DETAILED ACTION
Notice of Pre-AIA or AIA Status
The present application, filed on or after March 16, 2013, is being examined under the first inventor to file provisions of the AIA .
Claims Status
Claims 1-20 are pending and currently under examination.
Priority
This application claims the benefit of priority to US Application No. 63/285,437, filed December 2, 2021. The priority date of claim set filed on December 1, 2022, is determined to be December 2, 2021.
Specification
The title of the invention is not descriptive. A new title is required that is clearly indicative of the invention to which the claims are directed. The following title is suggested: 3’ FLAP OKAZAKI FRAGMENTS AND USES THEREOF or THREE PRIME FLAP OKAZAKI FRAGMENTS AND USES THEREOF.
The listing of references in the specification is not a proper information disclosure statement. The specification filed on 12/01/2022 includes a list of references on pages 68-69. 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.
The use of the drug names listed in Para. 105-111 (Pg 35-44), which appear to have trade names or a marks used in commerce, have been noted in this application. The term(s) should be accompanied by the generic terminology; furthermore the term should be capitalized wherever it appears or, where appropriate, include a proper symbol indicating use in commerce such as ™, SM , or ® following the term(s).
Although the use of trade names and marks used in commerce (i.e., trademarks, service marks, certification marks, and collective marks) are permissible in patent applications, the proprietary nature of the marks should be respected and every effort made to prevent their use in any manner which might adversely affect their validity as commercial marks.
Claim Objections
Claims 4 is objected to under 37 CFR 1.75 as being a substantial duplicate of claim 3. When two claims in an application are duplicates or else are so close in content that they both cover the same thing, despite a slight difference in wording, it is proper after allowing one claim to object to the other as being a substantial duplicate of the allowed claim. See MPEP § 608.01(m).
Claim Rejections - 35 USC § 112
The following is a quotation of 35 U.S.C. 112(b):
(b) CONCLUSION.—The specification shall conclude with one or more claims particularly pointing out and distinctly claiming the subject matter which the inventor or a joint inventor regards as the invention.
The following is a quotation of 35 U.S.C. 112 (pre-AIA ), second paragraph:
The specification shall conclude with one or more claims particularly pointing out and distinctly claiming the subject matter which the applicant regards as his invention.
Claims 17-19 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 17 appears to contain the trademarks/trade names AZD0156, KU-60019, or AZD1390. Where a trademark or trade name is used in a claim as a limitation to identify or describe a particular material or product, the claim does not comply with the requirements of 35 U.S.C. 112(b) or 35 U.S.C. 112 (pre-AIA ), second paragraph. See Ex parte Simpson, 218 USPQ 1020 (Bd. App. 1982). The claim scope is uncertain since the trademark or trade name cannot be used properly to identify any particular material or product. A trademark or trade name is used to identify a source of goods, and not the goods themselves. Thus, a trademark or trade name does not identify or describe the goods associated with the trademark or trade name. In the present case, the trademark/trade name is used to identify/describe ATM kinase inhibitors and, accordingly, the identification/description is indefinite.
Claim 18 appears to contain the trademarks/trade names berzosertib or elimusertib. Where a trademark or trade name is used in a claim as a limitation to identify or describe a particular material or product, the claim does not comply with the requirements of 35 U.S.C. 112(b) or 35 U.S.C. 112 (pre-AIA ), second paragraph. See Ex parte Simpson, 218 USPQ 1020 (Bd. App. 1982). The claim scope is uncertain since the trademark or trade name cannot be used properly to identify any particular material or product. A trademark or trade name is used to identify a source of goods, and not the goods themselves. Thus, a trademark or trade name does not identify or describe the goods associated with the trademark or trade name. In the present case, the trademark/trade name is used to identify/describe ATR kinase inhibitors and, accordingly, the identification/description is indefinite.
Claim 19 appears to contain the trademarks/trade names SRA737 or prexasertib. Where a trademark or trade name is used in a claim as a limitation to identify or describe a particular material or product, the claim does not comply with the requirements of 35 U.S.C. 112(b) or 35 U.S.C. 112 (pre-AIA ), second paragraph. See Ex parte Simpson, 218 USPQ 1020 (Bd. App. 1982). The claim scope is uncertain since the trademark or trade name cannot be used properly to identify any particular material or product. A trademark or trade name is used to identify a source of goods, and not the goods themselves. Thus, a trademark or trade name does not identify or describe the goods associated with the trademark or trade name. In the present case, the trademark/trade names are used to identify/describe Chk1 inhibitors and, accordingly, the identification/description is indefinite.
Claim Rejections - 35 USC § 103
The following is a quotation of 35 U.S.C. 103 which forms the basis for all obviousness rejections set forth in this Office action:
A patent for a claimed invention may not be obtained, notwithstanding that the claimed invention is not identically disclosed as set forth in section 102, if the differences between the claimed invention and the prior art are such that the claimed invention as a whole would have been obvious before the effective filing date of the claimed invention to a person having ordinary skill in the art to which the claimed invention pertains. Patentability shall not be negated by the manner in which the invention was made.
Claims 1 and 6-7 are rejected under 35 U.S.C. 103 as being unpatentable over Wang et al. (“Wang”; (2021). MIF is a 3' flap nuclease that facilitates DNA replication and promotes tumor growth. Nature communications, 12(1), 2954.) in view of Sriramachandran et al. (“Sriramachandran”; (2020). Genome-wide Nucleotide-Resolution Mapping of DNA Replication Patterns, Single-Strand Breaks, and Lesions by GLOE-Seq. Molecular cell, 78(5), 975–985.e7).
Wang discloses “How cancer cells cope with high levels of replication stress during rapid proliferation is currently unclear. Here, we show that macrophage migration inhibitory factor (MIF) is a 3’ flap nuclease that translocates to the nucleus in S phase. Poly(ADP-ribose) polymerase 1 co-localizes with MIF to the DNA replication fork, where MIF nuclease activity is required to resolve replication stress and facilitates tumor growth. MIF loss in cancer cells leads to mutation frequency increases, cell cycle delays and DNA synthesis and cell growth inhibition, which can be rescued by restoring MIF, but not nuclease-deficient MIF mutant. MIF is significantly upregulated in breast tumors and correlates with poor overall survival in patients. We propose that MIF is a unique 3’ nuclease, excises flaps at the immediate 3’ end during DNA synthesis and favors cancer cells evading replication stress-induced threat for their growth” (Abstract).
Regarding claim 1, Wang teaches “DNA replication produces both 5’ flap and 3’ flap DNA overhang structures, which are detrimental to cell proliferation. Resolving 3’ flap and 5’ flap DNA structures is equally important”, “Pol δ and Pol ε have been well recognized for their functions in the removal of mis-incorporated nucleotides in a 3’->5’ direction” and “mutant Pol δ and Pol ε identified in certain human cancers” (Pg. 2, Col. 1, Para. 3). Thus, Wang suggests a reason for detecting a 3’ flap Okazaki fragment in a patient having cancer.
However, Wang does not teach a method comprising detecting a 3’ flap Okazaki fragment in a biological sample obtained from a patient having cancer.
Sriramachandran discloses “DNA single-strand breaks (SSBs) are among the most common lesions in the genome, arising spontaneously and as intermediates of many DNA transactions. Nevertheless, in contrast to double-strand breaks (DSBs), their distribution in the genome has hardly been addressed in a meaningful way. We now present a technique based on genome-wide ligation of 3′-OH ends followed by sequencing (GLOE-Seq) and an associated computational pipeline designed for capturing SSBs but versatile enough to be applied to any lesion convertible into a free 3′-OH terminus. We demonstrate its applicability to mapping of Okazaki fragments without prior size selection and provide insight into the relative contributions of DNA ligase 1 and ligase 3 to Okazaki fragment maturation in human cells. In addition, our analysis reveals biases and asymmetries in the distribution of spontaneous SSBs in yeast and human chromatin, distinct from the patterns of DSBs” (Summary).
Regarding claims 1 and 6-7, Sriramachandran teaches a method comprising “Treatment of HCT116 and HCT116 LIG3−/−:mL3 cells with siRNA was carried out… post siRNA transfection, cells were passaged… and grown … before being harvested and immediately processed for GLOE-Seq” (Pg. 985 e.6, Ligase 1 Depletion in Human Cells, Para. 1). Sriramachandran teaches a method comprising “preparation of genomic DNA” (Pg. 985 e.7, Preparation of Mammalian Genomic DNA, Para. 1). Sriramachandran teaches a method comprising “GLOE-Seq protocol” (Pg. 985 e.7, Application of GLOE-Seq to Human Genomic DNA, Para. 1). “GLOE-Seq protocol” “HCT116” (Pg. 985 e.4, Cell lines, Para. 1). HCT116 reads on cells that originated from a patient's colon cancer. “GLOE-SEQ” reads on detecting 3’ flap of Okazaki fragment. Thus, Wang and Sriramachandran teach a method comprising detecting a 3' flap Okazaki fragment in a biological sample obtained from the patient having cancer; wherein the biological sample is a cancer cell; and wherein the biological sample is genomic DNA in a cancer cell.
Wang and Sriramachandran are considered to be analogous to the claimed invention because they are in the same field of DNA Damage Response. Therefore, it would have been obvious to someone of ordinary skill in the art before the effective filing date of the claimed invention to have utilized the teachings of 3’ flap Okazaki fragments in a patient having cancer as taught by Wang to incorporate the method assay of detecting 3’ end of Okazaki fragments as taught by Sriramachandran and provide a method for detecting a 3' flap Okazaki fragment in a patient having cancer. Doing so would allow for further characterization of Okazaki fragment maturation and DNA Damage Response in sample of a cancer patient.
Claim 2 is rejected under 35 U.S.C. 103 as being unpatentable over Wang et al. (“Wang”; (2021). MIF is a 3' flap nuclease that facilitates DNA replication and promotes tumor growth. Nature communications, 12(1), 2954.) in view of Sriramachandran et al. (“Sriramachandran”; (2020). Genome-wide Nucleotide-Resolution Mapping of DNA Replication Patterns, Single-Strand Breaks, and Lesions by GLOE-Seq. Molecular cell, 78(5), 975–985.e7.) as applied to claim 1 above, and further in view of Hanzlikova et al. (“Hanzlikova”; (2018). The importance of poly (ADP-ribose) polymerase as a sensor of unligated Okazaki fragments during DNA replication. Molecular cell, 71(2), 319-331).
The teachings of Wang and Sriramachandran are documented above in the rejection of claims 1 and 6-7 under 35 U.S.C. 103. Claim 2 depends on claim 1. Wang and Sriramachandran do not explicitly teach the limitation wherein the biological sample contains an elevated level of the 3' flap Okazaki fragment relative to a control.
Hanzlikova discloses “Poly(ADP-ribose) is synthesized by PARP enzymes during the repair of stochastic DNA breaks. Surprisingly, however, we show that most if not all endogenous poly(ADP-ribose) is detected in normal S phase cells at sites of DNA replication. This S phase poly(ADP-ribose) does not result from damaged or misincorporated nucleotides or from DNA replication stress. Rather, perturbation of the DNA replication proteins LIG1 or FEN1 increases S phase poly(ADP-ribose) more than 10-fold, implicating unligated Okazaki fragments as the source of S phase PARP activity. Indeed, S phase PARP activity is ablated by suppressing Okazaki fragment formation with emetine, a DNA replication inhibitor that selectively inhibits lagging strand synthesis. Importantly, PARP activation during DNA replication recruits the single-strand break repair protein XRCC1, and human cells lacking PARP activity and/or XRCC1 are hypersensitive to FEN1 perturbation. Collectively, our data indicate that PARP1 is a sensor of unligated Okazaki fragments during DNA replication and facilitates their repair” (Abstract).
Regarding claim 2, Hanzlikova teaches a method wherein “we first employed … human fibroblasts from a patient… resulting from the increased unligated Okazaki fragments that are present in …cells” (Pg. 323, Col. 1, Para.1). Thus, Wang, Sriramachandran and Hanzlikova teach a method wherein the biological sample contains an elevated level of the 3' flap Okazaki fragment relative to a control.
Wang, Sriramachandran and Hanzlikova are considered to be analogous to the claimed invention because they are in the same field of DNA Damage Response. Therefore, it would have been obvious to someone of ordinary skill in the art before the effective filing date of the claimed invention to modify the method of detecting a 3' flap Okazaki fragment in a patient having cancer as taught by Wang and Sriramachandran to incorporate the method wherein the sample contains elevated levels of 3’ flap Okazaki fragments as taught by Hanzlikova and provide a method for detecting a 3' flap Okazaki fragment in a patient having cancer wherein the sample contains an elevated level of the 3' flap Okazaki fragment relative to a control. Doing so would allow for further characterization of 3’ flap Okazaki fragment maturation and DNA Damage Response in sample of a cancer patient with elevated 3’ flap Okazaki fragments.
Claims 3, 16-17 and 19-20 are rejected under 35 U.S.C. 103 as being unpatentable over Wang et al. (“Wang”; (2021). MIF is a 3' flap nuclease that facilitates DNA replication and promotes tumor growth. Nature communications, 12(1), 2954.) in view of Sriramachandran et al. (“Sriramachandran”; (2020). Genome-wide Nucleotide-Resolution Mapping of DNA Replication Patterns, Single-Strand Breaks, and Lesions by GLOE-Seq. Molecular cell, 78(5), 975–985.e7.) as applied to claim 1 above, and further in view of Aguilar Cordova et al. (“Aguilar Cordova”; Patent App. Pub. No. WO 2020172671 A1, Aug. 27, 2020).
The teachings of Wang and Sriramachandran are documented above in the rejection of claim 1 under 35 U.S.C. 103. Claims 3, 16-17 and 19-20 depend on claim 1. Claim 17 depends on claim 16, which depends on claim 3, which depends on claim 1.
Sriramachandran suggests a method comprising “applications of GLOE-Seq to probe the effects of medically relevant factors or treatments associated with SSBs, such as … proteins involved in homologous recombination or protein-DNA crosslink repair, as well as pertinent inhibitors of such factors” (Pg. 982, Potential Applications of GLOE-Seq, Para. 1).
Sriramachandran does not explicitly teach the limitations of claim further comprising administering to the patient a therapeutically effective amount of a DNA Damage Response Inhibitor; wherein the DNA Damage Response Inhibitor is an ATM kinase inhibitor, an ATR kinase inhibitor, a Chk1 kinase inhibitor, a Chk2 kinase inhibitor, or a combination of two or more thereof; and wherein the ATM kinase inhibitor is AZD0156, KU-60019, or AZD1390 .
Aguilar Cordova discloses methods of treating a cancer in a subject, comprising treating the subject with a combination of gene-mediated cytotoxic immunotherapy and an inhibitor of a DNA damage repair agent which is not ATR.
Regarding claims 3 and 16, Aguilar Cordova teaches a method wherein “cancer therapy involves the administration of DNA damage response inhibitors (DDRI’s) which stop the repair of breaks in single- stranded and/or double- stranded DNA. Both DNA double- and single-strand break repair are highly coordinated processes utilizing signal transduction cascades and post-translational modifications such as phosphorylation, acetylation and ADP ribosylation. DDRI’s are a class of molecules which act on target proteins that function in pathway that perform DNA damage repair within a cell. DDRI targets include ataxia-telangiectasia mutated (ATM) kinase… checkpoint kinase 1 (CHK1), checkpoint kinase 2 (CHK2) …” (Para. 5; Para. 11; Para. 36). Aguilar Cordova teaches a method wherein “dosing of the DDRI, including the route of administration and dosage levels depend on the properties of the specific DDRI agent. These are typically characterized by balancing commonly used metrics of clinical efficacy (e.g. tumor shrinkage, survival, time to disease progression, improvements in symptoms)” (Para. 49). Thus, Wang, Sriramachandran and Aguilar Cordova teach a method further comprising administering to the patient a therapeutically effective amount of a DNA Damage Response Inhibitor; and wherein the DNA Damage Response Inhibitor is an ATM kinase inhibitor, an ATR kinase inhibitor, a Chk1 kinase inhibitor, a Chk2 kinase inhibitor, or a combination of two or more thereof.
Regarding claim 17, Aguilar Cordova teaches a method wherein “ATM inhibitors include AZD0156 … KU-60019,” (Para.37). Aguilar Cordova teaches a method wherein “Administration of the DDRI drug AZD1390“ (Para. 63). Thus, Wang, Sriramachandran and Aguilar Cordova teach a method wherein the ATM kinase inhibitor is AZD0156, KU-60019, or AZD1390.
Regarding claim 19, Aguilar Cordova teaches a method wherein “the DDRI comprises a CHK1 inhibitor… the CHK1 inhibitor comprises... LY2606368” (Para. 17). Prexasertib reads on LY2606368. Thus, Wang, Sriramachandran and Aguilar Cordova teach a method wherein the Chk1 kinase inhibitor is SRA737 or prexasertib.
Regarding claim 20, Aguilar Cordova teaches a method wherein “For example, the cytotoxicity delivered from treating a cancer with a combination of GMCI and an inhibitor of ataxia-telangiectasia mutated (ATM) kinase … checkpoint kinase 1 (CHK1), checkpoint kinase 2 (CHK2)… is unexpectedly greater compared to the cytotoxicity delivered when treating the cancer with GMCI or one of these inhibitors, alone (or greater than the cytotoxicity of both added together). In addition, the combination therapy results in more rapid killing of cancer cells and more rapid tumor shrinkage than was found when either therapy, alone, is used” (Para. 11). Aguilar Cordova teaches “Commonly used methods of treating cancer include surgical resection, radiation therapy, chemotherapy, immunotherapy, oncolytic viral therapy, and combinations thereof” (Para. 3). GMCI is interpreted as gene-mediated cytotoxic immunotherapy (Para. 4). Thus, Wang, Sriramachandran and Aguilar Cordova teach a method further comprising administering to the patient a therapeutically effective amount of an anticancer agent, a therapeutically effective amount of radiation therapy, or a combination thereof.
Wang, Sriramachandran and Aguilar Cordova are considered to be analogous to the claimed invention because they are in the same field of DNA Damage Response. Therefore, it would have been obvious to someone of ordinary skill in the art before the effective filing date of the claimed invention to modify the method of detecting a 3' flap Okazaki fragment in a patient having cancer as taught by Wang and Sriramachandran to incorporate the method of administering a therapeutically effective amount of a DNA Damage Response Inhibitor to a cancer patient as taught by Aguilar Cordova and provide a method for detecting a 3' flap Okazaki fragment in a patient having cancer further comprising administering to the patient a therapeutically effective amount of a DNA Damage Response Inhibitor. Doing so would allow for treatment of cancer patients with a therapeutic amount of DNA Damage Response Inhibitor.
Claim 4 is rejected under 35 U.S.C. 103 as being unpatentable over Wang et al. (“Wang”; (2021). MIF is a 3' flap nuclease that facilitates DNA replication and promotes tumor growth. Nature communications, 12(1), 2954.) in view of Sriramachandran et al. (“Sriramachandran”; (2020). Genome-wide Nucleotide-Resolution Mapping of DNA Replication Patterns, Single-Strand Breaks, and Lesions by GLOE-Seq. Molecular cell, 78(5), 975–985.e7.) and Aguilar Cordova et al. (“Aguilar Cordova”; Patent App. Pub. No. WO 2020172671 A1, Aug. 27, 2020).
Wang discloses “How cancer cells cope with high levels of replication stress during rapid proliferation is currently unclear. Here, we show that macrophage migration inhibitory factor (MIF) is a 3’ flap nuclease that translocates to the nucleus in S phase. Poly(ADP-ribose) polymerase 1 co-localizes with MIF to the DNA replication fork, where MIF nuclease activity is required to resolve replication stress and facilitates tumor growth. MIF loss in cancer cells leads to mutation frequency increases, cell cycle delays and DNA synthesis and cell growth inhibition, which can be rescued by restoring MIF, but not nuclease-deficient MIF mutant. MIF is significantly upregulated in breast tumors and correlates with poor overall survival in patients. We propose that MIF is a unique 3’ nuclease, excises flaps at the immediate 3’ end during DNA synthesis and favors cancer cells evading replication stress-induced threat for their growth” (Abstract).
Regarding claim 4, Wang teaches “DNA replication produces both 5’ flap and 3’ flap DNA overhang structures, which are detrimental to cell proliferation. Resolving 3’ flap and 5’ flap DNA structures is equally important”, “Pol δ and Pol ε have been well recognized for their functions in the removal of mis-incorporated nucleotides in a 3’->5’ direction” and “mutant Pol δ and Pol ε identified in certain human cancers” (Pg. 2, Col. 1, Para. 3). Thus, Wang suggests a reason for detecting a 3’ flap Okazaki fragment in a patient having cancer.
However, Wang does not teach a method comprising detecting a 3’ flap Okazaki fragment in a biological sample obtained from a patient having cancer.
Sriramachandran discloses “DNA single-strand breaks (SSBs) are among the most common lesions in the genome, arising spontaneously and as intermediates of many DNA transactions. Nevertheless, in contrast to double-strand breaks (DSBs), their distribution in the genome has hardly been addressed in a meaningful way. We now present a technique based on genome-wide ligation of 3′-OH ends followed by sequencing (GLOE-Seq) and an associated computational pipeline designed for capturing SSBs but versatile enough to be applied to any lesion convertible into a free 3′-OH terminus. We demonstrate its applicability to mapping of Okazaki fragments without prior size selection and provide insight into the relative contributions of DNA ligase 1 and ligase 3 to Okazaki fragment maturation in human cells. In addition, our analysis reveals biases and asymmetries in the distribution of spontaneous SSBs in yeast and human chromatin, distinct from the patterns of DSBs” (Summary).
Regarding claim 4, Sriramachandran teaches a method comprising “Treatment of HCT116 and HCT116 LIG3−/−:mL3 cells with siRNA was carried out… post siRNA transfection, cells were passaged… and grown … before being harvested and immediately processed for GLOE-Seq” (Pg. 985 e.6, Ligase 1 Depletion in Human Cells, Para. 1). Sriramachandran teaches a method comprising “preparation of genomic DNA” (Pg. 985 e.7, Preparation of Mammalian Genomic DNA, Para. 1). Sriramachandran teaches a method comprising “GLOE-Seq protocol” (Pg. 985 e.7, Application of GLOE-Seq to Human Genomic DNA, Para. 1). “GLOE-Seq protocol” “HCT116” (Pg. 985 e.4, Cell lines, Para. 1). HCT116 reads on cells that originated from a patient's colon cancer. "GLOE-SEQ” reads on detecting 3’ flap of Okazaki fragment. Thus, Wang and Sriramachandran teach a method comprising (i) detecting a 3' flap Okazaki fragment in a biological sample obtained from the patient; and
Sriramachandran suggests a method comprising “applications of GLOE-Seq to probe the effects of medically relevant factors or treatments associated with SSBs, such as … proteins involved in homologous recombination or protein-DNA crosslink repair, as well as pertinent inhibitors of such factors” (Pg. 982, Potential Applications of GLOE-Seq, Para. 1).
Wang and Sriramachandran do not explicitly teach the limitations of claim administering to the patient a therapeutically effective amount of a DNA Damage Response Inhibitor.
Aguilar Cordova discloses methods of treating a cancer in a subject, comprising treating the subject with a combination of gene-mediated cytotoxic immunotherapy and an inhibitor of a DNA damage repair agent which is not ATR.
Regarding claims 4, Aguilar Cordova teaches a method wherein “cancer therapy involves the administration of DNA damage response inhibitors (DDRI’s) which stop the repair of breaks in single- stranded and/or double- stranded DNA. Both DNA double- and single-strand break repair are highly coordinated processes utilizing signal transduction cascades and post-translational modifications such as phosphorylation, acetylation and ADP ribosylation. DDRI’s are a class of molecules which act on target proteins that function in pathway that perform DNA damage repair within a cell. DDRI targets include ataxia-telangiectasia mutated (ATM) kinase… checkpoint kinase 1 (CHK1), checkpoint kinase 2 (CHK2) …” (Para. 5). Aguilar Cordova teaches a method wherein “dosing of the DDRI, including the route of administration and dosage levels depend on the properties of the specific DDRI agent. These are typically characterized by balancing commonly used metrics of clinical efficacy (e.g. tumor shrinkage, survival, time to disease progression, improvements in symptoms)” (Para. 49). Thus, Wang, Sriramachandran and Aguilar Cordova teaches a method comprising: (ii) administering to the patient a therapeutically effective amount of a DNA Damage Response Inhibitor.
Wang, Sriramachandran and Aguilar Cordova are considered to be analogous to the claimed invention because they are in the same field of DNA Damage response. Therefore, it would have been obvious to someone of ordinary skill in the art before the effective filing date of the claimed invention to have utilized the teachings of 3’ flap Okazaki fragments in a patient having cancer as taught by Wang to incorporate the method assay of detecting 3’ end of Okazaki fragments as taught by Sriramachandran and method of administering a therapeutically effective amount of a DNA Damage Response Inhibitor to a cancer patient as taught by Aguilar Cordova and provide a method for detecting a 3' flap Okazaki fragment in a patient having cancer and administering to the patient a therapeutically effective amount of a DNA Damage Response Inhibitor. Doing so would allow for further characterization of Okazaki fragment maturation and DNA Damage Response in sample of a cancer patient and treatment of cancer patients with a therapeutic amount of DNA Damage Response Inhibitor.
Claim 5 is rejected under 35 U.S.C. 103 as being unpatentable over Aguilar Cordova et al. (“Aguilar Cordova”; Patent App. Pub. No. WO 2020172671 A1, Aug. 27, 2020) in view of Wang et al. (“Wang”; (2021). MIF is a 3' flap nuclease that facilitates DNA replication and promotes tumor growth. Nature communications, 12(1), 2954.).
Aguilar Cordova discloses “methods of treating a cancer in a subject, comprising treating the subject with a combination of gene-mediated cytotoxic immunotherapy and an inhibitor of a DNA damage repair agent ...” (Abstract).
Regarding claims 5, Aguilar Cordova teaches a method wherein “cancer therapy involves the administration of DNA damage response inhibitors (DDRI’s) which stop the repair of breaks in single- stranded and/or double- stranded DNA. Both DNA double- and single-strand break repair are highly coordinated processes utilizing signal transduction cascades and post-translational modifications such as phosphorylation, acetylation and ADP ribosylation. DDRI’s are a class of molecules which act on target proteins that function in pathway that perform DNA damage repair within a cell. DDRI targets include ataxia-telangiectasia mutated (ATM) kinase… checkpoint kinase 1 (CHK1), checkpoint kinase 2 (CHK2) …” (Para. 5). Aguilar Cordova teaches a method wherein “dosing of the DDRI, including the route of administration and dosage levels depend on the properties of the specific DDRI agent. These are typically characterized by balancing commonly used metrics of clinical efficacy (e.g. tumor shrinkage, survival, time to disease progression, improvements in symptoms)” (Para. 49). Thus, Aguilar Cordova teaches a method comprising administering to the patient a therapeutically effective amount of a DNA Damage Response Inhibitor.
However, Aguilar Cordova does not teach a method wherein a biological sample obtained from the patient contains a 3’ flap Okazaki fragment.
Wang discloses “How cancer cells cope with high levels of replication stress during rapid proliferation is currently unclear. Here, we show that macrophage migration inhibitory factor (MIF) is a 3’ flap nuclease that translocates to the nucleus in S phase. Poly(ADP-ribose) polymerase 1 co-localizes with MIF to the DNA replication fork, where MIF nuclease activity is required to resolve replication stress and facilitates tumor growth. MIF loss in cancer cells leads to mutation frequency increases, cell cycle delays and DNA synthesis and cell growth inhibition, which can be rescued by restoring MIF, but not nuclease-deficient MIF mutant. MIF is significantly upregulated in breast tumors and correlates with poor overall survival in patients. We propose that MIF is a unique 3’ nuclease, excises flaps at the immediate 3’ end during DNA synthesis and favors cancer cells evading replication stress-induced threat for their growth” (Abstract).
Regarding claim 5, Wang teaches “DNA replication produces both 5’ flap and 3’ flap DNA overhang structures, which are detrimental to cell proliferation. Resolving 3’ flap and 5’ flap DNA structures is equally important”, “Pol δ and Pol ε have been well recognized for their functions in the removal of mis-incorporated nucleotides in a 3’->5’ direction” and “mutant Pol δ and Pol ε identified in certain human cancers” (Pg. 2, Col. 1, Para. 3). Thus, Wang suggests a biological sample obtained from a patient having cancer contains a 3’ flap Okazaki fragment.
Aguilar Cordova and Wang are considered to be analogous to the claimed invention because they are in the same field of DNA Damage response. Therefore, it would have been obvious to someone of ordinary skill in the art before the effective filing date of the claimed invention to have modified the method of administering a therapeutically effective amount of a DNA Damage Response Inhibitor to a cancer patient as taught by Aguilar Cordova to incorporate the teachings of 3’ flap Okazaki fragments in a patient having cancer as taught by Wang and provide a method for treating cancer in a patient in need thereof. Doing so would allow for treatment of cancer patients with 3’ flap Okazaki fragments with a therapeutic amount of DNA Damage Response Inhibitor.
Claims 8-9 and 10-15 are rejected under 35 U.S.C. 103 as being unpatentable over Wang et al. (“Wang”; (2021). MIF is a 3' flap nuclease that facilitates DNA replication and promotes tumor growth. Nature communications, 12(1), 2954.) in view of Sriramachandran et al. (“Sriramachandran”; (2020). Genome-wide Nucleotide-Resolution Mapping of DNA Replication Patterns, Single-Strand Breaks, and Lesions by GLOE-Seq. Molecular cell, 78(5), 975–985.e7.) as applied to claim 1 above, and further in view of Zheng et al. (“Zheng”; (2011). Fen1 mutations that specifically disrupt its interaction with PCNA cause aneuploidy-associated cancer. Cell research, 21(7), 1052–1067.).
The teachings of Wang and Sriramachandran are documented above in the rejection of claim 1 under 35 U.S.C. 103. Claims 8-10 depend on claim 1. Claims 11-15 depends on claim 10, which depends on Claim 1.
Regarding claims 8-9, Zheng teaches a method wherein “FEN1 mutations exist in several different human cancer types… The genetic change and functional deficiency of the FEN1 gene contributes substantially to the development of cancer.” (Pg. 5, Discussion, Para. 1). Zheng teaches Table 1 indicating lymphoma occurs with Fen1 ED knock-in mutations (Pg. 816, Table 1). “Lymphoma” reads on the same type of cells involved in ALL, (i.e. lymphoid progenitor cells). “Cancer” reads on leukemia and acute lymphoblastic leukemia. Thus, Wang, Sriramachandran and Zheng teach a method wherein the cancer is leukemia and wherein the cancer is acute lymphoblastic leukemia.
Regarding claims 10-15, Zheng teaches a method wherein “FEN1 mutations exist in several different human cancer types… The genetic change and functional deficiency of the FEN1 gene contributes substantially to the development of cancer.” (Pg. 5, Discussion, Para. 1). Furthermore, Zheng teaches Table 1 indicating lung cancer occurs with Fen1 ED knock-in mutation (Pg. 816, Table 1). “Cancer” reads on EGFR-mutated lung cancer, small cell lung cancer, EGFR-mutated small cell lung cancer, non-small cell lung cancer, and EGFR-mutated non-small cell lung cancer. Thus, Wang, Sriramachandran and Zheng teach a method wherein the cancer is lung cancer; wherein the lung cancer is EGFR-mutated lung cancer; wherein the lung cancer is small cell lung cancer; wherein the lung cancer is EGFR-mutated small cell lung cancer, wherein the lung cancer is non-small cell lung cancer; and wherein the lung cancer is EGFR-mutated non-small cell lung cancer.
Wang, Aguilar Cordova and Zheng are considered to be analogous to the claimed invention because they are in the same field of DNA Damage Response. Therefore, it would have been obvious to someone of ordinary skill in the art before the effective filing date of the claimed invention to modify the method of detecting a 3' flap Okazaki fragment in a patient having cancer as taught by Wang and Sriramachandran to incorporate the method wherein the cancer is several different human cancer types as taught by Zheng and provide a method for detecting a 3' flap Okazaki fragment in a patient having cancer, wherein the cancer may develop in lymphoid progenitor cells or lung cells. Doing so would allow for further characterization of 3’ flap Okazaki fragment maturation and DNA Damage Response in sample of a cancer patient wherein the cancer is leukemia, acute lymphoblastic leukemia, EGFR-mutated lung cancer, small cell lung cancer, EGFR-mutated small cell lung cancer, non-small cell lung cancer or EGFR-mutated non-small cell lung cancer.
Claim 18 is rejected under 35 U.S.C. 103 as being unpatentable over Wang et al. (“Wang”; (2021). MIF is a 3' flap nuclease that facilitates DNA replication and promotes tumor growth. Nature communications, 12(1), 2954.) in view of Sriramachandran et al. (“Sriramachandran”; (2020). Genome-wide Nucleotide-Resolution Mapping of DNA Replication Patterns, Single-Strand Breaks, and Lesions by GLOE-Seq. Molecular cell, 78(5), 975–985.e7.) and Aguilar Cordova et al. (“Aguilar Cordova”; Patent App. Pub. No. WO 2020172671 A1, Aug. 27, 2020) as applied to claim 16 above, and further in view of Barnieh et al. (“Barnieh”; (2021). Progress towards a clinically-successful ATR inhibitor for cancer therapy. Current research in pharmacology and drug discovery, 2, 100017).
The teachings of Wang, Sriramachandran and Aguilar Cordova are documented above in the rejection of claims 1, 3 and 16 under 35 U.S.C. 103. Claim 18 depends on claim 16 which depends on claim 3 which depends on claim 1. Wang, Sriramachandran and Aguilar Cordova do not explicitly teach the limitations of claim wherein the ATR kinase inhibitor is berzosertib or elimusertib.
Barnieh discloses “The DNA damage response (DDR) is now known to play an important role in both cancer development and its treatment. Targeting proteins such as ATR (Ataxia telangiectasia mutated and Rad3-related) kinase, a major regulator of DDR, has demonstrated significant therapeutic potential in cancer treatment, with ATR inhibitors having shown anti-tumour activity not just as monotherapies, but also in potentiating the effects of conventional chemotherapy, radiotherapy, and immunotherapy. This review focuses on the biology of ATR, its functional role in cancer development and treatment, and the rationale behind inhibition of this target as a therapeutic approach, including evaluation of the progress and current status of development of potent and specific ATR inhibitors that have emerged in recent decades. The current applications of these inhibitors both in preclinical and clinical studies either as single agents or in combinations with chemotherapy, radiotherapy and immunotherapy are also extensively discussed. This review concludes with some insights into the various concerns raised or observed with ATR inhibition in both the preclinical and clinical settings, with some suggested solutions” (Abstract).
Regarding claim 18, Barnieh teaches “DDR pathways are crucial to both the development of cancers and their treatments, as cancer cells with defective DDR mechanisms exhibit high sensitivity to certain therapeutics” (Pg. 1, 1. Introduction: An overview of DNA damage response (DDR) machinery in cancer, Para. 2). Barnieh teaches “tumour cells are more likely to rely on residual pathways such as the ATR pathway in order to repair and survive this self-inflicted excessive DNA damage, and its consequential cell death. Targeting these residual DDR pathways may therefore be selectively toxic to cancer cells with mutations in certain DDR genes” (Pg. 2 Col. 2. Para. 1). Barnieh teaches “Berzosertib is the first ATR inhibitor to be evaluated in humans” (Pg. 9, 2.2. ATR inhibitors that have progressed to cancer clinical trials, Para.1; Table 1- Berzosertib; Table 2- Berzosertib). Thus, Wang, Sriramachandran, Aguilar Cordova and Barnieh teaches a method wherein the ATR kinase inhibitor is berzosertib or elimusertib.
Wang, Sriramachandran, Aguilar Cordova and Barnieh are considered to be analogous to the claimed invention because they are in the same field of DNA Damage Response. Therefore, it would have been obvious to someone of ordinary skill in the art before the effective filing date of the claimed invention to modify the method of detecting a 3' flap Okazaki fragment in a patient having cancer further comprising administering to the patient a therapeutically effective amount of a DNA Damage Response Inhibitor as taught by Wang, Sriramachandran and Aguilar Cordova to incorporate the method of administration of the ATR inhibitor Berzosertib in cancer patients as taught by Barnieh and provide a method of administering a therapeutically effective amount of a DNA Damage Response Inhibitor to a cancer patient wherein the ATR kinase inhibitor is berzosertib. Doing so would allow for treatment of cancer patients with a therapeutic amount of DNA Damage Response ATR Inhibitor Berzosertib as a monotherapy or in combination therapy.
Conclusion
No Claims are in condition for allowance.
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/KENDRA R VANN-OJUEKAIYE/Examiner, Art Unit 1682
/KATHERINE D SALMON/Primary Examiner, Art Unit 1682