DETAILED ACTION
Notice of Pre-AIA or AIA Status
1. The present application, filed on or after March 16, 2013, is being examined under the first inventor to file provisions of the AIA .
Continued Examination Under 37 CFR 1.114
2. A request for continued examination under 37 CFR 1.114, including the fee set forth in 37 CFR 1.17(e), was filed in this application after final rejection. Since this application is eligible for continued examination under 37 CFR 1.114, and the fee set forth in 37 CFR 1.17(e) has been timely paid, the finality of the previous Office action has been withdrawn pursuant to 37 CFR 1.114. Applicant's submission filed on 01 December 2025 has been entered.
3. Applicant's arguments and amendments to the claims presented in the reply of 01 December 2025 have been fully considered but do not place the application in condition for allowance. All rejections and objections not reiterated herein are hereby withdrawn.
Claim Status
4. Claims 21-23, 26, 27, 29, 32-45 and 47-52 are pending and have been examined herein.
The non-elected species of the PALB2 gene has been rejoined with the elected species of the RAD51B gene. Claims 32, 47, and 49 encompass the non-elected species of the homologous recombination repair genes other than RAD51B and PALB2. Prior to the allowance of claims, any non-elected subject matter which has not been rejoined with the elected subject matter will be required to be removed from the claims.
New Claim Rejections - 35 USC § 112(b) - Indefiniteness
5. 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.
Claim 42 is 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 42 is indefinite over the recitation of “the inhibitor of a polyadenosine diphosphate-ribose polymerase (PARP) enzyme” because this phrase lacks proper antecedent basis. Note that claim 41, from which claim 42 depends, was amended to omit the recitation of an inhibitor of a polyadenosine diphosphate-ribose polymerase (PARP) enzyme and now more generally recites “a homologous recombination deficient directed therapy.”
New Claim Rejections - 35 USC § 112(d) / Fourth paragraph
6. 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.
Claims 33 and 43 are 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.
Claim 33 depends from subsequent claim 47 and claim 43 depends from subsequent claim 49. As set forth in MPEP 608.01(n), the test for proper dependency requires that a dependent claim references a claim previously set forth:
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Herein, claims 33 and 43 depend from a subsequent / latter presented claim rather than “a claim previously set forth.”
Accordingly, claims 33 and 43 are not in proper dependent form.
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.
Modified and New Claim Rejections - 35 USC § 103
7. In the event the determination of the status of the application as subject to AIA 35 U.S.C. 102 and 103 (or as subject to pre-AIA 35 U.S.C. 102 and 103) is incorrect, any correction of the statutory basis (i.e., changing from AIA to pre-AIA ) for the rejection will not be considered a new ground of rejection if the prior art relied upon, and the rationale supporting the rejection, would be the same under either status.
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.
This application currently names joint inventors. In considering patentability of the claims the examiner presumes that the subject matter of the various claims was commonly owned as of the effective filing date of the claimed invention(s) absent any evidence to the contrary. Applicant is advised of the obligation under 37 CFR 1.56 to point out the inventor and effective filing dates of each claim that was not commonly owned as of the effective filing date of the later invention in order for the examiner to consider the applicability of 35 U.S.C. 102(b)(2)(C) for any potential 35 U.S.C. 102(a)(2) prior art against the later invention.
Claim(s) 21-22, 29, 32-45, 47 and 49-51 is/are rejected under 35 U.S.C. 103 as being unpatentable over Yen et al (U.S. 20220025468, published 27 January 2022; cited in the IDS).
Yen et al teaches a method comprising detecting homologous recombination deficiency (HRD) in a subject that has cancer or is suspected of having cancer by assaying nucleic acid in a biological sample from the subject to detect one or more breakpoints associated with one or more rearrangements and based on the presence of the one or more breakpoints associated with the one or more rearrangements, classifying the subject as HRD positive (e.g., para [0009], [0071], [0091-0093], [0100], [0180] and [0257-0259] and Figure 2). The chromosomal rearrangements of Yen are considered to be fusions since the rearrangements result in the fusion of two (previously) separate chromosomal sequences. It is disclosed that the gene in which the one or more breakpoints occurs is a homologous recombination repair (HRR) gene, such as the RAD51B gene (e.g., para [0096] and Table 2; para [0131], [0251], [0260], [0311] and Table 5 / para [0317]). Yen teaches that after subjects are identified as having a HRD positive score they are then treated by administering a PARP inhibitor (e.g., para [0011]) or a platin or cisplatin-based therapy (para [0319]). It is stated that “cells having a deficiency in a homologous recombination repair (HRR) pathway are vulnerable to increased DNA damage and have an increased sensitivity to DNA damage repair inhibitors (e.g., PARP inhibitors, etc.) and/or other therapies” (para [0015]).
Accordingly, Yen teaches a method of treating a subject that has or is suspected of having cancer, the method comprising: a) identifying a subject comprising a genome with a fusion, wherein the fusion comprises at least a portion of a homologous recombination repair (HRR) gene, such as RAD51B or any of the other HRR genes listed in Table 2 and para [0251]; and b) treating the subject so identified with a PARP inhibitor or a cisplatin/platin-based therapy, which therapies are homologous recombination deficient directed therapies.
Regarding claim 41, Yen does not specifically state that the “fusion comprises an intronic region of a homologous recombinant repair gene. Regarding claim 21, Yen does not specifically state that the fusion comprises an intronic region of a portion of a homologous recombination repair gene and w the fusion comprising an intronic region of a homologous recombination repair gene is to an intergenic region.
However, Yen does teach that the genomic location of regions to be assayed for breakpoints leading to rearrangements and translocations that involve the HRR genes include non-coding sequences, such as pseudogenes, repeat sequences, repetitive elements, transposons, viral elements, and telomeres, as well as non-coding RNA sequences (para [0130] and [0149]). Yen also teaches using probes that detect translocations, rearrangements and fusions that involve intron sequences (e.g., para [0149]
Accordingly, it would have been obvious to one of ordinary skill in the art before the effective filing date of the claimed invention to have modified the method of Yen so as to have specifically detected translocations and rearrangements that comprise intronic sequences of an HRR genes in which the fusion partner to the HRR gene is any of the sequences disclosed by Yen or is specifically an intergenic region since Yen teaches that the methods disclosed therein for detecting HRD include detecting rearrangements or translocations between any sequences in an HRR gene, including intron sequences, and genomic sequences that are non-coding sequences, such as repetitive elements / repeat sequences, pseudogenes, transposons, and sequences that encode for non-coding RNAs, which are sequences in intergenic regions. One would have been motivated to have done so because breakpoints in the HRR gene which disrupt the full length gene, such as a breakpoint in an HRR intron sequence and which result in the fusion of only a portion of the HRR gene to sequences of pseudogenes, repeat sequences / repetitive elements or transposons or for sequences encoding for non-coding RNA (i.e. intergenic sequences) potentially constitute fusions that result in homologous recombination deficiency, and thereby would aid in identifying subjects having cancer who will be responsive to PARP inhibitor therapy or platinum / cisplatin-based therapy.
Regarding claims 22, 41-45, 47 and 49-51, Yen teaches that the sample can be a solid tumor sample (e.g., para [0100]) and that the patient may have a solid tumor (e.g., breast or pancreatic or lung cancer, etc.) or a blood tumor (see para [0044]). For instance, Yen (para [0100]) states:
“Samples can include body tissues, whole blood, platelets, serum, plasma, stool, red blood cells, white blood cells or leucocytes, endothelial cells, tissue biopsies (e.g., biopsies from known or suspected solid tumors).”
Further, Yen teaches analyzing the nucleic acids present in the sample from the subject for the fusion by performing a nucleic acid sequencing assay, including a targeted sequencing assay or a genome-wide / whole genome sequencing assay (e.g., para [0081], [0118-0120], [0129] and Figure 2).
Regarding claims 29, Yen teaches that the fusion / translocation involves a HRR gene and another gene and that the fusion / translocation has a deleterious effect on the function of the HRR gene (e.g., para [0196], [0200], [0234], [0312], and [0318]).
Regarding claims 32, 33, 43 and 49, as discussed above, Yen teaches that the HRR gene is RAD51B (e.g., para [0096] / Table 2; [0131], [0251], and [0317] / Table 5).
Regarding claims 34-36, Yen teaches that the method is applicable to subjects having any type of cancer, including breast cancer or colorectal carcinoma (e.g., para [0044], and [0294]).
Regarding claims 37-40, 42 and 50-51, Yen teaches treating the cancer patients identified as having HRR deficiency with a PARP inhibitor that is olaparib, talazoparib, niraparib or rucaparib (e.g., para [0094], [0096] / Table 2 and [0272]), which PARP inhibitors have the property that they are effective in the treatment of cancer.
8. Claim(s) 23, 26, 27, 48 and 52 is/are rejected under 35 U.S.C. 103 as being unpatentable over Yen et al (U.S. 20220025468, published 27 January 2022; cited in the IDS) in view of Harewood et al (Genome Biology. 2017. 18:125, p. 1-11).
The teachings of Yen are presented above. As set forth above, Yen teaches that the rearrangements / translocations involving the fusion of HRR intron sequences to other chromosomal sequences, including intergenic sequences, can be detected by analyzing nucleic acids in the sample using any conventional method of sequencing, hybridization or amplification (e.g., para [0051]). Yen also teaches that the nucleic acids to be analyzed can be genomic DNA (e.g., para [0098]) and the samples may be cellular and/or tissue samples (para [0079] and [0100]). Yen further teaches that the sample is a solid tumor sample (e.g., para [0100]).
Yen does not teach analyzing the nucleic acids in the sample by performing a method that preserves spatial-proximal contiguity information, particularly wherein the method uses the proximity ligation technique of Hi-C.
However, Harewood teaches performing the proximity ligation method of Hi-C to detect chromosomal rearrangements, including translocations, in human tumor samples (e.g., p. 2 “Balanced and unbalanced translocation detection” and Figure 1). Harewood teaches that Hi-C can be used to detect both known and novel, balanced and unbalanced chromosomal rearrangements in tumor samples (p. 1, col. 2). It is further disclosed that Hi-C has the advantage that it can potentially defined chromosome breakpoints to bp resolution, rearrangements involving poorly mappable regions can be detected, and the method is less expensive than standard sequencing methods, such as deep whole genome sequencing (e.g., abstract and p. 8, col. 2).
In view of the teachings of Harewood, it would have been obvious to one of ordinary skill in the art before the effective filing date of the claimed invention to have modified the method of Yen so as to have analyzed cell or tissue samples from subjects having or suspected of having cancer using the Hi-C technique of Harewood to detect fusions / translocations that involve HRR genes. One would have been motivated to have done so in order to have achieved the advantages set forth by Harewood that the Hi-C method is less expensive than most deep sequencing methods and can be used to identify novel rearrangements / translocations, as well as the precise site of a breakpoint and rearrangements involving poorly mappable regions.
Regarding claim 52, Yen teaches treating the cancer patients identified as having HRR deficiency with a PARP inhibitor that is olaparib, talazoparib, niraparib or rucaparib (e.g., para [0094], [0096] / Table 2 and [0272]), which PARP inhibitors have the property that they are effective in the treatment of cancer.Response to Remarks:
Regarding the prior rejection, the response of 01 December 2025 states that independent claims 21 and 41 have been amended to recite that a "fusion comprises an intronic region of a homologous recombination repair gene." It is argued that Yen does not teach fusions events at an intronic region. Applicant argues that Yen defines a fusion event as "a fusion between at least two separate genes at a particular location.” The response states that the prior rejection suggests that “the first portion of the fusion is in exons of the HRR gene. Thus, Yen does not provide teaching or motivation to look at a fusion between an intronic region of an HRR gene and an intergenic region.”
These arguments have been fully considered but are not persuasive. First, the teachings of Yen are not limited to methods that detect only fusion events, which as defined at para [0056] of Yen are events that occur between two separate genes at different locations. Rather, Yen also teaches detecting any rearrangement or translocation that involves any portion of a homologous recombination repair (HRR) gene, which rearrangements or translocations involve a breakpoint in a HRR gene have a deleterious effect on the function of the HRR gene and lead to homologous recombination deficiency (HRD). Yen teaches that the detection of the rearrangement or translocation involves the use of probes that detect rearrangements or translocations that occur at any location of the HRR gene, including introns (e.g., para [0149]) and result in fusions with other intergenic sequences such as pseudogenes, repeat sequences, repetitive elements, transposons, viral elements, and telomeres, as well as non-coding RNA sequences (e.g., para [0130] and [0149]). Thus, Yen does teach and provide the motivation to detect a rearrangement or translocation that results in the fusion of an intronic sequence of an HRR gene with an intergenic region.
Note that claims 41-43, 45, and 48-50 do not require that the intronic sequence of an HRR gene is fused to an intergenic region. Thereby, the argument that “Yen does not provide teaching or motivation to look at a fusion between an intronic region of an HRR gene and an intergenic region” is not relevant to these claims.
Additionally, note that claim 21 and the claims that depend therefrom, and claim 44 recite “wherein the fusion comprises an intronic region of a homologous recombination repair gene.” In view of the “comprising” language, these claims do not require that a breakpoint occurs in an intron region of the HRR gene, but only that the region that is fused to an intergenic region comprises / includes intron sequences of an HRR gene. Accordingly, the argument that “Yen does not provide teaching or motivation to look at a fusion between an intronic region of an HRR gene and an intergenic region” does not apply to these claims because the claims do not require that the intronic region of the HRR gene is directly fused to the intergenic region.
Regarding the statement in the response that the prior rejection suggests that “the first portion of the fusion is in exons of the HRR gene,” the rejection in fact indicates that Yen teaches that the translocation or rearrangement resulting in a fusion of HRR gene sequences with other chromosomal sequences, including intergenic sequences, can involve a breakpoint at an intron in the HRR gene or a breakpoint that results in a fragment that includes intron sequences of the HRR gene as well as only a portion of exon sequences of the HRR gene. Yen teaches that the homologous recombination deficiency assay disclosed therein can be used to detect a deleterious effect of an alteration, including a translocation or rearrangement, involving the HRR gene.
The response asserts that Yen teaches away from the claimed subject matter. It is argued that:
“Paragraph 187 of Yen recites "[i]n certain embodiments, the criteria includes filtering criteria, such as the absence of a breakpoint near a probe, the absence of a breakpoint in a reportable gene, the rejection of small indels and intronic events ...". Thus, Yen teaches that fusions to intronic regions are not valuable or useful for treating patients. Applicant submits that, in light of Yen's instructions to reject cases involving intronic events (e.g., fusions involving an intronic region), one of skill would not be motivated to modify the disclosure of Yen to arrive at the presently claimed subject.”
These arguments have been fully considered but are not persuasive. First, Yen does not teach that the methods disclosed therein must “reject cases involving intronic events.” Rather para [0187] of Yen states:
“In certain embodiments, the criteria includes filtering criteria, such as the absence of a breakpoint near a probe, the absence of a breakpoint in a reportable gene, the rejection of small indels and intronic events, the running of a “pc_molecules” test (pc_molecules=n_molecules/n_reads) and discarding fusions with an average family size that is less than 1.7 in some embodiments, the addressing stitch-related known artifacts, the rejection of events if they could be a “template switch,” the application of a minimum robust molecules test, and/or the like.”
Thereby, Yen teaches that small intronic events can be filtered out of the sequence analysis. But, the filtering out of small intronic events is not a requirement of the detection assay and is only one of the alternative embodiments. Contrary to Applicant’s assertion, Yen does not teach away from detecting fusions that include intronic sequences of the HRR gene or in which the breakpoint occurs in/at an intron of the HRR gene. Rather, Yen teaches that the sequencing methods disclosed therein include “intron sequencing” (para [0081]; that “a panel that targets a plurality of different genes or genomic regions (e.g., transcriptional factor binding regions, distal regulatory elements (DREs), repetitive elements, intron-exon junctions, transcriptional start sites (TSSs), and/or the like) is selected such that a determined proportion of subjects having a cancer exhibits a genetic variant or tumor marker in one or more different genes in the panel” (para [0130]; and that the genomic locations in the panel of probes for detecting rearrangements and translocations “can comprise coding and/or non-coding sequences. For example, the genomic locations in the panel can comprise one or more sequences in exons, introns, promoters, 3′ untranslated regions, 5′ untranslated regions, regulatory elements, transcription start sites, and/or splice sites” (para [0149]).
New Grounds of Rejection:
9. Claim(s) 21, 29, 32, and 34-40 is/are rejected under 35 U.S.C. 103 as being unpatentable over Yang et al (Breast Cancer Research Treat. 2016. 160: 447-456).
Yen et al teaches a method for detecting a fusion between PALB2 (i.e., an HRR gene) gene sequences which fusion occurs between intron 12 of the PALB2 gene and a sequence that occurs 989bp downstream of the 3’ UTR of the PALB2 gene (e.g., p. 450, col. 2 and p. 452, col. 1 and Figures 3 and 4). The sequence 989 bp downstream of the 3’ UTR of the PALB2 gene is considered to be an intergenic region because it is not disclosed as being part of the PALB2 gene (since it is downstream of the 3’ UTR) and is not characterized as being part of another gene. It is disclosed that this fusion event results in duplication of exon 13 and an insertion that causes a frameshift, creating a premature stop codon leading to a loss of 41 amino acids in the WD domain of the C-terminus of the PALB2 protein (p. 452, col. 2). Yang (p. 453 col. 1) states: “This study identified the exact breakpoints of the PALB2 exon 13 duplication and demonstrated a large duplication involving AluSg in intron 12 and AluSc8 in the down-stream region of the PALB2 3’-UTR through a mechanism of Alu-mediated non-allelic homologous recombination (NAHR). ”
Accordingly, Yang teaches a method comprising: identifying a subject suffering from cancer who has a genome comprising a fusion, wherein the fusion comprises an intronic region (i.e., intron 12) of a homologous recombination repair gene ( i.e., the PALB2 gene) and a second chromosomal sequence (i.e., the intergenic sequence that is downstream of the 3’-UTR of the PALB2 gene), wherein the identifying comprises a nucleic acid analysis of genomic DNA from a sample from the subject.
Yang (p. 453, col. 2) also states:
“For the proband, identification of a pathologic germline PALB2 mutation identified her as a potential candidate for treatment with a DNA damage repair inhibitor such as a PARP inhibitor. Had this variant not been identified (since she was BRCA-negative), PARPi may not have been a therapeutic option for treatment of her ovarian cancer.”
It is also stated (P. 450, col. 2):
“Given that the PALB2 duplication was tracking with the cancers in the family, and the possibility of targeted therapeutic options becoming available for our patient should she be found to carry a deleterious mutation in a homologous recombination repair gene, we decided to investigate the biological effects of the exon 13 duplication.”
Yang does not specifically exemplify a method wherein the subject identified as having the fusion between intron 12 of the PALB2 gene (a HRR gene) and an intergenic region is treated with a PARP inhibitor, and particularly with the PARP inhibitor of Olaparib.
However, as set forth above, Yang teaches that the subject having the pathogenic germline PALB2 mutation / fusion can be treated with a PARP inhibitor. Yang (p. 448, col. 1) further states:
“Pennington KP et al. [21] hypothesize that patients with germline mutations in DNA homologous recombination genes will have a sensitivity to PARP inhibitors (PARPi). Inhibition of PARP is a potential synthetic lethal therapeutic approach to the treatment of patients with inherited mutations in genes such as BRCA1 and BRCA2 that are involved in DNA repair pathways [22–24]. Recently, Olaparib (AZD 2281), an oral PARP inhibitor, has been approved for the treatment of DNA repair-deficient highgrade ovarian tumors in BRCA1 or BRCA2 mutation carriers [25]. Prolonged responses to Olaparib were observed in patients harboring germline BRCA1/2 mutations with different tumor types including ovarian, breast, pancreatic, and prostate cancers [26, 27]. Like BRCA1 and BRCA2-deficient cells, cells with a genetic deficiency for PALB2 exhibit a defect in homologous repair [28] and display sensitivity to inhibition of PARP [28–31]. Since PALB2 protein participates in the same DNA repair pathway as BRCA2 [32], the synthetic lethal therapeutic strategy based on PARP inhibition could also be utilized for treatment of patients with germline mutations in PALB2. Determining PALB2 variant pathogenicity in patients with ovarian and related cancers is thus of significant clinical relevance, particularly for guiding targeted therapy regimens.”
Accordingly, it would have been obvious to one of ordinary skill in the art before the effective filing date of the claimed invention to have modified the method of Yang so as to have specifically administered the PARP inhibitor, and particularly Olaparib, to the subject having ovarian cancer and identified as having the germline mutation in the PALB2 gene (i.e., the fusion between intron 12 of the PALB2 gene and the intergenic sequences downstream of the 3’UTR of the PALB2 gene). One would have been motivated to have done so because Yang teaches that such PARP inhibitors can be used to effectively treat cancer subjects having mutations in HRR genes..
Regarding claim 32, as discussed above, Yang teaches that the HRR gene is PALB2.
Regarding claim 34, Yang teaches that the subject has ovarian cancer.
Regarding claim 35, Yang does not specifically teach administering a PARP inhibitor to a subject having breast cancer.
However, Yang teaches that the subject has a family history of breast and ovarian cancer and thereby is a subject at risk of having breast cancer. Further, Yang (p. 450, col. 1) states that “Therefore, the PALB2 duplication initially identified in the proband with high-grade serous ovarian cancer segregates with the breast cancers in this family.”
Accordingly, it would have been obvious to one of ordinary skill in the art before the effective filing date of the claimed invention to have modified the method of Yang so as to have treated any family members having the PALB2 fusion and having breast cancer by administering a PARP inhibitor. One would have been motivated to have done so because Yang teaches that PARP inhibitor therapy can be effective in other types of cancers, including breast cancer, when the subject has a pathogenic mutation in a HRR gene, such as the PALP2 gene (e.g., p. 448, col. 1). Note also that claim 35 does not set forth any criteria for what constitutes a subject suspected of having cancer and does not set forth a nexus between “a subject” in steps a) and b) and the subject in the preamble of the claim who is suspected of having breast cancer.
Regarding claim 36, Yang does not teach assaying to identify the PALB2 fusion in a subject suspected of having colon cancer.
However, Yang does teach the importance of assaying for the PALB2 fusion in family members to determine if the family members are carriers of the pathogenic mutation (e.g., p. 448, col. 2). It is disclosed that the subject’s maternal grandmother was diagnosed with colon cancer at age 67 (p. 448, col. 2).
Accordingly, it would have been obvious to one of ordinary skill in the art before the effective filing date of the claimed invention to have modified the method of Yang so as to have treated any family members having the PALB2 fusion and having or suspected of having colon cancer by administering a PARP inhibitor. One would have been motivated to have done so because Yang teaches that PARP inhibitor therapy can be effective in treating other types of cancers when the subject has a pathogenic mutation in a HRR gene, such as the PALP2 gene (e.g., p. 448, col. 1). Note also that claim 36 does not set forth any criteria for what constitutes a subject suspected of having cancer and does not set forth a nexus between “a subject” in steps a) and b) and the subject in the preamble of the claim who is suspected of having breast cancer.
Regarding claims 37-40, Yang teaches the PARP inhibitor of Olaparib (p. 448, col. 1).
10. Claim(s) 22-23, 26, 27, 41, 42, 44, 45, 48, and 50-52 is/are rejected under 35 U.S.C. 103 as being unpatentable over Yang et al (Breast Cancer Research Treat. 2016. 160: 447-456) in view of Harewood et al (Genome Biology. 2017. 18:125, p. 1-11).
The teachings of Yang are presented above.
Yang teaches detecting the PALB2 fusion in nucleic acids present in a blood sample from the subject (e.g., p. 448, col. 2). Yang does not teach detecting the PALB2 fusion in nucleic acids present in a tumor tissue sample and does not teach analyzing the nucleic acids in a tumor tissue sample by performing a method that preserves spatial-proximal contiguity information, particularly wherein the method uses the proximity ligation technique of Hi-C.
However, Harewood teaches performing the proximity ligation method of Hi-C to detect chromosomal rearrangements, including translocations, in human tumor samples (e.g., p. 2 “Balanced and unbalanced translocation detection” and Figure 1). Harewood teaches that Hi-C can be used to detect both known and novel, balanced and unbalanced chromosomal rearrangements in tumor samples (p. 1, col. 2). It is further disclosed that Hi-C has the advantage that it can potentially defined chromosome breakpoints to bp resolution, rearrangements involving poorly mappable regions can be detected, and the method is less expensive than standard sequencing methods, such as deep whole genome sequencing (e.g., abstract and p. 8, col. 2).
In view of the teachings of Harewood, it would have been obvious to one of ordinary skill in the art before the effective filing date of the claimed invention to have modified the method of Yang so as to have analyzed tumor tissue samples from subjects having or suspected of having cancer using the Hi-C technique of Harewood to detect the fusion involving the PALB2 (HRR) gene. One would have been motivated to have done so in order to have achieved the advantages set forth by Harewood that the Hi-C method is less expensive than most deep sequencing methods and can be used to identify novel rearrangements / translocations, as well as the precise site of a breakpoint and rearrangements involving poorly mappable regions.11.Claim(s) 21-22, 29, 32-35, 37-45, 47 and 49-51 is/are rejected under 35 U.S.C. 103 as being unpatentable over Xie et al (JCO Precis Oncol. 2022. 6:e2100404, p. 1-8).
Xie et al teaches a method for detecting a fusion involving RAD51B (i.e., an HRR gene) gene sequences in a subject having pancreatic ductal adenocarcinoma, which fusion occurs as a result of a breakpoint in intron 10 of the RAD51B gene and a breakpoint at chr16:64133026, located at a distance of 844631 bp from the CDH11 gene (Figure 1 and Table 2). The sequence 844631 bp from the CDH11 gene is considered to be an intergenic region because it is not disclosed as being part of the CDH11 gene or another gene. It is disclosed that this fusion is potentially clinically significant (Table 1) and has a deleterious effect on homologous recombination (p. 4, col. 1 and Table 3).
Xie teaches that the RAD51B gene fusion was detected by a method comprising isolating genomic DNA from tumor tissue samples from a subject and performing both whole-exome sequencing and whole genome sequencing (e.g., p. 2 “DNA Extraction, Library Preparation, and Sequencing”).
Accordingly, Xie teaches a method comprising: identifying a subject suffering from cancer who has a genome comprising a fusion, wherein the fusion comprises an intronic region (i.e., intron 10) of a homologous recombination repair gene ( i.e., the RAD51B gene) and a second chromosomal sequence (i.e., the intergenic sequence that is located 844631 bp from the CDH11 gene), wherein the identifying comprises a nucleic acid analysis of tumor tissue DNA isolated from a sample from the subject.
Xie does not specifically exemplify a method wherein the subject identified as having the fusion between intron 10 of the RAD51B gene and an intergenic region is treated with a PARP inhibitor, and particularly with the PARP inhibitor of Olaparib.
However, Xie (abstract) teaches that the methods disclosed therein are relevant because: “Including the RAD51B in germline test panel could allow more PDAC patients with HR-DDR pathway deficiency being identified, and these patients may benefit from HR-DDR pathway related therapies.” Xie also teaches that sensitivity to PARP inhibitors in cancer patients having different mutations is dependent on the homologous recombination deficiency (HRD) scores associated with the mutations (p. 6, col. 2). It is stated that “Breast and prostate cancers with BRCA1/2 mutations and ovarian
cancers in general demonstrated the response to polyADP ribose polymerase (PARP) inhibitor, which inhibits the alternative repair pathway and leads to the synthetic lethality in the tumor cells that have suffered a homologous recombination repair deficiency” (p. 1, col. 2). Further, treatment of pancreatic ductal adenocarcinoma with the PARP inhibitor Olaparib in a patient who had no progression after a minimum of 4-month first-line platinum-based chemotherapy, prolonged progression free survival (p. 1, col. 2).
Accordingly, it would have been obvious to one of ordinary skill in the art before the effective filing date of the claimed invention to have modified the method of Yang so as to have specifically administered the PARP inhibitor, and particularly Olaparib, to the subject having pancreatic ductal adenocarcinoma and identified as having the germline mutation in the RAD51B gene (i.e., the fusion between intron 10 of the RAD51B gene and the intergenic sequence). One would have been motivated to have done so because Xie teaches that such PARP inhibitors can be used to effectively treat cancer in subjects having mutations in HRR genes leading to homologous recombination deficiency.
Regarding claim 32, 33, 43, 47 and 49, as discussed above, Xie teaches that the HRR gene is RAD51B (e.g., abstract and Table 1 and 2).
Regarding claim 34, Xie teaches that the subject has pancreatic cancer (e.g., abstract, p. 2, col. 1 and Table 1 and Table 2).
Regarding claim 35, Xie does not specifically teach administering a PARP inhibitor to a subject having breast cancer or suspected of having breast cancer and having the RAD51B fusion.
However, Xie teaches that RAD51B mutations are associated with hereditary breast ovarian cancer (p. 6, col. 2). It is disclosed that testing for RAD51B fusions and other RAD51B mutations should be included in germline tests for HR-DDR pathway genes (p. 6, col. 2 and abstract). It is further stated that a 15 gene panel that includes the RAD51B gene has been chosen “ as a companion diagnostic HR-DDR gene panel for the US Food and Drug Administration–approved olaparib indication in prostate cancer” (p. 1 final para to p. 2 first para).
Accordingly, it would have been obvious to one of ordinary skill in the art before the effective filing date of the claimed invention to have modified the method of Xie as to have treated patients identified as having the RAD51B gene fusion and having or suspected of having breast cancer because Xie teaches that germline RAD51B mutations have been detected in breast cancer patients and that treatment with a PARP inhibitor therapy can be effective in other types of cancers, including breast cancer, when the subject has a pathogenic mutation in a HR-DDR gene, such as the RAD51B gene fusion mutation.
Regarding claims 37-40, Xie teaches the PARP inhibitor may be Olaparib (e.g., abstract; p. 1 col. 2 to p. 2 first para).
12. Claim 36 is/are rejected under 35 U.S.C. 103 as being unpatentable over Xie et al (JCO Precis Oncol. 2022. 6:e2100404, p. 1-8) in view of Yen et al (U.S. 20220025468, published 27 January 2022; cited in the IDS).
The teachings of Xie are presented above.
Regarding claim 36, Xie does not teach assaying a tumor tissue sample in a patient having or suspected of having colon cancer to identify the RAD51B gene fusion and then treating the patient with a PARP inhibitor.
However, Yen et al teaches a method comprising detecting homologous recombination deficiency (HRD) in a subject that has cancer or is suspected of having cancer by assaying nucleic acid in a biological sample from the subject to detect one or more breakpoints associated with one or more rearrangements and based on the presence of the one or more breakpoints associated with the one or more rearrangements, classifying the subject as HRD positive (e.g., para [0004], [0009], [0071], [0091-0093], [0100], [0180] [0257-0259] and Figure 2), particularly wherein the fusion occurs in the RAD51B gene (e.g., Table 1 and 2 and para [0121]. Yen teaches that after subjects are identified as having a HRD positive score they are then treated by administering a PARP inhibitor (e.g., para [0011] and [0272]). It is stated that “cells having a deficiency in a homologous recombination repair (HRR) pathway are vulnerable to increased DNA damage and have an increased sensitivity to DNA damage repair inhibitors (e.g., PARP inhibitors, etc.) and/or other therapies” (para [0015]).
Yen teaches that the method is applicable to subjects having any type of cancer, including colorectal carcinoma (e.g., para [0294]
Accordingly, it would have been obvious to one of ordinary skill in the art before the effective filing date of the claimed invention to have modified the method of Xie so have assayed for and identified the RAD51B fusion comprising a fusion between intron 10 of RAD51B and an intergenic region in subjects having or suspected of having other types of cancer, including colorectal carcinoma. One would have been motivated to have done so because Yen teaches methods of detecting RAD51B gene mutations causing HR deficiency in other types of cancers, including colorectal carcinomas and Xie and Yen both teach that PARP inhibitor therapy can be effective in treating cancer in those subjects that are carriers of a deleterious mutation in a HRR gene, such as the RAD51B gene.
13. Claim(s) 23, 26, 27, 48 and 52 is/are rejected under 35 U.S.C. 103 as being unpatentable over Xie et al (JCO Precis Oncol. 2022. 6:e2100404, p. 1-8) in view of Harewood et al (Genome Biology. 2017. 18:125, p. 1-11; previously cited).
The teachings of Xie are presented above.
Xie teaches detecting the fusion comprising the RAD51B intron and intergenic sequences in tumor tissue samples from subjects having pancreatic cancer. Xie does not teach detecting the fusion by performing a method that preserves spatial-proximal contiguity information, particularly wherein the method uses the proximity ligation technique of Hi-C.
However, Harewood teaches performing the proximity ligation method of Hi-C to detect chromosomal rearrangements, including translocations, in human tumor samples (e.g., p. 2 “Balanced and unbalanced translocation detection” and Figure 1). Harewood teaches that Hi-C can be used to detect both known and novel, balanced and unbalanced chromosomal rearrangements in tumor samples (p. 1, col. 2). It is further disclosed that Hi-C has the advantage that it can potentially defined chromosome breakpoints to bp resolution, rearrangements involving poorly mappable regions can be detected, and the method is less expensive than standard sequencing methods, such as deep whole genome sequencing (e.g., abstract and p. 8, col. 2).
In view of the teachings of Harewood, it would have been obvious to one of ordinary skill in the art before the effective filing date of the claimed invention to have modified the method of Xie so as to have analyzed tumor tissue samples from subjects having or suspected of having cancer using the Hi-C technique of Harewood to detect the fusion involving the RAD51B gene. One would have been motivated to have done so in order to have achieved the advantages set forth by Harewood that the Hi-C method is less expensive than most deep sequencing methods and can be used to identify novel rearrangements / translocations, as well as the precise site of a breakpoint and rearrangements involving poorly mappable regions.
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/CARLA J MYERS/Primary Examiner, Art Unit 1682