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 .
Applicants’ reply to the June 24, 2026 Office Action, filed August 11, 2026, is acknowledged. Applicants previously canceled claims 5, 18, and 26. Applicants amend claims 1, 6-8, 10-11, 13-14, 19-22, and 27-29. Claims 1-4, 6-17, 19-25, and 27-29 are pending in this application and are under examination.
In light of the new rejections set forth below, the finality of the June 24, 2026 Office Action is withdrawn and a new non-final Office Action is issued herewith.
Nucleotide and/or Amino Acid Sequence Disclosures
Summary of Requirements for Patent Applications Filed On Or After July 1, 2022, That Have Sequence Disclosures
37 CFR 1.831(a) requires that patent applications which contain disclosures of nucleotide and/or amino acid sequences that fall within the definitions of 37 CFR 1.831(b) must contain a “Sequence Listing XML”, as a separate part of the disclosure, which presents the nucleotide and/or amino acid sequences and associated information using the symbols and format in accordance with the requirements of 37 CFR 1.831-1.835. This “Sequence Listing XML” part of the disclosure may be submitted:
1. In accordance with 37 CFR 1.831(a) using the symbols and format requirements of 37 CFR 1.832 through 1.834 via the USPTO patent electronic filing system (see Section I.1 of the Legal Framework for Patent Electronic System (https://www.uspto.gov/PatentLegalFramework), hereinafter “Legal Framework”) in XML format, together with an incorporation by reference statement of the material in the XML file in a separate paragraph of the specification (an incorporation by reference paragraph) as required by 37 CFR 1.835(a)(2) or 1.835(b)(2) identifying:
a. the name of the XML file
b. the date of creation; and
c. the size of the XML file in bytes; or
2. In accordance with 37 CFR 1.831(a) using the symbols and format requirements of 37 CFR 1.832 through 1.834 on read-only optical disc(s) as permitted by 37 CFR 1.52(e)(1)(ii), labeled according to 37 CFR 1.52(e)(5), with an incorporation by reference statement of the material in the XML format according to 37 CFR 1.52(e)(8) and 37 CFR 1.835(a)(2) or 1.835(b)(2) in a separate paragraph of the specification identifying:
a. the name of the XML file;
b. the date of creation; and
c. the size of the XML file in bytes.
SPECIFIC DEFICIENCIES AND THE REQUIRED RESPONSE TO THIS NOTICE ARE AS FOLLOWS:
Specific deficiency - The incorporation by reference paragraph required by 37 CFR 1.834(c)(1), 1.835(a)(2), or 1.835(b)(2) is missing, defective or incomplete.
Required response - Applicant must:
• Provide a substitute specification in compliance with 37 CFR 1.52, 1.121(b)(3), and 1.125 inserting the required incorporation by reference paragraph, consisting of:
• A copy of the previously-submitted specification, with deletions shown with strikethrough or brackets and insertions shown with underlining (marked-up version);
• A copy of the amended specification without markings (clean version); and
• A statement that the substitute specification contains no new matter.
The Sequence Listing Incorporation by Reference paragraph filed August 28, 2024 does not list the size of the XML file. It is noted that the size of the XML file is 22,842 bytes.
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, 6-8, 10-11, 13-14, 19-22, and 27-29 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.
At claim 1, lines 10 and 14, both occurrences of “or” should be changed to “and” in order to have a correctly closed Markush group.
Claims 2-3, 6-12 depend from claim 1, and are therefore included in this rejection.
At claim 6, lines 6 and 10, both occurrences of “or” should be changed to “and” in order to have a correctly closed Markush group.
At claim 7, line 3, “or” should be changed to “and” in order to have a correctly closed Markush group.
At claim 8, line 6, “or” should be changed to “and” in order to have a correctly closed Markush group.
At claim 11, line 5, it is not clear if the information in the parentheses is intended to be a claim limitation or not.
At claim 13, lines 12 and 16, both occurrences of “or” should be changed to “and” in order to have a correctly closed Markush group.
At claim 14, lines 6 and 10, both occurrences of “or” should be changed to “and” in order to have a correctly closed Markush group.
Claims 15-17 and 19-21 depend from claim 14, and are therefore included in this rejection.
At claim 19, lines 3 and 10, both occurrences of “or” should be changed to “and” in order to have a correctly closed Markush group.
At claim 20, line 3, “or” should be changed to “and” in order to have a correctly closed Markush group.
At claim 21, line 6, “or” should be changed to “and” in order to have a correctly closed Markush group.
At claim 22, lines 6 and 10, both occurrences of “or” should be changed to “and” in order to have a correctly closed Markush group.
Claims 23-25 and 27-29 depend from claim 22, and are therefore included in this rejection.
At claim 27, lines 3 and 10, both occurrences of “or” should be changed to “and” in order to have a correctly closed Markush group.
At claim 28, line 3, “or” should be changed to “and” in order to have a correctly closed Markush group.
At claim 29, line 6, “or” should be changed to “and” in order to have a correctly closed Markush group.
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 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.
Claims 1-4, 9-17, and 22-25 are rejected under 35 U.S.C. 103 as being unpatentable over Abbou et al. (25 Modern Pathology 1022-1033 (2022), and cited in the ) in view of Afrin et al. (16(2) Molecular Cancer Research 279-285 (2017)), Fu et al. (127 American Journal of Clinical Pathology 24-30 (2007)), Panagopoulos et al. (18 Cancer Genomics & Proteomics 121-131 (2021)), Alonso et al. (50 Pediatric Blood & Cancer 869-871 (2008)), Hensel et al. (82 Journal of Cellular Biochemistry 299-309 (2001)), and Neuendorff et al. (133 Acta Haematologica 237-241 (2015)).
Regarding claims 1, 13-14, and 22, Abbou discloses methods for detecting somatic gene translocations, which can aid in making accurate diagnosis in cancer patients (abstract). Abbou discloses a multiplexed digital PCR-based approach that can identify gene partners of multiple somatic fusion transcripts (abstract). Abbou discloses that the assay is a multiplexed droplet digital PCT (ddPCR) (paragraph bridging pages 1022 and 1023). Abbou discloses obtaining samples from blood and bone marrow of patients (page 1023, column 1, final full paragraph). Abbou discloses extracting RNA from the sample and preparing a cDNA (page 1023, column 2, second full paragraph). Abbou discloses a forward PCR primer targeting a portion of an exonic cDNA and a reverse PCR primer targeting a portion of a partner exonic cDNA (page 1023, column 2, second and third full paragraphs). Abbou discloses using two different fluorescent reporter probes, such as FAM and HEX (page 1023, column 2, final two full paragraphs, paragraph bridging pages 1023 and 1024, page 1025, column 1, first paragraph, and Figures 1 and 5-6). Abbou discloses that the amount of expression of an oncogenic fusion based on the paired fluorescent intensities can be determined (page 1025, column 1, first paragraph and column 2, second paragraph). It is noted that claim 22 is a kit claim. Because Abbou discloses the components required to perform ddPCR on fusion sequences, Abbou is deemed to disclose a kit for performing the ddPCR assay. Abbou discloses monitoring the health and fusions of a subject (page 1023, columns 1-2). Abbou discloses that transcripts can be detected at level as little as 1 pg of RNA input and at an inexpensive cost (abstract).
Regarding claim 2, Abbou discloses using two different fluorescent reporter probes, such as FAM and HEX (page 1023, column 2, final two full paragraphs, paragraph bridging pages 1023 and 1024, page 1025, column 1, first paragraph, and Figures 1 and 5-6).
Regarding claims 9, 15, and 23, Abbou discloses obtaining samples from blood and bone marrow of patients (page 1023, column 1, final full paragraph).
Regarding claim 11, Abbou discloses that detection of translocation partners can aid in classification of a cancer diagnosis and in prognostication (page 1028, column 2, third paragraph). Abbou discloses
Regarding claim 12, Abbou discloses providing samples from pre-treatment and post-treatment biopsies and determining efficacy of treatment (paragraph bridging pages 1025-1027).
Abbou fails to disclose or suggest that the fusion includes gene partners KMT2A with AF9, AF4, AF6, ENL or ELL or the exons being targeted. Abbou fails to explicitly disclose classifying the subject based on a threshold value of 0.001 %.
Regarding claims 3-4, 10, 16-17, and 24-25, Afrin discloses methods of next generation sequencing that detects MLL (i.e., KMT2A) gene fusions in leukemia patients (abstract). Afrin disclose that there are numerous translocation partners of KMT2A, including AF4, AF6, AF9, ENL, and ELL (page 279, paragraph bridging columns 1 and 2).
Regarding claims 3-4, 10, 16-17, and 24-25, Fu discloses MLL (i.e., KMT2A)ENL gene fusions in patients with leukemia (abstract). Fu discloses that the MLL break point is at exon 7 and that the ENL breakpoint is at exon 7 (page 24, column 2, second paragraph). Fu discloses use of RT-PCR and panhandle PCR to determine the breakpoints (page 25).
Regarding claims 3-4, 10, 16-17, and 24-25, Panagopoulos discloses KMT2A-ELL fusion genes, with exon 9 or KMT2A fused to ENL at exon 3 (paragraph bridging pages 124 and 125).
Regarding claims 3-4, 16-17, and 24-25, Alonso discloses MLL (i.e., KMT2A)-AF9 fusions in leukemia patients (abstract). Alonso discloses that this is the most frequent MLL rearrangement in childhood acute myeloid leukemia (abstract). Alonso discloses that exon 6 of AF9 can be fused to an exon of MLL (page 870, column 1, second full paragraph and Figure 2).
Regarding claims 3-4, 10, 16-17, and 24-25, Hensel discloses breakpoints of translocations in human MLL (i.e., KMT2A)-AF4 fusions (abstract). Hensel discloses that the breakpoints can be at a breakpoint cluster of MLL at exons 8-14 and the exon cluster of AF4 at exons 2-7, which includes exon 5 (page 303 paragraph bridging columns 1 and 2 and page 307, column 1, first paragraph). Hensel discloses a negative control at exon 4 (i.e., non-fused) MLL (page 303 paragraph bridging columns 1 and 2 and page 307, column 1, first paragraph).
Regarding claims 3-4, 10, 16-17, and 24-25, Neuendorff discloses gene fusions of MLL (i.e., KMT2A) and AF6 in leukemia patients (abstract). Neuendorff discloses that fusions can be detected by RT-PCR with the MLL-AF6 transcript being detected by using a sense primer in MLL exon 9 and an antisense primer in AF6 exon 2 (page 238, column 2, first full paragraph).
It would have been obvious to one with ordinary skill in the art before the effective filing date of the claimed invention to subject the claimed KTM2A-AF9/AF4/AF6/ENL/ELL fusions disclosed by Afrin, Fu, Panogopoulos, Alonso, Hensel, and Neuendorff to the dual color ddPCR of Abbou because this assay can detect fusion partners in leukemia patients where the fusions are at a very low level and at a lower cost. One of ordinary skill in the art would have been motivated to detect the transcripts of the fusion partners using Abbou’s dual color ddPCR using primers and probes at exon 9 of KTM2A, exon 6 of AF-9, exon 5 of AF4, exon 2 of AF6, exon 7 of ENL, and exon 3 of ELL, as disclosed by Afrin, Fu, Panogopoulos, Alonso, Hensel, and Neuendorff, because the determination of the presence of such fusion transcripts will aid in the diagnosis, prognosis, and treatment of cancer patients, as well as the ability to monitor the efficacy of such treatments.
It would also have been obvious to one with ordinary skill in the art before the effective filing date of the claimed invention to determine all threshold levels of the abundance (or lack thereof) of the fusion transcripts and compare the levels to non-fusion genes in order to provide for accurate diagnosis, prognosis, treatment protocols and efficacy using the assay disclosed and suggested by Abbou, Afrin, Fu, Panogopoulos, Alonso, Hensel, and Neuendorff.
Claims 6-9, 19-21, and 27-29 are rejected under 35 U.S.C. 103 as being unpatentable over Abbou in view of Afrin, Fu, Panogopoulos, Alonso, Hansel, and Neuendorff, as applied to claims 1-4, 9-17, and 22-25 above, and further in view of Felix et al. (U.S. Patent Application Publication No. 2006/0063179, published March 23, 2006), Webster et al. (U.S. Patent Application Publication No. 2014/0017688), Narahara et al. (U.S. Patent Application Publication No. 2006/0134667, published June 22, 2006), Miller et al. (U.S. Patent Application Publication No. 2016/0281171, published September 29, 2016), and Zhuo (U.S. Patent Application Publication No. 2017/0009304, published January 12, 2017).
Abbou, Afrin, Fu, Panogopoulos, Alonso, Hansel, and Neuendorff disclose and suggest methods and kits for monitoring abundance of expression of KMT2A fusions with AF9, AF4, AF6, ENL, and ELL genes, as discussed above.
Abbou, Afrin, Fu, Panogopoulos, Alonso, Hansel, and Neuendorff fail to disclose or suggest the sequences of the primers or probes used in the method and kit.
Regarding claims 6, 19, and 17, Felix discloses method for identifying partner genes will MLL (i.e., KMT2A) (abstract). Felix discloses a sequence comprising instant SEQ ID NO: 2 (Appendix 1, SEQ ID NO: 20).
Regarding claims 6, 8, 19, 21, 27, and 29 Narahara discloses methods of detecting fusion genes transcripts resulting from chromosomal translocation (abstract). Narahara discloses two or more probes and primers containing partial base sequences of exons which sandwich a breakpoint of a fusion gene (abstract). Narahara discloses that the exons can be MLL (i.e., KMT2A) and AF9 (Table 1). Narahara discloses the sequence of instant SEQ ID NOS: 7 and 18 (Appendix III, SEQ ID NO: 25).
Regarding claims 6, 8, 19, 21, 27, and 29, Miller discloses targeted screening for mutations that involve translocations, which will also identify genomic breakpoints of such translocations (abstract). Miller discloses probes and primers to screen for leukemia (Example 1). Miller discloses sequences that comprise SEQ ID NOS: 9, 19, 5, 17, 14, and 23 (Appendices IV, V, VI, VII, and X, SEQ ID NOS: 158930, 158929, 148059, 148056, and 86267).
Regarding claims 6, 8, 19, 21, 27, and 29, Zhuo discloses methods of detecting fusion transcripts from a biological sample from a subject (abstract). Zhuo discloses the use of pairs of probes and primers in the detection method (abstract). Zhuo discloses primers and probes comprising the sequences of instant SEQ ID NOS: 13 and 21 (Appendices VIII and IX, SEQ ID NOS: 481840 and 762644).
Regarding claims 7, 20, and 28, Webster discloses methods for diagnosing subjects with leukemia by detection of fusion genes associated with the onset of leukemia (abstract). Webster discloses probes that can detect MLL fusion genes that comprise instant SEQ ID NO: 22 (Appendix II, SEQ ID NO: 189).
It would have been obvious to one with ordinary skill in the art before the effective filing date of the claimed invention to use to use the probes and primers of Felix, Narahara, Miller, Zhuo, and Webster in the method disclosed and suggested by Abbou, Afrin, Fu, Panogopoulos, Alonso, Hansel, and Neuendorff because each of the probes and primers is related to the genes of the fusion pairs. As such, one of ordinary skill in the art would have been motivated to use the probes and primers of Felix, Narahara, Miller, Zhuo, and Webster in the method of Abbou, Afrin, Fu, Panogopoulos, Alonso, Hansel, and Neuendorff in order to detect the translocations found in subjects having leukemia in order to provide diagnoses, prognoses, and treatment regimens, as well as monitoring the treatments for the subjects having leukemia. Because the probes of Felix, Narahara, Miller, Zhuo, and Webster are related to leukemia translocations, one of ordinary skill in the art would have had a predictable and reasonable expectation of success in using these sequences in the method of Abbou, Afrin, Fu, Panogopoulos, Alonso, Hansel, and Neuendorff
Conclusion
Any inquiry concerning this communication or earlier communications from the examiner should be directed to NANCY J LEITH whose telephone number is (313)446-4874. The examiner can normally be reached Monday - Thursday 8:00 AM - 6:30 PM.
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NANCY J. LEITH
Primary Examiner
Art Unit 1636
/NANCY J LEITH/Primary Examiner, Art Unit 1636
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