Abstract
SYNOPSIS
Oxymorphone is a drug that has long been used for the treatment of pain. The production of oxymorphone by prior art methods results in the presence of the ABUK form of oxymorphone (“oxymorphone ABUK”) as a contaminant at levels exceeding 10 ppm. At some point the Food and Drug Administration (FDA) determined that oxymorphone ABUK is genotoxic at such levels, and confidentially communicated to producers of oxymorphone (including the patentee) that FDA intended to impose a mandate prohibiting the marketing of oxymorphone containing 10 ppm oxymorphone ABUK. The inventors of the patent asserted in this case devised a process for producing oxymorphone containing less than 10 ppm oxymorphone ABUK, and were issued claims broadly reciting oxymorphone containing less than 10 ppm oxymorphone ABUK, i.e., the claims are not limited to any specific process for achieving the result. A divided panel of the Federal Circuit upheld the district court's determination that the patent claims are not invalid due to obviousness. The court found that while the FDA mandate created a market incentive for the claimed invention, it did not teach how to achieve the goal. The prior art of record did not provide any method for achieving the mandated level of purity that would have been deemed likely to succeed by one of skill in the art. The dissenting judge, on the other hand, argued that the district court had applied the wrong legal standard when assessing the prior art, “elevating the reasonable expectation of success standard to require that the prior art provide a definitive solution to the problem and proof of actual success.”
Wallach, Circuit Judge:
Appellees Endo Pharmaceuticals Inc. (“Endo Pharmaceuticals”) and Mallinckrodt LLC (“Mallinckrodt”) (collectively, “Endo”) sued Appellants Actavis LLC, Actavis South Atlantic LLC, and Teva Pharmaceuticals USA, Inc. (collectively, “Actavis”) in the U.S. District Court for the District of Delaware (“District Court”), alleging that two Abbreviated New Drug Applications filed by Actavis infringed claims 1–6 (“the Asserted Claims”) of Mallinckrodt's U.S. Patent No. 8,871,779 (“the ’779 patent”), which Endo Pharmaceuticals licenses. The District Court held that Actavis failed to “prove[ ] by clear and convincing evidence that any of the [A]sserted [C]laims … were invalid” as obvious or anticipated, and entered final judgment of infringement, based on a stipulation by Actavis.
Actavis appeals, challenging the invalidity determination. We affirm.
BACKGROUND
I. The ’779 patent
Entitled “Process for Preparing Morphinan-6-One Products with Low Levels of α,β-Unsaturated Ketone Compounds,” the ’779 patent generally relates to compounds known as “morphinan alkaloids,” such as “oxymorphone,” which have “great medical importance” and “are used extensively for pain relief.” In describing the prior art, the ’779 patent explains that “[v]arious processes for producing morphinan-6-one compounds are known,” and “many … involve some form of catalytic hydrogenation of α,β-unsaturated ketone intermediate compounds [(‘ABUKs’)],” i.e., applying catalytic hydrogenation to compounds containing ketone groups with double bonds between the α and β carbon atoms to convert the double bonds to single bonds. However, “[ABUKs] may persist as impurities in the final products.” These hydrogenation processes also “may tend to undesirably reduce the ketone[, a key functional part of morphinan-6-one compounds,] as well as reducing or removing the α,β-unsaturation.”
The ’779 patent discloses “processes for preparing highly pure morphinan-6-one products” having a relatively low concentration of ABUKs present as impurities, which “involve treating a reaction mixture including a morphinan-6-one compound and an [ABUK] with a sulfur-containing compound.” These processes can “effectively reduce[ ] the concentration of undesirable [ABUKs] to acceptable levels,” with the process employing a sulfur-containing compound that can reduce ABUK concentration “from levels of about 0.5% (by weight) or more to levels of not more than about 0.1% … , or lower (e.g., about 0.01% … , about 0.001% … , or lower), with minimal side reactions, ketone reduction, and/or any other undesirable effects.”
Claim 1, which is representative of the Asserted Claims, recites:
1. A hydrochloride salt of oxymorphone comprising less than 0.001% of 14-hydroxymorphinone [i.e., oxymorphone ABUK].
1
II. Prior art references
The District Court determined three references constitute the prior art in this case. We present each in turn.
A. Weiss
A scientific article from 1957, see Ulrich Weiss, Derivatives of Morphine. II. Demethylation of 14-Hydroxycodeinone. 14-hydroxymorphinone and 8,14-Dihydroxydihydromorphinone, 22 J. Organic Chemistry 1505, 1505–08 (1957) (“Weiss”), discloses, inter alia, the use of catalytic hydrogenation to convert oxymorphone ABUK to oxymorphone. Weiss also recounts 8,14-dihydroxy-7,8-dihydromorphinone (“oxymorphone diol”) as “the product of hydration of the double bond of [oxymorphone ABUK],” the “ready conversion of [oxymorphone ABUK] into [oxymorphone diol],” and the reversion of oxymorphone diol to oxymorphone ABUK through the application of hydrochloride.
B. Chapman
Entitled “Process for Preparing Oxycodone Hydrochloride Having Less Than 25 [Parts Per Million (‘ppm’) ] 14-hydroxycodeinone,” U.S. Patent Application No. 2005/0222188 (“Chapman”) discloses, inter alia, processes that employ catalytic hydrogenation to purify oxycodone ABUK into the salt form of oxycodone. Chapman recites processes that convert oxycodone ABUK to 8,14-dihydroxy-7,8-dihydrocodeinone (“oxycodone diol”), a precursor to oxycodone ABUK, which can revert to oxycodone ABUK through the compound's conversion to salt form and thereby frustrate purification. But Chapman provides a reaction that can remove oxycodone diol from a sample prior to the completion of purification, and prevent oxycodone diol's reversion to oxycodone ABUK.
C. Rapoport
A scientific article from 1967, see Henry Rapoport et al., The Synthesis of Thebaine and Northebaine from Codeinone Dimethyl Ketal, 89 J. Am. Chemical Soc'y 1942, 1942–47 (1967) (“Rapoport”), discloses, inter alia, a process involving the use of bisulfite addition to convert oxycodone ABUK to oxycodone. This process takes advantage of differences in solubility of the products of reactions between bisulfites and oxycodone ABUK to separate oxycodone from oxycodone ABUK.
DISCUSSION
Actavis contends that the District Court erred by, inter alia, (1) misconstruing the claim term 14-hydroxymorphinone, and (2) determining that the Asserted Claims were not obvious in light of the prior art. We address each argument in turn.
I. Claim construction—The District Court properly construed 14-hydroxymorphinone as 14-hydroxymorphinone hydrochloride
The District Court, relying on intrinsic and extrinsic evidence, determined that a PHOSITA would understand the 14-hydroxymorphinone limitations stated in claims 1–2 and 5 to mean “14-hydroxymorphinone hydrochloride,” i.e., the “salt form” of 14-hydroxymorphinone. Actavis argues that this limitation requires no construction because of “[t]he plain language of the claims, and the undisputed chemical difference between 14-hydroxymorphinone [i.e., oxymorphone ABUK] and its hydrochloride salt.” We disagree with Actavis.
The District Court correctly construed 14-hydroxymorphinone as 14-hydroxymorphinone hydrochloride. We begin with the claims. Independent claim 1 teaches “[a] hydrochloride salt of oxymorphone comprising” a certain amount of “14-hydroxymorphinone.” Claim 1 only claims 14-hydroxymorphinone as part of the salt-, or hydrochloride-, form of the claimed compound, and not as a separate non-salt, non-hydrochloride component. This indicates that, as used in the Asserted Claims, 14-hydroxymorphinone means 14-hydroxymorphinone hydrochloride.
Next, we turn to the broader specification. Relevant here, 14-hydroxymorphinone is mentioned in Example 3. No distinction is made between the 14-hydroxymorphinone in the oxymorphone hydrochloride and oxymorphone base samples, but it is presented as part of these compounds, not as discrete compounds or as possessing a separate hydrochloride or base form. Nevertheless, 14-hydroxymorphinone's use in the broader specification is relatively unsupportive of either proffered construction.
Finally, we look to extrinsic evidence. The District Court considered the testimony of Actavis's expert, in which he “agree[d]” that a PHOSITA reading Example 3 of the ’779 patent “would have to assume that the ABUK impurity there was the ABUK oxymorphone [hydrochloride], i.e., the salt form.” Indeed, Actavis's expert acknowledged that, “when you form[ ] the salt from a combination of the oxymorphone and the ABUK[, i.e., the 14-hydroxymorphinone], the [14-hydroxymorphinone] gets formed into a salt at the same time,” and that a “[PHOSITA] would be aware of that.” Accordingly, the intrinsic and extrinsic evidence support the District Court's construction of 14-hydroxymorphinone as 14-hydroxymorphinone hydrochloride.
II. Obviousness—The District Court did not clearly err in finding a PHOSITA would not have a reasonable expectation of success in combining the prior art
The District Court held that a PHOSITA “would have understood that it would not be feasible” to employ Chapman's solution to the reappearing ABUK problem to Weiss's catalytic hydrogenation process for oxymorphone. The District Court also explained that a PHOSITA would not have a reasonable expectation of success in employing “sulfur addition and separation as a method of producing low-ABUK oxymorphone,” because Rapoport does not “teach[ ] that low-ABUK oxymorphone can be achieved through bisulfite addition combined with extraction.” The District Court also considered certain confidential communications between the U.S. Food and Drug Administration (“FDA”) and producers of oxymorphone, including Mallinckrodt (“FDA communications”). The District Court held that the FDA communications did not provide a reasonable expectation of success because they “were not teachings and provided no substantive information about how the companies were to go about producing low-ABUK oxymorphone” and instead “recognized the challenge the mandate posed for the companies.” Actavis challenges the District Court's finding of a lack of reasonable expectation of success and argues the District Court's conclusions “must be reversed.” We disagree with Actavis.
The District Court did not clearly err in concluding that a PHOSITA would lack a reasonable expectation of success in combining Weiss, Chapman, and Rapoport. First, a PHOSITA would not have a reasonable expectation of success in employing Weiss's catalytic hydrogenation process for oxymorphone with Chapman's process to remove diol during hydrogenation. Although Weiss discloses a method of purifying oxymorphone ABUK through catalytic hydrogenation, it does not provide key reaction conditions, or any level of achieved purification of oxymorphone, let alone purification to the degree claimed by the Asserted Claims. Weiss also explains that the catalytic hydrogenation process produces oxymorphone diol, which is undesirable because it can revert to 14-hydroxymorphinone upon the process' completion and thereby frustrate purification. With respect to the comparative effect of catalytic hydrogenation on oxymorphone ABUK and oxycodone ABUK, Weiss discloses that the former produces oxymorphone diol much more readily than the latter produces oxycodone diol, indicating that the process is much less effective on oxymorphone ABUK because oxymorphone diol can revert to oxymorphone ABUK and thereby hinder purification.
In turn, Chapman discloses processes involving the catalytic hydrogenation of oxycodone ABUK, and that these processes create oxycodone diol, which can hinder purification by “revert[ing] to some ABUK and build[ing] up ABUK after an attempted purification,” Chapman also describes a process that can reduce oxycodone diol in an oxycodone sample, but Endo's expert explained that this would likely be ineffective in achieving the same purity as the oxymorphone claimed by the Asserted Claims. This is because the only example of this process provided by Chapman discloses a “long reaction time” of “nearly 22 hours” only reducing the oxyocodone diol content of an oxycodone sample from 2,900 ppm to 400 ppm, and “with 400 ppm [of diol], that's a lot of ABUK you can make,” Moreover, the longer the reaction runs, the less diol is progressively removed and the more “other side reactions are going to come in and compete,” such that one would “start to hydrogenate other parts of the molecule and introduce other material” and, therefore, would not “have any [of the desired] product … left at all.
A PHOSITA would not have had a reasonable expectation of success in combining Weiss and Chapman because Weiss disclosed a material difficulty with using catalytic hydrogenation to purify oxymorphone to the FDA-mandated level, i.e., the production of relatively large amounts of oxymorphone diol, and Chapman did not describe a viable solution to this difficulty. Moreover, Endo's expert testified that, because oxymorphone ABUK and oxycodone ABUK “are different molecules, … they are going to have different reactivities,” and, therefore, a PHOSITA would have been unlikely to apply Chapman to oxymorphone ABUK.
Second, the District Court did not clearly err in finding that a PHOSITA lacked a reasonable expectation of success in employing Rapoport's sulfur addition and separation process to remove oxymorphone impurities. Rapoport discloses a process for purifying oxycodone ABUK through the use of bisulfite additions, but it does not state that any resulting compounds have the purity levels of those in the Asserted Claims. According to Endo's expert, Rapoport explains that 25% of ABUK impurities remain following completion of the process, which is “not a very good partition ratio.” In addition, he recounted that the process described by Rapoport not only fails to remove a significant amount of ABUK, but “result[s] in a large loss of the desired compound” as well. Therefore, he explained that a PHOSITA would not believe that Rapoport “would ever be able to get to … 10 [ppm],” as claimed in the ’779 patent.
Third, based on the teachings of Weiss, Chapman, and Rapoport, the District Court did not clearly err in finding the FDA communications would not provide a PHOSITA with a reasonable expectation of success of achieving the claimed purity levels for oxymorphone. Relevant here, the FDA communications recount the FDA's “processes for addressing the problem of impurities” in oxymorphone that had been determined to be mutagenic. The FDA limited ABUK content in oxymorphone to 0.001%, i.e., 10 ppm, to satisfy FDA approval guidelines. The FDA communications introduced a market force incentivizing purification of oxymorphone to the level of the oxymorphone claimed by the Asserted Claims. However, the FDA communications recite a goal without teaching how the goal is attained. The FDA communications convey nothing that would have a led a PHOSITA to view Rapoport's teachings in a different light, or to believe that the sulfur process it describes might be more effective on oxymorphone ABUK. Therefore, these communications would not have been enough to overcome the disclosures of Weiss, Chapman, and Rapoport, which indicate that a PHOSITA would not reasonably believe their disclosed methods were fruitful avenues to achieve the FDA-mandated oxymorphone purity level. See Abbott Labs. v. Sandoz, Inc., 544 F.3d 1341, 1352 (Fed. Cir. 2008) (stating, in the context of certain FDA regulations on extended-release formulations, that “knowledge of the goal does not render its achievement obvious”).
This conclusion is further supported by the fact that the inventors of the ’779 patent engaged in extensive experimentation, involving much failure, to ultimately produce the oxymorphone of the Asserted Claims. The inventors also testified to their concerns when they became aware of the FDA's purity requirement because it represented a dramatic, and potentially problematic, change in light of then-current knowledge and capabilities.
For the reasons stated above, the District Court did not commit clear error in finding that a PHOSITA lacked a reasonable expectation of success, such that the Asserted Claims would not have been obvious.
CONCLUSION
We have considered Actavis's remaining arguments and find them unpersuasive. Accordingly, the Final Judgment of the U.S. District Court for the District of Delaware is
AFFIRMED
Stoll, Circuit Judge, dissenting:
I respectfully dissent. The FDA set a regulatory requirement that ABUK content in oxymorphone products be less than 0.001% (10 ppm). Mallinckrodt then claimed this requirement in the ’779 patent. Not only does the FDA's mandate disclose every limitation of claim 1, but it is the only prior art reference that discloses the 0.001% oxymorphone ABUK limitation. Yet, the district court determined that this mandate did not disclose “anything substantive relevant to obviousness.” It further erred by imposing a requirement that a reference must teach how to solve a problem to provide a motivation to combine, conflating enablement and reasonable expectation of success requirements with motivation. Finally, the district court applied an erroneously heightened standard for reasonable expectation of success by requiring a “definitive solution” and proof of actual success. The majority would disregard a number of these errors as harmless, affirming on the lack of a reasonable expectation of success. Given the significance of the court's errors, however, I cannot agree. While we owe deference to a district court's factual findings, such deference is not due where the trial court applies the incorrect standard to arrive at those findings. I would vacate the district court's decision and remand for a proper analysis under the correct legal standards.
I fail to see how the FDA Communications do not disclose “anything substantive relevant to obviousness,” when they disclose every limitation of claim 1 and are the only references that expressly disclose the limitation of oxymorphone ABUK content less than 0.001%. It can hardly be disputed that the FDA communications motivated the actual development of the ’779 invention. Indeed, as one of the inventors of the ’779 patent testified, “no special attention was focused on” ABUK impurities prior to the FDA's structural alert.
The district court also erred by elevating the reasonable expectation of success standard to require that the prior art provide a definitive solution to the problem and proof of actual success. For example, in addressing Rapoport, which discloses a sulfur addition reaction followed by extraction, the court required proof that Rapoport's technique was actually used and worked. Specifically, the district court found that a person of ordinary skill would not have thought Rapoport promising because of its poor extraction partition ratio combined with “the lack of any examples of this method being used successfully.” This is the wrong standard. Had Rapoport disclosed successful use of sulfur addition and extraction to achieve ABUK levels of less than 10 ppm, it would anticipate the claims. As we have repeatedly held, obviousness requires only a reasonable expectation of success, not proof of actual success. See PAR Pharm., Inc. v. TWI Pharm., Inc., 773 F.3d 1186, 1198 (Fed. Cir. 2014). The district court further erred by requiring proof of actual success regarding Dr. Gokel's proffered combination of Rapoport with conventional precipitation or chromatography. It discounted Dr. Gokel's suggestion as “purely hypothetical,” stating that there “is no evidence anyone ever combined these methods prior to the invention date and Dr. Gokel himself never did any experiments to show that they would work.” As mentioned above, obviousness does not require proof of successful use of a combination, and the court erred by requiring as much.
The district court may have recited the correct legal standard, but contrary to what the majority states, the district court certainly did not apply that standard in its analysis. For example, the district court's finding that a person of ordinary skill would not have found Rapoport “promising” was partially based on “the lack of any examples of [Rapoport] being used successfully.” Further, the district court noted that the Macfarlan Smith experiment—the “single experiment on a different compound”—did not show ABUK reduction to below 0.001%. In other words, there was no evidence that a sulfur addition technique actually worked. As mentioned above, a reasonable expectation of success does not require proof of actual success. These statements are thus not examples of the district court applying the correct standard, as the majority believes, and instead show the opposite.
The district court similarly erred when considering Chapman. After reviewing testimony from both experts, the district court credited Mallinckrodt's expert, Dr. Davies, and stated that “even if a person of ordinary skill would view the oxycodone art as informative in researching possible solutions to reducing ABUK levels in oxymorphone, he would not find a definitive solution in Chapman.” This heightened requirement also goes beyond the reasonable expectation of success standard and constitutes legal error. Further, the district court's finding that a person of ordinary skill “would have understood that it would not be feasible to simply run [Chapman's] reaction to completion as Dr. Gokel suggested,” focuses on the wrong question. It is not required for catalytic hydrogenation to be run to completion in order to achieve 10 ppm ABUK. In fact, Dr. Gokel testified that Chapman itself—which achieved 5 ppm ABUK—was not run to completion: “Q: Now, did he run that part of the process to completion to convert the diol into the ABUK so he could then hydrogenate it and make the oxycodone drug? … A: He did not, but he could have.”
Finally, the district court erred by conflating the requirements of reasonable expectation of success and motivation to combine. The district court required that the FDA Communications teach how to achieve the claimed invention in order to provide a motivation to combine. Whether a reference teaches how to achieve the claimed invention speaks to enablement or reasonable expectation of success—entirely separate inquiries from motivation to combine. “[O]ne must have a motivation to combine accompanied by a reasonable expectation of achieving what is claimed in the patent-at-issue.” Motivation to combine refers to “a reason that would have prompted a person of ordinary skill in the relevant field to combine the elements in the way the claimed new invention does.” A reasonable expectation of success, on the other hand, addresses whether a person of ordinary skill in the art would have understood that the proposed combination or modification would have been reasonably likely to be successful.
Our case law does not require that a reference teach how to achieve the claimed invention in order to provide a motivation to combine. The FDA Communications disclose all the limitations of claim 1. They also disclose a reason to modify Weiss, Chapman, or Rapoport to achieve ABUK levels of less than 10 ppm: the FDA required such levels because it had determined that ABUK levels higher than 10 ppm were genotoxic. If these communications also taught “how the goal is attained,” they would anticipate the asserted claims—we would have no need to address obviousness.
For all these reasons, I would vacate the district court's decision and remand to allow the district court to apply the correct obviousness test and properly consider the role of the FDA mandate—the sole reason for the ’779 patent's existence—in the obviousness analysis. This is not a typical Hatch-Waxman case where the patentee provided the public with a new drug, formulation, or manufacturing process. While Mallinckrodt's patent specification is directed to a specific process for achieving the FDA's objective, Mallinckrodt did not claim that process. Mallinckrodt instead claimed the FDA mandate. The FDA sought to make oxymorphone safer for the public and Mallinckrodt took advantage by claiming the directive itself, securing exclusive rights to a drug first approved in 1959. This is not the type of innovation that the patent system and the obviousness standard were designed to protect.