Obviousness

The obviousness of US patent 12138276 under 35 U.S.C. § 103 can be established by combining various prior art references that demonstrate a motivation to create halogenated psilocybin derivatives and a reasonable expectation of success in doing so, both chemically and biosynthetically, as well as their use in treating psychiatric disorders. The patent's priority date is September 1, 2020.

Obviousness of Halogenated Psilocybin Derivatives and Methods of Treatment (Claims related to Formula (I), formulations, and therapeutic use)

References:

1. Hofmann et al. (1959) / Hofmann and Troxler (1963 patent): These references disclose the chemical structure and synthesis of psilocybin and psilocin. Psilocybin was isolated in 1958 and synthesized in 1959 by Albert Hofmann and co-workers.
2. WO2021052989A1 (Priority Date: September 19, 2019): This patent application, despite its 2021 publication date, has an earlier priority date than US12138276, making it prior art. It explicitly states that "halogenated tryptamine derivatives might be of great therapeutic interest" and are "expected to have enhanced therapeutic properties compared to their non-halogenated counterparts." It further specifies that halogen atoms "may be present in position 2, 5, 6 and/or 7" of halogenated tryptophan derivatives.
3. Clinical Research on Psilocybin (various publications prior to 2020): Numerous studies and reviews published before 2020 demonstrated psilocybin's activity as a 5-HT2A receptor agonist and its therapeutic potential for psychiatric disorders such as major depressive disorder (MDD), treatment-resistant depression (TRD), anxiety, alcohol use disorders, and cancer-related distress.

Motivation to Combine and Obviousness:

A person having ordinary skill in the art (PHOSITA) in medicinal chemistry as of the priority date of September 1, 2020, would have been aware of the established structure of psilocybin (from Hofmann) and its known therapeutic effects on 5-HT2A receptors for treating various psychiatric conditions.

The common practice in medicinal chemistry to modify existing lead compounds to discover new drugs with improved properties, such as potency, selectivity, metabolic stability, or bioavailability, would provide a strong motivation to create derivatives of psilocybin. WO2021052989A1 directly teaches that halogenation is a valuable strategy for drug discovery, noting that "halogenated tryptamine derivatives" are "expected to have enhanced therapeutic properties." This reference explicitly points to the desirability of such compounds and specifies positions 2, 5, 6, and/or 7 on the indole ring as potential sites for halogenation.

Given these teachings, it would have been obvious for a PHOSITA to take the known psilocybin scaffold and systematically replace hydrogen atoms at positions R2, R4, R5, R6, or R7 with halogen atoms (e.g., fluorine, chlorine, bromine, or iodine), with a reasonable expectation of modulating 5-HT2A receptor activity and potentially improving therapeutic outcomes. The claims further encompass variations where R4, when not halogenated, can be a phosphate group, hydrogen atom, or an alkyl or O-alkyl group, and R3A/R3B can be a hydrogen atom, an alkyl group, an aryl group, or an acyl group. These modifications are routine in tryptamine chemistry and would be considered conventional explorations by a PHOSITA to fine-tune pharmacokinetic and pharmacodynamic properties. Therefore, the claimed halogenated psilocybin derivatives, and their use in pharmaceutical/recreational formulations and methods of treating psychiatric disorders, would have been obvious.

Obviousness of Methods of Making (Claims related to biosynthetic production)

References:

1. Hoffmeister et al. (2017): This research identified the enzymes (PsiD, PsiH, PsiK, PsiM) involved in the biosynthesis of psilocybin in mushrooms. It demonstrated that three of these enzymes could be used to synthesize psilocybin from 4-hydroxy-L-tryptophan in a one-pot reaction, laying the groundwork for bioengineered production.
2. WO2021052989A1 (Priority Date: September 19, 2019): This document explicitly discusses the "biotechnological production of halogenated tryptamines in a cell factory" as a method for drug discovery and for producing compounds with "enhanced therapeutic properties." It also mentions methods for producing psilocybin in a yeast cell using a heterologous biosynthesis pathway. The document indicates that halogenated psilocybin precursor compounds can be formed by contacting a host cell with a non-halogenated psilocybin precursor compound and a halogen, where the host cell comprises a halogenase.
3. General Knowledge in Metabolic Engineering and Synthetic Biology (prior to 2020): It was well-known in the field to engineer host cells (e.g., microbial cells like bacteria or yeast) to express heterologous enzymes for the biosynthesis of natural products and their derivatives, including the use of halogenases to introduce halogens into target molecules.

Motivation to Combine and Obviousness:

A PHOSITA in synthetic biology or metabolic engineering, aware of Hoffmeister et al.'s elucidation of the psilocybin biosynthetic pathway and the capability for bioengineered production, would have been motivated to extend these methods to produce halogenated psilocybin derivatives. This motivation is strongly reinforced by WO2021052989A1, which specifically teaches the desirability and feasibility of "biotechnological production of halogenated tryptamines in a cell factory" for therapeutic purposes.

Combining these teachings would lead a PHOSITA to predictably engineer a host cell to produce halogenated psilocybin derivatives. This could be achieved either by introducing a halogenated psilocybin precursor compound into a host cell equipped with the psilocybin biosynthetic enzyme complement, or by engineering a host cell to include a halogenase enzyme that acts on a non-halogenated psilocybin precursor in the presence of a halogen. Both approaches represent routine applications of established metabolic engineering principles to generate desired derivatives, especially given the explicit guidance in the prior art regarding halogenated tryptamines and their biosynthesis in host cells. The use of microbial cells, such as bacterial or yeast cells, as host cells for such biotechnological production was also a common and obvious choice.

Conclusion:

Based on the combination of these prior art references, the claimed halogenated psilocybin derivatives, their formulations, methods of treatment, and methods of making, would have been obvious to a person having ordinary skill in the art at the time of the invention. The explicit motivation to halogenate known therapeutic tryptamine compounds for enhanced properties, coupled with known chemical and biosynthetic methods for achieving such modifications, leads to a strong obviousness rejection under 35 U.S.C. § 103.