In Purdue Pharma L.P. v. Epic Pharma LLC, the Federal Circuit affirmed the district court decision holding four OxyContin patents invalid as obvious. In so doing, the court rejected Purdue’s arguments that its discovery of the source of the toxic impurity that was minimized in the claimed products did not support patentability, because the solution to the problem did not depend on the source of the impurity. 

The Perdue OxyContin Patents At Issue

There were four OxyContin® patents at issue, three of which claimed products having a low level of the toxic impurity referred to as “ABUKs” (α,β-unsaturated ketones) (U.S. Patent No. 7,674,799, U.S. Patent No. 7,674,800, and U.S. Patent No. 7,683,072), and one of which related to an abuse-resistant formulation (U.S. Patent No. 8,114,383). This article will focus on the court’s treatment of the “low-ABUK patents.”

According to the Federal Circuit decision, prior to the invention at issue oxycodone hydrochloride was made by a three-step process:

• oxidizing thebaine to form 14-hydroxycodeinone (referred to in the decision as “14-hydroxy”)

• converting 14-hydroxy to oxycodone free base by hydrogenation

• reacting oxycodone free base with hydrochloric acid to form oxycodone hydrochloride

However, this process resulted in a final product with “high levels of 14- hydroxy, on the order of 1500 parts per million.” Since  that compound was believed to be toxic, Purdue investigated how to make a product with lower levels of 14- hydroxy.

Its investigations led to the discovery that a particular isomer (8α, 14–dihydroxy–7,8– dihydrocodeinone (“8α”)) was produced during the first step of the prior art process, and that the isomer was converted to 14-hydroxy during step three of the process. To solve this problem, Purdue added an additional hydrogenation step as a fourth step of the process, such that 14-hydroxy present after step three is converted to oxycodone free base in new step four.

Claim 1 of the ‘072 patent recites:

1. An oxycodone hydrochloride active pharmaceutical ingredient having less than 25 ppm 14-hydroxycodeinone, wherein at least a portion of the 14:hydroxycodeinone is derived from 8α,14-dihydroxy-7,8-dihydrocodeinone.

Claim 1 of the ‘799 patent recites:

1. An oral dosage form comprising particles, the particles comprising from about 5 mg to about 320 mg oxycodone hydrochloride active pharmaceutical ingredient having less than 25 ppm 14-hydroxycodeinone, wherein at least a portion of the 14-hydroxycodeinone is derived from 8α,14-dihydroxy-7,8-dihydrocodeinone during conversion of oxycodone free base to oxycodone hydrochloride, said particles being coated with an amount of hydrophobic material effective to provide a sustained release of the oxycodone hydrochloride when the coated particles are exposed to an aqueous solution.

Claim 30 of the ‘800 patent recites “Oxycodone salt prepared according to the process of claim 1,” where claim 1 recites:

1. A process for preparing an oxycodone salt substantially free of 14-hydroxycodeinone, which process comprises steps of: (a) preparing a mixture of oxycodone free base, solvent and an acid, the oxycodone free base having an 8α,14-dihydroxy-7,8-dihydrocodeinone component; (b) incubating the mixture under conditions suitable to convert the oxycodone free base to an oxycodone salt, wherein said conditions promote an acid catalyzed dehydration consisting of conversion of the 8α,14-dihydroxy-7,8-dihydrocodeinone component to 14-hydroxycodeinone; and (c) preferentially removing the 14-hydroxycodeinone from the oxycodone salt.

The District Court Decision

Purdue commenced the district court litigation in response to Abbreviated New Drug Applications (ANDAs) filed by Amneal Pharmaceuticals, LLC, Epic Pharma, LLC, Mylan Pharmaceuticals Inc., and Teva Pharmaceuticals USA, Inc. As summarized in the Federal Circuit decision, the district court found that all asserted claims were obvious on the grounds that “the prior art taught that oxidation of thebaine produced 14- hydroxy and that it was well known in the art that 14- hydroxy could be removed using hydrogenation.” The district court “determined that the discovery of 8α was not necessary to the claimed invention,” because “a skilled artisan would recognize that hydrogenation could be used to remove the remaining 14-hydroxy, regardless of the source of the 14-hydroxy.” The court also “concluded that the claim limitation requiring that the remaining 14-hydroxy is at least in part ‘derived from 8α[]’ is a product-by-process limitation and thus immaterial in the obviousness determination.”

The Federal Circuit Decision

The Federal Circuit decision was authored by Chief Judge Prost and joined by Judge Reyna and Chief District Judge Stark of the U.S. District Court for the District of Delaware, sitting by designation.

Chief Judge Prost noted that the parent application of the low-ABUK patents was before the court in 2009, when the court affirmed the USPTO Board’s rejection of the claims as obvious. Those claims were directed to the four-step manufacturing method, but “did not require that some of the remaining 14-hydroxy be derived from the 8α isomer.”

The Federal Circuit decision addresses three main Purdue arguments:

In response to Purdue’s argument that its “discovery of 8α as the core of the claimed inventions” should have been given more weight, the Federal Circuit distinguished the Supreme Court decision Purdue relied upon (Eibel Process Co. v. Minnesota & Ontario Paper Co., 261 U.S. 45 (1923)), because the “problem [of the source of the 14-hydroxy] did not need to be solved to arrive at the claimed invention.”

The issue again comes down to whether it would be obvious to a person having ordinary skill in the art to use hydrogenation to remove the excess 14-hydroxy in the oxycodone API. One need not know that the 14-hydroxy was derived from 8α as opposed to 8β to answer that question.

In response to Purdue’s argument that the requirement that “the remaining 14-hydroxy in the oxycodone API is derived from 8α” supports nonobviousness “because 8α was not previously known in the art as being the source of 14-hydroxy,” the Federal Circuit agreed with the district court that “because the clause at issue “does not describe the structure of 14-hydroxy” it “thus is a process limitation.” The Federal Circuit also noted that “the fact that the 14-hydroxy is derived from 8α imparts no structural or functional differences in the low-ABUK hydrocodone API as compared to the prior art products.”

In response to Purdue’s arguments of secondary considerations (the commercial success of Purdue’s API supplier, failure of others, praise by competitors), the Federal Circuit found no clear error in the district court’s findings of lack of nexus to the claimed invention or inadequate factual support.

The court therefore affirmed the district court decision holding the asserted claims of the low-ABUK patents to be invalid.

The Importance Of Product Claims

Purdue’s efforts to obtain a variety of product claims may reflect the importance of obtaining product claims to protect a pharmaceutical product. Patents that only claim a method of manufacturing a drug cannot be listed in the Orange Book, which means that would-be generic companies do not need to file Paragraph IV certifications against them with their ANDA applications. Method of manufacture claims also may be more susceptible to design-around options. For example, the Federal Circuit noted that Teva did not use the Purdue process to make its product. Still, method of manufacture claims can be valuable, particularly if they protect a commercially advantageous way to make the drug, or result in an improved product.