Oxymorphone HCl – USA

On Mar 28, 2019 Federal Circuit reversed district court’s decision & found Opana® ER patent eligible under 35 U.S.C. § 101.

Endo owns U.S. Patent No. 8,808,737 (expiring on June 21, 2027) entitled “Method of treating pain utilizing controlled release oxymorphone pharmaceutical compositions and instruction on dosing for renal impairment.” The ’737 patent relates to his discovery that patients with renal impairment in need of pain relief can be treated in a new, different way than other patients. Specifically, the inventor discovered that patients with moderately or severely impaired kidney function need less oxymorphone than usual to achieve a similar level of pain management. And this can be determined based on correlation between plasma AUC for oxymorphone and a patient’s degree of renal impairment, as indicated by their creatinine clearance rate.

Claim 1 of the ’737 patent is representative and reads:

1. A method of treating pain in a renally impaired patient, comprising the steps of:

a. providing a solid oral controlled release dosage form, comprising:

i. about 5 mg to about 80 mg of oxymorphone or a pharmaceutically acceptable salt thereof as the sole active ingredient; and

ii. a controlled release matrix;

b. measuring a creatinine clearance rate of the patient and determining it to be

(a) less than about 30 ml/min,

(b) about 30 mL/min to about 50 mL/min,

(c) about 51 mL/min to about 80 mL/min, or

(d) above about 80 mL/min; and

c. orally administering to said patient, in dependence on which creatinine clearance rate is found, a lower dosage of the dosage form to provide pain relief;  wherein after said administration to said patient, the average AUC of oxymorphone over a 12-hour period is less than about 21 ng·hr/mL.

Endo and Mallinckrodt sued Actavis and Teva for allegedly infringing the ’737 patent’s claims 1−6. Actavis moved to dismiss Endo’s patent infringement claims, arguing that the patent claims were ineligible under § 101. The magistrate judge recommended granting Actavis’s motion. The magistrate judge first analyzed step 1 of the “Alice/Mayo” test, reasoning that the claims are directed to the natural law that the bioavailability of oxymorphone is increased in people with severe renal impairment. The magistrate judge then considered step 2 of the Alice/Mayo test, analyzing whether the ’737 patent claims, though directed to a law of nature, added enough to qualify as a patentable method that applies the law of nature. The magistrate judge separated claim 1 into three steps: (1) a “providing” step, (2) a “measuring” step, and (3) an “administering” step. First, the magistrate judge reasoned that the “providing” step is similar to the administering step in Mayo because it “merely identifies the specific drug for administration.” Second, the magistrate judge concluded that the measuring/determining step, like Mayo, “just directs one to use a well-known method to measure creatinine levels to obtain the necessary information to apply a law of nature.” Finally, the magistrate judge concluded that the “administering step” is indistinguishable from Mayo: “The administering step simply limits the relevant audience to patients and prescribing physicians, who treat chronic or acute pain with oxymorphone, and instructs the administration of the correct dosage of oxymorphone depending on the severity of the renal impairment, a step very similar to Mayo, which limited the relevant audience to “doctors who treat patients with certain diseases with thiopurine drugs.”

According to the magistrate judge, “the administering step merely instructs physicians to dispense oxymorphone for the treatment of pain in a well-known manner, while utilizing the natural law to manage the dosage.” Based on this analysis, the magistrate judge concluded that the patent was not directed to a patent-eligible application of a natural law. The district court adopted the magistrate judge’s recommendation, finding the patent claims ineligible.

During appeal Federal Circuit said that the Supreme Court has established a two-step framework to determine subject matter eligibility under § 101. [Alice Corp. Pty. v. CLS Bank Int’l, 573 U.S. 208, 217–18 (2014) (citing Mayo, 566 U.S. at 72–73, 75–80)]. Accordingly, at step one, “it is not enough to merely identify a patent-ineligible concept underlying the claim; we must determine whether that patent-ineligible concept is what the claim is ‘directed to.’” The Supreme Court has cautioned that “too broad an interpretation of” ineligible subject matter “could eviscerate patent law” because “all inventions at some level embody, use, reflect, rest upon, or apply laws of nature, natural phenomena, or abstract ideas.” Federal Circuit further said that the claims recite “[a] method of treating pain in a renally impaired patient” by providing, testing & administering limitations. Consistent with the claims, the abstract, patent title, and summary of the invention all describe the invention as a “method of treating pain” in patients with renal impairment. We held similar claims patent-eligible in “Vanda Pharmaceuticals Inc. v. West-Ward Pharmaceuticals International Ltd, 887 F.3d 1117 (Fed. Cir. 2018)”. The patent at issue in Vanda related to a method of treating schizophrenia patients with a drug (iloperidone), where the administered dose is adjusted based on whether or not the patient is a “CYP2D6 poor metabolizer.” The claims at issue here are legally indistinguishable from the representative claim in Vanda.

Also like the claims in Vanda, the claims here differ from those in Mayo in material respects. Although the representative claim in Mayo recited administering a thiopurine drug to a patient, the claim as a whole was not directed to the application of a drug to treat a particular disease. Furthermore, the administering step in Mayo is distinguishable from the administering step in the ’737 patent because the administering step in Mayo is the first step in the method that simply describes giving the drug to a patient with a certain disorder. By contrast, the administering step in the ’737 patent is the step that describes giving a specific dose of the drug based on the results of kidney function testing. The inventor here recognized the relationship between oxymorphone and patients with renal impairment, but that is not what he claimed. Rather he claimed an application of that relationship—specifically, a method of treatment including specific steps to adjust or lower the oxymorphone dose for patients with renal impairment. The claims are thus directed to more than just reciting the natural relationship. Moreover, the representative claim in Mayo stated that the metabolite level in blood simply “indicates” a need to increase or decrease dosage, without prescribing a specific dosage regimen or other added steps to take as a result of that indication. In contrast, the claims here recite the steps of carrying out a dosage regimen based on the results of kidney function testing. The claims require doctors to “orally administer to said patient, in dependence on which creatinine clearance rate is found, a lower dosage of the dosage form to provide pain relief” in such a way that after administering the dose, the patient’s “average AUC of oxymorphone over a 12-hour period is less than about 21 ng·hr/mL.” These are specific treatment steps. The claims prescribe a specific dosage regimen through the wherein clause, under which the physician administers oxymorphone to achieve a specific range of AUC of oxymorphone based on the patient’s creatinine clearance rate.

Federal Circuit disagreed with Actavis’s interpretation of the claims in view of Vanda. Court said that the wherein clause identifies the appropriate schedule and dose of oxymorphone to administer, as a function of how much oxymorphone is in the patient’s system. It is the combination of the administering step and wherein clause claim language, taken together, that make the claims-at-issue as specific as those in Vanda such that the patent claims do not “tie up the doctor’s subsequent treatment decision.” Like the administering step in Vanda, the administering step and wherein clause in the present claims allow the claims to do more than just recognize a need to lower or decrease a dose. Court finally held that the ’737 patent claims are not directed to patent-ineligible subject matter & therefore it reversed the district court’s decision.