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 .
The amendment filed on 04/16/2026 has been entered.
Claims 1, 4-5, 7-8, 11, 14, 17, 20 were amended in the claim set filed on 04/16/2026.
Please note, some amendments were not properly indicated in the claim amendments file 04/16/2026, such as amendments to claim 14 and 17. However for sake of compact prosecution the claim set filed on 04/16/2026 has been entered.
Claims 21-31 were added in the claim set filed on 04/16/2026. No new matter was added.
Claims 2-3, 6,9, 12-13, 15-16, 18-19 were canceled in the claim set filed on 04/16/2026.
Claims 1, 4-5, 7-8, 10-11, 14, 17 and 20-31 in the claim set filed on 04/16/2026 are currently under examination.
Response to the Arguments
Objections to the Claims and Specification in the previously mailed non-final have been withdrawn in light of applicants Claim and Specification amendments.
Applicant’s arguments regarding previous rejection(s) of claim(s) 17-19 under 35 U.S.C. 112 have been fully considered and are persuasive. The 35 U.S.C. 112 rejections documented in the previously mailed non-final have been withdrawn in light of applicants claim amendments and arguments on Pg. 9-10.
Applicant’s arguments regarding previous rejection(s) of claim(s) 1, 4-5, 7-8, 10-11, 14, and 17 and 20 under 35 U.S.C. 103 have been fully considered but are not persuasive. The 35 U.S.C. 103 rejections documented in the previously mailed non-final have been revised and maintained in light of applicants claim amendments and arguments on Pg. 9-14. Revised rejection for claims 1, 4-5, 7-8, 10-11, 14, and 17 and 20 are made as documented below in the 35 U.S.C. 103 rejection in this office action on Pg. 5-29.
As necessitated by amendment, new grounds of claim objections of claim(s) 20 and 26 have been made documented below in this office Final action on Pg. 3-4.
As necessitated by amendment, new grounds of rejections under 35 U.S.C. 112 of claim(s) 7 and 23 have been made as documented below in this Final office action on Pg. 4-5.
As necessitated by amendment, new grounds of rejections under 35 U.S.C. 103 of claim(s) 21-31 have been made as documented below in this Final office action on Pg. 5-29.
The new grounds of objection and rejection for claims 1, 4-5, 7-8, 10-11, 14, 17 and 21-31 are documented below in this Final Office Action are necessitated by claim amendments filed on 04/16/2026.
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.
Claim Objections
Claim 20 is objected to under 37 CFR 1.75 as being a substantial duplicate of claim 17. 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 26 is objected to under 37 CFR 1.75 as being a substantial duplicate of claim 14. 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 7, 23, and 29 are rejected under 35 U.S.C. 112(b) or 35 U.S.C. 112 (pre-AIA ), second paragraph, as being indefinite for failing to particularly point out and distinctly claim the subject matter which the inventor or a joint inventor (or for applications subject to pre-AIA 35 U.S.C. 112, the applicant), regards as the invention.
Claim 7, 23, and 29 recite the limitation "the biological sample" in line 1. There is insufficient antecedent basis for this limitation in the claim. In this regard, claim 7 depends from claim 1 and claim 1 does not recite “a biological sample”. Similarly, claim 23 depends from claim 4 and claim 4 does not recite “a biological sample” whereas claim 29 depends from claim 5 and claim 5 does not recite “a biological sample”.
The following is a quotation of 35 U.S.C. 112(d):
(d) REFERENCE IN DEPENDENT FORMS.—Subject to subsection (e), a claim in dependent form shall contain a reference to a claim previously set forth and then specify a further limitation of the subject matter claimed. A claim in dependent form shall be construed to incorporate by reference all the limitations of the claim to which it refers.
The following is a quotation of pre-AIA 35 U.S.C. 112, fourth paragraph:
Subject to the following paragraph [i.e., the fifth paragraph of pre-AIA 35 U.S.C. 112], a claim in dependent form shall contain a reference to a claim previously set forth and then specify a further limitation of the subject matter claimed. A claim in dependent form shall be construed to incorporate by reference all the limitations of the claim to which it refers.
Claim 7 is rejected under 35 U.S.C. 112(d) or pre-AIA 35 U.S.C. 112, 4th paragraph, as being of improper dependent form for failing to further limit the subject matter of the claim upon which it depends, or for failing to include all the limitations of the claim upon which it depends. The claim recites the limitation “The method of claim 1, wherein the biological sample is genomic DNA in the cancer cell”. Amended claim 1 does not recite “a biological sample”, rather claim 1 has already recited “in a cancer cell obtained from the patient having cancer”. Applicant may cancel the claim(s), amend the claim(s) to place the claim(s) in proper dependent form, rewrite the claim(s) in independent form, or present a sufficient showing that the dependent claim(s) complies with the statutory requirements.
Claim 23 rejected under 35 U.S.C. 112(d) or pre-AIA 35 U.S.C. 112, 4th paragraph, as being of improper dependent form for failing to further limit the subject matter of the claim upon which it depends, or for failing to include all the limitations of the claim upon which it depends. The claim recites the limitation “The method of claim 4, wherein the biological sample is genomic DNA in the cancer cell”. Amended claim 1 does not recite “a biological sample”, rather claim 4 has already recited “in a cancer cell obtained from the patient having cancer”. Applicant may cancel the claim(s), amend the claim(s) to place the claim(s) in proper dependent form, rewrite the claim(s) in independent form, or present a sufficient showing that the dependent claim(s) complies with the statutory requirements.
Claim 29 is rejected under 35 U.S.C. 112(d) or pre-AIA 35 U.S.C. 112, 4th paragraph, as being of improper dependent form for failing to further limit the subject matter of the claim upon which it depends, or for failing to include all the limitations of the claim upon which it depends. The claim recites the limitation “The method of claim 5, wherein the biological sample is genomic DNA in the cancer cell”. Amended claim 1 does not recite “a biological sample”, rather claim 5 has already recited “in a cancer cell obtained from the patient having cancer”. Applicant may cancel the claim(s), amend the claim(s) to place the claim(s) in proper dependent form, rewrite the claim(s) in independent form, or present a sufficient showing that the dependent claim(s) complies with the statutory requirements.
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, 7, and 21 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… 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). Furthermore, Wang teaches that “Tumor cells suffer with high levels of DNA replication stress, which poses a threat to their viability. Our oncogenic studies clearly showed that MIF promotes cancer cell growth in vitro and in vivo” (Pg. 14, Col.1 Para. 2). Wang also teaches “In addition, polymerase dissociation from DNA occurs when a second structure like R-loop, hairpin, stem-loop, G-quadruplex, fork reversal, or slippage replication is formed during replication. Pol δ and Pol ε are also less stringent in discriminating dNTPs and rNTPs. Misincorporation of rNTPs occurs and causes replication stress. Under these conditions, MIF may resolve second structures like hairpin and stem-loop and correct misincorporation, which is supported by our in vitro MIF nuclease assay and in vivo mutation analysis. Thus, MIF may also cooperate with nuclease-proficient Pol δ and Pol ε and allow them to maintain high speed of DNA replication. Further investigation is required to explore how MIF cooperates with polymerases during DNA replication”(Pg. 13). Wang also teaches that “we found that the proofreading ability of MIF is not as precise as that of Pol δ does, because more mutations were generated in gap-filling reactions carried out by proofreading-deficient δ supplemented with MIF than those conducted by Pol δ” (Pg. 13) Wang also teaches “These data indicate that MIF recognizes Y-shaped dsDNA as the substrate and possesses both 3’ exonuclease activity and 3’ flap endonuclease activity to selectively cleave away the short flap at the 3’ end, which depends on the substrate structure but not sequence”(Pg. 2). Lastly, Fig. 2A depicts four types of 5’ biotin-labeled short DNA primers complementary to the template DNA without or with 1–3 nt mismatched nucleotides at the 3’ end, indicative of Okazaki fragments with or without a 3’ flap of variable length. Fig. 2B depicts an In vitro DNA elongation assay mediated by Pol δ or 3’ nuclease-deficient Pol δ D402A mutant (Pol δ-M) in the presence or absence of MIF using a 99-bp DNA template and short primers listed in Fig. 2A. The EtBr stained gel appears to have elevated levels of 3’ flap primer complexed with template strand (T) indicative of the 3’ flap Okazaki fragment in Pol δM positive and Pol δM and MIF positive lanes compared to controls. Furthermore, the length indicative of 3’ flap of the Okazaki fragment appears to play a role in the level of MIF processing (elongation product) in the presence of Pol δ-M, which one of the skill in the art would also expect secondary structure formed in longer 3’ flaps to alter MIF processing and Pol δ gap-filling as well. (Figure 2A, see below)
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Hence, one of ordinary skill in the art would be motivated to further evaluate the proofreading accuracy and proficiency of high levels or homozygous loss of MIF in 3’ flaps processing or alterations thereof of 3’ flap Okazaki fragments in promoting cancer growth under stress with mutant Pol δ and Pol ε in cancer cells. Furthermore, one of skill in the art would be motivated to evaluate how longer 3’ flap Okazaki fragments and secondary structure of the 3’ flap affects nuclease activity, repair and elongation in cancer cells with Pol δ-M. Thus, Wang suggests motivation for detecting a 3’ flap Okazaki fragment in a cancer cell obtained from a patient having cancer with an expectation of detecting elevated levels of 3’ flap Okazaki fragments with Pol δ-M compared to a control in cancer cells.
However, Wang does not teach a method comprising detecting a 3’ flap Okazaki fragment in a cancer cell obtained from the 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 1, Sriramachandran teaches “We developed a method based on capturing SSBs via genome-wide ligation of 30-hydroxy (OH) ends followed by sequencing (GLOE-Seq)” (Pg. 975). 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). “HCT116” (Pg. 985 e.4, Cell lines, Para. 1). HCT116 reads on cancer cell obtained from a patient's having cancer. “GLOE-SEQ” reads on detecting 3’ end of Okazaki fragment. Thus, Wang and Sriramachandran suggest a method for detecting a 3' flap Okazaki fragment in a patient having cancer, the method comprising detecting an elevated level, relative to a control, of a 3' flap Okazaki fragment in a cancer cell obtained from the patient having cancer.
Wang and Sriramachandran are considered to be analogous to the claimed invention because they are in the same field of DNA Replication and DNA Damage in cancer cells. Wang suggests further investigation is required to explore how MIF cooperates with polymerases during DNA replication and one of ordinary skill in the art would be motivated to further evaluate the proofreading accuracy and proficiency of high levels or homozygous loss of MIF in 3’ flaps processing or alterations thereof of 3’ flap Okazaki fragments in promoting cancer growth under stress with mutant Pol δ and Pol ε in cancer cells. Therefore, it would have been obvious to someone of ordinary skill in the art before the effective filing date of the claimed invention to try the method of genome-wide ligation of 3′-OH ends followed by sequencing (GLOE-Seq) in a cancer cell obtained in a patient having cancer as suggested by Sriramachandran to detect levels 3’ flap Okazaki fragments in a cancer cell obtained in a patient having cancer with a reasonable expectation of detecting an elevated level of the 3' flap Okazaki fragment relative to a control in a cancer cell as suggested by Wang. 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.
The teachings of Wang and Sriramachandran are documented above in the rejection of claim 1 under 35 U.S.C. 103.
Regarding claim 7, Sriramachandran teaches a method comprising “preparation of genomic DNA” (Pg. 985 e.7, Preparation of Mammalian Genomic DNA, Para. 1). Thus, Wang and Sriramachandran suggest a method wherein the biological sample is genomic DNA in the cancer cell.
Regarding claim 21, Wang teaches ““In addition, polymerase dissociation from DNA occurs when a second structure like R-loop, hairpin, stem-loop, G-quadruplex, fork reversal, or slippage replication is formed during replication.”(Pg. 13). The “hairpin, stem-loop… formed during replication” reads on 3' flap invasion Okazaki fragment, a 3' flap fold-back Okazaki fragment, or a 3' flap fold-back and invasion Okazaki fragment. Thus, Wang and Sriramachandran suggest a method wherein the 3' flap Okazaki fragment is a 3' flap invasion Okazaki fragment, a 3' flap fold-back Okazaki fragment, or a 3' flap fold-back and invasion Okazaki fragment.
Response to Arguments
Applicant's arguments filed 04/06/2026 have been fully considered but they are not
persuasive. Arguments against Wang and Sriramachandran on Pg. 10-14 are not persuasive. To clarify some instances argued in the response filed 04/06/2026 see responses to each argument made by Applicant below:
Applicants’ argument: “Wang does not teach or suggest the existence of elevated levels of 3' flap Okazaki fragments relative to a control and Wang does not teach or suggest that elevate levels of 3' flap Okazaki fragments would be detectable in a cancer cell. ”(Pg. 11) and “the skilled artisan would not have been motivated, based on the teachings of Wang, to detect 3' flaps in a cancer cell and, further, would not have expected to detect elevated levels of 3' flaps. In other words, again, the skilled artisan would not have relied on Wang when developing the present invention which relates to "detecting an elevated level, relative to a control, of a 3' flap Okazaki fragment in a cancer cell” (Pg. 11)..
Response: Applicant' s arguments have been fully considered and found unpersuasive because as stated in the revised 103 rejection above “Lastly, Fig. 2A depicts four types of 5’ biotin-labeled short DNA primers complementary to the template DNA without or with 1–3 nt mismatched nucleotides at the 3’ end, indicative of Okazaki fragments with or without a 3’ flap of variable length. Fig. 2B depicts an In vitro DNA elongation assay mediated by Pol δ or 3’ nuclease-deficient Pol δ D402A mutant (Pol δ-M) in the presence or absence of MIF using a 99-bp DNA template and short primers listed in Fig. 2A. The EtBr stained gel appears to have elevated levels of 3’ flap primer complexed with template strand (T) indicative of the 3’ flap Okazaki fragment in Pol δM positive and Pol δM and MIF positive lanes compared to controls. Furthermore, the length indicative of 3’ flap of the Okazaki fragment appears to play a role in the level of MIF processing (elongation product) in the presence of Pol δ-M, which one of the skill in the art would also expect secondary structure formed in longer 3’ flaps to alter MIF processing and Pol δ gap-filling as well.
Hence, one of ordinary skill in the art would be motivated to further evaluate the proofreading accuracy and proficiency of high levels or homozygous loss of MIF in 3’ flaps processing or alterations thereof of 3’ flap Okazaki fragments in promoting cancer growth under stress with mutant Pol δ and Pol ε in cancer cells. Furthermore, one of skill in the art would be motivated to evaluate how longer 3’ flap Okazaki fragments and secondary structure of the 3’ flap affects nuclease activity, repair and elongation in cancer cells with Pol δ-M. Thus, Wang suggests motivation for detecting a 3’ flap Okazaki fragment in a cancer cell obtained from a patient having cancer with an expectation of detecting elevated levels of 3’ flap Okazaki fragments with Pol δ-M compared to a control in cancer cells.” Accordingly, Wang does suggest the existence of elevated levels of 3’ flap Okazaki fragments relative to a control.
Applicants’ argument: “Applicant notes that the presence of 3'-OH termini in SSBs is completely irrelevant to the detection of elevated levels of 3' flap Okazaki fragments in a cancer cell” (Pg. 12).
Response: Applicant’s arguments have been fully considered and found unpersuasive because as stated in the revised 103 rejection above, “Wang and Sriramachandran are considered to be analogous to the claimed invention because they are in the same field of DNA Replication and DNA Damage in cancer cells. Wang suggests further investigation is required to explore how MIF cooperates with polymerases during DNA replication and one of ordinary skill in the art would be motivated to further evaluate the proofreading accuracy and proficiency of high levels or homozygous loss of MIF in 3’ flaps processing or alterations thereof of 3’ flap Okazaki fragments in promoting cancer growth under stress with mutant Pol δ and Pol ε in cancer cells. Therefore, it would have been obvious to someone of ordinary skill in the art before the effective filing date of the claimed invention to try the method of genome-wide ligation of 3′-OH ends followed by sequencing (GLOE-Seq) in a cancer cell obtained in a patient having cancer as taught by Sriramachandran to detect levels 3’ flap Okazaki fragments in a cancer cell obtained in a patient having cancer with a reasonable expectation of detecting an elevated level of the 3' flap Okazaki fragment relative to a control in a cancer cell as suggested by Wang. 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.” Thus, the presence of 3'-OH termini in SSBs is not irrelevant to the detection of elevated levels of 3' flap Okazaki fragments in a cancer cell.
Applicants’ argument: “Wang does not provide any disclosure or data that correlates cancer with elevated levels of 3' flap Okazaki fragments.” (Pg. 12).
Response: Applicant’s arguments have been fully considered and found unpersuasive because as stated in the revised 103 rejection above and in addition to the previous response above, “mutant Pol δ and Pol ε identified in certain human cancers” (Pg. 2, Col. 1, Para. 3). Furthermore, Wang teaches that “Tumor cells suffer with high levels of DNA replication stress, which poses a threat to their viability. Our oncogenic studies clearly showed that MIF promotes cancer cell growth in vitro and in vivo” (Pg. 14, Col.1 Para. 2).” Thus, mutant Pol δ and MIF play a role in promoting cancer growth. Thus, Wang does provide a disclosure or data that correlates cancer with elevated levels of 3' flap Okazaki fragments.
Claim 4, 14, 17, 20, 22-23 and 26 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.) and 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 claims 1, 7 and 21 under 35 U.S.C. 103. Claim 4 is independent of claim 1, yet the scope of step i of Claim 4 is the same as the limitations of Claim 1. Claims 14, 17, 20, 22-23 and 26 depend on claim 4.
Regarding claim 4 step (i), the rejection of claim 1 as stated above over Wang and Sriramachandran is the same for claim 4 step (i). Sriramachandran further 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).
However, Wang and Sriramachandran do not explicitly teach the limitations of claim 4 step (ii).
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 claim 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; 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 suggest a method comprising: (ii) administering to the patient a therapeutically effective amount of an ATM kinase inhibitor, an ATR kinase inhibitor, a Chkl kinase inhibitor, a Chk2 kinase inhibitor, or a combination of two or more 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 have modified the method for detecting a 3' flap Okazaki fragment in a patient having cancer as suggested by Wang and Sriramachandran to incorporate the method of administering to the patient a therapeutically effective amount of an ATM kinase inhibitor, a Chkl kinase inhibitor, a Chk2 kinase inhibitor, or a combination of two or more thereof as suggested 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.
Regarding claims 14 and 26, 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). Aguilar Cordova teaches a method wherein “the DDRI comprises a CHK1 inhibitor… the CHK1 inhibitor comprises... LY2606368” (Para. 17). AZD0156 reads on 8-[6-[3- (dimethylamino)propoxy]-3-pyridinyl]-3-methyl-1-(oxan-4-yl)imidazo[4,5-c]quinolin-2-one. KU-60019 reads on 2- [(2S,6R)-2,6-dimethylmorpholin-4-yl]-N- [5-(6-morpholin-4-yl-4-oxopyran-2-yl)-9H-thioxanthen- 2-yl]acetamide. AZD1390 reads on 7-fluoro-3-methyl-8-[6-(3-piperidin-1-ylpropoxy)-3-pyridinyl]-1-propan-2- ylimidazo[4,5-c]quinolin-2-on. LY2606368 reads on Prexasertib. Thus, Wang, Sriramachandran and Aguilar Cordova suggest a method wherein the ATM kinase inhibitor is 8-[6-[3- (dimethylamino)propoxy]-3-pyridinyl]-3-methyl-1-(oxan-4-yl)imidazo[4,5-c]quinolin-2-one; 2- [(2S,6R)-2,6-dimethylmorpholin-4-yl]-N- [5-(6-morpholin-4-yl-4-oxopyran-2-yl)-9H-thioxanthen- 2-yl]acetamide; or 7-fluoro-3-methyl-8-[6-(3-piperidin-1-ylpropoxy)-3-pyridinyl]-1-propan-2- ylimidazo[4,5-c]quinolin-2-one; wherein the ATR kinase inhibitor is berzosertib or elimusertib; and wherein the Chkl kinase inhibitor is (R)-5-((4-((morpholin-2-ylmethyl)amino)-5- (trifluoromethyl)pyridin-2-yl)amino)pyrazine-2-carbonitrile or prexasertib.
Regarding claims 17 and 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 suggest 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.
Regarding claim 22, Wang teaches ““In addition, polymerase dissociation from DNA occurs when a second structure like R-loop, hairpin, stem-loop, G-quadruplex, fork reversal, or slippage replication is formed during replication.”(Pg. 13). The “hairpin, stem-loop… formed during replication” reads on 3' flap invasion Okazaki fragment, a 3' flap fold-back Okazaki fragment, or a 3' flap fold-back and invasion Okazaki fragment. Thus, Wang, Sriramachandran and Aguilar Cordova suggest a method wherein the 3' flap Okazaki fragment is a 3' flap invasion Okazaki fragment, a 3' flap fold-back Okazaki fragment, or a 3' flap fold-back and invasion Okazaki fragment.
Regarding claim 23, Sriramachandran teaches a method comprising “preparation of genomic DNA” (Pg. 985 e.7, Preparation of Mammalian Genomic DNA, Para. 1). Thus, Wang, Sriramachandran and Aguilar Cordova suggest a method wherein the biological sample is genomic DNA in the cancer cell.
Response to Arguments
Applicant's arguments filed 04/06/2026 have been fully considered but they are not
persuasive. Arguments against Wang and Sriramachandran on Pg. 10-14 are not persuasive as discussed above. Furthermore, to clarify some instances argued in the response filed 04/06/2026 see responses to each argument made by Applicant below:
Applicants’ argument: “Cordova is completely silent regarding 3' flap Okazaki fragments, the relevance of3' flap Okazaki fragments to cancer, and, specifically, elevated levels of3' flap Okazaki fragments in cancer ”(Pg. 13).
Response: In response to applicant's arguments against the references individually, one cannot show nonobviousness by attacking references individually where the rejections are based on combinations of references. See In re Keller, 642 F.2d 413, 208 USPQ 871 (CCPA 1981); In re Merck & Co., 800 F.2d 1091, 231 USPQ 375 (Fed. Cir. 1986).
Claims 5, 27-28 and 31 are 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; 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, Aguilar Cordova suggests a method comprising administering to the patient a therapeutically effective amount of an ATM kinase inhibitor, an ATR kinase inhibitor, a Chkl kinase inhibitor, a Chk2 kinase inhibitor, or a combination of two or more thereof.
However, Aguilar Cordova does not explicitly teach a method wherein a biological sample obtained from the patient contains an elevated level, relative to a control, of 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… 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). Wang teaches that “As a DNA damage sensor, PARP1 dynamically binds to DNA and recognizes DNA damage, thereby recruiting nucleases and DNA repair proteins to the sites of DNA damage to facilitate DNA repair. Recent studies revealed that PARP1 is activated by unligated Okazaki fragments in S phase” (Pg. 13). Accordingly, DNA damage proteins are targeted to the unligated Okazaki fragments. Furthermore, Wang teaches that “Tumor cells suffer with high levels of DNA replication stress, which poses a threat to their viability. Our oncogenic studies clearly showed that MIF promotes cancer cell growth in vitro and in vivo” (Pg. 14, Col.1 Para. 2). Wang also teaches “In addition, polymerase dissociation from DNA occurs when a second structure like R-loop, hairpin, stem-loop, G-quadruplex, fork reversal, or slippage replication is formed during replication. Pol δ and Pol ε are also less stringent in discriminating dNTPs and rNTPs. Misincorporation of rNTPs occurs and causes replication stress. Under these conditions, MIF may resolve second structures like hairpin and stem-loop and correct misincorporation, which is supported by our in vitro MIF nuclease assay and in vivo mutation analysis. Thus, MIF may also cooperate with nuclease-proficient Pol δ and Pol ε and allow them to maintain high speed of DNA replication. Further investigation is required to explore how MIF cooperates with polymerases during DNA replication”(Pg. 13). Wang teaches that “we found that the proofreading ability of MIF is not as precise as that of Pol δ does, because more mutations were generated in gap-filling reactions carried out by proofreading-deficient δ supplemented with MIF than those conducted by Pol δ” (Pg. 13). Wang also teaches “These data indicate that MIF recognizes Y-shaped dsDNA as the substrate and possesses both 3’ exonuclease activity and 3’ flap endonuclease activity to selectively cleave away the short flap at the 3’ end, which depends on the substrate structure but not sequence”(Pg. 2). Lastly, Fig. 2A depicts four types of 5’ biotin-labeled short DNA primers complementary to the template DNA without or with 1–3 nt mismatched nucleotides at the 3’ end, indicative of Okazaki fragments with or without a 3’ flap of variable length. Fig. 2B depicts an In vitro DNA elongation assay mediated by Pol δ or 3’ nuclease-deficient Pol δ D402A mutant (Pol δ-M) in the presence or absence of MIF using a 99-bp DNA template and short primers listed in Fig. 2A. The EtBr stained gel appears to have elevated levels of 3’ flap primer complexed with template strand (T) indicative of the 3’ flap Okazaki fragment in Pol δM positive and Pol δM and MIF positive lanes compared to controls. Furthermore, the length indicative of 3’ flap of the Okazaki fragment appears to play a role in the level of MIF processing (elongation product) in the presence of Pol δ-M, which one of the skill in the art would also expect secondary structure formed in longer 3’ flaps to alter MIF processing and Pol δ gap-filling as well. (Figure 2A, see below)
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Hence, one of ordinary skill in the art would be motivated to further evaluate the proofreading accuracy and proficiency of high levels or homozygous loss of MIF in 3’ flaps processing or alterations thereof of 3’ flap Okazaki fragments in promoting cancer growth under stress with mutant Pol δ and Pol ε in cancer cells. Furthermore, one of skill in the art would be motivated to evaluate how longer 3’ flap Okazaki fragments and secondary structure of the 3’ flap affects nuclease activity, repair and elongation in cancer cells with Pol δ-M. Thus, Wang suggests motivation for 3’ flap Okazaki fragment in a cancer cell obtained from a patient having cancer with an expectation of elevated levels of 3’ flap Okazaki fragments with Pol δ-M compared to a control in cancer cells.
Thus, Aguilar Cordova and Wang suggest a method according to the limitations of claim 5.
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 suggested by Aguilar Cordova to incorporate the suggestion of DNA repair proteins recruited to elevated 3’ flap Okazaki fragments in a patient having cancer as suggested 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 elevated 3’ flap Okazaki fragments with a therapeutic amount of DNA Damage Response Inhibitor.
Regarding claim 27, 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, Aguilar Cordova and Wang suggest 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.
Regarding claim 28, Wang teaches “In addition, polymerase dissociation from DNA occurs when a second structure like R-loop, hairpin, stem-loop, G-quadruplex, fork reversal, or slippage replication is formed during replication.”(Pg. 13). The “hairpin, stem-loop… formed during replication” reads on 3' flap invasion Okazaki fragment, a 3' flap fold-back Okazaki fragment, or a 3' flap fold-back and invasion Okazaki fragment. Thus, Wang, Sriramachandran and Aguilar Cordova suggest a method wherein the 3' flap Okazaki fragment is a 3' flap invasion Okazaki fragment, a 3' flap fold-back Okazaki fragment, or a 3' flap fold-back and invasion Okazaki fragment. Thus, Aguilar Cordova and Wang suggest a method wherein the 3' flap Okazaki fragment is a 3' flap invasion Okazaki fragment, a 3' flap fold-back Okazaki fragment, or a 3' flap fold-back and invasion Okazaki fragment.
Regarding claim 31, 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). Aguilar Cordova teaches a method wherein “the DDRI comprises a CHK1 inhibitor… the CHK1 inhibitor comprises... LY2606368” (Para. 17). AZD0156 reads on 8-[6-[3- (dimethylamino)propoxy]-3-pyridinyl]-3-methyl-1-(oxan-4-yl)imidazo[4,5-c]quinolin-2-one. KU-60019 reads on 2- [(2S,6R)-2,6-dimethylmorpholin-4-yl]-N- [5-(6-morpholin-4-yl-4-oxopyran-2-yl)-9H-thioxanthen- 2-yl]acetamide. AZD1390 reads on 7-fluoro-3-methyl-8-[6-(3-piperidin-1-ylpropoxy)-3-pyridinyl]-1-propan-2- ylimidazo[4,5-c]quinolin-2-on. LY2606368 reads on Prexasertib. Thus, Aguilar Cordova and Wang suggest a method wherein the ATM kinase inhibitor is 8-[6-[3- (dimethylamino)propoxy]-3-pyridinyl]-3-methyl-1-(oxan-4-yl)imidazo[4,5-c]quinolin-2-one; 2- [(2S,6R)-2,6-dimethylmorpholin-4-yl]-N- [5-(6-morpholin-4-yl-4-oxopyran-2-yl)-9H-thioxanthen- 2-yl]acetamide; or 7-fluoro-3-methyl-8-[6-(3-piperidin-1-ylpropoxy)-3-pyridinyl]-1-propan-2- ylimidazo[4,5-c]quinolin-2-one; wherein the ATR kinase inhibitor is berzosertib or elimusertib; and wherein the Chkl kinase inhibitor is (R)-5-((4-((morpholin-2-ylmethyl)amino)-5- (trifluoromethyl)pyridin-2-yl)amino)pyrazine-2-carbonitrile or prexasertib.
Response to Arguments
Applicant's arguments filed 04/06/2026 have been fully considered but they are not
persuasive. Arguments against Wang on Pg. 10-14 are not persuasive as discussed above. Furthermore, to clarify some instances argued in the response filed 04/06/2026 see responses to each argument made by Applicant below:
Applicants’ argument: “Cordova is completely silent regarding 3' flap Okazaki fragments, the relevance of 3' flap Okazaki fragments to cancer, and, specifically, elevated levels of3' flap Okazaki fragments in cancer ”(Pg. 13).
Response: In response to applicant's arguments against the references individually, one cannot show nonobviousness by attacking references individually where the rejections are based on combinations of references. See In re Keller, 642 F.2d 413, 208 USPQ 871 (CCPA 1981); In re Merck & Co., 800 F.2d 1091, 231 USPQ 375 (Fed. Cir. 1986).
Claims 8 and 10-11 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. However, Wang and Sriramachandran do not explicitly teach the limitations of claims 8 and 10-11. Claims 8 and 10 depend on claim 1. Claim 11 depends on claim 10, which depends on Claim 1.
Regarding claim 8, 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 suggest a method wherein the cancer is leukemia and/or the cancer is acute lymphoblastic leukemia.
Regarding claims 10-11, 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 suggested 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.
Response to Arguments
Applicant's arguments filed 04/06/2026 have been fully considered but they are not
persuasive. Arguments against Wang and Sriramachandran on Pg. 10-14 are not persuasive as discussed above. Furthermore, to clarify some instances argued in the response filed 04/06/2026 see responses to each argument made by Applicant below:
Applicants’ argument: “Zheng is completely silent regarding 3' flap Okazaki fragments, the relevance of 3' flap Okazaki fragments to cancer, and, specifically, elevated levels of 3' flap Okazaki fragments in cancer. ”(Pg. 14).
Response: In response to applicant's arguments against the references individually, one cannot show nonobviousness by attacking references individually where the rejections are based on combinations of references. See In re Keller, 642 F.2d 413, 208 USPQ 871 (CCPA 1981); In re Merck & Co., 800 F.2d 1091, 231 USPQ 375 (Fed. Cir. 1986).
Claims 24-25 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.) and Aguilar Cordova et al. (“Aguilar Cordova”; Patent App. Pub. No. WO 2020172671 A1, Aug. 27, 2020) as applied to claim 4 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 and Wang, Sriramachandran and Aguilar Cordova are documented above in the rejection of claims 4, 14, 17, 20, 22-23 and 26 under 35 U.S.C. 103. However, Wang, Sriramachandran and Aguilar Cordova and do not explicitly teach the limitations of claims 24-25.
Regarding claim 24, 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, Aguilar Cordova and Zheng suggest a method wherein the cancer is leukemia and/or the cancer is acute lymphoblastic leukemia.
Regarding claims 25, 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, Aguilar Cordova and Zheng suggest a method wherein the cancer is lung cancer selected from 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.
Wang, Sriramachandran, 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 for treating cancer in a patient in need thereof as suggested by Wang, Sriramachandran and Aguilar Cordova to incorporate the method wherein the cancer is several different human cancer types as suggested by Zheng and provide a method for treating a cancer patient wherein the cancer cell has elevated levels 3' flap Okazaki fragment compared to a control, wherein the cancer may develop in lymphoid progenitor cells or lung cells. Doing so would allow for treatment of leukemia or lung cancer patients from which the cancer cells have been characterized as having elevated levels of 3’ flap Okazaki fragment by targeting the DNA Damage Response proteins targeted to the DNA damage.
Claims 29 are 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.) as applied to claim 5 above, and further 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.) .
The teachings of Aguilar Cordova and Wang are documented above in the rejection of claims 5, 27-28 and 31 under 35 U.S.C. 103. However, Aguilar Cordova and Wang and do not explicitly teach the limitations of claim 29. Claim 29 depend on claim 5.
Regarding claim 29, Regarding claim 7, Sriramachandran teaches a method comprising “preparation of genomic DNA” (Pg. 985 e.7, Preparation of Mammalian Genomic DNA, Para. 1). Thus, Aguilar Cordova, Wang and Sriramachandran suggest a method wherein the biological sample is genomic DNA in the cancer cell.
Aguilar Cordova, 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 modify the method of a method for treating cancer in a patient in need thereof as suggested by Aguilar Cordova and Wang to incorporate the method wherein the sample is genomic DNA of a cancer cell as suggested by Sriramachandran and provide a method for treating a cancer patient wherein the genomic DNA in the cancer cell has elevated levels 3' flap Okazaki fragment compared to a control. Doing so would allow for treatment of cancer patients from which the genomic DNA of the cancer cell has been characterized as having elevated levels of 3’ flap Okazaki fragment by targeting the DNA Damage Response proteins targeted to the DNA damage.
Response to Arguments
Applicant's arguments filed 04/06/2026 have been fully considered but they are not
persuasive. Arguments against Wang, Aguilar Cordova and Sriramachandran on Pg. 10-14 are not persuasive as discussed above. Furthermore, to clarify some instances argued in the response filed 04/06/2026 see responses to each argument made by Applicant below:
Applicants’ argument: “Sriramachandran is completely silent regarding 3' flap Okazaki fragments let alone their relevance to cancer. ”(Pg. 12).
Response: In response to applicant's arguments against the references individually, one cannot show nonobviousness by attacking references individually where the rejections are based on combinations of references. See In re Keller, 642 F.2d 413, 208 USPQ 871 (CCPA 1981); In re Merck & Co., 800 F.2d 1091, 231 USPQ 375 (Fed. Cir. 1986).
Claims 30 are 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.) as applied to claim 5 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 Aguilar Cordova and Wang are documented above in the rejection of claims 5, 27-28 and 31 under 35 U.S.C. 103. However, Aguilar Cordova and Wang and do not explicitly teach the limitations of claim 30. Claim 30 depend on claim 5.
Regarding claim 30, 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, Aguilar Cordova, Wang and Zheng teach a method wherein the cancer is leukemia and/or the cancer is acute lymphoblastic leukemia, or the cancer is lung cancer selected from 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.
Aguilar Cordova, Wang, 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 a method for treating cancer in a patient in need thereof as suggested by Aguilar Cordova and Wang to incorporate the method wherein the cancer is several different human cancer types as suggested by Zheng and provide a method for treating a cancer patient wherein the cancer cell has elevated levels 3' flap Okazaki fragment compared to a control, wherein the cancer may develop in lymphoid progenitor cells or lung cells. Doing so would allow for treatment of leukemia or lung cancer patients from which cancer cell have been characterized as having elevated levels of 3’ flap Okazaki fragment by targeting the DNA Damage Response proteins targeted to the DNA damage.
Response to Arguments
Applicant's arguments filed 04/06/2026 have been fully considered but they are not
persuasive. Arguments against Wang and Aguilar Cordova on Pg. 10-14 are not persuasive as discussed above. Furthermore, to clarify some instances argued in the response filed 04/06/2026 see responses to each argument made by Applicant below:
Applicants’ argument: “Zheng is completely silent regarding 3' flap Okazaki fragments, the relevance of 3' flap Okazaki fragments to cancer, and, specifically, elevated levels of 3' flap Okazaki fragments in cancer. ”(Pg. 14).
Response: In response to applicant's arguments against the references individually, one cannot show nonobviousness by attacking references individually where the rejections are based on combinations of references. See In re Keller, 642 F.2d 413, 208 USPQ 871 (CCPA 1981); In re Merck & Co., 800 F.2d 1091, 231 USPQ 375 (Fed. Cir. 1986).
Conclusion of Response to Arguments
In view of the amendments, revised rejections, new grounds of rejections and above responses to arguments, no claims are in condition for allowance.
Conclusion
Applicant's amendment necessitated the new ground(s) of rejection presented in this Office action. Accordingly, THIS ACTION IS MADE FINAL. See MPEP § 706.07(a). Applicant is reminded of the extension of time policy as set forth in 37 CFR 1.136(a).
A shortened statutory period for reply to this final action is set to expire THREE MONTHS from the mailing date of this action. In the event a first reply is filed within TWO MONTHS of the mailing date of this final action and the advisory action is not mailed until after the end of the THREE-MONTH shortened statutory period, then the shortened statutory period will expire on the date the advisory action is mailed, and any nonprovisional extension fee (37 CFR 1.17(a)) pursuant to 37 CFR 1.136(a) will be calculated from the mailing date of the advisory action. In no event, however, will the statutory period for reply expire later than SIX MONTHS from the mailing date of this final action.
Any inquiry concerning this communication or earlier communications from the examiner should be directed to KENDRA R VANN-OJUEKAIYE whose telephone number is (571)270-7529. The examiner can normally be reached M-F 9:00 AM- 5:00 PM.
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/KENDRA R VANN-OJUEKAIYE/Examiner, Art Unit 1682
/WU CHENG W SHEN/Supervisory Patent Examiner, Art Unit 1682
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