and the prior art, and (4) any objective indicia of nonobviousness. A party seeking to invalidate a patent on obviousness grounds must demonstrate by clear and convincing evidence that a person of ordinary skill would have selected and combined and modified the subject matter of the references in the manner of the claimed invention, with a reasonable expectation of success. Judicial hindsight must be avoided.
Obviousness
In holding the ’330 Patent's claims invalid for obviousness, the district court cited the ’832 Patent to show that “the use of citric acid with an interactive mixture would also improve bioavailability.” The ’832 Patent is for a film that includes citric acid to lower the pH of the film. There is no suggestion of the different structure of the Zubsolv tablet and its advantage in deterring abuse. The Zubsolv structure is achieved solely upon the hindsight knowledge of the structure and benefits described in the ’330 Patent.
The district court cited the Orexo ’443 Application for its disclosure of particles of buprenorphine adhered to carrier particles. However, the ’443 Application does not mention citric acid in its extensive list of carriers, and does not suggest that citric acid carrier particles may provide benefits compared with the prior art. These benefits were not predicted or suggested in any reference.
The district court cited the EP ’725 Application for its general description of interactive mixtures as pharmaceutical formulations. This reference does not mention opioids, does not mention sublingual tablets, does not mention citric acid in its extensive list of carrier particles, and does not suggest the formulation in the ’330 Patent or its unexpected benefits.
The product herein is admittedly new. The district court acknowledged the undisputed testimony of Orexo's co-founder, Mr. Thomas Lundqvist, and Orexo's global chief medical officer, Dr. Michael Sumner. The district court wrote:
Lundqvist testified that the first clinical results showed that Zubsolv had a 66% improvement in bioavailability. According to a bioequivalence study, Zubsolv increases the bioavailability of buprenorphine, such that patients require a 29% lower dose using Zubsolv as compared to Suboxone. Orexo's pharmaceutical development report stated that “[d]ue to the anticipated improved dissolution of buprenorphine the selected dose of 6 mg buprenorphine is expected to give approximately the same systemic buprenorphine exposure in humans as a Suboxone® tablet with 8 mg buprenorphine.”
The district court nonetheless concluded that the Zubsolv formulation was obvious. The court cited Actavis's expert Dr. Dyar as showing that “citric acid is pharmaceutically acceptable, water soluble, and of the right size, so therefore it would act as a carrier particle, because it is in the Suboxone tablet.” Orexo points out that Dr. Dyar cited no reference, and describes this reasoning as “hindsight bias,” for it recreates the prior art from the teaching in the ’330 Patent. Orexo points out that citric acid is nowhere used or listed or suggested as a carrier particle, and it is not so used in the Suboxone tablet.
At the oral argument of this appeal, Actavis conceded that no reference teaches using citric acid as a carrier particle, or that citric acid should be used as a carrier particle.
Dr. Dyar did not testify that a skilled artisan would obviously select citric acid as a carrier for buprenorphine; he stated that if it were selected, the artisan would expect it to work. The district court's finding that “a person of ordinary skill in the art would not have excluded citric acid,” is not a teaching or suggestion to use citric acid. The record does not contain clear and convincing evidence of a teaching or suggestion to use citric acid particles as a carrier for this opioid product in substitution therapy, or that the actual beneficial results would be obtained.
The 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. Although the reference ’832 Patent showed that buprenorphine bioavailability in the film formulation is affected by pH, this is not a suggestion of the sublingual tablet interactive formulation in the ’330 Patent or a teaching of its benefit in deterring abuse.
The district court erred in discounting the enhanced bioavailability in the ’330 Patent's formulation as “a ‘difference in degree,’ not a difference in ‘kind,’” for the clinical studies reported in the ’330 Patent showing 66% improved bioavailability. Particularly in the context of this invention, this is more than a trivial “degree.”
Although the weight of this evidence was disputed, the FDA deemed the product worthy of approval for the efficacy that was established in the clinical trials. It was established that this novel formulation enables reduced dosage and enhanced efficacy in substitution therapy products, deterring abuse.
On the entirety of the record, Actavis did not establish obviousness by clear and convincing evidence. The judgment of invalidity is reversed. We remand for appropriate further proceedings.
REVERSED AND REMANDED