CTNF 18/575,098 CTNF 101747 DETAILED ACTION Notice of Pre-AIA or AIA Status 07-03-aia AIA 15-10-aia The present application, filed on or after March 16, 2013, is being examined under the first inventor to file provisions of the AIA. Information Disclosure Statement The information disclosure statement filed on December 28, 2023 is acknowledged and has been considered by the examiner. 06-49-06 AIA The listing of references in the specification is not a proper information disclosure statement. 37 CFR 1.98(b) requires a list of all patents, publications, or other information submitted for consideration by the Office, and MPEP § 609.04(a) states, "the list may not be incorporated into the specification but must be submitted in a separate paper." Therefore, unless the references have been cited by the examiner on form PTO-892, they have not been considered. Specification The abstract of the disclosure is objected to because it is too short in length (16 words). Applicant is reminded of the proper language and format for an abstract of the disclosure. The abstract should be in narrative form and generally be limited to a single paragraph on a separate sheet within the range of 50 to 150 words in length. The abstract should describe the disclosure sufficiently to assist readers in deciding whether there is a need for consulting the full patent text for details. A corrected abstract of the disclosure is required and must be presented on a separate sheet, apart from any other text. See MPEP § 608.01(b). Claim Objections 07-29-01 AIA Claim s 11, 12, and 13 are objected to because of the following informalities: In claim 11, the listing of possible Cg 1 and Cg 2 structures recites “C-“ in lines 9 and 15 of the claim. As this group is meant to link two moieties together, it should read as “-C-“ instead. In claim 12, the listing of possible Cg 3 and Cg 4 structures recites “C-“ in lines 10 and 16 of the claim. As this group is meant to link two moieties together, it should read as “-C-“ instead. In claim 13, the listing of possible Cg 3 and Cg 4 structures recites “C-“ in lines 8 and 14 of the claim. As this group is meant to link two moieties together, it should read as “-C-“ instead . Appropriate correction is required. 07-30-03-h AIA Claim Interpretation Claims 4, 18, and 19 require that the PARPi portion of the conjugate of claim 1 comprise a specific PARP inhibitor, such as olaparib or talazaporib. As linking another moiety to the PARPi will change the structure of the molecule (as the creation of a new bond will involve the breaking of at least one original bond), it is understood that the claimed conjugates will not retain the specifically recited PARP inhibitors in their complete original structures. In view of the disclosure as a whole, the examiner interprets these claims to mean that the conjugates comprise derivatives of the recited PARP inhibitors retaining the PARP-binding core of these molecules. Claim 7 requires the tumor targeting agent of the conjugate to be a single domain antibody fragment. In the specification, the applicant states that single domain antibody fragments are “also known as nanobodies and VHH antibodies” (pg. 14, lines 28-29). Therefore, art that teaches tumor targeting agents that are VHH antibodies or nanobodies will read on the limitation of single domain antibody fragment. Claim Rejections - 35 USC § 112(a) 07-30-01 AIA The following is a quotation of the first paragraph of 35 U.S.C. 112(a): (a) IN GENERAL.—The specification shall contain a written description of the invention, and of the manner and process of making and using it, in such full, clear, concise, and exact terms as to enable any person skilled in the art to which it pertains, or with which it is most nearly connected, to make and use the same, and shall set forth the best mode contemplated by the inventor or joint inventor of carrying out the invention. The following is a quotation of the first paragraph of pre-AIA 35 U.S.C. 112: The specification shall contain a written description of the invention, and of the manner and process of making and using it, in such full, clear, concise, and exact terms as to enable any person skilled in the art to which it pertains, or with which it is most nearly connected, to make and use the same, and shall set forth the best mode contemplated by the inventor of carrying out his invention. 07-31-01 Claims 11-13 are rejected under 35 U.S.C. 112(a) or 35 U.S.C. 112 (pre-AIA), first paragraph, as failing to comply with the written description requirement. The claims contains subject matter which was not described in the specification in such a way as to reasonably convey to one skilled in the relevant art that the inventor or a joint inventor, or for applications subject to pre-AIA 35 U.S.C. 112, the inventor(s), at the time the application was filed, had possession of the claimed invention. Claim 11 is drawn to a composition of the structure PARPi(Rd)-L-TTA in which the Rd has the structure Cg 1 -ArQ-Cg 2 . Claim 11 provides a wide scope of possible structures of the Cg subunits of the structure. While the disclosure provides examples and descriptions of PARPi(Rd)-L-TTA structures in which Rd is ArQ and the Cg groups are amides or esters in the final PARPi(Rd)-L-TTA structures, no examples or detailed descriptions are provided for Cg groups that are phenyl groups having two functional groups of any kind, maleimides, or succinimidyloxycarbonyl groups. The functional groups following “maleimide” (-OC(O)- through -C=N-N(R 1 )-) (lines 7-11) include and possess structural and chemical similarity to the taught amide and ester groups and are therefore supported in the written disclosure. Structures including maleimides and succinimidyloxycarbonyl groups are taught, but as intermediates in the synthesis process, not complete PARPi(Rd)-L-TTA structures, to which the claim is drawn. No embodiments are taught with Cg regions as phenyl groups and these large bulky groups are structurally distinct from the taught amides and esters. Therefore, there is insufficient written disclosure for Cg 1 -ArQ-Cg 2 structures in which the Cg groups are each independently a phenyl group having two functional groups, maleimides, or succinimidyloxycarbonyl groups. Claim 12 is drawn to a composition of the structure PARPi(Rd)-L-TTA in which the L has the structure ES 1 -SS-ES 2 and further in which ES 1 has the structure Cg 3 -SP- and ES 2 has the structure -SP-Cg 4 -. Claim 12 provides a wide scope of possible structures of the ES subunits of the structure. While the disclosure provides examples and descriptions of PARPi(Rd)-L-TTA structures in which L contains a disulfide and the ES groups comprise SP groups that are alkyl or mostly linear linkers and Cg groups that are amides or esters, no examples or detailed descriptions are provided for ES groups that contain Cg groups that are phenyl groups having two functional groups of any kind, maleimides, or succinimidyloxycarbonyl groups. The functional groups following “maleimide” (-OC(O)- through -C=N-N(R 1 )-) and before “or Cg 1 ” (lines 8-12) include and possess structural and chemical similarity to the taught amide and ester groups and are therefore supported in the written disclosure. Structures including maleimides and succinimidyloxycarbonyl groups are taught, but as intermediates in the synthesis process, not complete PARPi(Rd)-L-TTA structures, to which the claim is drawn. No embodiments are taught with Cg regions as phenyl groups and these large bulky groups are structurally distinct from the taught amides and esters. Therefore, there is insufficient written disclosure for disclosure for ES 1 -SS-ES 2 structures in which the ES groups comprise Cg groups that are each independently a phenyl group having two functional groups, maleimides, or succinimidyloxycarbonyl groups. Claim 13 is drawn to a composition of the structure PARPi(Rd)-L-TTA in which the L has the structure ES-ECL-SIG and further in which the ES group has the structure Cg 3 -SP-Cg 4 . Claim 13 provides a wide scope of possible structures of the Cg subunits of the structure. While the disclosure provides examples and descriptions of PARPi(Rd)-L-TTA structures in which L has an ES-ECL-SIG structure in which the ES groups comprise SP groups that are alkyl or mostly linear linkers and Cg groups that are amides or esters, no examples or detailed descriptions are provided for ES groups that contain Cg groups that are phenyl groups having two functional groups of any kind, maleimides, or succinimidyloxycarbonyl groups. The functional groups following “maleimide” (-OC(O)- through -C=N-N(R 1 )-) and before “or Cg 1 ” (lines 5-10) include and possess structural and chemical similarity to the taught amide and ester groups and are therefore supported in the written disclosure. Structures including maleimides and succinimidyloxycarbonyl groups are taught, but as intermediates in the synthesis process, not complete PARPi(Rd)-L-TTA structures, to which the claim is drawn. No embodiments are taught with Cg regions as phenyl groups and these large bulky groups are structurally distinct from the taught amides and esters. Therefore, there is insufficient written disclosure for disclosure for Cg 3 -SP-Cg 4 structures in which the Cg groups are each independently a phenyl group having two functional groups, maleimides, or succinimidyloxycarbonyl groups. Claim Rejections - 35 USC § 112(b) 07-30-02 AIA 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. 07-34-01 Claims 13 and 20-23 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. Claim 13 recites the limitation "the CL" in line 5 of page 5. There is insufficient antecedent basis for this limitation in the claim. The examiner interprets this phrase to refer to the term “ECL” previously recited within the same claim. For the purpose of examination, the examiner will interpret “the CL” to instead refer to “the ECL.” Claim 20 recites the limitation “the PARPi(Rd)-L” in line 1. There is insufficient antecedent basis for this limitation in the claim. This phrase is also not present in claim 1, from which claim 20 depends. In view of the specification, for the purpose of examination, the examiner will interpret claim 20 to depend from claim 2, as claim 2 includes the concept of a linker and recites that the conjugate has the structure PARPi(Rd)-L-TTA. Furthermore, even if claim 20 depends on claim 2, there is a further indefiniteness issue with defining the compound as PARPi(Rd)-L while depending on claim 2, which requires a conjugate of the formula PARPi(Rd)-L-TTA. The structure of formula (VI) does not contain a TTA group. Furthermore, this structure is taught to not be an embodiment of the PARPi(Rd)-L substructure region of a complete PARPi(Rd)-L-TTA structure. This structure possesses a p-nitrophenyl carbonate that acts as a leaving group to enable the conjugation of a TTA to a compound of formula (VI). Therefore, the claim is indefinite as it is unclear what a compound of formula (VI) is meant to represent. In view of the specification, the compound of formula (VI) will be interpreted for the purposes of examination to be a precursor in the synthesis of the full PARPi(Rd)-L-TTA structure. Claim 21 recites the limitation “the PARPi(Rd)-L” in line 1. There is insufficient antecedent basis for this limitation in the claim. This phrase is also not present in claim 1, from which claim 21 depends. In view of the specification, for the purpose of examination, the examiner will interpret claim 21 to depend from claim 2, as claim 2 includes the concept of a linker and recites that the conjugate has the structure PARPi(Rd)-L-TTA. Furthermore, even if claim 21 depends on claim 2, there is a further indefiniteness issue with defining the compound as PARPi(Rd)-L while depending on claim 2, which requires a conjugate of the formula PARPi(Rd)-L-TTA. The structure of formula (IX) does not contain a TTA group. Furthermore, this structure is taught to not be an embodiment of the PARPi(Rd)-L region of a complete PARPi(Rd)-L-TTA structure. This structure possesses a succinimidyloxycarbonyl group that acts as a leaving group to enable the conjugation of a TTA to a compound of formula (IX). Therefore, the claim is indefinite as it is unclear what a compound of formula (IX) is meant to represent. In view of the specification, the compound of formula (IX) will be interpreted for the purposes of examination to be a precursor in the synthesis of the full PARPi(Rd)-L-TTA structure. Claims 22 and 23 recite the limitation “the PARPi(Rd)-L” in line 1. There is insufficient antecedent basis for this limitation in the claims. This phrase is also not present in claim 1, from which claims 22 and 23 depend. In view of the specification, for the purpose of examination, the examiner will interpret claims 22 and 23 to depend from claim 2, as claim 2 includes the concept of a linker and recites that the conjugate has the structure PARPi(Rd)-L-TTA. The limitation “the PARPi(Rd)-L” is further interpreted to mean the PARPi(Rd)-L-TTA conjugate in these claims. Claim Rejections - 35 USC § 102 07-07-aia AIA 07-07 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 – 07-08-aia AIA (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. 07-12-aia AIA (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. 07-15 AIA Claim 24 is rejected under 35 U.S.C. 102( a)(1 ) as being anticipated by Ofori (Ofori, S. and Awuah, S.G., ACS Omega, 2019) . Ofori teaches the conjugation of an inhibitor of PARPi (a derivative of olaparib) and BMS-001, an inhibitor of PD-L1 (pg. 12586, Scheme 1). Ofori teaches three conjugates, which differ in the linker region chemistry (pg. 12858, Figure 1). The linkers connect the PARPi to the BMS-001 group. Ofori teaches that cancer cells may express PD-L1 (pg. 12588, left column, paragraph 5), thus, a PD-L1 inhibitor can be considered a tumor targeting agent. Therefore, conjugates 1, 2, and 3 of Ofori read on the instantly claimed structure of PARPi-L-TTA . Claim Rejections - 35 USC § 103 07-20-aia AIA 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. 07-23-aia AIA 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. 07-20-02-aia AIA 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. 07-21-aia AIA Claim s 1-4 and 18 are rejected under 35 U.S.C. 103 as being unpatentable over Ofori (Ofori, S. and Awuah, S.G., ACS Omega, 2019) in view of Jannetti (Jannetti, S.A.; et al, J. Nucl. Med., 2018) . As described above, Ofori teaches the conjugation of an inhibitor of PARPi (a derivative of olaparib) and BMS-001, an inhibitor of PD-L1 (pg. 12586, Scheme 1). Ofori teaches three conjugates, which differ in the linker region chemistry (pg. 12858, Figure 1). Ofori teaches that the parent molecule olaparib is a PARP-1 inhibitor (pg. 12586, left column, last paragraph) and that all the conjugates dock well into the catalytic domain of the PARP-1 protein (pg. 12589, left column, last paragraph). The linkers connect the PARPi to the BMS-001 group. Ofori teaches that cancer cells may express PD-L1 (pg. 12588, left column, paragraph 5), thus, a PD-L1 inhibitor can be considered a tumor targeting agent. As described above, the conjugates 1, 2, and 3 of Ofori read on the structure of PARPi-L-TTA. Ofori also teaches that compounds 1, 2, and 3 all display improved efficacy over olaparib or BMS-001 alone in killing MDA-MB-231 cancer cells (pg. 12588, Figure 3). Ofori does not teach a radiolabeled PARP inhibitor. Janetti teaches a 131 I-radiolabeled PARP-1 therapeutic molecule (pg. 1225, Abstract). Janetti teaches that the 131 I-radiolabeled PARP inhibitor effectively decreases tumor volume and increases survival compared to a non-radioactive control in a glioblastoma mouse model (pg. 1231, Figure 4). Jannetti also teaches that this radiolabeled PARP inhibitor specifically delivered radiation to tumor cells and not healthy tissue (pg. 1231, Figure 3 and pg. 1232, Figure 5). A person of ordinary skill in the art would have recognized that both Ofori and Jannetti teach olaparib-derived PARP-1 inhibitor molecules for the purpose of cancer treatment. It would be recognized that the radiolabel of Jannetti improved efficacy compared to the non-radiolabeled PARP inhibitor analog. It would also be understood that a practitioner in the art could simply substitute the 131 I-radiolabeled PARP-1 inhibitor of Jannetti into the PARP inhibitor portion of the conjugate of Ofori. Therefore, it would have been obvious to a person of ordinary skill in the art before the effective filing date of the claimed invention to modify the PD-L1-targeting PARP inhibiting conjugate of Ofori by a simple substitution to the 131 I-radiolabeled PARP-1 inhibitor of Jannetti in the PARP inhibiting portion of the conjugate (MPEP § 2143(I)(B)). This would result in the predictable result of a more effective PARP inhibiting conjugate that delivers more targeted radiation. Regarding claim 1 , as described above, the PD-L1-PARPi conjugates of Ofori possess a tumor targeting agent (PD-L1 inhibitor portion) coupled to a PARP inhibitor (pg. 12585, Figure 1). Furthermore, Jannetti teaches an 131 I-radiolabeled PARP inhibitor (pg. 1229, Figure 1A). Therefore, the combined teachings of Ofori and Jannetti render claim 1 obvious. Regarding claim 2 , Ofori teaches connecting the PARPi region and the TTA region (PD-L1 inhibitor) of the molecule through linkers: a bond in conjugate 1, an ethyl ester linkage in conjugate 2, and a PEG-based linkage in conjugate 3 (pg. 12586, Scheme 1). Thus, the conjugated of Ofori read on the formula PARPi-L-TTA. Jannetti teaches an 131I-radiolabeled PARP inhibitor (pg. 1229, Figure 1A) that reads on PARPi(Rd). Therefore, the combined teachings of Ofori and Jannetti render claim 2 obvious. Regarding claim 3 , Ofori teaches that the parent molecule olaparib is a PARP-1 inhibitor (pg. 12586, left column, last paragraph) and that all the conjugates dock well into the catalytic domain of the PARP-1 protein (pg. 12589, left column, last paragraph). Furthermore, Janetti teaches the 131 I-radiolabeled therapeutic molecule is a PARP-1 inhibitor (pg. 1225, Abstract). Therefore, the combined teachings of Ofori and Jannetti render claim 3 obvious. Regarding claims 4 and 18 , Ofori teaches that the parent molecule of the PD-L1-PARPi conjugates is olaparib (pg. 12585, Figure 1). Furthermore, the core PARP inhibiting portion of the radiolabeled PARP inhibitor of Jannetti is identical to that of Ofori (pg. 1229, Figure 1A) and is taught to have a binding profile akin to Olaparib and Olaparib-based imaging agents (pg. 1231, right column, paragraph 3). Thus, it is understood that the PARPi(Rd) conjugate taught by combining Ofori and Jannetti contains an olaparib derivative PARPi region. Therefore, the combined teachings of Ofori and Jannetti render claims 4 and 18 obvious . 07-21-aia AIA Claim 7 is rejected under 35 U.S.C. 103 as being unpatentable over Ofori in view of Jannetti, as applied to claims 1-4 and 18 above, further in view of Stenton (Stenton, B.J.; et al, Chem. Sci., 2018) . As described above, Ofori and Jannetti combine to teach the conjugate of claim 1 comprising a PARPi(Rd) region coupled to a TTA region. Ofori teaches the conjugation of an inhibitor of PARPi (a derivative of olaparib) and BMS-001, an inhibitor of PD-L1 (pg. 12586, Scheme 1). Ofori teaches that the parent molecule olaparib is a PARP-1 inhibitor (pg. 12586, left column, last paragraph) and that all the conjugates dock well into the catalytic domain of the PARP-1 protein (pg. 12589, left column, last paragraph). Ofori teaches that cancer cells may express PD-L1 (pg. 12588, left column, paragraph 5), thus, a PD-L1 inhibitor can be considered a tumor targeting agent. As described above, the conjugates 1, 2, and 3 of Ofori read on the structure of PARPi-L-TTA. Ofori also teaches that compounds 1, 2, and 3 all display improved efficacy over olaparib or BMS-001 alone in killing MDA-MB-231 cancer cells (pg. 12588, Figure 3). Furthermore, Janetti teaches a 131 I-radiolabeled PARP-1 therapeutic molecule (pg. 1225, Abstract). Janetti teaches that the 131 I-radiolabeled PARP inhibitor effectively decreases tumor volume in a glioblastoma mouse model (pg. 1231, Figure 4). The combination of Ofori and Jannetti fails to teach a TTA coupled PARPi(Rd) conjugate wherein the TTA is a single domain antibody fragment. Stetson teaches a TTA-coupled chemotherapeutic in the form of a nanobody conjugated to the anticancer drug doxorubicin (pg. 4185, Abstract and pg. 4188, Fig. 4). Stetson teaches that the 2Rb17c nanobody used is used to target the HER2 antigen, which is a tumor antigen, making the 2Rb17c nanobody a tumor targeting agent (pg. 4187, right column, second paragraph). Stetson teaches that the linker used to connect doxorubicin to the nanobody can be cleaved by the introduction of a palladium catalyst (pg. 4187, Fig. 3a). Stetson teaches that the anti-HER2 nanobody-doxorubicin conjugate is able to kill HER2+ cancer cells in the presence of the palladium catalyst as effectively as free doxorubicin (pg. 4188, Fig. 4d). A person of ordinary skill in the art would have recognized that Ofori, Jannetti, and Stetson teach different molecules for the purpose of cancer treatment. As described above, it would be understood that the 131 I-labeled olaparib derivative could be substituted into the PARPi-L-TTA conjugate of Ofori. In view of Stetson, it would be recognized that the 2Rb17c anti-HER2 nanobody is an alternative attractive TTA for cancer targeting. It would be recognized that while the conjugate of Stetson is not more potent than doxorubicin at killing cancer cells, the nanobody would enable a more targeted therapy, decreasing chemotherapeutic damage to non-cancerous cells, while maintaining similar potency at tumor cells. It would also be understood that a practitioner in the art could simply substitute the PD-L1 TTA and linker regions of the combined Jannetti-Ofori conjugate for the nanobody TTA and Pd cleavable linker regions of the compound 2Rb17c-16 taught by Stetson. Therefore, it would have been obvious to a person of ordinary skill in the art before the effective filing date of the claimed invention to modify the PD-L1-targeting, PARP-inhibiting, 131 I-radiolabeled conjugate of Ofori and Jannetti by a simple substitution to the 2Rb17c TTA and linker of Stetson in the TTA portion of the conjugate (MPEP § 2143(I)(B)). This would result in the predictable result of an effective PARP inhibiting conjugate that delivers the chemotherapeutic specifically to HER2+ tumor cells. Regarding claim 7 , as described above, the PD-L1-PARPi conjugates of Ofori possess a tumor targeting agent (PD-L1 inhibitor portion) coupled to a PARP inhibitor (pg. 12585, Figure 1). Additionally, Jannetti teaches an 131 I-radiolabeled PARP inhibitor (pg. 1229, Figure 1A), the combination of which with Ofori would result in a TTA coupled PARPi(Rd) conjugate. Furthermore, Stetson teaches a conjugate of the anticancer drug doxorubicin coupled to the HER2+ tumor targeting agent 2Rb17c nanobody (which reads on single domain antibody fragment – see Claim Interpretation) (pg. 4188, Fig. 4). Therefore, the combined teachings of Ofori, Jannetti, and Stetson render claim 7 obvious . 07-21-aia AIA Claim 8 is rejected under 35 U.S.C. 103 as being unpatentable over Ofori in view of Jannetti, as applied to claims 1-4 and 18 above, further in view of Ivanenkov (Ivanenkov, Y.A.; et al, Bioorg. Med. Chem. Lett., 2019) . As described above, Ofori and Jannetti combine to teach the conjugate of claim 1 comprising a PARPi(Rd) region coupled to a TTA region. Ofori teaches the conjugation of an inhibitor of PARPi (a derivative of olaparib) and BMS-001, an inhibitor of PD-L1 (pg. 12586, Scheme 1). Ofori teaches that the parent molecule olaparib is a PARP-1 inhibitor (pg. 12586, left column, last paragraph) and that all the conjugates dock well into the catalytic domain of the PARP-1 protein (pg. 12589, left column, last paragraph). Ofori teaches that cancer cells may express PD-L1 (pg. 12588, left column, paragraph 5), thus, a PD-L1 inhibitor can be considered a tumor targeting agent. As described above, the conjugates 1, 2, and 3 of Ofori read on the structure of PARPi-L-TTA. Ofori also teaches that compounds 1, 2, and 3 all display improved efficacy over olaparib or BMS-001 alone in killing MDA-MB-231 cancer cells (pg. 12588, Figure 3). Furthermore, Janetti teaches a 131 I-radiolabeled PARP-1 therapeutic molecule (pg. 1225, Abstract). Janetti teaches that the 131 I-radiolabeled PARP inhibitor effectively decreases tumor volume in a glioblastoma mouse model (pg. 1231, Figure 4). The combination of Ofori and Jannetti fails to teach a TTA coupled PARPi(Rd) conjugate wherein the TTA is a PSMA inhibitor/ligand. Ivanenkov teaches TTA-coupled chemotherapeutics in the form of a PSMA ligand linked to doxorubicin (pg. 1250, Scheme 4). Ivanenkov also teaches that PSMA is a highly attractive target for anticancer treatments because PSMA is abundantly expressed in prostate cancer compared to its expression in other cell types (pg. 1251, right column, last paragraph). Ivanenkov teaches that the linker of conjugate 34 (pg. 1250, Scheme 4) hydrolyzes under weakly acidic conditions (Figure S1), resulting in release of doxorubicin after cellular uptake, enabling good nuclear accumulation of the anticancer drug (pg. 1253, right column, first paragraph). A person of ordinary skill in the art would have recognized that Ofori, Jannetti, and Ivanenkov teach different molecules for the purpose of cancer treatment. As described above, it would be understood that the 131 I-labeled olaparib derivative could be substituted into the PARPi-L-TTA conjugate of Ofori. In view of Ivanenkov, it would be recognized that PSMA is an alternative attractive TTA for prostate cancer targeting and that the linker of compound 34 being able to be hydrolyzed enables release of an anticancer drug, allowing nuclear localization. It would also be understood that a practitioner in the art could simply substitute the PD-L1 TTA and linker regions of the combined Jannetti-Ofori conjugate for the PSMA TTA and hydrolyzable linker regions of the compound 34 taught by Ivanenkov. Therefore, it would have been obvious to a person of ordinary skill in the art before the effective filing date of the claimed invention to modify the PD-L1-targeting, PARP-inhibiting, 131 I-radiolabeled conjugate of Ofori and Jannetti by a simple substitution to the PSMA TTA and hydrolyzable linker of Ivanenkov in the TTA portion of the conjugate (MPEP § 2143(I)(B)). This would result in the predictable result of an effective PARP inhibiting conjugate that delivers the chemotherapeutic specifically to prostate cancer tumor cells and releases the PARPi(Rd) intracellularly. Regarding claim 8 , as described above, the PD-L1-PARPi conjugates of Ofori possess a tumor targeting agent (PD-L1 inhibitor portion) coupled to a PARP inhibitor (pg. 12585, Figure 1). Additionally, Jannetti teaches an 131 I-radiolabeled PARP inhibitor (pg. 1229, Figure 1A), the combination of which with Ofori would result in a TTA coupled PARPi(Rd) conjugate. Furthermore, Ivanenkov teaches a conjugate of the anticancer drug doxorubicin coupled to the prostate cancer tumor targeting agent PSMA ligand through a hydrolyzable linker (pg. 1250, Scheme 4). Therefore, the combined teachings of Ofori, Jannetti, and Ivanenkov render claim 8 obvious . 07-21-aia AIA Claim 9 is rejected under 35 U.S.C. 103 as being unpatentable over Ofori in view of Jannetti, as applied to claims 1-4 and 18 above, further in view of Pirovano (Pirovano, G.; et al, Clin. Cancer Res., 2020) . As described above, Ofori and Jannetti combine to teach the conjugate of claim 1 comprising a PARPi(Rd) region coupled to a TTA region. Ofori teaches the conjugation of an inhibitor of PARPi (a derivative of olaparib) and BMS-001, an inhibitor of PD-L1 (pg. 12586, Scheme 1). Ofori teaches that the parent molecule olaparib is a PARP-1 inhibitor (pg. 12586, left column, last paragraph) and that all the conjugates dock well into the catalytic domain of the PARP-1 protein (pg. 12589, left column, last paragraph). Ofori teaches that cancer cells may express PD-L1 (pg. 12588, left column, paragraph 5), thus, a PD-L1 inhibitor can be considered a tumor targeting agent. As described above, the conjugates 1, 2, and 3 of Ofori read on the structure of PARPi-L-TTA. Ofori also teaches that compounds 1, 2, and 3 all display improved efficacy over olaparib or BMS-001 alone in killing MDA-MB-231 cancer cells (pg. 12588, Figure 3). Furthermore, Janetti teaches a 131 I-radiolabeled PARP-1 therapeutic molecule (pg. 1225, Abstract). Janetti teaches that the 131 I-radiolabeled PARP inhibitor effectively decreases tumor volume in a glioblastoma mouse model (pg. 1231, Figure 4). The combination of Ofori and Jannetti fails to teach a TTA coupled PARPi(Rd) conjugate wherein the Rd comprises a radionuclide that emits short-range radiation and/or wherein the Rd decays by the emission of Auger electrons and/or alpha particles. Pirovano teaches a radioiodine-labeled derivative of olaparib (pg. 2872, Figure 1C). This molecule is identical to that of Jannetti except instead of being labeled with 131 I, it is labeled with 123 I, which is an Auger electron emitting isotope (pg. 2872, right column, first paragraph). Pirovano teaches that Auger emitting compounds possess the ability to cause complex, lethal DNA damage and act at a short range (pg. 2871, right column, last paragraph). A person of ordinary skill in the art would have recognized that Ofori, Jannetti, and Pirovano teach olaparib-based PARP inhibitor molecules for the purpose of cancer treatment. As described above, it would be understood that the 131 I-labeled olaparib derivative could be substituted into the PARPi-L-TTA conjugate of Ofori. It would also be recognized that the 123 I-radiolabeled olaparib derivative is an alternative PARPi(Rd) molecule and that it possesses useful radiotherapeutic properties. It would also be understood that a practitioner in the art could simply substitute the 131 I radiolabel of Jannetti in the combined Jannetti-Ofori conjugate for the 123 I radiolabel taught by Pirovano (or substitute the full analogous PARPi(Rd) structure). Therefore, it would have been obvious to a person of ordinary skill in the art before the effective filing date of the claimed invention to modify the PD-L1-targeting, PARP-inhibiting, 131 I-radiolabeled conjugate of Ofori and Jannetti by a simple substitution to the 123 I radiolabel of Pirovano in the PARPi(Rd) portion of the conjugate (MPEP § 2143(I)(B)). This would result in the predictable result of an effective PARP inhibiting conjugate that delivers targeted short-range radiation through Auger electron emission. Regarding claim 9 , as described above, the PD-L1-PARPi conjugates of Ofori possess a tumor targeting agent (PD-L1 inhibitor portion) coupled to a PARP inhibitor (pg. 12585, Figure 1). Additionally, Jannetti teaches an 131 I-radiolabeled PARP inhibitor (pg. 1229, Figure 1A), the combination of which with Ofori would result in a TTA coupled PARPi(Rd) conjugate. Furthermore, Pirovano teaches a radiolabeled derivative of olaparib that is identical to that of Jannetti except with a different radioiodide nuclide, 123 I (pg. 2872, Figure 1C) that can substitute the derivative of Jannetti (or just the radionuclide thereof). The 123I radionuclide possesses short-range Auger electron radiation properties (pg. 2871, right column, last paragraph). Therefore, the combined teachings of Ofori, Jannetti, and Pirovano render claim 9 obvious . 07-21-aia AIA Claim s 11 and 22 are rejected under 35 U.S.C. 103 as being unpatentable over Ofori in view of Jannetti and Ivanenkov, as applied to claim 8 above, further in view of Vaidyanathan (Vaidyanathan, G.; et al., Bioorg. Med. Chem., 2012) and Zhang (Zhang, H.; et al., Eur. J. Nucl. Med. Mol. Imaging, 2007) . As described above, Ofori, Jannetti, and Ivanenkov combine to teach the conjugate of claim 8 comprising a PARPi(Rd) region coupled to a PSMA ligand. Ofori teaches the conjugation of an inhibitor of PARPi (a derivative of olaparib) and BMS-001, an inhibitor of PD-L1 (pg. 12586, Scheme 1). Ofori teaches that the parent molecule olaparib is a PARP-1 inhibitor (pg. 12586, left column, last paragraph) and that all the conjugates dock well into the catalytic domain of the PARP-1 protein (pg. 12589, left column, last paragraph). Ofori teaches that cancer cells may express PD-L1 (pg. 12588, left column, paragraph 5), thus, a PD-L1 inhibitor can be considered a tumor targeting agent. As described above, the conjugates 1, 2, and 3 of Ofori read on the structure of PARPi-L-TTA. Ofori also teaches that compounds 1, 2, and 3 all display improved efficacy over olaparib or BMS-001 alone in killing MDA-MB-231 cancer cells (pg. 12588, Figure 3). Furthermore, Janetti teaches a 131 I-radiolabeled PARP-1 therapeutic molecule (pg. 1225, Abstract). Janetti teaches that the 131 I-radiolabeled PARP inhibitor effectively decreases tumor volume in a glioblastoma mouse model (pg. 1231, Figure 4). Ivanenkov teaches TTA-coupled chemotherapeutics in the form of a PSMA ligand linked to doxorubicin (pg. 1250, Scheme 4). Ivanenkov also teaches that PSMA is a highly attractive target for anticancer treatments because PSMA is abundantly expressed in prostate cancer compared to its expression in other cell types (pg. 1251, right column, last paragraph). The combination of Ofori, Jannetti, and Ivanenkov fails to teach a TTA coupled PARPi(Rd) conjugate wherein the conjugate has a structure in which the radiolabel is connected to the PARPi region and the linker by an amide linkage and the linker is a PEG-based linker (fails to teach the structure claimed in claim 22). Vaidyanathan teaches a trifunctional radiolabeling prosthetic group for enabling the targeting of a radiolabeled molecule to tumors (pg. 6929, Abstract). Specifically, Vaidyanathan teaches a trifunctional group containing a radioiodine label (pg. 6930, Scheme 1, molecule 2). Vaidyanathan teaches that the N-hydroxysuccinimide groups of compound 2 can be used for further functionalization to chelating groups (pg. 6931, Scheme 3), and antibodies (pg. 6937, Section 4.3.1). Vaidyanathan teaches that this is an effective way to incorporate radioiodine into targeted radiopharmaceuticals (pg. 6935, Table 2). Zhang teaches a tumor targeting radiotherapeutic compound (pg. 1198, Abstract). This compound contains a peptide portion that targets the bombesin receptor (pg. 1198, Abstract). It is connected to a DOTA chelating group via a 4xPEG linker (pg. 1202, Fig. 1). The DOTA can be used to chelate a radionuclide, which could be used for delivering radiation to the targeted tumor (pg. 1200, left column, paragraph 3). A person of ordinary skill in the art would have recognized that Ofori, Jannetti, Ivanenkov, Zhang, and Vaidyanathan all teach anticancer pharmaceuticals. Furthermore, it would be recognized that Jannetti, and Zhang, and Vaidyanathan teach anticancer radiopharmaceuticals. As described above, it would be obvious to combine the 131 I-labeled olaparib derivative of Jannetti with the PARPi-L-TTA conjugate of Ofori and to substitute in the PSMA targeting TTA of Ivanenkov. The work of Zhang and Vaidyanathan indicate that PEG linkers and trifunctional radioiodine prosthetic groups are known and understood in the art of anticancer conjugate pharmaceutical medicinal chemistry. It would be recognized that instead of radiolabeling an olaparib derivative using radioiodobenzoic acid, as taught by Jannetti, this labeling could be done using the trifunctional group of Vaidyanathan. This would produce the following product (wherein the iodine is 131 I). PNG media_image1.png 200 400 media_image1.png Greyscale Furthermore, it would be understood that the 4xPEG linker of Zhang is an effective linker for connecting a tumor targeting peptide group (such as PSMA) to a radiolabeled group (such as PARPi(Rd)) and connecting the groups at amide linkages. Additionally, a person of ordinary skill in the art would recognize that the 4xPEG group is an oligomeric unit that can be readily adjusted or substituted in length to other forms such as a 3xPEG linker (as evidenced by Ofori conjugate 3). It would be recognized that specifically using the 3xPEG group as the linker connecting the PSMA targeting group to the above structure would result in the following product (wherein the iodine is 131 I). PNG media_image2.png 200 400 media_image2.png Greyscale Therefore, it would have been obvious to a person of ordinary skill in the art before the effective filing date of the claimed invention to modify the PSMA-targeting, PARP-inhibiting, 131 I-radiolabeled conjugate of Ofori, Jannetti, and Ivanenkov by modified synthesis using the PEG linker of Zhang and the trifunctional radioiodoaryl group of Vaidyanathan, as these are known substructures and synthesis methods in the art (MPEP § 2143(I)(A)). This would result in the predictable result of an effective PARP-inhibiting PSMA-targeting conjugate that would effectively provide targeted cancer treatment. Regarding claim 11 , the second compound above, contains an Rd portion of the PARPi(Rd)-L-TTA structure that can be described in the form of Cg 1 -ArQ-Cg 2 . In this instance, the Ar group is an aryl group and the Q radionuclide is 131 I. Additionally, the Cg 1 group is -N(R 1 )C(O)- in which R 1 is alkyl and the Cg 2 group is -C(O)N(R 1 )- in which R 1 is hydrogen. Therefore, the combination of Ofori, Jannetti, Ivanenkov, Zhang, and Vaidyanathan render claim 11 obvious. Regarding claim 22 , the second compound above is identical to the claimed compound. For the reasons discussed above, the combination of Ofori, Jannetti, Ivanenkov, Zhang, and Vaidyanathan render claim 22 obvious . 07-21-aia AIA Claim 12 is rejected under 35 U.S.C. 103 as being unpatentable over Ofori in view of Jannetti, as applied to claims 1-4 and 18 above, further in view of Kellogg (Kellogg, B.A.; et al., Bioconjugate Chem., 2011) . As described above, Ofori and Jannetti combine to teach the conjugate of claim 1 comprising a PARPi(Rd) region coupled to a TTA region. Ofori teaches the conjugation of an inhibitor of PARPi (a derivative of olaparib) and BMS-001, an inhibitor of PD-L1 (pg. 12586, Scheme 1). Ofori teaches that the parent molecule olaparib is a PARP-1 inhibitor (pg. 12586, left column, last paragraph) and that all the conjugates dock well into the catalytic domain of the PARP-1 protein (pg. 12589, left column, last paragraph). Ofori teaches that cancer cells may express PD-L1 (pg. 12588, left column, paragraph 5), thus, a PD-L1 inhibitor can be considered a tumor targeting agent. As described above, the conjugates 1, 2, and 3 of Ofori read on the structure of PARPi-L-TTA. Ofori also teaches that compounds 1, 2, and 3 all display improved efficacy over olaparib or BMS-001 alone in killing MDA-MB-231 cancer cells (pg. 12588, Figure 3). Furthermore, Janetti teaches a 131 I-radiolabeled PARP-1 therapeutic molecule (pg. 1225, Abstract). Janetti teaches that the 131 I-radiolabeled PARP inhibitor effectively decreases tumor volume in a glioblastoma mouse model (pg. 1231, Figure 4). The combination of Ofori and Jannetti fails to teach a TTA coupled PARPi(Rd) conjugate wherein the linker comprises a structure described by the structure ES 1 -SS-ES 2 wherein ES 1 has the structure Cg 3 -SP and ES 2 has the structure SP-Cg 4 , and SS represents a disulfide bond. Kellogg teaches tumor targeting antibody-drug conjugates comprising disulfide linkages between the antibody and drug (pg. 718, Table 1). Kellogg teaches that the antibody recognizes CanAg, a tumor-specific antigen (pg. 717, right column, first paragraph). Kellogg teaches that the disulfide linker may include unbranched or branched alkyl chains (pg. 718, Table 1) and that the branched alkyl chains increase steric hindrance, slowing disulfide reduction and preparing a more stable conjugate (pg. 724, right column, third paragraph. Kellogg teaches that the disulfide linker can be attached to the drug and the antibody via amide coupling groups (pg. 717, Abstract Figure). Kellogg teaches that linkers with moderate stability have the greatest in vivo potency (pg. 724, right column, last paragraph). A person of ordinary skill in the art would have recognized that Ofori, Jannetti, and Kellogg teach anticancer therapeutics. It would also be recognized that both Ofori and Kellogg teach tumor-targeting drug delivering therapeutics. It would be understood that a practitioner in the art could simply replace the linker of Ofori in the Ofori-Jannetti PARPi(Rd)-L-TTA conjugate that reads on claims 1 and 2 (as described above) with the disulfide-containing linker of Kellogg, as this is another linking group known in the art of targeted cancer therapy. It would also be recognized that a disulfide linker enables the reduction-induced release of the active drug molecule from the tumor targeting agent. Therefore, it would have been obvious to a person of ordinary skill in the art before the effective filing date of the claimed invention to modify the PD-L1-targeting, PARP-inhibiting, 131 I-radiolabeled conjugate of Ofori and Jannetti by a simple substitution to the disulfide-containing linker of Kellogg in the “L” portion of the conjugate (MPEP § 2143(I)(B)). This would result in the predictable result of an effective PARP inhibiting conjugate that can be cleaved by reduction reaction to release free PARPi(Rd). Regarding claim 12 , as described above, the PD-L1-PARPi conjugates of Ofori possess a tumor targeting agent (PD-L1 inhibitor portion) coupled to a PARP inhibitor (pg. 12585, Figure 1). Additionally, Jannetti teaches an 131 I-radiolabeled PARP inhibitor (pg. 1229, Figure 1A), the combination of which with Ofori would result in a TTA coupled PARPi(Rd) conjugate that reads on the structure of claim 2. Furthermore, Kellogg teaches a linker region for a targeted cancer therapeutic derivative with the structure ES 1 -SS-ES 2 wherein ES 1 has the structure Cg 3 -SP and ES 2 has the structure SP-Cg 4 , and SS represents a disulfide bond (pg. 717, Abstract Figure and pg. 718, Table 1). Kellogg teaches an embodiment in which ES 1 contains a Cg 3 structure of -N(R 1 )C(O)- in which R 1 is C 1 alkyl connecting the maytansinoid drug to a C 2 alkylene SP structure that connects to the disulfide group and the ES2 group connects to the disulfide with a C 2 alkylene SP region and couples to the antibody with a -C(O)N(R 1 )- Cg 4 coupling group in which R 1 is hydrogen (pg. 717, Abstract Figure). Therefore, the combined teachings of Ofori, Jannetti, and Kellogg render claim 12 obvious . 07-21-aia AIA Claim 13 is rejected under 35 U.S.C. 103 as being unpatentable over Ofori in view of Jannetti, as applied to claims 1-4 and 18 above, further in view of Hu (Hu, X.; et al., Eur. J. Med. Chem., 2021) . As described above, Ofori and Jannetti combine to teach the conjugate of claim 1 comprising a PARPi(Rd) region coupled to a TTA region. Ofori teaches the conjugation of an inhibitor of PARPi (a derivative of olaparib) and BMS-001, an inhibitor of PD-L1 (pg. 12586, Scheme 1). Ofori teaches that the parent molecule olaparib is a PARP-1 inhibitor (pg. 12586, left column, last paragraph) and that all the conjugates dock well into the catalytic domain of the PARP-1 protein (pg. 12589, left column, last paragraph). Ofori teaches that cancer cells may express PD-L1 (pg. 12588, left column, paragraph 5), thus, a PD-L1 inhibitor can be considered a tumor targeting agent. As described above, the conjugates 1, 2, and 3 of Ofori read on the structure of PARPi-L-TTA. Ofori also teaches that compounds 1, 2, and 3 all display improved efficacy over olaparib or BMS-001 alone in killing MDA-MB-231 cancer cells (pg. 12588, Figure 3). Furthermore, Janetti teaches a 131 I-radiolabeled PARP-1 therapeutic molecule (pg. 1225, Abstract). Janetti teaches that the 131 I-radiolabeled PARP inhibitor effectively decreases tumor volume in a glioblastoma mouse model (pg. 1231, Figure 4). The combination of Ofori and Jannetti fails to teach a TTA coupled PARPi(Rd) conjugate wherein the linker comprises a structure described by the structure ES-ECL-SIG wherein the ES group has the structure Cg 3 -SP-Cg 4 , the ECL group is an enzyme cleavable linker, and the SIG group is a self-immolative group. Hu teaches tumor targeting antibody-drug conjugates comprising enzyme cleavable linkers and self-immolative groups (pg. 1, Abstract and pg. 2, Fig. 1). Hu teaches that these molecules can have various spacers, enzyme cleaving target structures, and self-immolative groups (pg. 2, Table 1). Hu specifically teaches an enzyme cleavable linker that is cleaved by cathepsin B (pg. 5, Fig. 2B), which is a lysosomal protease (pg. 2, left column, paragraph 2). In most embodiments, the enzyme cleavable portion includes a valine-citrulline dipeptide, but Hu also teaches additional catabolizing areas that include up to four amino acids (pg. 2, Table 1). Hu also teaches using a PABC self-immolative group adjacent to the enzyme cleavable position (pg. 2, Fig. 1) and states that PABC is the most widely used self-immolative group (pg. 2, right column, last paragraph). Hu teaches several possible spacer regions connecting to the enzyme-cleavable region. These include alkyl and aryl groups connected to other components by amides, esters, or amines (pg. 3, Scheme 1). A person of ordinary skill in the art would have recognized that Ofori, Jannetti, and Hu teach anticancer therapeutics. It would also be recognized that both Ofori and Hu teach tumor-targeting drug delivering therapeutics. It would be understood that a practitioner in the art could simply replace the linker of Ofori in the Ofori-Jannetti PARPi(Rd)-L-TTA conjugate that reads on claims 1 and 2 (as described above) with the spacer, enzyme cleavable site, self-immolative group linker of Hu, as this is another linking group known in the art of targeted cancer therapy. It would also be recognized that an enzyme cleavable linker and self-immolative group enable release of the active drug molecule from the tumor targeting agent. Furthermore, while Hu teaches attaching the chemotherapeutic to the self-immolative group and the antibody TTA to the spacer region, it would be understood by a person of ordinary skill in the art that linkers in this context serve to connect two components and that the sides on which the components are attached can be switched. Therefore, it would have been obvious to a person of ordinary skill in the art before the effective filing date of the claimed invention to modify the PD-L1-targeting, PARP-inhibiting, 131 I-radiolabeled conjugate of Ofori and Jannetti by a simple substitution to the enzyme cleavable, self-immolating linker of Hu in the “L” portion of the conjugate (MPEP § 2143(I)(B)). This would result in the predictable result of an effective PARP inhibiting conjugate that can be cleaved by a lysosomal protease to release free PARPi(Rd). Regarding claim 13 , as described above, the PD-L1-PARPi conjugates of Ofori possess a tumor targeting agent (PD-L1 inhibitor portion) coupled to a PARP inhibitor (pg. 12585, Figure 1). Additionally, Jannetti teaches an 131 I-radiolabeled PARP inhibitor (pg. 1229, Figure 1A), the combination of which with Ofori would result in a TTA coupled PARPi(Rd) conjugate that reads on the structure of claim 2. Furthermore, Hu teaches a linker region for a targeted cancer therapeutic derivative with the structure ES-ECL-SIG (spacer-catabolizing area-self immolative) (pg. 2, Fig. 1). Hu teaches that the ES region can be C 6 alkylene or an arylene group coupled to the adjacent groups through linkages including -C(O)N(R 1 )- in which R 1 is H, or -C(O)N(R 1 )- in which R 1 is alkyl (pg. 3, Scheme 1, R regions and structure after step e). Hu also teaches enzyme cleavable linkers of 2-4 amino acid sequences (pg. 3, Scheme 1, AA regions) that can be cleaved by cathepsin B, a lysosomal protease (pg. 2, left column, second paragraph). The linker of Hu also contains a self-immolative group, PABC (pg. 2, Table 1). In the arrangement in which the linker has been flipped (as described above), the combined structure of Ofori, Jannetti, and Hu would read as PARPi(Rd)-ES-ECL-SIG-TTA. In this instance, upon cleavage of the PABC SIG, the SIG would decompose and release the TTA from the ECL. Therefore, the combined teachings of Ofori, Jannetti, and Hu render claim 13 obvious . 07-21-aia AIA Claim 19 is rejected under 35 U.S.C. 103 as being unpatentable over Ofori in view of Jannetti, as applied to claims 1-4 and 18 above, further in view of Zhou (Zhou, D.; et al, Biomedicines, 2021) . As described above, Ofori and Jannetti combine to teach the conjugate of claim 1 comprising a PARPi(Rd) region coupled to a TTA region. Ofori teaches the conjugation of an inhibitor of PARPi (a derivative of olaparib) and BMS-001, an inhibitor of PD-L1 (pg. 12586, Scheme 1). Ofori teaches that the parent molecule olaparib is a PARP-1 inhibitor (pg. 12586, left column, last paragraph) and that all the conjugates dock well into the catalytic domain of the PARP-1 protein (pg. 12589, left column, last paragraph). Ofori teaches that cancer cells may express PD-L1 (pg. 12588, left column, paragraph 5), thus, a PD-L1 inhibitor can be considered a tumor targeting agent. As described above, the conjugates 1, 2, and 3 of Ofori read on the structure of PARPi-L-TTA. Ofori also teaches that compounds 1, 2, and 3 all display improved efficacy over olaparib or BMS-001 alone in killing MDA-MB-231 cancer cells (pg. 12588, Figure 3). Furthermore, Janetti teaches a 131 I-radiolabeled PARP-1 therapeutic molecule (pg. 1225, Abstract). Janetti teaches that the 131 I-radiolabeled PARP inhibitor effectively decreases tumor volume in a glioblastoma mouse model (pg. 1231, Figure 4). The combination of Ofori and Jannetti fails to teach a TTA coupled PARPi(Rd) conjugate wherein the PARPi comprises talazoparib. Zhou teaches a radiolabeled derivative of talazoparib, [ 18 F]talazoparib (3a”) (pg. 6, Scheme 1). This molecule only differs from the parent talazoparib molecule in that one of the fluorine atoms is replaced with the 18 F radionuclide (pg. 2, Figure 1). Zhou teaches that the 18 F-talazoparib compound has good prostate tumor uptake and has longer retention in the tumor than radioiodine-labeled olaparib derivatives (pg. 10, Section 3.5). A person of ordinary skill in the art would have recognized that Ofori, Jannetti, and Zhou teach PARP inhibitor molecules for the purpose of cancer treatment. As described above, it would be understood that the radioiodine-labeled olaparib derivative could be substituted into the PARPi-L-TTA conjugate of Ofori. It would also be recognized that the 18 F-talazoparib is an alternative PARPi(Rd) molecule and that it possesses good tumor retention properties. It would also be understood that a practitioner in the art could simply substitute the 131 I-radiolabeled PARP inhibitor of Jannetti in the combined Jannetti-Ofori conjugate for the 18 F-radiolabeled talazoparib PARP inhibitor taught by Zhou. Therefore, it would have been obvious to a person of ordinary skill in the art before the effective filing date of the claimed invention to modify the PD-L1-targeting, PARP-inhibiting radiolabeled conjugate of Ofori and Jannetti by a simple substitution to the 18 F-radiolabeled talazoparib molecules of Zhou in the PARPi(Rd) portion of the conjugate (MPEP § 2143(I)(B)). This would result in the predictable result of an effective PARP inhibiting conjugate that delivers targeted radiation. Regarding claim 19 , as described above, the PD-L1-PARPi conjugates of Ofori possess a tumor targeting agent (PD-L1 inhibitor portion) coupled to a PARP inhibitor (pg. 12585, Figure 1). Additionally, Jannetti teaches an 131 I-radiolabeled PARP inhibitor (pg. 1229, Figure 1A), the combination of which with Ofori would result in a TTA coupled PARPi(Rd) conjugate. Furthermore, Zhou teaches a radiolabeled derivative of talazoparib, [ 18 F]talazoparib (3a”) (pg. 6, Scheme 1) that can substitute the radioiodine- labeled olaparib derivative of Jannetti. Therefore, the combined teachings of Ofori, Jannetti, and Zhou render claim 19 obvious . 07-21-aia AIA Claim s 26 and 30 are rejected under 35 U.S.C. 103 as being unpatentable over Shammo (WO 2019/213217 A) in view of Ofori (Ofori, S. and Awuah, S.G., ACS Omega, 2019) . Shammo teaches methods and compositions for the treatment of cancer using PARP inhibitors (Abstract). Shammo teaches that several different PARP inhibitors may be used, including olaparib (pg. 5, [0028]). Shammo specifically teaches that the treatment of cancer may include combination of a PARP inhibitor with chemotherapeutic agents and/or radiation therapy (pg. 9, [0040]). Shammo also teaches that the PARP inhibitor may be provided as a pharmaceutical composition comprising the PARP inhibitor and a pharmaceutically acceptable carrier or excipient (pg. 11, [0051]). Shammo provides detailed descriptions of formulations and possible additives for use in the pharmaceutical composition ([0055] – [0071]). Shammo also teaches that the PARP inhibitor treatment can be administered to subjects with cancers that include ovarian cancer, breast cancer, glioblastoma, and prostate cancer (pg. 30, [0095]) or other cancers with deficiency in homologous recombination (pg. 7, [0034]). Shammo does not teach a pharmaceutical compositions or methods of treating cancers using a conjugate of the formula PARPi-L-TTA wherein the formula describes a PARP inhibitor connected to a tumor targeting agent via a linker. As described above, Ofori teaches the conjugation of an inhibitor of PARPi (a derivative of olaparib) and BMS-001, an inhibitor of PD-L1 (pg. 12586, Scheme 1). Ofori teaches three conjugates, which differ in the linker region chemistry (pg. 12858, Figure 1). The linkers connect the PARPi to the BMS-001 group. Ofori teaches that cancer cells may express PD-L1 (pg. 12588, left column, paragraph 5), thus, a PD-L1 inhibitor can be considered a tumor targeting agent. As described above, the conjugates 1, 2, and 3 of Ofori read on the structure of PARPi-L-TTA. Ofori also teaches that compounds 1, 2, and 3 all display improved efficacy over olaparib or BMS-001 alone in killing MDA-MB-231 cancer cells (pg. 12588, Figure 3). A person of ordinary skill in the art would have recognized that both Shammo and Ofori teach using PARP inhibitors for the purpose of cancer treatment. It would also be recognized that the PARP inhibiting conjugate of Ofori is more effective than the original PARP inhibitor from which it was derived. It would also be understood that a practitioner in the art could simply substitute the PARP inhibitor of Shammo for the conjugate of Ofori. Therefore, it would have been obvious to a person of ordinary skill in the art before the effective filing date of the claimed invention to modify the pharmaceutical composition and method of treating cancer using PARP inhibitors as taught by Shammo by a simple substitution to the PD-L1-targeted PARP inhibitor conjugate of Ofori (MPEP § 2143(I)(B)). This would result in the predictable result of a more effective cancer treatment and an alternative pharmaceutical composition. Regarding claim 26 , Ofori teaches conjugates comprising a tumor-targeting PD-L1 inhibitor linked to a PARP inhibitor (pg. 12858, Figure 1), which are compounds possessing the structure PARPi-L-TTA. Shammo teaches that PARP inhibitor compounds may be prepared as pharmaceutical compositions comprising the PARP inhibitor and a pharmaceutically acceptable carrier or excipient (pg. 11, [0051]). Substituting the conjugate of Ofori in place of the PARP inhibitor of Shammo would result in a pharmaceutical composition comprising a pharmaceutically acceptable carrier and a molecule that can be described by the formula PARPi-L-TTA. Therefore, the combined teachings of Shammo and Ofori render claim 26 obvious. Regarding claim 30 , Shammo also teaches that PARP inhibitor treatment can be administered to subjects with cancers that include ovarian cancer, breast cancer, glioblastoma (which reads on brain cancer), and prostate cancer (pg. 30, [0095]) or other cancers with deficiency in homologous recombination (pg. 7, [0034]). Shammo also teaches that the method of treating cancer includes administering the PARP inhibitor and this administration may be done in combination with chemotherapeutic agents and/or radiation therapy (which reads on ionizing radiation) (pg. 8, [0040]). Therefore, the combined teachings of Shammo and Ofori render claim 30 obvious . 07-21-aia AIA Claim 29 is rejected under 35 U.S.C. 103 as being unpatentable over Russo (Russo, A.L.; et al., Clin. Cancer Res., 2009) in view of Shammo and Ofori . Russo teaches a method of radiosensitization of a glioblastoma cancer model of mice with xenograft tumors (pg. 609, In vivo s.c. tumor growth delay). In this method, U251 glioblastoma cells are implanted in mice and tumors modeling glioblastoma are grown (pg. 609, In vivo s.c. tumor growth delay). Russo teaches that the combination of temozolomide chemotherapy with radiotherapy is an effective treatment of glioblastoma (pg. 607, left column, paragraph 1). Russo teaches treating the glioblastoma mouse model with either the E7016 PARP inhibitor, the combination of temozolomide with radiotherapy, or the combination of temozolomide and radiotherapy with E7016 (pg. 609, In vivo s.c. tumor growth delay). Russo demonstrates that the combination of the PARP inhibitor with temozolomide and radiotherapy inhibited tumor growth more effectively than either the PARP inhibitor alone or the combination of temozolomide and radiotherapy (pg. 611, Fig. 6). Russo also demonstrates that γH2AX, a marker of radiosensitivity, is elevated after radiotherapy in cells pre-treated with E7016 (pg. 611, Fig. 4). Russo concludes that this data demonstrates that the PARP inhibitor E7016 radiosensitized the glioblastoma tumor in the model studied (pg. 612, right column, first paragraph). Russo does not teach a method of radiosensitizing a tumor in a subject using a pharmaceutical composition comprising a conjugate of the formula PARPi-L-TTA wherein a PARP inhibitor is connected to a tumor targeting agent via a linker. As described above, Shammo teaches methods and compositions for the treatment of cancer using PARP inhibitors (Abstract). Shammo teaches that several different PARP inhibitors may be used, including olaparib (pg. 5, [0028]). Shammo specifically teaches that the treatment of cancer may include combination of a PARP inhibitor with chemotherapeutic agents and/or radiation therapy (pg. 9, [0040]). Shammo also teaches that the PARP inhibitor may be provided as a pharmaceutical composition comprising the PARP inhibitor and a pharmaceutically acceptable carrier or excipient (pg. 11, [0051]). Shammo provides detailed descriptions of formulations and possible additives for use in the pharmaceutical composition ([0055] – [0071]). As described above, Ofori teaches the conjugation of an inhibitor of PARPi (a derivative of olaparib) and BMS-001, an inhibitor of PD-L1 (pg. 12586, Scheme 1). Ofori teaches three conjugates, which differ in the linker region chemistry (pg. 12858, Figure 1). The linkers connect the PARPi to the BMS-001 group. Ofori teaches that cancer cells may express PD-L1 (pg. 12588, left column, paragraph 5), thus, a PD-L1 inhibitor can be considered a tumor targeting agent. As described above, the conjugates 1, 2, and 3 of Ofori read on the structure of PARPi-L-TTA. Ofori also teaches that compounds 1, 2, and 3 all display improved efficacy over olaparib or BMS-001 alone in killing MDA-MB-231 cancer cells (pg. 12588, Figure 3). A person of ordinary skill in the art would have recognized that Russo, Shammo, and Ofori teach using PARP inhibitors for the purpose of cancer treatment. It would also be recognized that the PARP inhibiting conjugate of Ofori is more effective than the original PARP inhibitor from which it was derived. It would also be understood that a practitioner in the art could simply substitute the E7016 PARP inhibitor of Russo for the conjugate of Ofori. Additionally, it would be understood that the pharmaceutical composition preparation including a pharmaceutically acceptable carrier, as taught by Shammo, could be applied to the conjugate of Ofori, as preparing a biologically active therapeutic compound in the form of a pharmaceutical formulation is a practice known in the art to prepare such compounds for administration. Therefore, it would have been obvious to a person of ordinary skill in the art before the effective filing date of the claimed invention to modify the tumor radiosensitization method of Russo by a simple substitution of the PD-L1-targeted PARP inhibitor conjugate of Ofori (MPEP § 2143(I)(B)). This would result in the predictable result of a more effective cancer treatment. Additionally, it would have been obvious to first prepare the conjugate of Ofori as a pharmaceutical composition using a pharmaceutically acceptable carrier, as taught by Shammo, as this is a modification known in the art of pharmaceuticals (MPEP § 2143(I)(A)). This would result in the predictable result of an active therapeutic compound prepared for administration to a subject. Regarding claim 29 , Ofori teaches conjugates comprising a tumor-targeting PD-L1 inhibitor linked to a PARP inhibitor (pg. 12858, Figure 1), which are compounds possessing the structure PARPi-L-TTA. Shammo teaches that PARP inhibitor compounds may be prepared as pharmaceutical compositions comprising the PARP inhibitor and a pharmaceutically acceptable carrier or excipient (pg. 11, [0051]). Substituting the pharmaceutical composition comprising the PARPi-L-TTA conjugate of Ofori in place of the E7016 PARP inhibitor of Russo would result in an effective tumor radiosensitization method. Therefore, the combined teachings of Russo, Shammo, and Ofori render claim 29 obvious. Allowable Subject Matter Claims 20, 21, and 23 would be allowable if rewritten to overcome the rejections under 35 U.S.C. 112(b) or 35 U.S.C. 112 (pre-AIA), 2nd paragraph, set forth in this Office action and to include all of the limitations of the base claim and any intervening claims (so as to overcome being objected to as being dependent upon a rejected base claim). Regarding claim 20 , the examiner considers Hu (Hu, X.; et al., Eur. J. Med. Chem., 2021), as applied to claim 13 above, to be the most relevant prior art regarding the linker portion of the claimed structure, teaching the linker region similar to that required in claim 20. Combination of Hu with the other art cited above (such as Ofori and Jannetti, which teach a PARPi(Rd)-L-TTA structure) fails to read on or render obvious claim 20. While Hu teaches a linker that reads on the ES-ECL-SIG structure of claim 13 in the same way the linker of structure (VI) in claim 20 does (as described in the rejection of claim 13) and Hu teaches a nitrophenyl precursor compound (pg. 3, Scheme 1, after step d) (see Claim Interpretation), Hu fails to teach connecting the linker to the chemotherapeutic via an alkyl spacer group coupled by an amide bond, as is required in claim 20. Regarding claim 21 , the examiner considers Kellogg (Kellogg, B.A., et al., Bioconjugate Chem., 2011), as applied to claim 12 above, to be the most relevant prior art regarding the linker portion of the structure, teaching a targeted cancer therapeutic comprising a disulfide linker. Combination of Kellogg with the other art cited above (such as Ofori and Jannetti) would result in a PARPi(Rd)-L-TTA structure with a disulfide-containing linker. However, the combination fails to render obvious structure (IX) of claim 21. Kellogg fails to teach conjugating a chemotherapeutic to an N-hydroxysuccinimide terminated alkyl group via a linker containing a disulfide, as is required in claim 21. Regarding claim 23 , the examiner considers Kellogg (Kellogg, B.A., et al., Bioconjugate Chem., 2011), as applied to claim 12 above, to be the most relevant prior art regarding the linker portion of the claimed molecule, teaching a targeted cancer therapeutic comprising a disulfide linker. Combination of Kellogg with the other art cited above (such as Ofori, Jannetti, and Ivanenkov) would result in a PARPi(Rd)-L-TTA structure with a disulfide linker wherein a PSMA ligand is the TTA. However, the combination fails to render obvious the claimed structure of claim 23. Kellogg fails to teach conjugating a chemotherapeutic to a TTA group through a diamide ether spacer group (as is required in claim 23) and connecting the diethyl disulfide region with amides in the required orientation. Conclusion All claims are rejected. Any inquiry concerning this communication or earlier communications from the examiner should be directed to Eric P Mosher whose telephone number is (571)272-3258. The examiner can normally be reached Monday-Friday 9am-5pm. Examiner interviews are available via telephone, in-person, and video conferencing using a USPTO supplied web-based collaboration tool. To schedule an interview, applicant is encouraged to use the USPTO Automated Interview Request (AIR) at http://www.uspto.gov/interviewpractice. If attempts to reach the examiner by telephone are unsuccessful, the examiner’s supervisor, Sahana Kaup can be reached at (571) 272-6897. 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If you would like assistance from a USPTO Customer Service Representative, call 800-786-9199 (IN USA OR CANADA) or 571-272-1000. /E.P.M./Examiner, Art Unit 1612 /SAHANA S KAUP/Supervisory Primary Examiner, Art Unit 1612 Application/Control Number: 18/575,098 Page 2 Art Unit: 1612 Application/Control Number: 18/575,098 Page 3 Art Unit: 1612 Application/Control Number: 18/575,098 Page 4 Art Unit: 1612 Application/Control Number: 18/575,098 Page 5 Art Unit: 1612 Application/Control Number: 18/575,098 Page 6 Art Unit: 1612 Application/Control Number: 18/575,098 Page 7 Art Unit: 1612 Application/Control Number: 18/575,098 Page 8 Art Unit: 1612 Application/Control Number: 18/575,098 Page 9 Art Unit: 1612 Application/Control Number: 18/575,098 Page 10 Art Unit: 1612 Application/Control Number: 18/575,098 Page 11 Art Unit: 1612 Application/Control Number: 18/575,098 Page 12 Art Unit: 1612 Application/Control Number: 18/575,098 Page 13 Art Unit: 1612 Application/Control Number: 18/575,098 Page 14 Art Unit: 1612 Application/Control Number: 18/575,098 Page 15 Art Unit: 1612 Application/Control Number: 18/575,098 Page 16 Art Unit: 1612 Application/Control Number: 18/575,098 Page 17 Art Unit: 1612 Application/Control Number: 18/575,098 Page 18 Art Unit: 1612 Application/Control Number: 18/575,098 Page 19 Art Unit: 1612 Application/Control Number: 18/575,098 Page 20 Art Unit: 1612 Application/Control Number: 18/575,098 Page 21 Art Unit: 1612 Application/Control Number: 18/575,098 Page 22 Art Unit: 1612 Application/Control Number: 18/575,098 Page 23 Art Unit: 1612 Application/Control Number: 18/575,098 Page 24 Art Unit: 1612 Application/Control Number: 18/575,098 Page 25 Art Unit: 1612 Application/Control Number: 18/575,098 Page 26 Art Unit: 1612 Application/Control Number: 18/575,098 Page 27 Art Unit: 1612 Application/Control Number: 18/575,098 Page 28 Art Unit: 1612 Application/Control Number: 18/575,098 Page 29 Art Unit: 1612 Application/Control Number: 18/575,098 Page 30 Art Unit: 1612 Application/Control Number: 18/575,098 Page 31 Art Unit: 1612 Application/Control Number: 18/575,098 Page 32 Art Unit: 1612 Application/Control Number: 18/575,098 Page 33 Art Unit: 1612 Application/Control Number: 18/575,098 Page 34 Art Unit: 1612
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