Obviousness

The obviousness analysis under 35 U.S.C. § 103 for US patent 12234236 is conducted based on the arguments presented in the Post-Grant Review (PGR) case PGR2025-00057, as the complete text of the patent's claims is not provided in the authoritative document. This analysis will interpret the petitioner's arguments as indicative of how a Person Having Ordinary Skill in the Art (PHOSITA) would perceive the inventiveness of the claimed subject matter.

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

Challenged Claims and Primary Prior Art:
The Post-Grant Review (PGR2025-00057) challenges independent Markush claims 1 and 24, along with associated dependent claims, which are directed to GLP-1R modulating compounds, including specific examples such as Compound 1, Compound 19, Compound 20, and Compound 65.

The primary prior art reference identified in the petition is orforglipron, a known GLP-1R agonist developed by Eli Lilly & Co.

Proposed Modification and Secondary Prior Art:
The petitioner's argument centers on the idea that a PHOSITA would have been motivated to modify orforglipron. Specifically, the challenge asserts obviousness for modifications such as "replacing a methyl group with a cyclopropyl group." This proposed modification is alleged to be taught or suggested by prior art references including Yoshino, Kawai, and Talele.

Motivation for Combination (PHOSITA Perspective):

A PHOSITA, seeking to develop or improve GLP-1R agonists, would start with known active compounds like orforglipron. The motivation to modify such a lead compound typically arises from a desire to enhance desirable properties (e.g., potency, selectivity, pharmacokinetic profile, metabolic stability) or to overcome liabilities (e.g., side effects, poor bioavailability).

In this context, the petitioner argues that a PHOSITA would have been motivated to replace a methyl group present in orforglipron with a cyclopropyl group. This motivation is asserted to stem from the collective teachings of references such as Yoshino, Kawai, and Talele. The PTAB's decision to institute the trial indicates that these arguments provided a "reasonable likelihood" of success, suggesting the Board recognized plausible motivations for such modifications in the art.

The specific motivations for replacing a methyl group with a cyclopropyl group, as implied by the institution of the PGR, could include:

1. Bioisosteric Replacement: Cyclopropyl groups are often considered bioisosteric replacements for methyl or isopropyl groups in medicinal chemistry. Such replacements can sometimes lead to improved metabolic stability due to reduced susceptibility to oxidative metabolism, altered lipophilicity, or modified steric interactions with target receptors or enzymes, potentially enhancing the compound's half-life or efficacy.
2. Conformational Restriction: A cyclopropyl group introduces a degree of conformational restriction compared to a rotatable methyl group. This can impact the binding affinity and selectivity of a compound by favoring a particular conformation that is more optimal for receptor interaction.
3. Electronic Effects: Cyclopropyl groups exhibit unique electronic properties (e.g., "bent bonds" that confer some π-character) which can influence the electron density and reactivity of adjacent functional groups, potentially leading to favorable interactions within the GLP-1R binding site.
4. Known Chemical Principles: The "other references discussing substitutions that preserve or enhance biological activity" (e.g., Yoshino, Kawai, and Talele) would likely teach that such structural modifications (like methyl-to-cyclopropyl) are common strategies in drug discovery to optimize physicochemical and biological properties of lead compounds without necessarily diminishing their core activity. A PHOSITA would understand that small alkyl group modifications, particularly replacements with cyclopropyl, are routine explorations in analog synthesis.

Therefore, starting with the known GLP-1R agonist orforglipron, and armed with the general knowledge in the field (as exemplified by Yoshino, Kawai, and Talele) that cyclopropyl groups can serve as effective replacements for methyl groups to modulate metabolic stability, potency, or other pharmacokinetic properties, a PHOSITA would have been motivated to synthesize compounds incorporating such a change, with a reasonable expectation of achieving a GLP-1R agonist with desirable therapeutic properties. The PTAB's decision to institute the PGR on these grounds supports the contention that such a combination of prior art and motivation for modification would render claims 1 and 24 obvious.