Obviousness

Obviousness Analysis of US Patent 12569491 under 35 U.S.C. § 103

This section analyzes the obviousness of US Patent 12569491B2, focusing on combinations of prior art that a person having ordinary skill in the art (PHOSITA) would have been motivated to combine to arrive at the claimed invention with a reasonable expectation of success. The analysis is conducted as of April 26, 2026.

Understanding the Claims

The key independent claims of US12569491B2 are:

• Claim 1: A method of treating or preventing testicular adrenal rest tumors (TART) or ovarian adrenal rest tumors (OART), comprising administering to a subject in need thereof a corticotropin-releasing factor type-1 (CRF1) antagonist or a pharmaceutically acceptable salt thereof.
• Claim 11: A pharmaceutical composition comprising from about 5 mg to about 1000 mg of a compound of Formula (I), or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable excipient. (Formula (I) is a specific CRF1 antagonist).
• Claim 13: A method for treating or preventing TART or OART, comprising administering to a subject in need thereof a CRF1 antagonist or a pharmaceutically acceptable salt thereof, and further administering an additional chemotherapeutic agent (e.g., glucocorticoid, mineralocorticoid, ACAT1 inhibitor, or anti-androgen).
• Claim 15: A method for treating or preventing TART or OART, comprising administering to a subject in need thereof a CRF1 antagonist of structural Formula (I), or a pharmaceutically acceptable salt thereof, and further comprising an additional treatment selected from surgical resection of the tumors and radiation therapy, or a combination thereof, wherein the additional treatment is prior to, after, and/or concurrent with administration of the compound or pharmaceutical composition.

Prior Art References

The provided patent text itself includes a "Prior art date" of 2018-04-27. Additionally, several relevant prior art concepts and references are discussed within the patent document and supplemented by recent search results.

• General understanding of TART/OART and CAH: Testicular adrenal rest tumors (TART) and ovarian adrenal rest tumors (OART) are known complications of congenital adrenal hyperplasia (CAH), linked to adrenocorticotropic hormone (ACTH) hypersecretion.
• CRF1 Antagonists: The patent states that "Compound 1 may be a potent, selective, nonsteroidal, oral corticotropin-releasing factor type-1 (CRF1) receptor antagonist that reduces excess ACTH, 17OHP, and A4 to improve clinical and biochemical sequelae of CAH." It further notes the identification of compounds that modulate CRF function and downstream processes is an ongoing challenge.
• Known treatments for TART: "Currently, there are no non-steroidal, non-surgical solutions to control, shrink, or reduce TART." However, it is also stated that "Medical management is preferred, as surgery has not been shown to demonstrate a return to normal testicular function or restoration of fertility." Furthermore, "Tumors tend to regress under adequate adrenal suppression with steroids."
• Crinecerfont (CRENESITY®): Recent information (June 15, 2026) reveals that CRENESITY® (crinecerfont) is a potent and selective oral CRF1 antagonist approved by the U.S. FDA in December 2024 for treating classic CAH. It is used with glucocorticoids to control androgen levels. CRENESITY has been shown to reduce and control excess ACTH and adrenal androgens through a non-glucocorticoid mechanism. High ACTH levels are known to cause TART. CRENESITY is administered orally, typically 100 mg twice daily for adults.

Obviousness Analysis

To establish obviousness, there must be a motivation for a PHOSITA to combine prior art references with a reasonable expectation of success. The mere existence of elements in prior art is insufficient.

Combination 1: CRF1 Antagonist for Treating TART/OART (Claim 1)

• Prior Art Elements:

  • Knowledge that TART/OART are caused by ACTH hypersecretion in CAH patients.
  • Knowledge of CRF1 antagonists as a means to reduce ACTH levels. The patent itself describes "Compound 1" as a CRF1 antagonist that reduces excess ACTH to improve CAH symptoms.
  • The understanding that medical management is preferred for TART, and that adrenal suppression with steroids can cause tumor regression.

• Motivation to Combine: A PHOSITA facing the problem of TART/OART in CAH patients would be motivated to explore therapeutic agents that reduce ACTH, given that TART/OART are known to be ACTH-responsive lesions. The patent itself highlights that "Testicular adrenal rest tumors and ovarian adrenal rest tumors (OART) are ACTH-responsive lesions... In response to high ACTH, hyperplasia of this tissue occurs, resulting in single or multiple lesions that may cause pain and infertility." Since CRF1 antagonists are known to reduce ACTH, and the underlying cause of TART is ACTH overproduction, a PHOSITA would have a clear motivation to try a CRF1 antagonist to treat or prevent these tumors. The patent explicitly states, "the identification of compounds that modulate CRF function and downstream processes is an ongoing challenge." This acknowledges the need for such solutions.

• Reasonable Expectation of Success: Given that CRF1 antagonists are known to reduce ACTH, and TART/OART are ACTH-responsive, there would be a reasonable expectation that reducing ACTH via a CRF1 antagonist would impact the growth or formation of these tumors. The subsequent FDA approval of Crinecerfont (CRENESITY®) in December 2024, a CRF1 antagonist specifically for CAH and noting its effect on TARTs, further supports this. Even at the patent's priority date (2018-04-27), the mechanism of action would suggest a high likelihood of success.

• Conclusion for Claim 1: Claim 1 appears obvious in light of the understanding of TART/OART etiology and the known mechanism of action of CRF1 antagonists in reducing ACTH.

Combination 2: Pharmaceutical Composition with a Specific CRF1 Antagonist (Claim 11)

• Prior Art Elements:

  • The general concept of pharmaceutical compositions comprising an active ingredient and a pharmaceutically acceptable excipient.
  • The existence of Compound 1 (Formula (I)) as a known CRF1 antagonist. The patent describes "Compound 1" as a potent, selective, nonsteroidal, oral CRF1 receptor antagonist.
  • Typical dosage ranges for oral administration. The patent itself mentions dosage ranges for a compound of Formula (I) from 5 mg to 1000 mg.

• Motivation to Combine: If the use of a CRF1 antagonist for TART/OART is considered obvious (as per the analysis for Claim 1), then formulating a known CRF1 antagonist like Compound 1 into a pharmaceutical composition with standard excipients and within a typical therapeutic dosage range would be a routine matter for a skilled artisan. Pharmaceutical formulation is a well-established field, and choosing appropriate excipients and dosage forms (e.g., capsules or tablets, as mentioned in the patent) would be within the ordinary skill.

• Reasonable Expectation of Success: There is a high expectation of success in formulating a known active pharmaceutical ingredient (like Compound 1) into a stable and effective dosage form using standard pharmaceutical techniques.

• Conclusion for Claim 11: Claim 11, which defines a pharmaceutical composition with a specific compound (Formula I) and excipients within a broad dosage range, appears obvious as a routine formulation of a known active agent for its intended purpose.

Combination 3: CRF1 Antagonist with Additional Chemotherapeutic Agent (Claim 13)

• Prior Art Elements:

  • Administration of a CRF1 antagonist for TART/OART (as analyzed for Claim 1).
  • Current medical management of CAH, which often involves glucocorticoids. For instance, CRENESITY® (crinecerfont) is used together with glucocorticoids to control androgen levels in CAH patients.
  • The patent itself lists glucocorticoids, mineralocorticoids, ACAT1 inhibitors, or anti-androgens as additional chemotherapeutic agents. It also states that ACTH stimulates the synthesis of cortisol, glucocorticoids, mineralocorticoids, and DHEA, which glucocorticoids and mineralocorticoids aim to manage.
  • Knowledge that "Tumors tend to regress under adequate adrenal suppression with steroids."

• Motivation to Combine: A PHOSITA would be motivated to combine a CRF1 antagonist with existing or complementary treatments for CAH and its complications, like TART/OART. Since TART is a complication of CAH, and standard CAH management often involves glucocorticoids, combining a novel ACTH-reducing agent (CRF1 antagonist) with established steroid therapy (which also helps with adrenal suppression and tumor regression) would be a logical approach to enhance therapeutic effect or manage broader CAH symptoms. The patent itself suggests combinations with "an additional chemotherapeutic agent" including "a glucocorticoid, a mineralocorticoid, an ACAT1 inhibitor, or an anti-androgen." This indicates these agents are recognized as relevant for the underlying condition or symptoms.

• Reasonable Expectation of Success: Combining agents with complementary mechanisms (reducing ACTH via CRF1 antagonism and directly supplementing or suppressing hormones via glucocorticoids/mineralocorticoids) would have a reasonable expectation of improved outcomes in managing CAH and its associated tumors. The clinical practice of using Crinecerfont with glucocorticoids further supports this.

• Conclusion for Claim 13: Claim 13, which involves co-administering a CRF1 antagonist with other known chemotherapeutic agents relevant to CAH and adrenal disorders, appears obvious.

Combination 4: CRF1 Antagonist with Surgical Resection or Radiation Therapy (Claim 15)

• Prior Art Elements:

  • Administration of a CRF1 antagonist (Formula (I)) for TART/OART (as analyzed for Claim 1).
  • Surgical resection and radiation therapy are well-established methods for treating tumors in general, and the patent explicitly lists them as "additional treatment[s]". For TART, surgical removal is a known option, though medical management is often preferred due to potential impact on gonadal function. The patent also states that "the method further comprises an additional treatment selected from surgical resection of the tumors and radiation therapy, or a combination thereof."

• Motivation to Combine: When treating tumors, it is common practice to combine systemic drug therapy with local treatments like surgery or radiation. A PHOSITA would be motivated to combine the ACTH-reducing effects of a CRF1 antagonist with physical removal or destruction of the tumors to achieve more comprehensive treatment, especially for larger or problematic lesions. The timing of such combined therapies (prior to, after, or concurrent with drug administration) is also a standard consideration in oncology and would be determined by the specific clinical scenario.

• Reasonable Expectation of Success: Given the known efficacy of both drug therapy and surgical/radiation interventions in tumor treatment, there would be a reasonable expectation of success in combining these modalities to treat TART/OART.

• Conclusion for Claim 15: Claim 15, which combines administration of a CRF1 antagonist with surgical resection or radiation therapy, appears obvious as a standard combinatorial approach in tumor management.