Obviousness

The current task is to perform an obviousness analysis of US patent 8268847 under 35 U.S.C. § 103, using the provided "Prior Art" section. The analysis must identify combinations of prior art references that would render the claims obvious and explain the motivation for a person having ordinary skill in the art (PHOSITA) to combine them.

First, I will reiterate the relevant claims of US8268847 for clarity:

• Claim 1: A product containing the compound of formula (I) (an endothelin receptor antagonist) in free or pharmaceutically acceptable salt form, in combination with at least one compound having PDE5-inhibitory properties, in free or a pharmaceutically acceptable salt form, for therapeutic use, simultaneously, separately or over a period of time, in the treatment of a disease wherein vasoconstriction is involved.
• Claims 2-4: Specify preferred PDE5 inhibitors (sildenafil, vardenafil, tadalafil, and udenafil; more preferably sildenafil or tadalafil).
• Claim 5: Specifies diseases where vasoconstriction is involved (hypertension, pulmonary hypertension, diabetic arteriopathy, heart failure, erectile dysfunction and angina pectoris; more preferably hypertension and pulmonary hypertension).
• Claim 6: A pharmaceutical composition containing the compound of formula (I) and a PDE5 inhibitor, plus at least one excipient.
• Claims 7-9: Specify preferred PDE5 inhibitors for the pharmaceutical composition.
• Claim 10: A method for the treatment of hypertension or pulmonary hypertension comprising administering to a patient in need thereof an effective amount of the compound of formula (I) and a PDE5 inhibitor.
• Claim 11: Specifies preferred PDE5 inhibitors for the method of treatment.

The patent itself identifies the core of its invention as the combination of compound of formula (I) (an endothelin receptor antagonist) with a PDE5 inhibitor, asserting a "surprising... unexpected synergistic effect".

The "Prior art date" for US8268847 is 2006-08-29. Therefore, any document published before this date is considered prior art.

Analysis of Obviousness under 35 U.S.C. § 103:

A claim is obvious under 35 U.S.C. § 103 if "the differences between the claimed invention and the prior art are such that the claimed invention as a whole would have been obvious before the effective filing date of the claimed invention to a person having ordinary skill in the art to which the claimed invention pertains."

Here, we will analyze two primary combinations of prior art references that would render the claims of US8268847 obvious.

Combination 1: WO 02/053557 in view of U.S. Pat. No. 5,250,534, EP 1097 711, WO 99/24433, U.S. Pat. No. 5,859,006, and/or WO 00/27848.

• Teaching of WO 02/053557: This PCT publication describes endothelin receptor antagonists, including the specific compound of formula (I) found in US8268847. It further discloses the use of these endothelin receptor antagonists in treating various diseases where vasoconstriction is involved, such as heart failure, angina pectoris, pulmonary and systemic hypertension, and erectile dysfunction.

• Teaching of the PDE5 Inhibitor References:

  • U.S. Pat. No. 5,250,534: This patent describes pyrazolopyrimidinone derivatives as PDE-5 inhibitors, specifically mentioning sildenafil, and their use for conditions including hypertension and heart failure.
  • EP 1097 711: This document specifically describes sildenafil for the treatment of pulmonary hypertension.
  • WO 99/24433: This publication describes vardenafil as a PDE5 inhibitor and its use for hypertension, angina pectoris, and erectile dysfunction.
  • U.S. Pat. No. 5,859,006: This patent describes tadalafil as a PDE5 inhibitor and its use for hypertension, pulmonary hypertension, angina, and congestive heart failure.
  • WO 00/27848: This publication describes udenafil and its use for impotence (erectile dysfunction).

• Motivation to Combine: A person having ordinary skill in the art (PHOSITA) would have been motivated to combine the teachings of WO 02/053557 with those of the cited PDE5 inhibitor references for the following reasons:

  1. Shared Therapeutic Targets: Both endothelin receptor antagonists (like compound I) and PDE5 inhibitors are known to exert vasodilatory effects and are used to treat diseases involving vasoconstriction, such as hypertension, pulmonary hypertension, heart failure, angina pectoris, and erectile dysfunction. The prior art explicitly teaches the utility of both classes of compounds for these overlapping conditions.
  2. Complementary Mechanisms of Action: Endothelin receptor antagonists block the vasoconstrictive effects of endothelin, while PDE5 inhibitors increase cGMP levels, leading to smooth muscle relaxation and vasodilation. A PHOSITA would recognize that combining agents with distinct but complementary mechanisms of action to address the same physiological problem (vasoconstriction) is a common and logical strategy in pharmaceutical development. This approach could lead to enhanced therapeutic efficacy or potentially allow for lower doses of individual components, thereby reducing side effects.
  3. Reasonable Expectation of Success: Given the known therapeutic profiles of both ERAs and PDE5 inhibitors for vasoconstriction-related disorders, a PHOSITA would have a reasonable expectation that combining them would yield at least additive, and potentially synergistic, therapeutic benefits. The goal of such combinations is often to improve patient outcomes.

• Conclusion for Combination 1: Claims 1-5, 7-9, and 11, which cover products, compositions, and methods for treating vasoconstriction-related diseases using the compound of formula (I) in combination with a PDE5 inhibitor, would be rendered obvious by the combination of WO 02/053557 and any of the aforementioned PDE5 inhibitor prior art references. The specific PDE5 inhibitors recited in the claims are explicitly taught in the prior art for related indications. The various modes of administration (simultaneous, separate, or over a period of time) are also routine considerations for drug combinations within the skill of a PHOSITA. Claims 6 and 10, pertaining to pharmaceutical compositions and methods of treatment, would also be obvious given the obviousness of the underlying combined active ingredients.

Combination 2: WO 2006/026395 A1, further combined with WO 02/053557 and selected PDE5 inhibitor references.

• Teaching of WO 2006/026395 A1: This reference, titled "Endothelin a receptor (eta) antagonists in combination with phosphodiesterase 5 inhibitors (pde5) and uses thereof," directly and explicitly teaches the combination of an Endothelin A (ETA) receptor antagonist with a PDE5 inhibitor. It further discloses the use of such combinations for treating diseases like pulmonary hypertension. This document is highly relevant as it teaches the very concept of the claimed combination.

• Teaching of WO 02/053557: As noted above, this reference discloses the compound of formula (I) as an endothelin receptor antagonist.

• Teaching of selected PDE5 Inhibitor References: As noted above, these references teach specific PDE5 inhibitors such as sildenafil, vardenafil, tadalafil, and udenafil, and their uses in vasoconstriction-related diseases.

• Motivation to Combine: WO 2006/026395 A1 provides a clear and explicit motivation to combine an ERA and a PDE5 inhibitor. A PHOSITA, seeking to develop improved treatments for conditions like pulmonary hypertension (a disease explicitly mentioned in both US8268847 and the prior art for both ERAs and PDE5 inhibitors), would look to known ERAs and PDE5 inhibitors. Given the broad teaching of WO 2006/026395 A1, a PHOSITA would be directly led to combine specific, well-known examples from each class, such as the compound of formula (I) (from WO 02/053557) and specific PDE5 inhibitors (e.g., sildenafil or tadalafil, from their respective prior art documents).

• Conclusion for Combination 2: The explicit disclosure in WO 2006/026395 A1 that combinations of ETA antagonists and PDE5 inhibitors are useful for treating conditions like pulmonary hypertension would make the core combination claimed in US8268847 prima facie obvious. If the compound of formula (I) is an ETA antagonist, or a dual ETA/ETB antagonist encompassed by the general teaching of "endothelin receptor antagonists" in the context of WO 2006/026395 A1, then combining it with any known PDE5 inhibitor for the claimed indications would be obvious. The identification of a synergistic effect, as noted in US8268847, while potentially unexpected, might not be sufficient to overcome this strong prima facie case of obviousness, particularly if a PHOSITA would have reasonably expected at least additive benefits from such a combination.