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 .
Information Disclosure Statement
The information disclosure statement (IDS) submitted on 08/15/2023 are in compliance with the provisions of 37 CFR 1.97. Accordingly, the information disclosure statement is being considered by the examiner.
Specification
The disclosure is objected to because page 16, para. [0095], line 2 of the specification contains an embedded hyperlink and/or other form of browser-executable code. Applicant is required to delete the embedded hyperlink and/or other form of browser-executable code; references to websites should be limited to the top-level domain name without any prefix such as http:// or other browser-executable code. See MPEP § 608.01.
Status of Claims
This office action is in response to an amendment filed on February 13, 2026.
Claims 1-64 were previously pending. Applicant amended claims 1, 3, 22, 38 and 46.
Claims 1-64 are currently pending, with claims 6-8, 10-12, 17, 19-20, 22-37, 41-43, 45-64 withdrawn.
Claims 1-5, 9, 13-16, 18, 21, 38-40 and 44 are under consideration. This is the first action on the merits.
Election/Restrictions
Applicant’s election with traverse of Group I (claims 1-21, 38-45) in the Reply filed on February 13, 2026 is acknowledged 1.
In the Reply, Applicant amended claims 22 and 46 with additional limitations and asserts that the amended claims of Groups I-III:
"… share a set of technical features that distinguish the present invention over the cited art, including: (i) DNA enrichment to obtain a target nucleic acid, (ii) probing the enriched target nucleic acid using at least a first split probe and a second split probe, and (iii) detecting independent signals generated from the respective split probe-target DNA hybrids." (Remarks, page 17).
Applicant's traversal has been fully considered but is not persuasive.
First, the kit claims in Group III cannot be limited by method steps such as enriching and detecting. Accordingly, the process steps identified by Applicant cannot constitute the common technical feature between the kit claims and method claims.
Second, the alleged feature of "detecting independent signals generated from the respective split probe-target DNA hybrids" is not required by any of the method claims in Groups I and II. The claims 1 and 22 merely recite "detecting a signal that reflects a binding between the split probe and the target nucleic acid," with the split probe defined as comprising a first split probe and a second split probe. Thus the methods of Groups I and II do not require detection of independent signals.
Third, the inventions listed as groups I-II do not relate to a single general inventive concept under PCT Rule 13.1 because, under PCT Rule 13.2, they lack the same or corresponding special technical features because they lack a common feature that makes a ‘contribution’ over the prior art. As discussed in the 102 rejections below, the method in claim 1 is anticipated by prior art. Accordingly, any technical feature that it may share with the non-elected invention groups would likewise be anticipated.
Moreover, gene fusion detection methods comprising enriching DNA with a set of oligonucleotides and probing enriched target nucleic acid with split probes is well-known in the art 2.
Since a special technical feature must define the invention over the prior art, there is no special technical feature that links the groups.
Therefore, these groups recite independent and distinct inventions that lack unity. The restriction requirement is still deemed proper and is therefore made FINAL.
Applicant’s election with traverse of the following species in the reply filed on February 13, 2026 is acknowledged:
Species of split probe:
D) a first split probe being complementary to the 3' end of a partner DNA fragment and a second split probe being complementary to the 5' end of a target DNA fragment (claim 1,22, 46) 3;
Species of first split probe:
O) the first split probe targets within a distance of 0-40 bp from a DNA fragment joining boundary (claim 9) 4;
Species of second split probe
R) the second split probe targets within a distance of 0-40 bp from a DNA fragment joining boundary (claim 9) 5;
Species of partner DNA fragment sequence : ETV6 6;
Species of target DNA fragment sequence : NTRK3;
Species of DNA fragment joining event:
Z) wherein the partner DNA fragment and the target DNA fragment each comprises a sequence from a different gene (claim 18)7;
Species of treatment :
BB) administering a therapeutically effective amount of an inhibitor of a fusion protein (claim 38);
Species of cancer: FF) Carcinoma (claim 44) 8;
Species of determining step:
GGG) determining the partner DNA fragment as an upstream DNA fragment and the target DNA fragment as a downstream DNA fragment through confirming the signal based on the first split probe binding to the 3' end of the partner DNA fragment and the second split probe binding to the 5' end of the target DNA fragment (claim 4);
Species of gene specific primers:
PPP) at least two pairs of the gene-specific primers are designed to obtain the target nucleic acid from the partner DNA fragment as an upstream DNA fragment (claim 5) 9;
Species of enriching step:
TTT) wherein the DNA is amplified by multiplex PCR with at least two pairs of a gene-specific primers in step (b) (claim 3) 10.
Applicant's traversal is on the ground that the species are not patentably distinct, and examination of the species in the context of the elected Group I does not impose an undue burden on the Office. (Remarks, page 18)
This is not found persuasive because the applicant used the incorrect/irrelevant standard, for national stage applications submitted under 35 USC 371, unity of invention standard should be applied. Because applicant did not distinctly and specifically point out the supposed errors in the restriction requirement, the election has been treated as an election without traverse (MPEP § 818.01(a)).
Claims 6-8, 10-12, 17, 19-20, 22-37, 41-43, 45-64 are withdrawn from further consideration pursuant to 37 CFR 1.142(b) as being drawn to a nonelected invention.
Claims 1-5, 9, 13-16, 18, 21, 38-40 and 44 are under consideration.
When all the claims directed to the elected invention are in condition for allowance, and the nonelected invention(s) will be considered for rejoinder. Rejoinder involves withdrawal of a restriction requirement between an allowable elected invention and a nonelected invention and examination of the formerly nonelected invention on the merits.
In order to be eligible for rejoinder, a claim to a nonelected invention must depend from or otherwise require all the limitations of an allowable claim. A withdrawn claim that does not require all the limitations of an allowable claim will not be rejoined.
In order to retain the right to rejoinder, applicant is advised that the claims to the nonelected invention(s) should be amended during prosecution to require the limitations of the elected invention. Failure to do so may result in a loss of the right to rejoinder. See MPEP 821.04.
Priority
The priority date of the instant claims 1-5, 9, 13-16, 18, 21, 38-40 and 44 is 02/17/2021, filling date of the US provisional application NO. 63/150,095.
Claim Interpretation
In evaluating the patentability of the claims presented in this application, claim terms have been given their broadest reasonable interpretation (BRI) consistent with the specification, as understood by one of ordinary skill in the art, as outlined in MPEP§ 2111.
Regarding claim 1, it recites an "enriching" step. The application's disclosure does not expressly define the term "enriching." The specification provides relevant descriptions pertaining to PCR enrichment using primers (e.g., [0166-0167]; [0176-0177]; [0182-0183]).
Accordingly, under BRI, the term "enriching" is understood as encompassing PCR.
Claim 1 recites the terms "partner DNA fragment" and "target DNA fragment," which are defined by the specification as follows:
"The term “target DNA fragment” refers to any nucleic acid molecule, polynucleotide sequence, or any fragment comprising a portion of a specific gene or genetic locus in the genomic DNA. The term “partner DNA fragment” refers to the fragment whose 3′ or 5′ sequence is joined to the 5′ or 3′ sequence of the “target DNA fragment.” The target DNA fragment or the partner DNA fragment includes an intact gene, an exon or intron, a regulatory sequence, or any region between genes. The DNA fragment at the 5′ end of the hybrid DNA fragment is referred to as “upstream DNA fragment”, and the DNA fragment at the 3′ end of the hybrid DNA fragment is referred to as “downstream DNA fragment."([0087])
Accordingly, under BRI and in view of the specification, "partner DNA fragment" and "target DNA fragment" are understood as joined DNA segments.
Claim 9 recites "DNA fragment joining boundary," which is defined by the specification as follows:
"The hybrid DNA fragment has a “DNA fragment joining boundary” which is the region where one DNA fragment is joined to another DNA fragment. For example, the regions that the partner DNA fragment is joined to the target DNA fragment, or the regions that the partner DNA fragment is joined to another DNA fragment or fusion junction." ([0088])
Accordingly, the term "DNA fragment joining boundary" is interpreted under BRI as encompassing a region of any range/size where two DNA fragments are joined, for example, a region within ± 1kb of a gene fusion junction site.
Claim Rejections - 35 USC § 112(b)
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.
Claims 1-5, 9, 13-16, 18, 21, 38-40 and 44 are rejected under 35 U.S.C. 112(b), 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.
A) Regarding claim 1, it recite
"probing the target nucleic acid with a split probe comprising:
(i) a first split probe being complementary to the 3' end of a partner DNA fragment,
a second split probe being complementary to the 5' end of a target DNA fragment"
and further recites "wherein a gap of the first and second split probes targeting sites on the target nucleic acid is within 0-80 bp."
This claim language is indefinite because the relationship between the "target nucleic acid," the "partner DNA fragment," and the "target DNA fragment" is unclear.
The claim first recites probing a "target nucleic acid" with a split probe, but then describes the split probe as comprising "a first split probe" and "a second split probe," each complementary to regions of a "partner DNA fragment," and a "target DNA fragment," respectively.
However, the claim does not specify which regions of the "target nucleic acid" the probes are intended to bind. It is unclear whether the "target nucleic acid" comprises the "partner DNA fragment," and the "target DNA fragment," or whether these are separate elements.
If they are separate elements, the recitation that the split probes are complementary to the "partner DNA fragment" and "target DNA fragment" would not limit the claimed method, because the claim does not require these fragments to be present in the steps nor require the probes to bind to them.
If the "target nucleic acid" is intended to comprise the "partner DNA fragment" and "target DNA fragment," the scope of the claim is further confounded by contradictory language. The claim requires the "first split probe" and "second split probe" to be complementary to the 3' end and 5' end of the respective fragments, while also requiring a gap between the probe binding sites. Accordingly to the specification, the "partner DNA fragment" and "target DNA fragment" are joined segments. Probes that are complementary to their respective termini at the junction site would not be expected to have a gap between their binding sites.
Furthermore, the claim recites "a split probe" comprising "a first split probe" and "a second split probe," which creates additional ambiguity. It is unclear whether the claim requires a single probe comprising two connected sequence segments, or two separate probes. It is unclear how a single probe can simultaneously comprise two probes having different structures.
Accordingly, the metes and bounds of the claim cannot be determined with reasonable certainty, rendering the claim indefinite.
For the purpose of compact prosecution and applying prior art under 35 USC§ 102 and 103, the "target nucleic acid" is interpreted as comprising the "partner DNA fragment" and "target DNA fragment." Additionally, the recited "3' end" and "5' end" are interpreted as referring to 3' and 5' regions of the respectively fragments, such that a gap between the probe targeting sites is possible and the claim may be examined.
Claims 2-5, 9, 13-16, 18, 21, 38-40 and 44 are rejected for depending from claim 1 and not remedying the indefiniteness.
B) Regarding claim 14, it recites "wherein in step (c), the target nucleic acid is probed with a split probe and a single probe targeting a DNA fragment joining boundary. "
This claim language is indefinite.
First, the recitation "a split probe" is unclear. The base claim 1 already recites a split probe. Accordingly, it is unclear whether "a split probe" in claim 14 refers to the previously introduced split probe or to a different split probe.
Second, claim 1 already recites two split probes binding to the junction region between two joined DNA fragments (i.e., a first split probe being complementary to the 3' end of a partner DNA fragment, a second split probe being complementary to the 5' end of a target DNA fragment ), with as few as 0 bp between their target sites. Thus, there is no space left for binding of another probe at the region. It is unclear where the recited "single probe targeting a DNA fragment joining boundary" is intended to bind on the target nucleic acid, when region where the DNA fragments are joined is already occupied by the first and second split probes.
Thus, the exact scope of claim 14 cannot be determined without applying considerable speculation and assumption. Consequently, claim 14 is excluded from prior art search in this examination, as any rejection based on prior art cannot be based on speculations and assumptions, see In re Steele, 305 F.2d 859, 862 (CCPA 1962).
C) Regarding claim 38, it recites "determining whether a subject is at risk of cancer or a genotype," which is indefinite.
Specifically, it is unclear what is meant by "at risk of a genotype," a genotype refers to the genetic constitution of an individual rather than a condition or a disease for which a subject may be "at risk."
Accordingly, the scope of this limitation cannot be determined with reasonable certainty.
Claims 39-40 and 44 are rejected for depending from claim 38 and not remedying the indefiniteness.
Claim Rejections - 35 USC § 112(a)
The following is a quotation of the first paragraph of 35 U.S.C. 112(a):
(a) IN GENERAL.—The specification shall contain a written description of the invention, and of the manner and process of making and using it, in such full, clear, concise, and exact terms as to enable any person skilled in the art to which it pertains, or with which it is most nearly connected, to make and use the same, and shall set forth the best mode contemplated by the inventor or joint inventor of carrying out the invention.
Claims 38-40 and 44 are rejected under 35 U.S.C. 112(a) as failing to comply with the written description requirement. The claims contains subject matter which was not described in the specification in such a way as to reasonably convey to one skilled in the relevant art that the inventor or a joint inventor, or for applications subject to pre-AIA 35 U.S.C. 112, the inventor(s), at the time the application was filed, had possession of the claimed invention.
Regarding claim 38, it recites:
"(a) determining whether a subject is at risk of cancer or a genotype, comprising detecting a DNA fragment joining event by the method of claim 1; and
(b) administering a therapeutically effective amount of an inhibitor of a fusion protein encoded by the DNA fragment joining event."
However, the applicant's disclosure lacks sufficient detail to demonstrate possession of the claimed invention, as required under 35 U.S.C. 112(a).
Accordingly to MPEP 2163 (written description requirement), the specification must clearly demonstrate that the inventor was in possession of the claimed invention at the time of filling.
First, the disclosure lacks any detailed description supporting the determining of cancer risk. While the specification describes detection of specific gene mutations or fusion events using probe hybridization assays (see Examples 1-6), it does not describe how the results of these assays are used to determine whether a subject is at risk of cancer. The disclosure does not describe any analysis steps, threshold, or criteria for determining cancer risk based on the detection of DNA fragment joining events. The mere repetition of claim terms in the specification is not sufficient in meeting the written description requirement under 35 U.S.C. 112(a).
Second, the disclosure lacks sufficient support for determining cancer risk in a subject and administering an inhibitor to a subject merely at risk of cancer. An individual "at risk of cancer" refers to a person having a likelihood of developing cancer but who may not currently have the disease 11. Without a diagnosis, it is unconventional to administer treatment for a disease when only a possibility of the disease's development exists. The disclosure lacks any detailed description that can support determining cancer risk in a subject and then administering a therapeutically effective amount of an inhibitor of a fusion protein encoded by the DNA fragment joining event to treat such a subject.
Paragraph [0139] describes detecting NTRK gene fusions in a sample from a cancer patient and indicates that the patient is expected to respond to a TRK inhibitor. However, in this description, the patient is already known to have cancer before the fusion detection and administration of inhibitor.
Third, by attempting to claim all fusion inhibiting therapeutics based on the presence of any and all DNA fragment joining event, the claim extends beyond the disclosed invention, constituting a "reach-through claim." Such language improperly seeks to claim any and all inhibitor treatments for any and all DNA fragment joining events, both known and unknown at the time of the invention, thus failing to meet the written description requirement of 35 U.S.C. 112(a) or pre-AIA 35 U.S.C. 112, first paragraph.
In other words, by broadly claiming the administration of an inhibitor based on detecting a "DNA fragment joining event," rather than specifying a particular gene fusion event, its associated disease or condition, and a specific therapeutic, the applicant attempts to claim an indefinite number of combinations of DNA fragment joining events, their associated conditions, and treatments. These combinations are neither disclosed nor adequately described in the specification.
Therefore, the application's disclosure does not meet the written description requirement under 35 U.S.C. 112(a), for there is insufficient disclosure that convey to a person skilled in the art that the inventor was in possession of the full breadth of the claim at the time of filling.
Claims 39-40 and 44 are rejected because they depend from claim 38 and inherit the deficiencies of the base claim.
Claim Rejections - 35 USC § 102
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 the appropriate paragraphs of 35 U.S.C. 102 that form the basis for the rejections under this section made in this Office action:
A person shall be entitled to a patent unless –
(a)(1) the claimed invention was patented, described in a printed publication, or in public use, on sale, or otherwise available to the public before the effective filing date of the claimed invention.
Claims 1-5, 9, 13 and 21 are rejected under 35 U.S.C. 102(a)(1) as being anticipated by Barany (Barany et al. US20180265917A1 - Method for identification and quantification of nucleic acid expression, splice variant, translocation, copy number, or methylation changes; published 2018-09-20).
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Regarding claim 1, Barany teaches a method for detecting a DNA fragment joining event (Figure 54), comprising:
(a) obtaining a DNA or a DNA from an extracted RNA in a sample (Figure 54, B);
(b) enriching the DNA with a set of oligonucleotides to obtain a target nucleic acid (Figure 54, B);
(c) probing the target nucleic acid with a split probe (Figure 54, C) comprising:
(i) a first split probe being complementary to the 3' end of a partner DNA fragment (Figure 54, B, junction-specific probe binding to exon 1),
a second split probe being complementary to the 5' end of a target DNA fragment (Figure 54, B, junction-specific probe binding to exon b),
wherein a gap of the first and second split probes targeting sites on the target nucleic acid is within 0-80 bp (Figure 54, gap between two probes is zero); or
(d) detecting a signal that reflects a binding between the split probe and the target nucleic acid (Figure 54, C, detection using real-time PCR).
Regarding claim 2, Barany teaches wherein the set of oligonucleotides is a gene-specific primer or a gene-specific probe (Figure 54).
Regarding claim 3, Barany teaches wherein the DNA is amplified by multiplex PCR with at least two pairs of gene-specific primers in step (b) (Figure 54).
Regarding claim 4, Barany teaches determining the partner DNA fragment as an upstream DNA fragment and the target DNA fragment as a downstream DNA fragment through confirming the signal based on the first split probe binding to the 3' end of the partner DNA fragment and the second split probe binding to the 5' end of the target DNA fragment (Figure 54).
Regarding claim 5, Barany teaches at least two pairs of the gene-specific primers are designed to obtain the target nucleic acid from the partner DNA fragment as an upstream DNA fragment (Figure 54B, 3 different primer pairs using forward primers to exons 1, 2, and 3).
Regarding claim 9, Barany teaches wherein the first split probe or the second split probe targets within a distance of 0-40 bp from a DNA fragment joining boundary (Figure 54).
Regarding claim 13, Barany teaches wherein a length of the split probe is 10-60 bp ([0701] example of LDR oligo, 60bp).
Regarding claim 21, Barany teaches the signal is fluorescent (Figure 54).
Claim Rejections - 35 USC § 103
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.
Claims 15-16, 18, 38-40 and 44 are rejected under 35 U.S.C. 103 as being unpatentable over Barany (Barany et al. US20180265917A1 - Method for identification and quantification of nucleic acid expression, splice variant, translocation, copy number, or methylation changes; published 2018-09-20), in view of Amatu (Amatu et al., NTRK gene fusions as novel targets of cancer therapy across multiple tumour types. ESMO Open. 2016 Mar 18;1(2):e000023. doi: 10.1136/esmoopen-2015-000023. PMID: 27843590; PMCID: PMC5070277).
A) The teachings of Barany are recited above and applied as for base claim 1.
Regarding claims 15, 16, and 18, Applicant elected ETV6, as partner DNA fragment sequence; and NTRK3 as target DNA fragment sequence. Accordingly, the DNA fragment joining event (e.g., gene fusion) in claim 18 corresponds to ETV6-NTRK3.
Barany teaches, in Figure 54, methods for detecting fusion events between two genes, and its teachings meet all limitations recited in base claim 1.
Although Barany does not explicitly disclose detecting the specific gene fusion ETV6-NTRK3, a person of ordinary skill in the art would have found it obvious to apply the fusion detection method of Barany to detect the ETV6-NTRK3, this is supported by Amatu.
As extensively discussed in Amatu, which is a review article addressing ETV6-NTRK3 fusion across multiple cancer types (Table 1, ETV6-NTRK3) and therapeutic strategies targeting such fusions (Table 2), the ETV6-NTRK3 fusion is well-known and have been widely studied (see Table 1). Amatu further teaches that ETV6-NTRK3 fusion, which is the most studied NTRK3 fusion, is among the fusion targets investigated in several cancer therapies undergoing clinical evaluation (see Tables 1 and 2). Therefore, the prior art demonstrates strong interest in detecting and monitoring ETV6-NTRK3 fusion for clinical applications, such as patient stratification and monitoring therapeutic response in clinical trials directed to such gene fusions.
Thus, in view of the above, it would have been prima facie obvious to a person of ordinary skill in the art before the effective filing date of the claimed invention to apply the gene fusion detection methods of Barany to detect the ETV6-NTRK3 fusion disclosed in Amatu.
This combination would have been obvious as it represents the KSR principle of predictable use of prior art elements (i.e., known ETV6-NTRK3 fusion) according to a known method (i.e., gene fusion detection method in Barany) to yield predictable results. (See MPEP §2143).
B) Regarding claim 38, Amatu teaches administering a therapeutically effective amount of an inhibitor of a fusion protein encoded by the DNA fragment joining event (Table 2, in clinical trials therapeutically effective amount of inhibitors are administered to patients).
Regarding claims 39-40, Amatu teaches ETV6-NTRK3 fusion (Table 1).
Regarding claim 44, Amatu teaches carcinoma (Table 1, ETV6-NTRK3, Ductal carcinoma).
Conclusion
No claims are allowed.
Any inquiry concerning this communication or earlier communications from the examiner should be directed to TIAN NMN YU whose telephone number is (703)756-4694. The examiner can normally be reached Monday - Friday 8:30 am - 5:30 pm.
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/TIAN NMN YU/Examiner , Art Unit 1681 /AARON A PRIEST/Primary Examiner, Art Unit 1681
1 Claims 22-37 and 46-64 are withdrawn as being drawn to non-elected groups II-III.
2 See Mityaeva et al. Analysis of Chromosome Translocations Involving MML by Hybridization with an Oligonucleotide Microarray. Molecular Biology 38, 376–382 (2004); doi.org/10.1023/B:MBIL.0000032208.13834.8b ;
Giusiano et al.; Development of a biochip-based assay integrated in a global strategy for identification of fusion transcripts in acute myeloid leukemia: a work flow for acute myeloid leukemia diagnosis. Int J Lab Hematol. 2010 Aug 1;32(4):398-409. doi: 10.1111/j.1751-553X.2009.01201.x. Epub 2009 Nov 23. PMID: 19930410;
Xiong et al., A Pipeline with Multiplex Reverse Transcription Polymerase Chain Reaction and Microarray for Screening of Chromosomal Translocations in Leukemia, BioMed Research International, 2013, 135086, 13 pages, 2013. doi.org/10.1155/2013/135086;
Nasedkina et al. Biological microchip for establishing the structure of fusion transcripts involving MLL in children with acute leukemia. Mol Biol 50, 852–859 (2016). doi.org/10.1134/S0026893316060145;
Qing et al.; A sensitive array-based assay for identifying multiple TMPRSS2:ERG fusion gene variants, Nucleic Acids Research, Volume 36, Issue 20, 1 November 2008, Page e130, doi.org/10.1093/nar/gkn585;
Maroc et al.; A diagnostic biochip for the comprehensive analysis of MLL translocations in acute leukemia. Leukemia 18, 1522–1530 (2004). doi.org/10.1038/sj.leu.2403439;
Chun et al. ; Identification of leukemia-specific fusion gene transcripts with a novel oligonucleotide array. Mol Diagn Ther. 2007;11(1):21-8. doi: 10.1007/BF03256220. PMID: 17286448.
3 Claims 12 and 19 are withdrawn as being drawn to non-elected species C, e, F, G, J, L-N, requiring a third split probe being complementary to a third DNA fragment.
4 Claim 10 is withdrawn as being drawn to non-elected species P, Q. There is no disclosure of relationship between the probes in claims 9 and 10 in the specification.
5 Claim 11 is withdrawn as being drawn to non-elected species S, T. There is no disclosure of relationship between the probes in claims 9 and 11 in the specification.
6 Claim 42 is withdrawn as being drawn to non-elected species BCR.
7 Claims 17, 41, 43 are withdrawn as being drawn to non-elected species Y.
8 Claim 45 is withdrawn as being drawn to non-elected species KK-ZZ.
9 Claims 6-8 are withdrawn as being drawn to non-elected species QQQ, RRR, SSS.
10 Claim 20 is withdrawn as being drawn to non-elected species UUU.
11 see Lewis-Patterson et al. Cancer Prevention in the Survivorship Setting. Semin Oncol Nurs. 2016 Aug;32(3):291-305. doi: 10.1016/j.soncn.2016.05.009. Epub 2016 Jul 29. PMID: 27539283;
see also "Cancer risk: What the numbers mean" ; mayoclinic.org/diseases-conditions/cancer/in-depth/cancer/art-20044092.