In Corcept Therapeutics, Inc. v. Teva Pharmaceuticals U.S.A., Inc., C.A. 18-03632, December 29, 2023, the Chief Judge Bumb of the New Jersey District Court wrestled with the question of infringement under 35 U.S.C. 271(e)(2) where the drug labels of the generic and ethical drug were identical in the relevant parts.

The drug was Korlym (mifepristone) used to treat Cushing's syndrome as were strong CYP3A inhibitors. Using Korlym combined with a CYP3A was discouraged as CYP3A played a role in the metabolism of drugs and its inhibition was expected to increase mifepristone plasma level which could lead to severe adverse effects including death if both were administered concomitantly to the patient. The two drugs were administered concomitantly in very sick patients in isolated cases. As a condition for Korlym's approval, the FDA required Corcept to conduct post-marketing studies because ketoconazole (an exemplary strong CYP3A inhibitor) was widely used off-label to treat Cushing's syndrome and that increased exposure to mifepristone might result from coadministration, potentially leading to severe hypokalemia and adrenal insufficiency. Corcept discovered that coadministration of mifepristone and a strong CYP3A increased blood levels only marginally and that a physician could prescribe up to 900 mg of mifepristone with a strong CYP3A inhibitor if dosed appropriately. Corcept filed United States patents 10,195,214 and 10,842,800 directed to a method of controlling hyperglycemia when administering Korlym (mifepristone) with a strong CYP3A inhibitor. Corcept also added its data to the drug label and modified the label's discussion regarding concomitant administration with CYP3A inhibitors.

Corcept asserted infringement of its patents under 35 U.S.C §§ 271(b) and 271(e)(2)(A). Both patents are directed to a method of controlling hyperglycemia when administering Korlym (mifepristone) with a strong CYP3A inhibitor. Both the 2012 and 2019 labels contained:

2.5 Concomitant Administration with CYP3A Inhibitors

Ketoconazole and other strong inhibitors of CYP3A, such as itraconazole, nefazodone, ritonavir, nelfinavir, indinavir, atazanavir, amprenavir and fosamprenavir, clarithromycin, conivaptan, lopinavir/ritonavir, posaconazole, saquinavir, telithromycin, or voriconazolem may increase exposure to mifepristone. KORLYM should be used in combination with strong CYP3A inhibitors only when necessary. [See Warnings and Precautions (5.6), Drug Interactions (7.2)]

Administration of KORLYM to patients already being treated with strong CYP3A inhibitors:

  • Start at a dose of 300 mg. If clinically indicated, titrate to a maximum of 900 mg.

Administration of strong CYP3A inhibitors to patients already being treated with KORLYM:

  • Adjust the dose of KORLYM according to Table 1.

7.2 CYP3A Inhibitors

Medications that inhibit CYP3A could increase plasma mifepristone concentrations and dose reduction of KORLYM may be required. Ketoconazole and other strong inhibitors of CYP3A, such as itraconazole, nefazodone, ritonavir, nelfinavir, indinavir, atazanavir, amprenavir and fosamprenavir, clarithromycin, conivaptan, lopinavir/ritonavir, posaconazole, saquinavir, telithromycin, or voriconazole may increase exposure to mifepristone. Caution should be used when strong CYP3A inhibitors are prescribed in combination with KORLYM. The benefit of concomitant use of these agents should be carefully weighed against the potential risks. The dose of KORLYM should be limited to 900 mg, and strong inhibitors of CYP3A should be used only when necessary. [See Dosage and Administration (2.4), Warnings & Precautions (5.6), and Clinical Pharmacology (12.3)]

[Bolding added]

Corcept argued that the instructions found on Teva's label, as required by the FDA, instructs the physician to perform the patented method when prescribing mifepristone which Teva countered with the label's discouraging the concomitant use of Korlym with a CYP3A inhibitor. The case law required that the label's instructions teach an infringing use of the device in such a way as to allow one to infer from those instructions an affirmative intent to infringe the patent. Teva argued there was no evidence that anyone had practiced the claimed methods. Corcept acknowledged that many ways of concomitant administration of Korlym and a strong CYP3A inhibitor would not infringe the Corcept claims where the doses of Korlym differed from that claimed. This was emphasized by the lack of evidence of anyone practicing the claimed methods.

Teva also argued its label discouraged the concomitant use of Korlym and a CYP3A inhibitor. Further, Corcept had provided no evidence that anyone, during the ten-year span since Korlym® was approved, had practiced the claimed method with Korlym.

The Court found the facts to be similar to Genentech, Inc. v. Sandoz Inc., 55 F.4th 1368, 1380 (Fed. Cir. 2022) where a method of avoiding adverse drug interactions with pirfenidone caused by a strong CYP1A2 inhibitor such as fluvoxamine were patented. The Federal Circuit affirmed a holding of no infringement primarily because, first, there was no evidence that physicians had performed the claimed method noting that past conduct is relevant as to what will probably happen in the future. And second, evidence from the generic company that doctors had not prescribed pirfenidone with fluvoxamine and that the doctors would prescribe a non-infringing alternative instead. Here Teva introduced evidence that the doctors would also prescribe a non-infringing alternative instead of the concomitant administration of Korlym with a CYP3A inhibitor. Based on these facts the Court found no infringement.

The key take-aways are the need to provide proof that infringement will occur which can be done by showing how the patented product has been used in the method of the drug label and the patent claims. In prosecuting the patent application, care should be taken in drafting claims which will be infringed by the practice of the label's method. Close cooperation between IP and regulatory is key to achieving this goal.

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