Obviousness

Obviousness Analysis of US Patent 11,623,920 under 35 U.S.C. § 103

This analysis addresses the obviousness of US Patent 11,623,920 under 35 U.S.C. § 103, focusing on Independent Claim 1, which defines a specific crystalline form of pitolisant hydrochloride. For an invention to be obvious, a person having ordinary skill in the art (PHOSITA) would have been motivated to combine prior art references with a reasonable expectation of success, leading to the claimed invention.

Independent Claim 1 of US Patent 11,623,920

Independent Claim 1 protects pitolisant hydrochloride sesquihydrate, characterized by specific Powder X-ray Diffraction (PXRD) peaks at 5.3, 7.3, 10.0, 11.8, and 26.1 ±0.2° two-theta. This form is a hydrate, meaning it incorporates 1.5 molecules of water per molecule of pitolisant hydrochloride. The patent indicates this sesquihydrate has a water content of about 7.7% w/w. [cite: "One aspect relates to pitolisant hydrochloride of Formula-(II), where x is 1.5. For this aspect, the pitolisant hydrochloride of Formula-(II) (viz., pitolisant hydrochloride sesquihydrate) has a water content of about 7.7% w/w."]

Prior Art References and Their Disclosures

The relevant prior art references disclosed within US11623920B2 for this analysis include:

1. Schwartz: Discloses a process for preparing pitolisant and its pharmaceutically acceptable salts, including pitolisant hydrochloride. [cite: "Schwartz discloses a process for preparing pitolisant and its pharmaceutically acceptable salts such as hydrochloride, hydrobromide, hydrogen maleate, and hydrogen oxalate."] This establishes that pitolisant hydrochloride itself is a known compound.
2. Meier: Discloses a three-step process for preparing pitolisant hydrochloride, reacting pitolisant (1) with gaseous hydrochloric acid to obtain pitolisant hydrochloride. [cite: "Meier discloses a three step process for preparing pitolisant hydrochloride starting with piperidine and 3-chloropropanol, to give the intermediate 3-(piperidin-1-yl)propan-1-ol (2), which is reacted with 3-(4-chlorophenyl)propyl methanesulfonate (3) in the presence of sodium hydride and 15-crown-5 to give pitolisant (1) which is finally reacted with gaseous hydrochloric acid to obtain pitolisant hydrochloride, as shown in Scheme-1."] This further confirms the existence and a method of preparing pitolisant hydrochloride.
3. Raga: Discloses "a crystalline form of pitolisant monohydrochloride having a moisture content of 2.7 to 6.5% and its preparation thereof." [cite: "Raga discloses a crystalline form of pitolisant monohydrochloride having a moisture content of 2.7 to 6.5% and its preparation thereof."] This is highly relevant as it teaches the existence of a crystalline form of pitolisant hydrochloride that contains moisture, strongly suggesting a hydrated form. The term "monohydrochloride" refers to the salt form (one HCl molecule), not necessarily a monohydrate. Given the molecular weight of pitolisant hydrochloride (~351.94 g/mol), a moisture content of 2.7% corresponds to approximately 0.53 moles of water, while 6.5% corresponds to approximately 1.27 moles of water. This range covers various hydrate possibilities, including hemihydrates, monohydrates, and potentially mixtures thereof. Raga also notes that pitolisant hydrochloride exhibits different properties (e.g., aqueous solubility and stability) compared to other salts. [cite: "Raga discloses that pitolisant hydrochloride exhibits different properties (e.g., aqueous solubility and stability) when compared to pitolisant oxalate and pitolisant maleate."]

Combination of Prior Art References and Motivation

A PHOSITA in the pharmaceutical field would be motivated to investigate and characterize different solid-state forms of known active pharmaceutical ingredients (APIs), such as pitolisant hydrochloride, for several reasons, including improving physicochemical properties (e.g., stability, solubility, dissolution rate, bioavailability), enhancing manufacturability, and extending intellectual property protection. The patent itself lists "to provide new solid-state forms of pitolisant and its pharmaceutically acceptable salts" as an objective. [cite: "Another objective of the present disclosure is to provide new solid-state forms of pitolisant and its pharmaceutically acceptable salts."]

The combination of Schwartz or Meier (establishing the known nature of pitolisant hydrochloride [cite: "Schwartz discloses a process for preparing pitolisant and its pharmaceutically acceptable salts such as hydrochloride...", "Meier discloses a three step process for preparing pitolisant hydrochloride... to obtain pitolisant hydrochloride"]) with Raga (teaching a crystalline form of pitolisant monohydrochloride with a moisture content of 2.7 to 6.5% [cite: "Raga discloses a crystalline form of pitolisant monohydrochloride having a moisture content of 2.7 to 6.5% and its preparation thereof."]) would lead a PHOSITA to explore various hydrated forms of pitolisant hydrochloride. Raga's explicit disclosure of moisture content in a crystalline form directly points towards the existence and relevance of hydrates.

A PHOSITA would routinely screen for different hydration states of an API, using conventional methods such as recrystallization from aqueous or mixed aqueous/organic solvents, controlled humidity studies, and varying drying conditions. The patent itself describes a method for preparing hydrate forms of pitolisant hydrochloride by dissolving it in water or a water/organic solvent mixture, followed by solvent removal through techniques like evaporation, spray drying, or freeze drying. [cite: "In one more embodiment of the present disclosure provides a method for preparing hydrate forms of pitolisant hydrochloride by dissolving pitolisant hydrochloride of Formula-(I) in water or mixture of water and organic solvent, optionally treating with carbon, filtering and precipitating the solid by adding solvent in which pitolisant hydrochloride is not soluble.", "In one more embodiment of the present disclosure provides a method for preparing a pitolisant hydrochloride hydrate form comprising a) providing a solution on pitolisant hydrochloride b) removing solvent from the reaction mass to obtain solid wherein the removal of solvent from the reaction mass is carried out by evaporation, spray drying, air drying, freeze drying, etc."] For instance, Example 12 describes preparing pitolisant hydrochloride sesquihydrate by simply spray drying an aqueous solution of pitolisant hydrochloride. [cite: "10 g of pitolisant hydrochloride was dissolved in 100 mL water, the obtained solution was filtered and the filtrate was spray dried to obtain pitolisant hydrochloride sesquihydrate."] This demonstrates the use of a conventional technique to obtain the claimed form.

Given Raga's disclosure of a crystalline form with moisture (2.7-6.5% w/w), which is close to or overlapping with the theoretical water content for a sesquihydrate (~7.13% w/w) and the patent's disclosed 7.7% w/w, the discovery of a pitolisant hydrochloride sesquihydrate would be a predictable outcome of routine experimentation by a PHOSITA. The specific PXRD peaks, while characterizing the claimed form, represent a routine characterization of a discovered hydrate rather than an unexpected structural discovery. Without evidence of unexpected advantageous properties of the sesquihydrate over other known or readily discoverable hydrated forms (e.g., Raga's crystalline form), merely identifying a new PXRD pattern for a predictable hydrate would not overcome an obviousness challenge. The patent does not present evidence of such unexpected properties for the sesquihydrate specifically.

Conclusion

Independent Claim 1 of US Patent 11,623,920, claiming pitolisant hydrochloride sesquihydrate characterized by specific PXRD peaks, would likely be considered obvious under 35 U.S.C. § 103. This is based on the combination of prior art references Schwartz and/or Meier (teaching the known compound pitolisant hydrochloride [cite: "Schwartz discloses a process for preparing pitolisant and its pharmaceutically acceptable salts such as hydrochloride...", "Meier discloses a three step process for preparing pitolisant hydrochloride... to obtain pitolisant hydrochloride"]) with Raga (teaching a crystalline form of pitolisant monohydrochloride with a moisture content of 2.7 to 6.5% [cite: "Raga discloses a crystalline form of pitolisant monohydrochloride having a moisture content of 2.7 to 6.5% and its preparation thereof."]). A PHOSITA would be motivated to investigate and characterize various hydrated forms of pitolisant hydrochloride, and discovering the sesquihydrate through conventional methods would be a predictable result of such routine experimentation, especially since Raga's disclosure already points to hydrated forms.