“The inherent feature need not be disclosed or suggested in a single prior art. If there is a motivation to combine prior art elements as well as a reasonable expectation of success, then the inherent feature can result from a combination of prior art elements.”
When can an inherent property add patentable weight in the context of obviousness? Over the years, the Federal Circuit has shed light on this question in a number of cases. Persion Pharmaceuticals v. Alvogen Malta Operations Ltd., Docket No. 2018-2361 (Fed. Cir. Dec. 27, 2019) (Persion v. Alvogen) is the most recent decision to address this question. In Persion, the Federal Circuit affirmed the conclusion of the U.S. District Court for the District of Delaware that asserted claims of U.S. Patent Nos. 9,265,760 (“the ’760 patent”) and 9,339,499 (“the ’499 patent”) are invalid as obvious because the feature at issue was inherent in the prior art.
Present and Predictable
Establishing obviousness of an inherent feature requires that the feature be necessarily present and not be unpredictable or unexpected. In Persion, the feature was pharmacokinetic properties of a formulation for treating pain. The feature was found to be both necessarily present and expected. Importantly, on the practice of relying on measurements of an inherent property for patentability, the Federal Circuit explained that “an obvious formulation cannot become nonobvious simply by administering it to a patient and claiming the resulting serum concentrations,” because “[t]o hold otherwise would allow any formulation – no matter how obvious – to become patentable merely by testing and claiming an inherent property.” Persion v. Alvogen at 11 (internal citation omitted).
The ’760 and ’499 patents cover the formulation for Persion’s extended-release hydrocodone-only drug product known as Zohydro ER. The patents contain two types of claims: “non-adjustment” claims and “pharmacokinetic” claims. The non-adjustment claims are directed to a method of treating pain in a patient having mild or moderate hepatic impairment and require administering to the patient a starting dose of a hydrocodone formulation having hydrocodone bitartrate as the only active ingredient without adjusting the dose relative to a patient with a healthy liver.
The pharmacokinetic claims are similarly directed but recite pharmacokinetic parameters, and require, for example, that the dosage unit provide a release profile of hydrocodone that does not increase average hydrocodone AUC0–inf in subjects suffering from mild hepatic impairment in an amount of more than 14%, and in those suffering from moderate hepatic impairment in an amount of more than 30%, relative to subjects not suffering from renal or hepatic impairment. The pharmacokinetic claims are the focus of the discussion below.
Alvogen contended that the asserted claims were obvious over U.S. Patent Publ. No. 2006/0240105 (“Devane”) in view of one or more of U.S. Patent Publ. No. 2010/0010030 (“Jain”), the 2011 label for Vicodin, and/or the 2011 label for Lortab. Devane is directed to a controlled-release composition that provides both immediate and extended release of one or more active ingredients. Importantly, Devane describes an in vivo study in which the Zohydro ER formulation was used to treat pain. Jain discloses an opioid formulation known as Vicodin CR that contains hydrocodone bitartrate and acetaminophen. Jain further describes several clinical studies involving Vicodin CR, including one for determining the effects of hepatic insufficiency on the pharmacokinetics of Vicodin. The results of the hepatic insufficiency study showed that the pharmacokinetic parameters for hydrocodone were “similar” in normal subjects and subjects with mild or moderate hepatic impairment. Vicodin and Lortab are both immediate-release formulations of hydrocodone and acetaminophen that are used to treat pain, and although their labels state that the drugs “should be used with caution in . . . those [patients] with severe impairment of hepatic . . . function,” they are silent about precautions or dosage restrictions for patients with mild or moderate hepatic impairment. Persion v. Alvogen at 7.
The district court found that, in light of the state of the art, and based on the Jain patent application and the Lortab and Vicodin labels, it would have been obvious to a person of ordinary skill in the art to administer Devane’s formulation to patients suffering from mild or moderate hepatic impairment. Pernix Ireland Pain DAC v. Alvogen Malta Operations Ltd., 323 F.Supp.3d 566, 607 (D. Del. 2018). In particular, the court found that the pharmacokinetic limitations were “inherent in any obviousness combination that [contained] the Devane formulation” because the recited pharmacokinetic parameters were “necessarily present” in the Zohydro ER formulation described in both Devane and the asserted patents. Persion v. Alvogen at 8.
On appeal, Persion argued that Devane does not teach administering its hydrocodone-only formulation to patients with mild or moderate hepatic impairment and thus the district court had erred in applying the inherency doctrine in its obviousness analysis. Id. at 12. Persion asserted that the natural result flowing from the operation as taught in Devane could not be the claimed pharmacokinetic values for hepatically impaired patients (since the hydrocodone-only formulation was not administered to hepatically impaired patients) Id. The Federal Circuit disagreed and clarified that inherency may supply a missing claim limitation in an obviousness analysis where the limitation at issue is the natural result of the combination of prior art elements. Id. at 12-13 (internal quotation marks and citation omitted). In other words, the inherent feature need not be disclosed or suggested in a single prior art. If there is a motivation to combine prior art elements as well as a reasonable expectation of success, then the inherent feature can result from a combination of prior art elements. The court noted that Devane, together with Jain, the state of the prior art at the time of invention, and the Vicodin and Lortab labels, taught the combination of elements that inherently result in the claimed pharmacokinetic parameters. Id. at 13.
The Federal Circuit explained that “an obvious formulation cannot become nonobvious simply by administering it to a patient and claiming the resulting serum concentrations,” because “[t]o hold otherwise would allow any formulation – no matter how obvious – to become patentable merely by testing and claiming an inherent property.” Id. at 11 (citing Santarus, Inc. v. Par Pharm., Inc., 694 F.3d 1344, 1354 (Fed. Cir. 2012) (“Santarus”)).
Santarus was cited also by Alvogen during the trial. In response, Pernix cited Honeywell Int’l Inc. v. Mexichem Amanco Holding, S.A., 865 F.3d at 1348, 1355 (Fed. Cir. 2017) for the proposition that “[w]hat is important regarding properties that may be inherent, but unknown, is whether they are unexpected.” According to Pernix, the effects of the extended-release hydrocodone-only formulation in Devane could not have been predicted absent quantitative pharmacokinetic data, which was not presented in Devane or Jain, or in the Lortab or Vicodin labels.
The district court found that Honeywell did not apply. In Honeywell, the patent was directed to a combination of a particular compound and a specified lubricant. The compound was known, but combining it with the specified lubricant was not taught in the prior art. The patentee argued that the combination was not obvious due to the unpredictability of finding suitable lubricants and the unexpected stability and miscibility of the combination. The Patent Trial and Appeal Board (“Board”) disagreed, finding the stability and miscibility of the combination to be inherent properties that could not confer patentable weight. The Federal Circuit reversed, noting that the Board had ignored the unpredictability in the art and erroneously relied on inherent but unknown properties in finding a motivation to combine.
In contrast to Honeywell, in Persion, a person of ordinary skill in the field of administering or developing pharmaceuticals would have been familiar with articles showing that hydrocodone could be administered to hepatically impaired patients, and with the opioid drug labels introduced at the trial, the district court noted. And, while the person might not have known with certainty the proper dose to administer to hepatically impaired patients, that person would have had a reasonable expectation of success in safely treating pain in such patients using Devane’s formulation.
Pernix had also argued that no motivation would have existed to combine Devane, an opioid-only formulation, with Lortab, Vicodin, and Jain’s Vicodin CR because each of the latter three formulations is a combination product containing acetaminophen. To the contrary, the district court found that a motivation would have existed for several reasons. First, unlike hydrocodone, acetaminophen is hepatotoxic. Thus, removing acetaminophen, as in the Devane formulation, would make the drug safer for patients with hepatic impairment. Next, the new drug application for Zohydro ER relied in part on Vicoprofen (an immediate-release combination hydrocodone-ibuprofen drug as a reference product). Finally, the person would have known that acetaminophen was metabolized differently from hydrocodone and would not have had a significant impact on the pharmacokinetic profile of hydrocodone.
Inherency in obviousness does not require that an alleged inherent feature be found in a single piece of prior art. If a combination of prior art elements naturally results in the feature on which obviousness depends, then the feature would be considered inherent unless it was shown to be unexpected.
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