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 .
Continued Examination Under 37 CFR 1.114
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and the fee set forth in 37 CFR 1.17(e) has been timely paid, the finality of the previous Office action has been withdrawn pursuant to 37 CFR 1.114.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 9/23/2025 has been entered.
Application Status
This action is written in response to applicant’s correspondence received 9/23/2025. Claims 1-29 are currently pending and under examination.
Rejections and objections of prior Office action overcome by amendment:
35 U.S.C. § 112(a) enablement rejection of claims 1-29, withdrawn in view of amendment.
35 U.S.C. § 112(b) Claim 11 indefiniteness rejection over “abundance” is withdrawn in view of amendment.
35 U.S.C. § 112(b) Claim 13 “generating an initial sequencing is withdrawn upon further consideration.
Specification objection (browser executable code) withdrawn in view of amendment.
Information Disclosure Statement
The information disclosure statements (IDS’s) submitted on 10/29/25 is in compliance with the provisions of 37 CFR 1.97. Accordingly, the information disclosure statements is being considered by the examiner.
Drawings
The specification ([0016]) and Fig 1A do not indicate the same scenario, and FIG1A would not function, as described. The Specification Description of Drawings ([0016]) recites that probes enable detection of KMT2A-AF4 fusions and probes recognize unique sequences in KMT2A (FAM) and AFF1-AF4(HEX). However, the figure depicts two probes, FAM-KMT2A and HEX-KMT2A, and this would only detect KMT2A, but not a fusion with a different partner gene.
The drawings are objected to under 37 CFR 1.83(a). The drawings must show every feature of the invention specified in the claims. Therefore, the fluorescent probe for the partner gene must be shown or the feature(s) canceled from the claim(s). No new matter should be entered.
Corrected drawing sheets in compliance with 37 CFR 1.121(d) are required in reply to the Office action to avoid abandonment of the application. Any amended replacement drawing sheet should include all of the figures appearing on the immediate prior version of the sheet, even if only one figure is being amended. The figure or figure number of an amended drawing should not be labeled as “amended.” If a drawing figure is to be canceled, the appropriate figure must be removed from the replacement sheet, and where necessary, the remaining figures must be renumbered and appropriate changes made to the brief description of the several views of the drawings for consistency. Additional replacement sheets may be necessary to show the renumbering of the remaining figures. Each drawing sheet submitted after the filing date of an application must be labeled in the top margin as either “Replacement Sheet” or “New Sheet” pursuant to 37 CFR 1.121(d). If the changes are not accepted by the examiner, the applicant will be notified and informed of any required corrective action in the next Office action. The objection to the drawings will not be held in abeyance.
Specification
The use of the term QX200 Droplet Digital PCR at [0067], which is a trade name or a mark used in commerce, has been noted in this application. The term should be accompanied by the generic terminology; furthermore the term should be capitalized wherever it appears or, where appropriate, include a proper symbol indicating use in commerce such as ™, SM , or ® following the term.
Although the use of trade names and marks used in commerce (i.e., trademarks, service marks, certification marks, and collective marks) are permissible in patent applications, the proprietary nature of the marks should be respected and every effort made to prevent their use in any manner which might adversely affect their validity as commercial marks.
Claim 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 1-29 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 1 is indefinite over the recitation of probe configured to anneal to the KMT2A exonic cDNA between the KMT2A forward PCR primer and the fusion site. The primer is not part of the cDNA. If it is the intent, this would be more clear if it recited a location on KMT2A, such as, “the primer binding site on the KMT2A exonic cDNA”. Step iii and iv of claim 13 has the same issue, where the probe anneals to the cDNA and the forward primer is not part of that cDNA.
Claims 2-13 depend from claim 1 and are indefinite for the same reason.
Claim 10 similarly recites (step b) that the partner probe anneals to the partner gene between the partner reverse PCR primer and the fusion site. The partner pcr reverse primer is not part of the gene.
Claim 14 step b, c similarly recites the probe configured to anneal to the cDNA between the primer and the fusion site, where again, the primer is not part of the cDNA. Claims 15-21 depend from claim 14 and are indefinite for the same reason.
Claim 22 steps b, c also recite the probe anneals to KMT2A cDNA between the primer and fusion site, where the primer is not part of the cDNA.
Claims 23-29 depend from claim 22 and are indefinite for the same reason.
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.
The following is a quotation of the first paragraph of pre-AIA 35 U.S.C. 112:
The specification shall contain a written description of the invention, and of the manner and process of making and using it, in such full, clear, concise, and exact terms as to enable any person skilled in the art to which it pertains, or with which it is most nearly connected, to make and use the same, and shall set forth the best mode contemplated by the inventor of carrying out his invention.
Claims 1, 3, 4, 10, 11, 12, 13, 14, 16, 17, 22, 24, 25 are rejected under 35 U.S.C. 112(a) or 35 U.S.C. 112 (pre-AIA ), first paragraph, as failing to comply with the written description requirement. The claim(s) 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.
MPEP 2163.II.A.3.(a).i) states, “Whether the specification shows that applicant was in possession of the claimed invention is not a single, simple determination, but rather is a factual determination reached by considering a number of factors. Factors to be considered in determining whether there is sufficient evidence of possession include the level of skill and knowledge in the art, partial structure, physical and/or chemical properties, functional characteristics alone or coupled with a known or disclosed correlation between structure and function, and the method of making the claimed invention”.
For claims drawn to a genus, MPEP § 2163 states the written description requirement for a claimed genus may be satisfied through sufficient description of a representative number of species by actual reduction to practice, reduction to drawings, or by disclosure of relevant, identifying characteristics, i.e., structure or other physical and/or chemical properties, by functional characteristics coupled with a known or disclosed correlation between function and structure, or by a combination of such identifying characteristics, sufficient to show the applicant was in possession of the claimed genus. See Eli Lilly, 119 F.3d at 1568, 43 USPQ2d at 1406.
Breadth of the claims: Very broad, inclusive of any partner gene in any oncogenic fusion with KMT2A, in any organism (or for the subset of claims, a designated subset of fusions)
Nature of invention: Claims 1, 3, 4, 10, 11, 12, 13, 14, 16, 17, 22, 24, 25 are drawn to monitoring abundance of fusions expression of the large Genus of any KMT2A oncogenic fusions in any subject with any cancer that employe primers, fluorescent probes, ddPCR and expression estimation by fluorescent intensities. Of these, claims 3, 4, 10, 16, 17, 24, 25 are drawn to fusions with any of a subset of partners (AF9, AF4, AF6, ENL, ELL), and claims 3, 10, 11, 12, 16, and 24 also include any KMT2A fusion from a subject’s cancer, and claim 13 limited to leukemia fusions.
State of art: Unpredictable and challenging. Biotechnology, in general, is considered an unpredictable field. Over 80 fusions are known (Specification [0135]), however the Specification indicates that it is challenging to detect these fusions using qPCR [0135]. New oncogenic fusions continue to be identified (Kosasih et al 2020 Blood Advances 4 19; Meyer et al Leukemia, 5 Apr 2023 37, 988-100) for which the methods have not been tested, optimized, or known to succeed. The art appears silent on other taxonomic species harboring oncogenic KMT2A fusions thus the scope of our knowledge base relates to human fusions and cancer (e.g. Meyer et al 2023; Burmeister et al, 2015 Leukemia Res 242-247; 39 Choudhury et al US 2023/0250482 A1, published 8/10/2023).
What the specification does and does not teach: The specification [0062] generally disclosed that assays may be configured to detect a plurality of different KMT2A fusions, and points to a list in Table 1 which recites fusions associated with leukemias, where in one example the assay is said to be configured to detect multiple KMT2A fusion partners to cover 80% of the most common fusions in t-AML: AF9(MLLT1), AF4(AFF1), AF6(AFDN), ENL (MLLT1) and ELL [0062]. The assay here is said to be a novel mechanism to target and detect these fusions. The experimental work uses only a subset of exons (addressed below). The specification further addressed pooled assays to detect two or more fusions simultaneously [0065]. The specification teaches that prior efforts to develop digital quantification have been limited due to the promiscuous nature of KMT2A fusions [0063].
Not taught, are working examples outside of a subset of exons of the most common fusions, that are depicted in patients; the instant invention pertains largely to work in cell lines, plus from a few patient samples. The vast majority of the known oncogenic KMT2A fusions are not addressed or tested with these methods. Nor are most exons in the fusions considered. Further, most of the work presented uses cell lines with introductions (CRISPR-Cas9), and new gRNAs for CRISPR that would be required for non-disclosed, and emerging, fusions can be challenging and time consuming to construct/test and would require functionality and efficiency proof (Wilson et al., 2018, Front in Pharma, 9: 1-6, e.g. Pg 1, Introduction Para 1), and even then, would not disclosed in claim 1, which is considered a method for monitoring fusion abundance, in subjects (not cell lines).
Fig 1 appears scientifically incorrect and would not produce a fluorescent signal, reflective of KMT2A and a partner gene fusion.
Examples: Fusions are disclosed as challenging to detect with other methods, so ddPCR is used to detect the five most common fusions in t-AML, via cell lines and patient samples (undisclosed are the total number of patients/types of their fusions here) [0136]. Human cell lines are described with five fusions. One patient sample was used to design / test MET2A-ELL reagents. RNA was extracted from cell lines and patient samples (# samples used in this procedure, or patients samples, was not disclosed) [0139]. Primers were designed, with reference to identifying fusions from the cancer dependency map [0140], referencing Fig 1A (KMT2A+AFF1-AF4), FIG 4 (primer seq for KMT2A e7, e9 forward primers, KMT2A e9, e11, reverse, AF4-AFF1 two reverse, MLLT3 two reverse, AFDN e2 rev, (repeated, for this exon with another primer, “rev2”), ENL-MLLT1 e2, e4, e7 reverse, ELL-ELL e3, e4 reverse, and FIG 6 (mapped fusions: KMT2A AFDN(AF6), MLLT(AF9), MLLTT1(ENL) and ELL). Cell line fusions were sequenced to verify primer pair fidelity [0140]. ddPCR reaction conditions were disclosed as being used at 60 degrees C for one minute for annealing/extension, apparently for all primers [0141], which would require attention were new primers to be developed. KMT2A exon 7-9 was amplified (targeting wildtype KMT2A for wt transcript abundance, which is not oncogenic fusion). A pooled assay was conducted with KMT2A exon 7, AF9 exon 6, AF4 exon 5, AF6 exon 2, enl exon7, ell exon 3.
Fusion dilutions were performed [0143] for cell lines with fusion THP-1 (KMT2A) X OCI-MAL3 for detection at low frequency. Fusions were generated using CRISPR/Cas9 (break point exon 10 and 11 of KMT2A), with gRNA for KMT2A and MLLT3/AF9 [0144]. CRISPR/Cas9 “reagents” would require different optimization for additional work (e.g. Wilson et al, 2018).
FAM-KMT2A/HEX-partner probe assay combined with primers for detection of low frequency fusion in DDPCR [0145]. Pooling was performed [0148].
The working examples and dilutions disclose ELL (one patient sample and reagent testing with human cell lines), and the other KMT2A partners that contribute to 80% of fusions appear to be partially disclosed (a few exons as discussed), along with a few primers for them, KMT2A: e7, e9 forward primers, and e9, e11, reverse primers plus AF9(MLLT1) e2, e4, e7 reverse primer, AF4(AFF1) two reverse primers, AF6(AFDN) e2 reverse primer(s), ENL (MLLT1) and ELL-ELL e3, e4 reverse primers. FIG 6 depicts the mapped fusions: KMT2A AFDN(AF6), MLLT(AF9), MLLTT1(ENL) and ELL.
Summary: The specification indicates that the promiscuous nature of fusions results in limited detection, and as such, substantive disclosure is necessary regarding the over 80 KMT2A partners and relevant fusion details [0070] to demonstrate possession of the claimed invention.
Claims 1, 3, 4, 10, 11, 12, 13, 14, 16, 17, 22, 24, 25 are directed to monitoring abundance of fusion expression of the large Genus of any KMT2A fusion in any subject with any cancer (or for claim 3, 4, 10, 16, 17 and 24, 25 a subset of fusions is disclosed, which in claims 3, 10 and 11, 12, 16, and 24 also include any KMT2A fusion from a subjects cancer; and claim 13 limits patients to leukemia patients), using primers and probes, whereas the work conducted relates to a subset of particular exons of the common KMT2A fusion partners, with work largely conducted in cell lines with known fusions (which, one of ordinary skill recognizes simplifies background issues relative to actual patient samples), with additionally an undisclosed number, seemingly few, of patient samples (2 AML patient samples with known fusions in Fig11A; 2 additional patients with ‘fusions’ in Fig 11B, AML patients’ data, FIG11C, and 4 AML patients 1 AF9, 1 ELL, 2 AF6 transcript disclosed in FIG 15). The Specification does not include functional material on additional fusions, or other subjects, or relevant details. The presentation of primers recited (relevant SEQ ID NOs) is taken to amplify particular, specific fusion exons disclosed as targeted for the common fusions.
Conclusion regarding possession: Taking into consideration the factors outlined above, including the nature of the invention, the state of the art, the guidance provided by the applicant and the specific example, it is the conclusion that Applicant does not possess the invention as recited in the claims.
There is not sufficient specific written example in the Specification that would lead one with ordinary skill in the art to a different conclusion.
Claim 11 is rejected under 35 U.S.C. 112(a) or 35 U.S.C. 112 (pre-AIA ), first paragraph, as failing to comply with the written description requirement. The claim(s) 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. The claim recites classifying measureable residual disease if the abundance of expression of the fusion falls above a threshold value of .001% as measured by ddPCR for the oncogenic KMT2A fusion as a fraction of all KMT2A expressed transcripts. There is not support for a threshold of 0.001% for an oncogenic KMT2A fusion as a fraction of all KMT2A transcripts.
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.
The factual inquiries for establishing a background for determining obviousness under 35 U.S.C. 103 are summarized as follows:
1. Determining the scope and contents of the prior art.
2. Ascertaining the differences between the prior art and the claims at issue.
3. Resolving the level of ordinary skill in the pertinent art.
4. Considering objective evidence present in the application indicating obviousness or nonobviousness.
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) 1-4, 9 are rejected under 35 U.S.C. 103 as being unpatentable over Meyer et al (Leukemia, 5 Apr 2023 37, 988-1005) in view of Burmeister et al (2015 Leukemia Res 242-247; 39) in view of Choudhury et al (US20230250482 A1, filed 5/26/2022) in view of Petrova et al (Clin Biochem 2018 61 34-39) in view of Abbou et al (2022 Modern Path 35: 1022-1033).
Claim 1 disclosed a method for monitoring abundance of expression in at least one oncogenic KMT2A fusion in a subject with cancer, extracting RNA and synthesizing cDNA, using forward primer targeting KMT2A exonic cDNA upstream of fusion, and partner gene exonic cDNA downstream of fusion, with KMT2A and partner gene fluroescent probes, and estimating fusion expression abundance after ddPCR.
Re: claim 1-4, 9 Meyer et al. taught a suite of chromosomal rearrangements of KMT2A associated with leukemia, from over 3,000 leukemia patients (Abstract). Meyer’s workflow allowed for identifying KMT2A rearrangements, where breakpoints were determined within KMT2A gene and partner genes (Abstract), and a KMT2A patient specific fusion was used in a patient-specific qPCR assay to monitor MRD (Pg 988, right col, para 1; Pg. 1003, left col, final para). KMT2A rearrangement partner locations were recited (e.g. Pg 1002, Fig 6) thus upstream or downstream of KMT2A (11q23.3) was disclosed, as were the 37 exons of KMT2A (e.g. Fig 4). Meyer disclosed the fusions (breakpoint sequences) were of value to monitor MRD and for direct translation to patients to meet clinical needs and improve patient survival (Abstract). Re claim 9, the sample comprises peripheral blood from leukemia patients (Pg 988, right col, final para).
Meyer used DNA for this work, not RNA.
Burmeister specifically recited RT-PCR (requiring RNA, synthesis of cDNA) use for addressing KMT2A rearrangements in leukemia (Pg 242, left col, para 1) and disclosed RT primers for the most frequent KMT2A fusions (Pg 243, left col para 2), that were used on patient samples. Forward primers were designed for KMT2A targeting exon 7 or 8 and reverse primers for AF4 targeting exons 6 and 11 (Pg 243 right col paras 1-2).
Burmeister did not conduct ddPCR.
Choudhury et al., also disclosed detecting fusion genes including many KMT2A fusions: CENPK-KMT2A, KMT2A-ABI1, KMT2A-ACTN4, KMT2A-AFF3, KMT2A-AFF4, KMT2A-ARHGAP26, KMT2A-ARHGEF12, KMT2A-BTBD18, KMT2A-CASP8AP2, KMT2A-CBL, KMT2A-CEP170B, KMT2A-CIP2A, KMT2A-CREBBP, KMT2A-EEFSEC, KMT2A-ELL, KMT2A-EP300, KMT2A-EPS15, KMT2A-FOXO4, KMT2A-FRYL, KMT2A-GAS7, KMT2A-GMPS, KMT2A-GPHN, KMT2A-KNL1, KMT2A-LASP1, KMT2A-LPP, KMT2A-MAPRE1, KMT2A-MLLT1, KMT2A-MLLT11, KMT2A-MLLT3, KMT2A-MLLT6, KMT2A-MYO1F, KMT2A-NCKIPSD, KMT2A-NRIP3, KMT2A-PDS5A, KMT2A-PICALM, KMT2A-SARNP, KMT2A-SH3GL1, KMT2A-TET1, KMT2A-ZFYVE19 ([0241]).
The fusions included a sequence of a first region fused to a sequence of a second region at a fusion junction, which included KMT2A gene or portion thereof [0242], which could be from patient extracted RNA [0245], and in the method target mRNA was converted to cDNA [0293]. Fig 1 depicts the use of cfDNA, which one of ordinary skill knows may have low quantity of material of interest. Re: claim 3 and 4 , specifically KMT2A-ENL is recited [0241]. Samples arose from subjects with or suspected of having leukemia, hence subject specific fusion would be detected [0160]
Choudhury does not teach ddPCR and related probes.
Petrova et al., taught ddPCR for MRD detection using gene markers for AML, a category of leukemia inclusive of MLL, that can be induced by KMT2A (aka MLL mutations) (Abstract). The ddPCR method employed included primers and labelled probes (HEX and FAM), and specifically noted the low sensitivity of ddPCR (Pg 35 right col, para 1).
Petrova did not focus on the literal detection of the fusion.
Abbou et al., developed a fusion detection (identifying partners) assay with ddPCR (Pg. 1022, right col, final para). Here, primers and probes were designed to target exons in fusions (translocations) with two probes per transcript, one for each gene, and generating cDNA from RNA (Pg 1023, right col, para 3). Sensitive fluorescent detection occurred of fusions (Fig 3, Pg 1027, left col). Re claim 2, FAM and HEX were employed on probes such that unique signal rose from each type of fusion partner (Pg 1024 left col, final para, right col final para).
Prior to effective filing date it would have been prima facie obvious to one of ordinary skill in the art to have incorporated the methods of Burmeister, who developed KMT2A and partner exon based primers, and Choudhury who disclosed many KMT2A fusions and used methods of detection related to RNA of patients, and the idea of Petrova who recognized the value of ddPCR for MRD detection in fusions, and used this method for gene markers for oncogenic fusions (AML), and Abbou who refined a ddPCR particularly for fusion detection with probes identifying each fusion combination with two fluorescent probes, into the methods of Meyer to have improved the work of Meyer who emphasized and would have been motivated by the value of fusion detection to monitor MRD in leukemia patients, to improve the survival of those with KMT2A recombinations.
Conclusion
All claims rejected. Any inquiry concerning this communication or earlier communications from the examiner should be directed to Lisa Horth whose telephone number is (703)756-4557. The examiner can normally be reached Monday-Friday 8-4 EST.
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/LISA HORTH/Examiner, Art Unit 1681
/GARY BENZION/Supervisory Patent Examiner, Art Unit 1681