What role does inherency have in an obviousness analysis?
| February 22, 2020
Persion Pharmaceuticals LLC v. Alvogen Malta Operations Ltd.
December 27, 2019
Before O’Malley, Reyna, and Chen (Opinion by Reyna).
Summary
The Federal Circuit affirmed the district court’s decision invalidating as obvious patents directed to method of using a hydrocodone-only formulation to treat pain in patients with hepatic impairment. Important to the obviousness determination was the concept of “inherency”. Specifically, the Federal Circuit agreed with the District Court that where the claimed method of would have been obvious from the prior art, claim limitations directed to the pharmacokinetic properties of the formulation would be inherent in the combination of the prior art.
Details
Hydrocodone is an opioid pain medication commonly prescribed to treat prolonged, severe pain. The bulk of metabolism of many opioids, including hydrocodone, occurs in the liver. People suffering from hepatic impairment (i.e., liver dysfunction) are at increased risk of opioid overdose, because their livers cannot clear the drugs from their bloodstreams as quickly and effectively as would be the case for people with healthy livers. As such, when prescribed to patients with impaired livers, dosages of opioids are often adjusted to prevent build-ups.
Persion Pharmaceuticals, LLC (“Persion”) commercializes a hydrocodone drug under the brand name Zohydro ER. The drug is an extended-released hydrocodone-only product—that is, it contains no other active ingredients. Clinical trials on Zohydro ER revealed, to its inventors’ surprise, that the concentration of hydrocodone in the bloodstream of subjects with mild and moderate hepatic impairment was not dramatically higher than in patients with unimpaired livers. The inventors of Zohydro ER filed U.S. patent applications that eventually issued as U.S. Patent Nos. 9,265,760 (“760 patent”) and 9,339,499 (“499 patent”).
The 760 and 499 patents were directed specifically to methods of treating pains in patients with mild or moderate hepatic impairment, and the claims emphasized the similar effects that the hydrocodone-only formulation had on patients with and without hepatic impairment.
The relevant claims of the two patents fell into two categories. The “non-adjustment” claims recited the lack of need to adjust the dosage for patients with mild or moderate hepatic impairment relative to patients without hepatic impairment. Meanwhile, the “pharmacokinetic” claims recited certain pharmacokinetic (PK) parameters that highlighted the similarity in the results of administering the claimed formulation to patients with and without hepatic impairment.
Claim 1 of the 760 patent is representative of the “non-adjustment” claims:
1. A method of treating pain in a patient having mild or moderate hepatic impairment, the method comprising:
administering to the patient having mild or moderate hepatic impairment a starting dose of an oral dosage unit having hydrocodone bitartrate as the only active ingredient, wherein the dosage unit comprises an extended release formulation of hydrocodone bitartrate, and wherein the starting dose is not adjusted relative to a patient without hepatic impairment.
Claim 12 of the 760 patent is representative of the “pharmacokinetic” claims:
12. A method of treating pain in a patient having mild or moderate hepatic impairment, the method comprising:
administering to the patient having mild or moderate hepatic impairment an oral dosage unit having hydrocodone bitartrate as the only active ingredient, wherein the dosage unit comprises an extended release formulation of hydrocodone bitartrate,
wherein the dosage unit provides a release profile of hydrocodone that:
(1) does not increase average hydrocodone AUC0-inf in subjects suffering from mild hepatic impairment relative to subjects not suffering from renal or hepatic impairment in an amount of more than 14%;
(2) does not increase average hydrocodone AUC0-inf in subjects suffering from moderate hepatic impairment relative to subjects not suffering from renal or hepatic impairment in an amount of more than 30%;
(3) does not increase average hydrocodone Cmax in subjects suffering from mild hepatic impairment relative to subjects not suffering from renal or hepatic impairment in an amount of more than 9%; and
(4) does not increase average hydrocodone Cmax in subjects suffering from moderate hepatic impairment relative to subjects not suffering from renal or hepatic impairment in an amount of more than 14%.
When Alvogen Malta Operations, Ltd. (“Alvogen”) filed an Abbreviated New Drug Application (ANDA) seeking to market a generic version of Zohydro ER, Persion sued Alvogen for infringing the 760 and 499 patents.
Naturally, Alvogen sought to invalidate those patents.
The prior art at issue were Devane (US2006/0240105), Jain (US2010/0010030), Vicodin label, and Lortab label.
Devane disclosed the same formulation as Zohydro ER, and disclosed an in vivo study in which the formulation was administered to treat post-operative pains in patients following their bunionectomy surgery. Devane did not disclose patients with mild or moderate hepatic impairment.
Jain disclosed a hepatic impairment PK study on Vicodin CR, a hydrocodone-acetaminophen combination formulation. Jain reported that the PK parameters (Cmax and AUC values) for hydrocodone in Vicodin CR were similar in normal and hepatically impaired subjects.
The Vicodin and Lortab labels disclosed the dosing instructions for those drugs. Vicodin contains hydrocodone and acetaminophen. Lortab contains hydrocodone and ibruprofen. The labels did not provide any precautions or dosing restrictions for individuals with mild or moderate hepatic impairment.
The district court found that the claims were obvious over the cited prior art.
As to the “non-adjustment” claims, the district court found that a person of ordinary skill in the art would have been motivated to administer Devane’s formulation to patients with mild or moderate hepatic impairment, because Jain taught that the hydrocodone exhibited similar PK parameters in normal and hepatically impaired patients, while the Vicodin and Lortab labels did not require different dosages for patients with mild or moderate hepatic impairment.
As to the “pharmacokinetic” claims, the district court found that the claimed PK values were “inherent in any obviousness combination that contains the Devane formulation”, because Devane disclosed what was essentially Zohydro ER, i.e., the claimed formulation, and the claimed values were “necessarily present” in Zohydro ER.
On appeal, the Federal Circuit honed in on Persion’s challenge of the district court’s “inherency” determination. Persion argued that Devane did not teach administering its formulation to hepatically impaired patients, so that “the natural result flowing from the operation as taught” in Devane could not be the claimed pharmacokinetic properties.
The Federal Circuit disagreed, distinguishing between the applications of “inherency” in the obviousness and anticipation contexts:
To the extent Persion contends that inherency can only satisfy a claim limitation when all other limitations are taught in a single reference, that position is contrary to our prior recognition 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.”
As the Federal Circuit noted, the longstanding rule is that “an obvious formulation cannot become nonobvious simply by administering it to a patient and claiming the resulting serum concentrations.”
Notably, there was no dispute that if administered under the same conditions, Devane’s formulation, which was identical to Zohydro ER, would necessarily exhibit the claimed PK values.
Related was Persion’s argument that the person skilled in the art would not have combined the cited prior art as the district court had. In particular, Persion argued that the district court should not have relied on the combination formulations disclosed in Jain and the Vicodin and Lortab labels.
Here also, the Federal Circuit disagreed. The Federal Circuit focused primarily on Jain’s teachings that its hydrocodone-acetaminophen combination formulation produced similar PK results for normal and hepatically impaired patients. That is, if Jain disclosed that its combination formulation was safe for patients with hepatic impairment, then it would be reasonable to expect the acetaminophen-free, hydrocodone-only formulation to be even safer. Further, considering Jain’s reported similarity in PK results for both hepatically impaired and unimpaired patients, it would have been obvious to the person skilled in the art to forgo dose adjustments when administering the same hydrocodone formulation to patients with hepatic impairment.
Where a claim defines some property of the claimed invention, it is not uncommon to find Examiners relying on inherency for those properties to complete their obviousness analyses. Reliance may be especially prevalent in chemical arts, as it has long been established that a chemical composition and its properties are inseparable. The Persion decision seems to reinforce the idea of inherency as a powerful argument that allows a missing limitation to be supplied based on some hypothetical combination of the prior art. That said, I suspect that the reach of the Persion decision will limited, as the fact that Persion’s claimed hydrocodone formulation already existed may have made it easier for the Federal Circuit to accept the finding of inherency.
Takeaway
- If the claim is directed to a new use of a known compound, then the claim should be more specific than a single, generic step of “applying the compound”. Consider defining the specific population or subpopulation that is helped by the compound, the specific conditions under which the compound is applied, and/or combination of the compound with other ingredients.
- If one can help it, avoid reciting intended results, which continue to be a complicated strategy. Not only could such a recitation force the issue of inherency, it could also raise the question of whether the recitation is even entitled to patentable weight, which is often a difficult argument to win with Examiners.
