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 1-29 are pending in the instant application and subject to examination herein.
Information Disclosure Statement
The information disclosure statement (IDS) submitted on 09/30/2024 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 3-4 are objected to because of the following informalities: The words “heteroaryl” and “polyheteroaryl” have been misspelled as “hetroaryl” and “polyhetroaryl”, respectively. Appropriate correction is required.
Claim Rejections - 35 USC § 112(b)
The following is a quotation of 35 U.S.C. 112(b):
(b) CONCLUSION.—The specification shall conclude with one or more claims particularly pointing out and distinctly claiming the subject matter which the inventor or a joint inventor regards as the invention.
The following is a quotation of 35 U.S.C. 112 (pre-AIA ), second paragraph:
The specification shall conclude with one or more claims particularly pointing out and distinctly claiming the subject matter which the applicant regards as his invention.
Claims 1-9, 11-20, 22-26 and 29 are rejected under 35 U.S.C. 112(b) or 35 U.S.C. 112 (pre-AIA ), second paragraph, as being indefinite for failing to particularly point out and distinctly claim the subject matter which the inventor or a joint inventor (or for applications subject to pre-AIA 35 U.S.C. 112, the applicant), regards as the invention.
Claims 1 and 20 are each drawn to a method, and each method requires a compound of a structural genus, the structural requirements being a core structure of Formula 1 that describes a piperazinyl-tetrahydro-6-methylpyrido-pyrimidine with R1 and R2 substituents, and includes a structural limitation coded in functional language: “such that the compound inhibits biological functionality of KIF15”. Thus, the genus of compounds is limited to those structures that achieve the required function; however, neither claim 1 nor claim 20 further elaborates what is/are the structural limitation(s) that further limit the genus of compounds to satisfy the required function of inhibiting biological functionality of KIF15.
The instant Specification discloses that specific compounds of the instant invention were discovered by a series of high throughput screens of compound libraries, with an initial “AlphaScreen” of ~200K compounds (paragraph [00102]) that identified three compounds as hits: these compounds are alternately identified as compounds A1, A2 and B1 or as compounds 10, 21 and 14, respectively (paragraph [0067]). Then a second screen of 191,852 compounds identified further compounds (paragraphs [0090] and [00106]). Compounds that were identified through one or both of these screens are assigned an HTS code, shown in Table 1 (page 49) along with their potency as KIF15 inhibitors and counterscreen inhibitions (to eliminate false positives), as well as results of a magnetic resonance assay for protein-protein interaction. In the list of 20 compounds shown in Table 1, four compounds are included, those being compounds 16, 17, 19 and 20, for which no HTS code is supplied, no KIF15-TX2 binding inhibition assay or counterscreen assay data is provided, and no magnetic resonance assay data is provided – for these four compounds, no evidence is provided to disclose that they “inhibit biological functionality of KIF15”, and no principles of structure-activity relationship or binding site geometry(s) are discussed anywhere in the Specification to explain why a person of ordinary skill in the art would expect a compound that otherwise complies with the chemical structure requirements of claims 1 and/or 20 to also fulfill or not fulfill the functional requirement of being a compound that “inhibits the biological functionality of KIF15”. Thus, a person of ordinary skill in the arts could not at once envisage the metes and bounds of either claim 1 or claim 20 from the claim(s) language or the supporting disclosure. All that can be discerned is that the instantly disclosed compounds 1-15, 18 and 21 meet the structural and functional requirements of claims 1 and 20. Whether any additional compounds meet the requirements of these claims is uncertain.
A search of the field of art of KIF15 inhibitors does not find any other report on any compounds similar to those of the instant invention as KIF15 inhibitors, thus the prior art does not shed light on whether all compounds within the structural limitations of instant Formula 1 or only some compounds within the structural limitations of instant Formula 1 can fulfill the functional requirements of claims 1 and/or 20. Exemplary reports on studies of other KIF15 inhibitor compounds include the study of dihyropyrazole and dihyrdropyrrole compounds by Sebastian (Sebastian, J.; Computational Biology and Chemistry, v68, pp164-174; 2017) and the study of oxindole and quinazelinedione compounds by Dumas (Dumas, M.E., et al.; Bioorganic & Medicinal Chemistry Letters, v29, pp148-154; 2019)1. The structures of these compound classes are shown below. The prior art teaches an array of disparate structures that bind KIF15 and thus does not shed light on how a person of ordinary skill in the art would differentiate between those compounds of instant Formula 1 that do or do not fulfill the functional requirements being a compound that “inhibits the biological functionality of KIF15”.
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(Dihydropyrazole and dihydropyrrole compounds taught by Sebastian)
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(oxoindole compounds (left) and quinazolinedione compound (right) taught by Dumas)
Claims 1-9 and 11-20 depend from claim 1 and do not resolve the indefiniteness of the functional requirement of being a compound that “inhibits the biological functionality of KIF15”. Specifically, while claim 9 limits the genus of Formula 1 to a Markush group of compounds disclosed in the instant Specification, it includes compounds 16-17 and 19-20 that, as discussed above, are uncharacterized by any assay to evaluate their behavior as potential inhibitors of KIF15 biological activity. Claims 22-26 depend from claim 20 and do not resolve the indefiniteness of the functional requirement of being a compound that “inhibits the biological functionality of KIF15”. Specifically, while claim 26 limits the genus of Formula 1 to a Markush group of compounds disclosed in the instant Specification, it includes compounds 16-17 and 19-20 that, as discussed above, are uncharacterized by any assay to evaluate their behavior as potential inhibitors of KIF15 biological functionality.
Claim 20 is further indefinite because claim 20 is drawn to a method of treatment for which the patient population is indeterminate, as the claim does not specify or identify the subject to be treated. Claims 22-26 depend from claim 20 and do not resolve the indefiniteness of the indeterminate patient population.
Claim 20 is further indefinite because claim 20 is drawn to a method for which no step(s) is/are provided to be performed in the method. Claims 21 and 23-27 depend from claim 20 and also do not further provide any step(s) to be performed in the claimed method.
Claim 29 is indefinite because claim 29 is drawn to a method for which no step(s) is/are provided to be performed in the method.
Claim Rejections - 35 USC § 102
The following is a quotation of the appropriate paragraphs of 35 U.S.C. 102 that form the basis for the rejections under this section made in this Office action:
A person shall be entitled to a patent unless –
(a)(1) the claimed invention was patented, described in a printed publication, or in public use, on sale, or otherwise available to the public before the effective filing date of the claimed invention.
(a)(2) the claimed invention was described in a patent issued under section 151, or in an application for patent published or deemed published under section 122(b), in which the patent or application, as the case may be, names another inventor and was effectively filed before the effective filing date of the claimed invention.
Claims 20 and 23-27 are anticipated by Sayedyahossein.
Claims 20 and 23-27 are rejected under 35 U.S.C. 102(a)(1) as being anticipated by Sayedyahossein (Sayedyahossein, S., et al.; Scientific Reports, v12, article 17372, pp1-15; 2022).
Claim 20 is drawn to method of treating a cancer or neoplasm, comprising inhibiting biological functionality of KIF15 in the subject with a compound comprising a structure of Formula 1 (shown below), a genus of piperazinyl-tetrahydro-6-methylpyrido-pyrimidine compounds bearing R1 and R2 substituents as further defined in the claim, and “such that the compound inhibits biological functionality of KIF15”. While claim 20 does not elaborate on what further structural limitation provides for the functional limitation of inhibiting the biological functionality of KIF15 (as discussed in the rejection above), dependent claim 26 does further limit claim 20 to a Markush group of specific compounds.
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(instant Formula 1 as claimed in instant claim 20)
Sayedyahossein teaches a study in the disruption of protein-protein interaction between Cdc42, a small GTPase, and IQGAP, a scaffold protein, with the motivation that this interaction enhances migration and invasion of cancer cells (Abstract, page 1). Sayedyahossein screened 78,500 compounds to identify small molecules that can disrupt the IQGAP1-Cdc42 interaction, and selected 44 compounds for further screening, leading to a final set of four compounds, including one compound that is included in the Markush group of instant claim 26, which is Sayedyahossein’s compound “NCGC00131308”2 and corresponds to instant compound 18, shown below:
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(NCGC00131308 / instant compound 18)
Sayedyahossein teaches that NCGC00131308 showed a dose-dependent inhibitory effect on proliferation of MCF7 and MDA-MB-231 cancer cell lines (page 5 and page 7/Figures 5a-b), as well as a dose-dependent inhibition of the cell mobility of MDA-MB-231 cancer cells in a scratch wound assay (page 5 and page 7/Figure 5c). Sayedyahossein further teaches that NCGC00131308 abrogated the expected increase in Cdc42 that would be otherwise expected in serum-starved MDA-MB-231 cells treated with Epidermal Growth Factor (EGF) (page 6 and page 8/Figures 6b, 6d) and that NCGC00131308 significantly decreased the length, area and number of filopodia/cell of MDA-MB-231 cancer cells (page 6 and page 8/Figure 6f).
Thus, claims 20 and 26 are anticipated by the teaching of Sayedyahossein.
Claims 22-25 further limit claim 20, each to a narrower structural genus of compounds that continues to include in its scope the structure of instant compound 18, corresponding to Sayedyahossein’s compound NCGC00131308.
Claim 27 further limits claim 26 to a narrower Markush group of specific compound that continues to include instant compound 18, corresponding to Sayedyahossein’s compound NCGC00131308.
Thus, claims 22-25 and 27 are anticipated by the teaching of Sayedyahossein.
Claims Free of the Prior Art
Claim 28 is allowed. Prior art does not teach or suggest, alone or in combination, a method of inhibiting KIF15 comprising administering to the KIF15 a compound of the structure of instant compound 14/B1 or a stereoisomeric form or a mixture of stereoisomeric forms, prodrugs, or pharmaceutically acceptable salts of the compound.
Claims 10 and 21 are objected to as being dependent upon a rejected base claim, but would be allowable if rewritten in independent form including all of the limitations of the base claim and any intervening claims.
Conclusion
Any inquiry concerning this communication or earlier communications from the examiner should be directed to W. JUSTIN YOUNGBLOOD whose telephone number is (703)756-5979. The examiner can normally be reached on Monday-Thursday from 8am to 5pm. The examiner can also be reached on alternate Fridays.
If attempts to reach the examiner by telephone are unsuccessful, the examiner’s supervisor, Jeffrey S. Lundgren, can be reached at telephone number (571) 272-5541. The fax phone number for the organization where this application or proceeding is assigned is 571-273-8300.
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/W.J.Y./Examiner, Art Unit 1629
/JEFFREY S LUNDGREN/Supervisory Patent Examiner, Art Unit 1629
1 Cited in Applicant’s Information Disclosure Statement dated 09/30/2024.
2 6-((4-bromothiophen-2-yl) methyl)-2-(4-ethylpiperazin-1-yl)-5,6,7,8-tetrahydropyrido[4,3-d]pyrimidine
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