Oxymorphone - USA

On Aug. 30, 2017, Judge Richard G. Andrews of District of Delaware upheld a patent related to OPANA ER (Oxymorphone) tablet challenged by Teva/Actavis.

Plaintiffs Endo Pharma / Mallinckrodt brought this patent infringement action against Actavis defendants on Nov. 7, 2014, alleging that they had infringed U.S. Patent No. 8,871,779 ("the '779 patent") by filing ANDA 20-3930 seeking to enter the market with a generic version of Plaintiffs' Opana ER product, which is an extended-release oxymorphone tablet. The asserted claims of the '779 patent are all product claims directed to low-ABUK oxymorphone which is an impurity. In 2004, the FDA mandated that opioid manufacturers lower the levels of ABUK in opioid pharmaceuticals to less than 10 ppm.

Defendants argued that claims 1-6 of the '779 patent are invalid as obvious over the prior art.  Specifically, Defendants argued that a person of ordinary skill in the art would have been able to use routine methods known in the art to produce low-ABUK oxymorphone at the levels required by the FDA mandate. Defendants presented three "commonplace organic techniques" that they contend could be performed by "any graduate student" to produce low ABUK oxymorphone:

1) catalytic hydrogenation of the ABUK impurities;

2) sulfur addition to 10 separate out the ABUK impurities; and

 3) 0-demethylation of low-ABUK oxycodone into low ABUK oxymorphone.

Court rejected all arguments put forward by defendant & instead found Plaintiff’s expert testimony more convincing than defendant’s in reaching the decision on obviousness.

With respect to catalytic hydrogenation of the ABUK impurities, court found that that a person of ordinary skill in the art would have understood that it would not be feasible to simply run the reaction to completion as Dr. Gokel (Defendant’s expert) suggested. Longer the experiment runs, "the slower the reaction to remove the last bit of the material is going to be." Running the experiment for longer allows for side reactions to compete with the primary reaction and then "you'll start to hydrogenate other parts of the molecule and introduce other material.

With respect to sulfur addition to 10 separate out the ABUK impurities, court agreed with Plaintiffs and said that as an initial matter, court do not think Rapoport teaches that low- ABUK oxymorphone can be achieved through bisulfite addition combined with extraction. It seems that the poor partition ratio, combined with the lack of any examples of this method being used successfully, would not inform a person of ordinary skill that this was a promising method.

With respect to 0-demethylation of low-ABUK oxycodone into low ABUK oxymorphone, court again agreed with Plaintiffs and said that the starting material matters in evaluating whether a person of ordinary skill would have found low-ABUK oxymorphone obvious because 0-demethylation was available as a known method for converting oxycodone into oxymorphone. The person of ordinary skill at the time of invention would not have had access to the low-AB UK oxycodone Mallinckrodt used. As Plaintiffs point out, the prior art low-AB UK oxycodone had a different impurity profile that would result in differences in the final product of an 0-demethylation reaction. Therefore, Mallinckrodt's experiment is not relevant to the obviousness analysis.

Court also denied other grounds such as “anticipation” & “written description requirement”  and concluded that Defendants failed to prove by clear and convincing evidence that claims 1-6 of the '779 patent are invalid.