Notice of Pre-AIA or AIA Status
The present application, filed on or after March 16, 2013, is being examined under the first inventor to file provisions of the AIA .
DETAILED ACTION
Claims 7-9, 11-17 and 19-27 are pending and are under consideration in the instant office action.
Information Disclosure Statement
The information disclosure statement (IDS) submitted on 10/30/2023 and 3/5/2024 complies with the provisions of 37 CFR 1.97, 1.98 and MPEP § 609. Accordingly, it has been placed in the application file and the information therein has been considered as to the merits. See attached copy of the PTO-1449.
Priority
This application is a U.S. National Phase of International PCT Application No. PCT/CN2022/089419 filed on April 27, 2022, which claims priority to Chinese Application No. 202110468491.2 filed on April 28, 2021.
Claim Rejections - 35 USC § 103
The following is a quotation of 35 U.S.C. 103 which forms the basis for all obviousness rejections set forth in this Office action:
A patent for a claimed invention may not be obtained, notwithstanding that the claimed invention is not identically disclosed as set forth in section 102, if the differences between the claimed invention and the prior art are such that the claimed invention as a whole would have been obvious before the effective filing date of the claimed invention to a person having ordinary skill in the art to which the claimed invention pertains. Patentability shall not be negated by the manner in which the invention was made.
The factual inquiries set forth in Graham v. John Deere Co., 383 U.S. 1, 148 USPQ 459 (1966), that are applied for establishing a background for determining obviousness under 35 U.S.C. 103 are summarized as follows:
1. Determining the scope and contents of the prior art.
2. Ascertaining the differences between the prior art and the claims at issue.
3. Resolving the level of ordinary skill in the pertinent art.
4. Considering objective evidence present in the application indicating obviousness or nonobviousness.
This application currently names joint inventors. In considering patentability of the claims the examiner presumes that the subject matter of the various claims was commonly owned as of the effective filing date of the claimed invention(s) absent any evidence to the contrary. Applicant is advised of the obligation under 37 CFR 1.56 to point out the inventor and effective filing dates of each claim that was not commonly owned as of the effective filing date of the later invention in order for the examiner to consider the applicability of 35 U.S.C. 102(b)(2)(C) for any potential 35 U.S.C. 102(a)(2) prior art against the later invention.
Claims 7-9, 11-17 and 19-27 are rejected under 35 U.S.C. 103(a) as being unpatentable over by Su et al. (US 2023/0076435, priority date 10/29/2019 ) in view of Ando et al (Remington, 2000, 20th Edition, chapter 38, pages 704-712) and Callear (Thesis , “PREPARATION, CHARACTERISATION AND STRUCTURAL ASSESSMENT OF SALTS AND CO-CRYSTALS OF ORGANIC COMPOUNDS” University of Southampton, 2008, pages 1-222)
Instant claims are drawn to the acid salt according to claim 3, characterized in that formula (II) is further as shown in An acid salt of a compound of formula (III) or a stereoisomer thereof;
PNG
media_image1.png
185
443
media_image1.png
Greyscale
Wherein R₅ is selected from the group consisting of hydrogen, amino, C1-3 alkyl, C1- 3 alkoxy, C1-3 hydroxyalkyl, C3-8 cycloalkyl, phenyl, oxiranyl, thiiranyl, aziridinyl, oxetanyl, azetidinyl, thietanyl, tetrahydrofuryl, tetrahydrothienyl, furyl, thienyl, pyrrolyl, pyrazolyl, imidazolyl, oxazolyl, isoxazolyl, thiazolyl, isothiazolyl, pyridyl, pyridazinyl, pyrimidinyl, pyrazinyl, 1,3,5-triazinyl, benzofuryl, benzothienyl, indolyl, benzimidazolyl, indazolyl, benzoxazolyl, benzotriazolyl, quinolinyl and isoquinolyl, the amino, C1-3 alkyl, C1-3 alkoxy, C1-3 hydroxyalkyl, C3-8 cycloalkyl, phenyl, oxiranyl, thiiranyl, aziridinyl, oxetanyl, azetidinyl, thietanyl, tetrahydrofuryl, tetrahydrothienyl, furyl, thienyl, pyrrolyl, pyrazolyl, imidazolyl, oxazolyl, isoxazolyl, thiazolyl, isothiazolyl, pyridyl, pyridazinyl, pyrimidinyl, pyrazinyl, 1,3,5- triazinyl, benzofuryl, benzothienyl, indolyl, benzimidazolyl, indazolyl, benzoxazolyl, benzotriazolyl, quinolinyl and isoquinolyl are each optionally further substituted by one or more substituents selected from the group consisting of deuterium, halogen, hydroxy, cyano, oxo, C1-3 alkyl, C1-3 alkoxy and C1-3 hydroxyalkyl , wherein the acid in the acid salt is an inorganic acid or an organic acid; wherein, the inorganic acid is selected from the group consisting of hydrochloric acid, sulfuric acid, nitric acid, hydrobromic acid, hydrofluoric acid, hydroiodic acid and phosphoric acid; the organic acid is selected from the group consisting of 2,5-dihydroxybenzoic acid, 1-hydroxy-2-naphthoic acid, acetic acid, dichloroacetic acid, trichloroacetic acid, acetohydroxamic acid, adipic acid, benzenesulfonic acid, 4-chlorobenzenesulfonic acid, benzoic acid, 4-acetamidobenzoic acid, 4-aminobenzoic acid, decanoic acid, caproic acid, caprylic acid, cinnamic acid, citric acid, cyclamic acid, camphorsulfonic acid, aspartic acid, camphoric acid, gluconic acid, glucuronic acid, glutamic acid, isoascorbic acid, lactic acid, malic acid, mandelic acid, pyroglutamic acid, tartaric acid, dodecyl sulfuric acid, dibenzoyl tartaric acid, ethane-1,2-disulfonic acid, ethanesulfonic acid, formic acid, fumaric acid, galactonic acid, gentisic acid, glutaric acid, 2-ketoglutaric acid, glycolic acid, hippuric acid, isethionic acid, lactobionic acid, ascorbic acid, aspartic acid, lauric acid, camphoric acid, maleic acid, malonic acid, methanesulfonic acid, 1,5-naphthalenedisulfonic acid, naphthalene-2-sulfonic acid, nicotinic acid, oleic acid, orotic acid, oxalic acid, palmitic acid, embonic acid, propionic acid, salicylic acid, 4-aminosalicylic acid, decanedioic acid, stearic acid, succinic acid, thiocyanic acid, pamoic acid, methanoic acid, undecylenic acid, trifluoroacetic acid, benzenesulfonic acid, p-toluenesulfonic acid and L-malic acid;
Independent claim 16 is drawn to a method of preparing the acid salt claimed in claim 1
Su et al. discloses compound, the stereoisomer thereof or the pharmaceutically acceptable salt thereof according to claim 4, wherein the compound is as shown in formula (XII)
PNG
media_image2.png
128
306
media_image2.png
Greyscale
Wherein R₈ is selected from the group consisting of hydrogen, deuterium, halogen, amino, nitro, hydroxy, cyano, C1-6 alkyl, C₁-₆ deuterated alkyl, C1-6 haloalkyl, C1-6 hydroxyalkyl, C₁-₆ alkoxy, C1-6 haloalkoxy, C2-6 alkenyl, C2-6 alkynyl, C3-8 cycloalkyl, 3 to 8 membered heterocyclyl, C6-12 aryl and 5 to 12 membered heteroaryl, wherein the amino, C1-6 alkyl, C1-6 deuterated alkyl, C1-6 haloalkyl, C1-6 hydroxyalkyl, C1-6 alkoxy, C1-6 haloalkoxy, C2-6 alkenyl, C2-6 alkynyl, C3- 8 cycloalkyl, 3 to 8 membered heterocyclyl, C6-12 aryl and 5 to 12 membered heteroaryl are each optionally further substituted by one or more substituents selected from the group consisting of deuterium, halogen, amino, nitro, hydroxy, cyano, C1-6 alkyl, C1-6 deuterated alkyl, C1-6 haloalkyl, C1-6 hydroxyalkyl, C1-6 alkoxy, C1-6 haloalkoxy, C26 alkenyl, C26 alkynyl, C3-8 cycloalkyl, 3 to 8 membered heterocyclyl, C6-12 aryl and 5 to 12 membered heteroaryl and discloses the compounds instantly claimed in 9 (Claims 10-14). Su et al. discloses a method pf preparing the their inventive compounds, pharmaceutical composition comprising the same and their method of use in treating or preventing central nervous system disease or psychiatric disease (Claims 15-21)
Su et al while they disclose the salt form of their compounds, fails to specify the acid salts and also do not teach the crystal form of the compounds or their X-ray diffraction patterns.
However, Ando et al teach that the unionized (free) form of weak acids and bases of compounds may not be the ideal molecular form for preparation into a suitable active pharmaceutical ingredient (API) (p. 704, column 1, first full paragraph). Salts have different physical properties than their free forms. The process of salt selection explores whether a particular salt might have properties that are more appropriate for an API than its parent form. Table 38-2 lists common counter-acids and counter-bases (p. 704). Ando et al discloses that improving oral absorption by increasing the dissolution rate is often a goal of the salt expansion step (p. 704, column 2, second paragraph). Salts generally dissolve faster in water than their free forms because dissolution is enhanced by the rapid hydration of the ionized salt species with water (p. 704, column 2, second paragraph). Ando additionally teaches that for weak bases, salt-forming counter-acids can be used to alter an API’s solubility, hygroscopicity, stability and processing (page 705, right col., 4th paragraph). Ando et al Details the salt selection decision-making process which is a multi-tiered approach or a goal oriented approach (page 712). Ando et al further discloses crystal formation requirements, stating that crystalline solids make the most promising APIs and is special characteristic of a solid in which the molecules self-organize into regular repeating molecular patterns (page 705, under crystal formation requirements). They further disclose the single-crystal X-ray diffraction is the most definitive characterization tool because the exact relative locations of atoms in the molecular crystal can be determined (page 710, col.1, 3rd para).
Callear discloses that It is well documented that the properties of a drug can be altered by using various salt formers, and recently there has also been work involving the use of drugs in neutral solid forms known as co-crystals. Salt and co-crystal formation is usually achieved by combination of an API with a salt or co-crystal
former. Through the selection of an appropriate salt or co-crystal former the physicochemical, formulation, biopharmaceutical, and therapeutic properties of a drug can be altered without modifying its basic chemical structure. It is a relatively simple chemical manipulation; an estimated half of all the drug molecules used in medicinal therapy are administered as salts They disclose that the salt formation has become the ‘most commonly applied technique [for] increasing solubility and dissolution rate in drug product development.’7 Salt formation is also commonly employed for improving mechanical properties which affect the solid form processing properties ((page 15. Section 2.3).They also disclose that research into co-crystals has increased where they have been found to improve solubility, crystallinity and stability e.g. itraconazole20 and carbamazepine (page 16, 1st para). They also disclose that a salt of co-crystal formation can improve a desired property, a range of other properties will also be affected. An increase in melting point by maximizing or encouraging crystal symmetry (and hence an increase crystallinity) improves stability for easier formulation processing and storage, and the new form of the drug can also enhance desired physicochemical properties (page 16, para 2). Callear discloses selection of salt and co-crystal formers (section 2.3.1) and the different methods of crystallization of salts and co-crystals process (section 2.3.2) , They disclose using basic drugs or bases as the active pharmaceuticals and acids as the slat/co-crystal formers giving a table of various organic acids and Inorganic acids used in the process (section 2.6, 2.6.1). In Chapter 3, Callear details the analytical techniques used in crystallography, including the X-ray crystallography which is the study of crystals and their structure by means of the diffraction of X-rays by the regularly spaced atoms of crystalline materials. When an X-ray beam is directed at a crystalline sample, the atomic structure of the lattice causes the X-rays to be scattered in a defined manner creating a diffraction pattern. The electron density in the crystal may be deduced from this diffraction pattern, enabling an accurate molecular structure to be determined (page 34, section 3.2)
Accordingly, formation of acid salts and crystals and their characterization is very well known in the pharmaceutical arts and is often used in drug development. As such, it would have been obvious to one of ordinary skill in the art at the time of the invention to combine the teachings of Su et al., who discloses the specific compounds which is instantly claimed with the teachings of Ando et al and Callear regarding salt selection and formation of weak acids and bases of compounds as the API. Since Su et al explicitly teaches that the instantly claimed compounds or its salt have utility in treatment of CNS or psychiatric disease, one would have been motivated to combine the teachings in order to receive the expected benefit, as suggested by Ando et al and Callear, that salts generally dissolve faster in water than their free forms because dissolution is enhanced by the rapid hydration of the ionized salt species with water (p. 704, column 2, second paragraph), thereby improving oral absorption and the teaching of methods of co-crystal formation and analysis using X-ray diffraction studies to develop a specific form of the drug which provides a version with better solubility, better stability and more specific receptor binding ability and better physicochemical properties than the basic drug or amorphous drug, absence of evidence to the contrary. Furthermore, according to Pfizer v. Apotex (Fed. Cir. 2006-1261), in the case of a medicinal or pharmaceutical chemist developing an active agent for pharmaceutical use, “irrefutable evidence shows that a skilled chemist at the time would simply make known pharmaceutically-acceptable salts of whatever active ingredient with which he or she was working at the time.”
With regards to claims 12-13 which reads on the number of acids in the compounds, as the compounds of Su et al., for example compounds 7, 7A, 8, 8A, of claim 14 have two basic nitrogen atoms, it is implicitly discloses to the person of ordinary skill in the art that the pharmaceutically acceptable salts thereof would have one or two acid groups, absence of evidence to the contrary.
As such a person of ordinary skill in the art would be imbued with a reasonable expectation of success in creating the salt and crystal forms of the compounds taught by Su et al., with an abundance of art detailing creation of the salt and crystal forms of basic drugs with a goal to improve stability and other properties as taught by Ando et al and Callear.
Conclusion
Claims 7-9, 11-17 and 19-27 are rejected. No claims are allowed
Any inquiry concerning this communication or earlier communications from the examiner should be directed to SAVITHA RAO whose telephone number is (571)270-5315. The examiner can normally be reached on Mon-Fri 7 am to 4 pm..
If attempts to reach the examiner by telephone are unsuccessful, the examiner’s supervisor, Dierdre (Renee) Claytor can be reached on (571) 272-8394. The fax phone number for the organization where this application or proceeding is assigned is 571-273-8300.
Information regarding the status of an application may be obtained from the Patent Application Information Retrieval (PAIR) system. Status information for published applications may be obtained from either Private PAIR or Public PAIR. Status information for unpublished applications is available through Private PAIR only. For more information about the PAIR system, see http://pair-direct.uspto.gov. Should you have questions on access to the Private PAIR system, contact the Electronic Business Center (EBC) at 866-217-9197 (toll-free). If you would like assistance from a USPTO Customer Service Representative or access to the automated information system, call 800-786-9199 (IN USA OR CANADA) or 571-272-1000.
/SAVITHA M RAO/Primary Examiner, Art Unit 1691