PTAB

IPR2025-01139

United Therapeutics Corp v. Actelion Pharmaceuticals Ltd

Title: Combination of an Endothelin Receptor Antagonist with a PDE5 Inhibitor
Brief Description: The ’847 patent relates to products, compositions, and methods for treating diseases involving vasoconstriction, such as pulmonary hypertension. The invention is a combination therapy comprising macitentan (an endothelin receptor type A (ETA) antagonist) and a phosphodiesterase-5 (PDE5) inhibitor.

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 limitations of the challenged claims. Bolli taught macitentan as an "especially preferred" ETA antagonist for treating diseases associated with vasoconstriction, including pulmonary hypertension (PH) and erectile dysfunction (ED). Critically, Bolli expressly taught combining macitentan with "vasodilators ... which serve to treat high blood pressure or any cardiac disorders." Petitioner asserted that a person of ordinary skill in the art (POSA) would have immediately understood this class of "vasodilators" to include the well-known and commercially dominant PDE5 inhibitors sildenafil and tadalafil, as they were blockbuster drugs used to treat the very same conditions (PH and ED) mentioned in Bolli. Bolli also disclosed dosage ranges that overlap or encompass the claimed ranges.
- Key Aspects: The core of this argument rested on the assertion that a POSA, possessing knowledge of the leading treatments for PH and ED at the time, would have necessarily understood Bolli's generic disclosure of "vasodilators" to include the specific PDE5 inhibitors recited in the dependent claims.

Prior Art Relied Upon: Bolli (WO 2002/053557) and Keyser (WO 2006/026395).
Core Argument for this Ground:
- Prior Art Mapping: Petitioner contended that Bolli taught macitentan and its general use in combination with vasodilators. Keyser explicitly taught combination therapies comprising an ETA antagonist and a PDE5 inhibitor (specifically naming sildenafil and tadalafil) for treating the same cardiac disorders, such as PH. The combination of references therefore expressly disclosed a product containing macitentan and a PDE5 inhibitor for treating hypertension.
- Motivation to Combine: A POSITA would combine Bolli's specific, preferred ETA antagonist (macitentan) with Keyser's explicit teaching of the general combination therapy. Both references were in the same field, addressed the same problem of vasoconstrictive diseases, and taught that combination therapy could provide complementary effects, reduce dosages, and/or lower side effects.
- Expectation of Success: A POSITA would have had a reasonable expectation of success. Bolli taught macitentan was an effective drug, and Keyser taught that ETA antagonists and PDE5 inhibitors were effective and that their combination was well-tolerated in a pharmacokinetic study. The known complementary biological pathways of ETA antagonists and PDE5 inhibitors would have further supported this expectation.

Prior Art Relied Upon: Hoeper (a 2004 journal article), Morice (a 2005 journal article), and Bolli (WO 2002/053557).
Core Argument for this Ground:
- Prior Art Mapping: Hoeper and Morice described the successful and well-tolerated clinical use of combination therapy using the ET antagonist bosentan with the PDE5 inhibitors sildenafil (Hoeper) and tadalafil (Morice) to treat idiopathic pulmonary arterial hypertension (PAH). Bolli disclosed macitentan as a potent and highly selective ETA antagonist.
- Motivation to Combine: A POSITA would have been motivated to substitute Bolli's preferred and more potent ETA antagonist, macitentan, for bosentan in the established and effective combination therapies taught by Hoeper and Morice. The motivation was a straightforward optimization to improve upon a known, successful treatment regimen by using a superior compound from the same therapeutic class.
- Expectation of Success: Because Hoeper and Morice had already demonstrated that combining an ET antagonist with a PDE5 inhibitor was a safe and effective treatment strategy for PAH, a POSITA would have reasonably expected that substituting one known ET antagonist for another, more potent one would yield a predictable, successful result.

Petitioner stated that, for the purposes of the petition, it interpreted claim terms according to their plain and ordinary meaning, adopting the explicit definitions provided in the ’847 patent’s specification. This included definitions for administration terms such as "simultaneously," "separately," and "over a period of time," which were central to mapping the prior art to the claims.

Rebuttal of Secondary Considerations: A central thrust of the petition was a preemptive rebuttal of the Patent Owner's arguments regarding secondary considerations of non-obviousness, particularly unexpected synergistic results. Petitioner argued these arguments were flawed for three primary reasons:
- Not Commensurate with Claim Scope: The alleged synergistic effects were supported only by limited data from acute, single-dose studies in two specific rat models. Petitioner argued this was not commensurate with the broad claims covering any species, any vasoconstrictive disease, chronic dosing, and various administration timings.
- Improper Reliance on Post-Priority Art: During prosecution, Patent Owner relied on post-priority date publications (Iglarz 2008, Bolli 2012) to argue that macitentan had properties that would have "surprised" a POSA. Petitioner contended this was an improper use of post-priority evidence to redefine the knowledge of a POSA at the time of the invention.
- Synergy Was Expected: Petitioner argued that a POSA would have expected complementary or synergistic results from combining an ETA antagonist and a PDE5 inhibitor. The two drug classes operate on different but complementary biological pathways (endothelin and nitric oxide) known to regulate vasodilation, making their combined use an attractive and logical therapeutic strategy.

Petitioner requests institution of IPR and cancellation of claims 1-57 of the ’847 patent as unpatentable.