DETAILED ACTION
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 .
Status of the Claims
Claims 1 – 20 are pending.
Claims 1 – 15 are rejected.
Claims 16 – 20 are withdrawn.
Election/Restriction
Applicant’s election without traverse of Group I (claims 1 – 15) in the reply filed on June 22, 2026 is acknowledged. Applicant specifically elected compound 5a, 5-methyl-N- (2-methyl-5-(3-(4-methylpiperazin-1-yl)-5-(trifluoromethyl)benzamido)phenyl)isoxazole-3- carboxamide. Compound 5a is presented below:
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252
582
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.
The compound reads on the structure of Chemical Formula 1:
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114
242
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, wherein:
R1 and R3 are each hydrogen,
R2 is C1 alkyl (methyl),
X1 is carbon,
R4 is
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109
116
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,
R5 is -CF3, and
R6 is C4 heterocyclic (piperazinyl) ring.
Examination: The elected species is not allowable over the prior art. Claims 1 – 4 and 8 – 12 are withdrawn from further consideration pursuant to 37 CFR 1.142(b) as being drawn to a nonelected invention, there being no allowable generic or linking claim.
Priority
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90
362
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Acknowledgment is made of applicant's claim for foreign priority based on an application filed in Korea on November 24, 2021. It is noted, however, that applicant has not filed a certified copy of the KR 10-2021-0163159 application as required by 37 CFR 1.55.
Information Disclosure Statement
The information disclosure statement (IDS) submitted on March 1, 2024 is in compliance with the provisions of 37 CFR 1.97. Accordingly, the information disclosure statement is being considered by the examiner.
Claim Objections
Claims 1 – 8 are objected to because of the following informalities:
Claims 1 – 8: The phrase “…isoxazole derivative or a pharmaceutically acceptable salt thereof” in each of the claims is grammatically incorrect because it is missing proper punctuations. In order to overcome the objections, Applicant may amend to insert commas (,) in the phrase as follows: “…isoxazole derivative, or a pharmaceutically acceptable salt thereof,”.
Claim 4, line 1 of the claim: The term “tje” contains typographical error. The term should read as “the”.
Appropriate correction is required.
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 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.
Claims 1-15 are rejected under 35 U.S.C. 103 as being unpatentable over El-Gamal et al., Journal of Medicinal Chemistry, January 2, 2018, 64 pages, vol. 61, ACS Publications, Washington DC, cited in IDS dated March 1, 2024.
Determining the scope and contents of the prior art
El-Gamal et al. teach 4-arylamido-5-methylisoxazole derivatives. See, e.g., page 36, 2nd paragraph – page 39. El-Gamal specifically teach Compound 20a:
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160
340
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. See, e.g., Figure 7.
Compared to claim 1, the compound has a structure of Chemical Formula 1 as presented below:
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114
242
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, wherein:
R1 and R3 are each hydrogen,
R2 is C1 alkyl (methyl),
X1 is carbon,
R4 is
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109
116
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,
R5 is -CF3, and
R6 is C4 heterocyclic (piperazinyl) ring.
Ascertaining the differences between the prior art and the claims at issue
The difference between compound 20a and the claims is that the isoxazole ring is attached to the 4-position of the amide moiety in compound 20a instead of the 3-position as required in claim 1.
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Rationale for a prima facie case of obviousness
Compound 20a in El-Gamal et al. and the compound as claimed in the instant claims are considered positional isomers. It is well established that positional isomers are prima facie structurally obvious even in the absence of an explicit teaching to modify. The isomer is expected to be preparable by the same method and to have generally the same properties. This expectation is then deemed the motivation for preparing the positional isomers. MPEP 2144.09(II) states “Compounds which are position isomers (compounds having the same radicals in physically different positions on the same nucleus) … are generally of sufficiently close structural similarity that there is a presumed expectation that such compounds possess similar properties”. For example, “Position isomerism is a fact of close structural similarity which is to be taken into consideration …”. See, In re Mehta, 52 CCPA 1615, 146 USPQ 284, 347 F.2d 859 (1965). Note also In re Deuel 34 USPQ2d 1210, 1214 which states, “Structural relationships may provide the requisite motivation or suggestion to modify known compounds to obtain new compounds.” See, also MPEP 2144.08(II)(A)(4)(c).
According to MPEP §2141(III), one of the rationales in the KSR decision states “(G) Some teaching, suggestion, or motivation in the prior art that would have led one of ordinary skill to modify the prior art reference or to combine prior art reference teachings to arrive at the claimed invention”. KSR, 550 U.S. at 418, 82 USPQ2d at 1396. El-Gamal teaches compound 20a is a highly potent and selective CSF-1R inhibitor. Compound 20a was tested in U937 (human histocystic lymphoma) and A375P (human melanoma) cells and showed excellent inhibitory effect on CSF-1R (IC50 = 9.95 nM in cell-free kinase assay). See, e.g., page 36, 1st paragraph – page 39. Thus, a person of ordinary skill in the art would have been motivated to make positional isomers of the compound 20a as taught by El-Gamal because the compound is a lead compound. The PHOSITA would have found it obvious to move the amide moiety from the 4-position to the neighboring 3-position of the isoxazole ring to optimize the pharmaceutical properties. The PHOSITA would have a reasonable expectation that the positional isomer of the compound 20a would successfully make pharmaceutical compositions comprising said compounds because similar pharmaceutical properties would have been expected from structurally similar compounds.
The prior art would have rendered the instant claims prima facie obvious as presented below:
Claims 1 – 3 directed to the compound of Chemical Formula 1:
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114
242
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, wherein:
R1 and R3 are each hydrogen,
R2 is C1 alkyl (methyl),
X1 is carbon,
R4 is
PNG
media_image3.png
109
116
media_image3.png
Greyscale
,
R5 is -CF3, and
R6 is C4 heterocyclic (piperazinyl) ring.
Claim 4, wherein the compound is 5-methyl-N- (2-methyl-5-(3-(4-methylpiperazin-1-yl)-5-(trifluoromethyl)benzamido)phenyl)isoxazole-3- carboxamide (5a).
Regarding claims 5 – 10 and 12 – 15, please note that the limitation “for preventing or treating a disease related to the colony-stimulating factor 1 receptor” is intended use limitation as governed by MPEP §2111.02(II). Intended use limitations are interpreted based on the structural limitations they impart to the invention. In this case, the intended use only requires the pharmaceutical composition comprising the compound for preventing or treating a disease related to the colony-stimulating factor 1 receptor, but does not impart any specific limitations to the structure. Based on the teachings of El-Gamal et al., the compound is a highly potent and selective CSF-1R inhibitor. Therefore, the pharmaceutical composition comprising compound 20a is capable of being effective for preventing or treating a disease related to the colony-stimulating factor 1 receptor.
Regarding claim 11, El-Gamal teaches that “microglial loss due to CSF-1R inhibition disrupted brain development… [m]any neurological disorders such as Alzheimer’s disease, Krabbe’s disease, Charcot-Marie-Tooth disease, glioma, and multiple sclerosis can be modulated by CSF-1R ligands and inhibitors”. See, e.g., bridging paragraph between pages 12 – 13.
Conclusion
Any inquiry concerning this communication or earlier communications from the examiner should be directed to Sagar Patel whose telephone number is (571)272-1317. The examiner can normally be reached Monday - Friday: 9am to 5pm EST.
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/Sagar Patel/Examiner, Art Unit 1626
/MATTHEW P COUGHLIN/Primary Examiner, Art Unit 1626
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