Obviousness

The claims of US patent 12280146 primarily relate to a topical formulation comprising an oil-in-water nanoemulsion and an active agent with a carboxylic acid group, characterized by being essentially free of propylene glycol (i.e., less than 1% w/w of propylene glycol or no propylene glycol). The nanoemulsion itself comprises an aqueous component and a carrier component, which includes at least one lipophilic component, at least one surfactant, and at least one alcohol.

An analysis under 35 U.S.C. § 103 for obviousness would consider whether a person having ordinary skill in the art (POSA) would have been motivated to combine existing prior art references to arrive at the claimed invention, with a reasonable expectation of success.

Combination of Prior Art References:

1. Reinhold, Future Oncology, 2017 November; 13 (27): 2413-2428: This reference establishes the prior existence of nanoemulsion formulations containing 5-aminolevulinic acid (ALA) for topical use, even if these formulations exhibited instability at higher temperatures. ALA is explicitly identified in US12280146 as an active agent with a carboxylic acid group. This prior art therefore teaches a nanoemulsion comprising an aqueous component, a carrier component (implicitly containing lipophilic components, surfactants, and alcohols necessary for nanoemulsion formation), and an active agent comprising a carboxylic acid group (ALA).

2. Carrer et al., Arch Dermatol Res 312, 337-352 (2020) and McGowan M A et al., Dermatitis, 2018; 29 (1): 6-12, in conjunction with general knowledge in the field as acknowledged by US12280146: These references, or the general knowledge they represent as described within the US12280146 patent, highlight various properties of propylene glycol. While propylene glycol is known for advantageous properties such as penetration enhancement and preservative effects, the patent explicitly acknowledges its drawbacks, stating: "However, cases have been reported in which patients with atopic dermatitis show allergic reactions to propylene glycol and it is known to be irritating to the eyes." Crucially, the patent further details a specific technical problem: "active agents comprising a carboxylic acid group may undergo nucleophilic reactions to form undesired products, such as esters, with propylene glycol." This problem is also relevant for derivatives of carboxylic acid groups via transesterification. The patent concludes that "Omission of propylene glycol may thus lead to less undesired side products."

Motivation to Combine:

A person having ordinary skill in the art (POSA), faced with the challenge of formulating a stable topical nanoemulsion containing an active agent with a carboxylic acid group (such as ALA, as generally known from Reinhold), would be motivated to modify existing formulations. The motivation to remove or significantly reduce propylene glycol would arise from several recognized problems, as detailed in the background of US12280146:

• Patient Safety and Tolerability: The awareness that propylene glycol can cause allergic reactions and irritation in patients, particularly those with conditions like atopic dermatitis, would motivate a POSA to develop formulations free of, or with significantly reduced, propylene glycol to improve patient tolerability and reduce adverse effects.
• Impurity Reduction and Stability: More specifically, a POSA would recognize that active agents containing carboxylic acid groups, like ALA, can undergo undesired nucleophilic reactions (e.g., esterification or transesterification) with propylene glycol, leading to the formation of impurities and side products. To enhance the chemical stability and impurity profile of the active agent within the nanoemulsion, and thereby improve the shelf-life of the product, a POSA would be motivated to eliminate or minimize a known reactant like propylene glycol. The patent itself states that "Omission of propylene glycol may thus lead to less undesired side products."

Therefore, a POSA, seeking to develop a more tolerable and chemically stable nanoemulsion for an active agent like ALA, would have a clear motivation to combine the known nanoemulsion technology for ALA (Reinhold) with the understanding of propylene glycol's drawbacks, particularly its propensity to form undesirable impurities with carboxylic acid-containing active agents and its potential for causing adverse patient reactions. The goal would be to produce a formulation with an improved impurity profile and better patient compatibility by reducing or eliminating propylene glycol. While US12280146 highlights the surprising discovery of improved penetration upon removal of propylene glycol, the initial motivation to remove it due to its known drawbacks (allergic reactions, irritation, and impurity formation with carboxylic acid-containing active agents) would still render the act of removing it obvious to a POSA.