FINAL REJECTION
Receipt is acknowledged of Applicants' Amendments and Remarks, filed Apr. 20, 2026.
Rejections and/or objections not reiterated from previous Office Actions are hereby withdrawn. The rejections and/or objections set forth below are either maintained or newly applied, and constitute the complete set presently applied to the instant claims.
STATUS OF THE CLAIMS
Claims 2-10, 12-15, 17-20, 22, 23, 25-27, 29, and 32-54 have been canceled.
Claim 1 has been amended and incorporates no new matter.
No new claims have been added.
Claims 16, 24, 30, 31, and 61-65 stand withdrawn as drawn to nonelected inventions and/or species.
Thus, claims 1, 11, 21, 28, 55-60, and 66 now represent all claims currently pending and under consideration.
INFORMATION DISCLOSURE STATEMENT
The information disclosure statement (IDS) submitted on Apr. 20, 2026 was filed after the mailing date of the non-final action on Jan. 23, 2026. The submission is in compliance with the provisions of 37 CFR 1.97. Accordingly, the information disclosure statement is being considered by the examiner.
MAINTAINED REJECTIONS
Claim Rejections – 35 U.S.C. § 103
Claims 1, 11, 21, 28, 55-60, and 66 stand rejected under U.S.C. 103 as being unpatentable over Wang et al. (US Pub. 2022/0324868, of record) in view of Ledermann et al. (Eur. J. Cancer 60, pp. 49-58 (2016), of record).
Wang et al. claim methods for treating or preventing cancer comprising administering to a patient a therapeutically effective amount of a combination comprising substance X and an anticancer drug, wherein substance X is a compound of formula (I) or a pharmaceutically acceptable salt or solvate thereof (claims 18 and 25).
Compounds of formula (I) of Wang et al. include compound I-16 (claim 11), shown side-by-side for comparison with the claimed compound:
Compound of claim 1 (azenosertib)
Compound I-16 of Wang et al.
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Wang et al. disclose that the cancer to be treated includes the elected disease, ovarian cancer (paras. [0522]-[0531]; [0550]-[0555]; [0569]), as recited by claims 1, 11, 21, and 66.
Wang et al. disclose that suitable anticancer drugs to be administered in combination with compounds of formula (I) include the elected chemotherapeutic agent, paclitaxel (paras. [0540], [0560], [0574], [0594]), as recited by claims 1, 59, 60, and 66.
Wang et al. differs from the instant claims only in that compound I-16 bears a 7-methyl substituent rather than a 7-ethyl group.
However, it would have been predictable to one of ordinary skill in the art as of the filing date to modify compound I-16 of Wang et al. by exchanging methyl for ethyl with a reasonable expectation of success, because the claimed compound is a homologous form of compound (I-16) of Wang et al.
As recognized by MPEP § 2144.09, homologous compounds which differ by the successive addition of the same functional group (e.g., CH2) are generally of sufficiently close structural similarity that there is a presumed expectation that such compounds possess similar properties. See In re Wilder, 563 F.2d 457, 195 USPQ 426 (CCPA 1977).
A homologous form of the prior art compound is unpatentable unless it possesses some unexpected advantage or property not possessed by the prior art compound.
“[N]ovel members of a homologous series of chemical compounds must possess some unobvious or unexpected beneficial properties not possessed by a homologous compound disclosed in the prior art.” We stated that novelty alone, without invention, is not sufficient to lend patentability to a claim. . . . [C]hemists understand that members of a homologous series of chemical compounds possess the same principal characteristics which vary gradually from member to member, and that knowing the chemical and physical properties of one of the members suggests the properties of the other members.” In re Norris, 179 F.2d 970, 84 USPQ 458 (CCPA 1950).
In addition, where a prior art compound shares the same utility as those claimed, one of ordinary skill in the art would have a reasonable expectation that modifying the compound by the interchange of hydrogen and alkyl would yield compounds having similar properties. Hydrogen and methyl substitutions are known in the art and have been held to be obvious variants of each other. See MPEP § 2144.09 and In re Dillon, 919 F.2d 688, 16 USPQ2d 1897 (Fed. Cir. 1990).
Thus, Wang et al. disclose, teach, and suggest a method of treating ovarian cancer by administering an effective amount of compound (A) and an effective amount of compound (B) to a subject in need thereof, wherein compound (A) is the claimed compound, azenosertib, and compound (B) is paclitaxel, as recited by independent claim 1.
Regarding the dependent claims, the compounds of Wang et al. are disclosed as inhibitors of WEE1 kinase, which regulates the phosphorylation state of cyclin-dependent kinase 1 (CDK1), thus playing an important role in regulating DNA damage checkpoints. WEE1 is a key gene in G2/M phase block, and is overexpressed in some cancers. Since P53 mutation often exists in tumor cells, making the G1 checkpoint defective, the regulation of cell division cycle in P53-mutated cells depends on the G2/M checkpoint (paras. [0004]-[0005]).
In addition, Ledermann et al. disclose that around 70% of epithelial ovarian cancers (EOC) are high-grade serous adenocarcinomas, a defining feature of which is the presence of mutations within the tumor suppressor gene p53 (i.e., TP-53 mutated ovarian cancer). In addition, molecular analysis of high-grade serous ovarian cancer found that around half have aberrations in homologous recombination repair (HRR), a critical DNA damage response pathway. Several genetic lesions causing homologous recombination deficiency (HRD) include germline and somatic BRCA mutations as well as mutations of other genes (Introduction; Fig. 1).
Thus, Wang et al. and Ledermann et al. disclose, teach, and suggest that a majority of ovarian cancers are TP53-mutated ovarian cancers, as recited by claim 21; and/or are positive for homologous recombination deficiency (HRD), as recited by claim 28.
Wang et al. further disclose that the components in the combination can be used simultaneously or separately (e.g., sequentially). The components of the combination may be prepared as a single pharmaceutical composition for simultaneous use, or the components may be individually prepared as a single independent pharmaceutical composition (e.g., in kit form), which may be administered simultaneously or separately (e.g., sequentially) (paras. [0547]-[0548]), as recited by claims 55-58.
For the foregoing reasons, claims 1, 11, 21, 28, 55-60, and 66 would have been prima facie obvious under U.S.C. § 103 over Wang et al. in view of Ledermann et al.
Double Patenting
1. Claims 1, 11, 21, 28, 55-60, and 66 stand rejected on the ground of nonstatutory double patenting as being unpatentable over claims 16-23 of USPN 12,606,567 (previously
copending Application No. 18/004,628) in view of Wang et al. (US Pub. 2022/0324868) and Ledermann et al. (Eur. J. Cancer 60, pp. 49-58, 2016) (of record).
Reference claims 16-23 are drawn to methods of ameliorating or treating a malignant growth or tumor comprising administering an effective amount of a polymorphic form of azenosertib, or a pharmaceutically acceptable salt thereof, to a subject in need thereof, wherein the malignant growth or tumor is due to a cancer selected from, inter alia, ovarian cancer, uterine cancer, or osteosarcoma, as recited by examined claim 1.
The reference claims differ from the examined claims in that they do not recite administering azenosertib in combination with a chemotherapeutic agent, e.g., paclitaxel; or specify that the cancer is a TP53-mutated cancer, or is positive for homologous recombination deficiency (HRD).
Wang et al. claim methods for treating or preventing cancer comprising administering to a patient a therapeutically effective amount of a combination comprising a compound of formula (I) and an anticancer drug (claims 18 and 25).
The compounds of formula (I) of Wang et al. are disclosed as WEE1 inhibitors, including, e.g., compound I-16, which differs from azenosertib, as recited by reference claim 1 and examined claim 1, by only one methyl group, as shown below:
Azenosertib
Compound I-16 of Wang et al.
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Wang et al. disclose that the cancer to be treated includes ovarian cancer (paras. [0522]-[0531]; [0550]-[0555]; [0569]), as recited by examined claims 1, 11, 21, and 66.
The compounds of Wang et al. are disclosed as inhibitors of WEE1 kinase, which regulates the phosphorylation state of cyclin-dependent kinase 1 (CDK1), thus playing an important role in regulating DNA damage checkpoints. WEE1 is a key gene in G2/M phase
block, and is overexpressed in some cancers. Since P53 mutation often exists in tumor cells, making the G1 checkpoint defective, the regulation of cell division cycle in P53-mutated cells depends on the G2/M checkpoint (paras. [0004]-[0005]).
In addition, Ledermann et al. disclose that around 70% of epithelial ovarian cancers (EOC) are high-grade serous adenocarcinomas, a defining feature of which is the presence of mutations within the tumor suppressor gene p53 (i.e., TP-53 mutated ovarian cancer). In addition, molecular analysis of high-grade serous ovarian cancer found that around half have aberrations in homologous recombination repair (HRR), a critical DNA damage response pathway. Several genetic lesions causing homologous recombination deficiency (HRD) include germline and somatic BRCA mutations as well as mutations of other genes (Introduction; Fig. 1).
Thus, Wang et al. and Ledermann et al. disclose, teach, and suggest that a majority of ovarian cancers are TP53-mutated ovarian cancers, as recited by examined claim 21; and/or are positive for homologous recombination deficiency (HRD), as recited by examined claim 28.
Wang et al. disclose that suitable anticancer drugs to be administered in combination with compounds of formula (I) include, e.g., paclitaxel (paras. [0540], [0560], [0574], [0594]), as recited by examined claims 1, 59, 60, and 66.
Wang et al. further disclose that the components in the combination can be used simultaneously or separately (e.g., sequentially). The components of the combination may be prepared as a single pharmaceutical composition for simultaneous use, or the components may be individually prepared as a single independent pharmaceutical composition (e.g., in kit form), which may be administered simultaneously or separately (e.g., sequentially) (paras. [0547]-[0548]), as recited by examined claims 55-58.
Compound I-16 of Wang et al. differs from azenosertib only in that it bears a 7-methyl substituent rather than a 7-ethyl group.
However, it would have been predictable to one of ordinary skill in the art as of the filing date to modify the reference claims by administering azenosertib in combination with paclitaxel to treat ovarian cancer with a reasonable expectation of success, because Wang et al. disclose the treatment of ovarian cancer with compound I-16, a WEE1 inhibitor differing from azenosertib by only one methyl group, in combination with paclitaxel.
As recognized by MPEP §2144.06, “it is prima facie obvious to combine two compositions each of which is taught by the prior art to be useful for the same purpose, in order to form a third composition to be used for the very same purpose.... [T]he idea of combining them flows logically from their having been individually taught in the prior art." In re Kerkhoven, 626 F.2d 846, 850, 205 USPQ 1069, 1072 (CCPA 1980).
2. Claims 1, 11, 21, 28, 55-60, and 66 stand rejected on the ground of nonstatutory double patenting as being unpatentable over claims 1, 19-21, 26, and 27 of U.S. Patent No. 11/261,192 in view of Wang et al. (US Pub. 2022/0324868) and Ledermann et al. (Eur. J. Cancer 60, pp. 49-58, 2016) (of record).
The reference claims are drawn to methods for ameliorating or treating a cancer comprising administering to a subject an effective amount of a compound of formula (I), or a pharmaceutically acceptable salt thereof, wherein the cancer is selected from, inter alia, ovarian cancer; and the compound of formula (I) as recited by reference claims 26-27 is identical to compound (A) as recited by examined claim 1 (azenosertib).
The reference claims differ from the examined claims in that they do not recite administering azenosertib in combination with a chemotherapeutic agent, e.g., paclitaxel; or specify that the cancer is a TP53-mutated cancer, or is positive for homologous recombination deficiency (HRD).
Wang et al. claim methods for treating or preventing cancer comprising administering to a patient a therapeutically effective amount of a combination comprising a compound of formula (I) and an anticancer drug (claims 18 and 25).
The compounds of formula (I) of Wang et al. are disclosed as WEE1 inhibitors, including, e.g., compound I-16, which differs from azenosertib, as recited by reference claim 1 and examined claim 1, by only one methyl group, as shown below:
Azenosertib
Compound I-16 of Wang et al.
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Wang et al. disclose that the cancer to be treated includes ovarian cancer (paras. [0522]-[0531]; [0550]-[0555]; [0569]), as recited by examined claims 1, 11, 21, and 66.
The compounds of Wang et al. are disclosed as inhibitors of WEE1 kinase, which regulates the phosphorylation state of cyclin-dependent kinase 1 (CDK1), thus playing an important role in regulating DNA damage checkpoints. WEE1 is a key gene in G2/M phase
block, and is overexpressed in some cancers. Since P53 mutation often exists in tumor cells, making the G1 checkpoint defective, the regulation of cell division cycle in P53-mutated cells depends on the G2/M checkpoint (paras. [0004]-[0005]).
In addition, Ledermann et al. disclose that around 70% of epithelial ovarian cancers (EOC) are high-grade serous adenocarcinomas, a defining feature of which is the presence of mutations within the tumor suppressor gene p53 (i.e., TP-53 mutated ovarian cancer). In addition, molecular analysis of high-grade serous ovarian cancer found that around half have aberrations in homologous recombination repair (HRR), a critical DNA damage response pathway. Several genetic lesions causing homologous recombination deficiency (HRD) include germline and somatic BRCA mutations as well as mutations of other genes (Introduction; Fig. 1).
Thus, Wang et al. and Ledermann et al. disclose, teach, and suggest that a majority of ovarian cancers are TP53-mutated ovarian cancers, as recited by examined claim 21; and/or are positive for homologous recombination deficiency (HRD), as recited by examined claim 28.
Wang et al. disclose that suitable anticancer drugs to be administered in combination with compounds of formula (I) include, e.g., paclitaxel (paras. [0540], [0560], [0574], [0594]), as recited by examined claims 1, 59, 60, and 66.
Wang et al. further disclose that the components in the combination can be used simultaneously or separately (e.g., sequentially). The components of the combination may be prepared as a single pharmaceutical composition for simultaneous use, or the components may be individually prepared as a single independent pharmaceutical composition (e.g., in kit form), which may be administered simultaneously or separately (e.g., sequentially) (paras. [0547]-[0548]), as recited by examined claims 55-58.
Compound I-16 of Wang et al. differs from azenosertib only in that it bears a 7-methyl substituent rather than a 7-ethyl group.
It would have been predictable to one of ordinary skill in the art as of the filing date to modify the reference claims by administering azenosertib in combination with paclitaxel to treat ovarian cancer with a reasonable expectation of success, because Wang et al. disclose the treatment of ovarian cancer with compound I-16, a WEE1 inhibitor differing from azenosertib by only one methyl group, in combination with paclitaxel.
As recognized by MPEP §2144.06, “it is prima facie obvious to combine two compositions each of which is taught by the prior art to be useful for the same purpose, in order to form a third composition to be used for the very same purpose.... [T]he idea of combining them flows logically from their having been individually taught in the prior art." In re Kerkhoven, 626 F.2d 846, 850, 205 USPQ 1069, 1072 (CCPA 1980).
3. Claims 1, 11, 55-60, and 66 stand provisionally rejected on the ground of nonstatutory double patenting as being unpatentable over claims 1, 2, 6, 8, 9, 29-33, 37, 38, 42, 47, 49, 55, 57, and 58 of copending Application No. 19/201,378.
The reference claims are drawn to methods of treating cancer comprising administering to a subject in need thereof a daily dose of azenosertib, or a pharmaceutically acceptable salt thereof, at or greater than 350 mg, or an equivalent thereof, in accordance with an intermittent dosing cycle, further comprising administering a second therapeutic agent during the intermittent dosing cycle, wherein the second therapeutic agent, or a pharmaceutically acceptable salt thereof, is selected from, inter alia, paclitaxel, or a PARP inhibitor; and wherein the cancer is selected from, inter alia, ovarian cancer.
Thus, the reference claims read on and would anticipate the examined claims.
This is a provisional nonstatutory double patenting rejection because the patentably indistinct claims have not in fact been patented.
RESPONSE TO ARGUMENTS
Applicant's arguments filed Apr. 20, 2026 have been fully considered but they are not persuasive.
With regard to the rejections under U.S.C. § 103 over Wang et al. in view of Ledermann et al. and on the grounds of obviousness-type double patenting, Applicant contends that a case of prima facie obviousness has not been established because the Office Action improperly identifies Compound I-16 of Wang as a lead compound. Further or in the alternative, Applicant argues that one skilled in the art would have no reasonable expectation of success of modifying
Compound I-16 of Wang (Remarks, p. 5).
First, Applicant argues that selecting Compound I-16 of Wang as a lead compound is improper, because Wang discloses at least 43 compounds, 20 of which have an IC₅₀ more active against WEE1. Moreover, the Office Action does not provide any reason for one of ordinary skill in the art to select Compound I-16 instead of another compound, such as Compound I-19, which has an IC50 of 1.89 nM as compared to an IC50 of 3.99 nM for compound I-16 (Table 3), and thus is twice as active. Thus, because Compound I-16 was improperly selected as a lead compound, a case of prima facie obviousness has not been properly established (Remarks, p. 6).
Second, Applicant argues that Wang teaches away from modifying compound I-16 because replacing the hydrogen of compound I-1 with methyl decreased WEE1 activity:
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Table 3 of Wang discloses that compound I-16 has an IC50 of 3.99 nM, while Compound I-1 has an IC50 of 2.85 nM. Based on this data, adding an alkyl group to the same carbon that is substituted with -OH decreases WEE1 inhibitory activity. This teaches away from adding an alkyl substitution to the carbon already substituted with -OH. Rather, based on the data of Compounds I-16 and I-1, one skilled in the art would expect an even less active compound with the lengthening of the alkyl group. Accordingly, there is no reasonable expectation of success
(Remarks, pp. 6-7).
Applicant asserts that the PTO Examination Guidelines (75 FR 53643, September 1, 2010), Eisai Co. Ltd. v. Dr. Reddy's Laboratories, Inc., 533 F.3d 1353, 1359 (Fed. Cir. 2008), and Takeda Chem. Indus. v. Alphapharm Pty., Ltd., 492 F.3d 1350, 1359 (Fed. Cir. 2007) require the selection of a lead compound for modification. The Examination Guidelines specifically state that "there must be some reason for starting with that lead compound other than the mere fact that the 'lead compound' merely exists." Further, "in cases involving new chemical compounds, it remains necessary to identify some reason that would have led a chemist to modify a known compound in a particular manner to establish prima facie obviousness of a new claimed compound." Takeda at 1357. If there is "no discernable reason for a skilled artisan to begin with [the lead compound and modify it to obtain the] advantageous property," the claimed compound is not obvious (Remarks, pp. 5-6). However, after KSR Int'l Co. v. Teleflex Inc., 550 U.S. 398 (2007), there is no rigid requirement to identify a single lead compound or apply lead compound analysis in all cases where the prior art discloses a structurally similar compound. The more flexible KSR standard requires only that a person of ordinary skill in the art would have had a reason to modify the prior art compound, and would have had a reasonable expectation of success in doing so.
But even under lead compound analysis, the choice of compound (I-16) is reasonable, as it is an exemplified, potent member of the same scaffold that contains every other structure feature of the claimed compound (azenosertib). The fact that compound (I-16) is not the most potent of the compounds exemplified by Wang et al. does not teach away and would not have deterred a skilled artisan from homologation of a small alkyl group attached to a tertiary alcohol, which is a conservative change routinely explored by medicinal chemists. The structural similarity itself supplies the motivation to make the ethyl analog with a reasonable expectation of similar activity.
Further, the data presented in Wang et al. does not teach away from the claimed compound. The change in activity from hydrogen (compound I-1, IC50 of 2.85 nM) to methyl (compound I-16, IC50 of 3.99 nM) shows that the 7-position tolerates a small alkyl substituent while retaining nanomolar potency. Wang et al. do not disclose any alkyl substituent at the 7-position larger than methyl, or indicate any pattern wherein longer alkyl chains greatly reduce or abolish activity. Therefore, a skilled artisan would have reasonably expected the next homolog (ethyl) to remain active.
For the foregoing reasons, the rejections under U.S.C. § 103 over Wang et al. in view of Ledermann et al. and on the grounds of obviousness-type double patenting are maintained.
Citation of Additional Prior Art
Additional references made of record are considered pertinent to applicant's disclosure:
Zentalis Pharmaceuticals, News Release dated 12/18/2019; CAS Registry Record for 2376146-48-2 (a.k.a. azenosertib, ZN-c3); entry date 9/30/2019) (both cited on PTO-892).
CONCLUSION
No claims are allowed.
THIS ACTION IS MADE FINAL. Applicant is reminded of the extension of time policy as set forth in 37 CFR 1.136(a).
A shortened statutory period for reply to this final action is set to expire THREE MONTHS from the mailing date of this action. In the event a first reply is filed within TWO MONTHS of the mailing date of this final action and the advisory action is not mailed until after the end of the THREE-MONTH shortened statutory period, then the shortened statutory period will expire on the date the advisory action is mailed, and any nonprovisional extension fee (37 CFR 1.17(a)) pursuant to 37 CFR 1.136(a) will be calculated from the mailing date of the advisory action. In no event, however, will the statutory period for reply expire later than SIX MONTHS from the mailing date of this final action.
CORRESPONDENCE
Any inquiry concerning this communication or earlier communications from the examiner should be directed to SARA E. TOWNSLEY whose telephone number is 571-270-7672. The examiner can normally be reached on Mon-Fri from 10:00 am to 6:00 pm (EST). If attempts to reach the examiner by telephone are unsuccessful, the examiner's supervisor, Jeff S. Lundgren, can be reached at 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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/SARA E. TOWNSLEY/Examiner, Art Unit 1629
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