PTAB

IPR2025-01139

United Therapeutics Corporation v. Actelion Pharmaceuticals Ltd.

Title: Combination of an Endothelin Receptor Antagonist with a PDE5 Inhibitor
Brief Description: The ’847 patent is directed to products, pharmaceutical compositions, and methods of use involving the combination of an endothelin receptor type A (ETA) antagonist, specifically macitentan (compound of formula I), with a phosphodiesterase 5 (PDE5) inhibitor. The claimed combinations are for treating diseases involving vasoconstriction, such as hypertension and pulmonary hypertension.

Prior Art Relied Upon: Bolli (International Publication No. WO 2002/053557).
Core Argument for this Ground:
- Prior Art Mapping: Petitioner argued that Bolli disclosed all elements of the challenged claims. Bolli explicitly disclosed macitentan as an "especially preferred" endothelin receptor antagonist for use in pharmaceutical compositions. Bolli further taught combining these compounds with "vasodilators... which serve to treat high blood pressure or any cardiac disorders," such as pulmonary hypertension (PH) and erectile dysfunction (ED). Petitioner contended that a person of ordinary skill in the art (POSA) would have immediately understood that the well-known, blockbuster "vasodilators" for these exact conditions included the PDE5 inhibitors sildenafil and tadalafil. Bolli also disclosed dosage ranges for macitentan (0.1-50 mg/kg) that overlap or encompass the claimed ranges, and a POSA would have known the standard dosages for sildenafil and tadalafil, which fall within the claimed ranges.

Prior Art Relied Upon: Bolli (WO 2002/053557) and Keyser (International Publication No. WO 2006/026395).
Core Argument for this Ground:
- Prior Art Mapping: Petitioner asserted that Bolli taught the use of macitentan as a potent and selective ETA antagonist. Keyser taught combination therapies comprising an ETA antagonist and a PDE5 inhibitor (such as sildenafil or tadalafil) for treating the same vasoconstrictive diseases, including PH.
- Motivation to Combine: A POSA would combine Bolli’s preferred ETA antagonist (macitentan) with the combination therapy framework taught by Keyser. Keyser provided the express rationale for the combination: to "act in a complementary fashion to provide superior efficacy and/or dosage regimes and/or reduction in side effects." Both references addressed the same problem in the same field, making the combination a logical and straightforward step.
- Expectation of Success: A POSA would have had a reasonable expectation of success. Bolli demonstrated macitentan's effectiveness, and Keyser taught that combining ETA antagonists and PDE5 inhibitors was beneficial and well-tolerated. Keyser provided data showing minimal drug interaction, reinforcing the predictability of a successful outcome.

Prior Art Relied Upon: Hoeper (a 2004 journal article), Morice (a 2005 letter responding to Hoeper), and Bolli (WO 2002/053557).
Core Argument for this Ground:
- Prior Art Mapping: Hoeper and Morice collectively taught the successful and safe combination of the ETA antagonist bosentan with the PDE5 inhibitors sildenafil and tadalafil for treating idiopathic pulmonary arterial hypertension (PAH). Bolli disclosed macitentan as an especially preferred ETA antagonist with superior potency and selectivity compared to compounds like bosentan.
- Motivation to Combine: A POSA would be motivated to substitute the improved ETA antagonist from Bolli (macitentan) for bosentan in the established, successful combination therapies described by Hoeper and Morice. The motivation was the simple, well-established practice of optimizing a known combination therapy by substituting a component with a known, superior alternative to achieve better efficacy, safety, or both.
- Expectation of Success: The expectation of success was high, as it was based on replacing a component in a proven clinical combination (bosentan + PDE5 inhibitor) with a structurally similar compound (macitentan) known to be a more potent and selective agent for the same biological target.

Refutation of "Unexpected Results": Petitioner argued that the Patent Owner's reliance on "unexpected results" to overcome obviousness during prosecution was flawed. The argument was based on three key points:
- The results were not commensurate with the claim scope. The patent’s data was limited to single-dose acute effects in specific rat models, whereas the claims covered chronic dosing, any species, any vasoconstrictive disease, and broad dosage ranges.
- The synergistic effect was not unexpected. A POSA would have expected complementary or synergistic results from combining two drugs that target different but related biological pathways (endothelin and nitric oxide) known to be involved in vasoconstriction.
- The Patent Owner improperly relied on post-priority references (Iglarz) to redefine macitentan's selectivity and create a "teaching away" argument against Keyser that did not exist at the time of the invention. Petitioner contended that the in vitro data available from the prior art (Bolli) showed macitentan met Keyser's preference for selectivity.

Petitioner argued that the Board should decline to exercise its discretion to deny institution under 35 U.S.C. §325(d). It noted that the anticipation ground based on Bolli and the obviousness ground based on Hoeper and Morice were never substantively considered during prosecution or reexamination. Therefore, the petition raised new arguments and art not previously before the Office.

Petitioner requested institution of an inter partes review and cancellation of claims 1-57 of Patent 8,268,847 as unpatentable.