DETAILED CORRESPONDENCE
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 .
This action is in response to the papers filed June 4, 2026. Currently, claims 64-65, 67-70, 72-73, 75-77, 81, 84, 85, 87-92 are pending. All arguments have been thoroughly reviewed but are deemed non-persuasive for the reasons which follow.
Any objections and rejections not reiterated below are hereby withdrawn.
The limitations of Claim 83 have been added to Claim 64 with the exception that BRAF does not appear in Claim 64, but appeared in Claim 83.
Election of Species
Applicant elected the combination of the translocation t(4:14) and the copy number variation 1q21 amplification in the papers filed June 4, 2026 for examination.
The response traverses the requirement on the grounds the generic claim includes sufficiently few species that there would not be a serious burden on the examiner. This argument has been reviewed but is not persuasive, each translocation and copy number variation requires a separate search and consideration.
Priority
This application
PNG
media_image1.png
82
666
media_image1.png
Greyscale
Drawings
The drawings are acceptable.
Requirement for Information
Applicant and the assignee of this application are required under 37 CFR 1.105 to provide the following information that the examiner has determined is reasonably necessary to the examination of this application.
The Mishima reference used in this office action was authored, in part, by the inventor of this application, namely Yuji Mishima and Irene Gobrial. The examiner requires further information in order to make further determinations about the patentability of the instant claims. In response to this requirement, please provide answers to each of the following interrogatories eliciting factual information:
The Mishima references states “we identified a total of 347 somatic mutations which included 199 CTC specific mutations. Several known driver mutations were observed, i.e. BRaf V60)E mutation present in the CTC samples…”. The claims have been amended to remove BRaf from the Markush group. Therefore, it has become necessary for the examiner to determine whether Mishima sequences one or more genetic abnormalities from the amended Markush group. The examiner requests information about these 347 somatic and 199 CTC specific mutations. Are these mutations genetic abnormalities within the scope of the genetic abnormalities listed in the claims? If so, which genes and mutations were analyzed in Mishima that overlap in scope with the claimed genetic abnormalities in Claim 64. Are there any MM driver genes listed in Claim 64, for example, that were not among the genes where 347 somatic mutations or 199 CTC specific mutations were found as performed by Mishima.
Response
The response asserts the request seeks information beyond that reasonably necessary to examination and would require Applicant to reconstruct historical research results. It is noted that the Mishima reference is applicant’s own work. Applicant was merely requested to provide a list of the mutations that were studied in the reference. The examiner understands this information is not available. In the event this information becomes available the Examiner requests Applicant provide this information.
The response filed a publicly available contemporaneous material associated with the Mishima abstract, namely a slide presentation believed to correspond to the abstract. The presentation provided December 2013 has been considered and is cited below in the 103 rejections.
Claim Objections
Applicant is advised that should claim 84 be found allowable, claim 87 will be objected to under 37 CFR 1.75 as being a substantial duplicate thereof. When two claims in an application are duplicates or else are so close in content that they both cover the same thing, despite a slight difference in wording, it is proper after allowing one claim to object to the other as being a substantial duplicate of the allowed claim. See MPEP § 608.01(m).
Claim Rejections - 35 USC § 112
The following is a quotation of 35 U.S.C. 112(b):
(b) CONCLUSION.—The specification shall conclude with one or more claims particularly pointing out and distinctly claiming the subject matter which the inventor or a joint inventor regards as the invention.
The following is a quotation of 35 U.S.C. 112 (pre-AIA ), second paragraph:
The specification shall conclude with one or more claims particularly pointing out and distinctly claiming the subject matter which the applicant regards as his invention.
Claims 65, 69, 72-73, 75-77, 89-90 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.
Regarding claim 65 and 69, the phrase "optionally" renders the claim indefinite because it is unclear whether the limitations following the phrase are part of the claimed invention. See MPEP § 2173.05(d).
Claims 72-73, 75-77, 89-90 are indefinite because the claim requires sequencing the cfDNA to detect one or more genetic abnormalities in one or more multiple myeloma drive genes, however the claim then defines the abnormalities as translocation or CNV. It is unclear whether the genetic abnormalities are “in” a gene or are translocation/amplifications/deletions. Clarification is required.
Claim Rejections - 35 USC § 103
The following is a quotation of 35 U.S.C. 103 which forms the basis for all obviousness rejections set forth in this Office action:
A patent for a claimed invention may not be obtained, notwithstanding that the claimed invention is not identically disclosed as set forth in section 102, if the differences between the claimed invention and the prior art are such that the claimed invention as a whole would have been obvious before the effective filing date of the claimed invention to a person having ordinary skill in the art to which the claimed invention pertains. Patentability shall not be negated by the manner in which the invention was made.
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.
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) 64-65, 68, 70, 81, 84-85, 87-92 is/are rejected under 35 U.S.C. 103 as being unpatentable over Mishima et al. (Blood, Vol. 122, No. 21, Abstract 533, October 21, 2013) in view of Mishima et al. (Molecular analysis of circulating tumor cells identifies mutations that are distinct from those present in the bone marrow of patients with multiple Myeloma, Dana-Farber Cancer Institute, 2013 ASH Annual Meeting and Exposition, December 9th, 2013) and further in view of Van Dongen et al. (WO2013/187765, December 19, 2013).
Mishima et al. teaches analyzing peripheral blood samples of 466 multiple myeloma (MM) patients. The peripheral blood was processed to obtain white blood cell fractions and CTCs were purified by gating. The DNA was extracted from sorted cells. Following collecting a CTC sample DNA was sequences to analyzing somatic mutation using whole exome sequencing. Genomic DNA was extracted from sorted cells and sequenced on Illumina HiSeq flow cells. The sequencing identified a substantial number or protein coding mutations. A total of 347 somatic mutations which included 199 CTC specific mutations were detected. Mishima specifically teaches BRAF V600E was detected. With respect to Claims 65, “Gating” refers to the selection of successive subpopulation of cells for analysis in flow cytometry. Mishima inherently teaches CTC are isolated using flow cytometry (limitations of Claim 65). The cells were purified by gating on CD19-/CD38+ and CD138+.
Mishima does not teach selecting a CTC based on downregulation of CD45 or analysis of a translocation or copy number variations.
However, Van Dongen teaches flow cytometric minimal residual myeloma (MM) using fluorochromes based on CD38, CD138, CD19 and CD45 (see page 8, (o) and (r)). Van Dongen teaches CD138, CD38, CD56, Cd19 are four “core markers” and CD45 is a preferred fifth marker (page 8). Thus, Van Dongen teaches isolating MM cells with CD45. Van Dongen teaches CD45 is under expressed in malignant plasma cells compared to normal plasma cells (page 20).
Further, Mishima-ASH teaches analysis of circulating myeloma tumor cells to investigate cytogenetic abnormalities. Slide 5 provides the characteristics of patients including MGUS, SMM and MM patients. Mishima-ASH teaches CTC detection and sorting using blood and flow cytometry using CD38+, CD138+ and CD19- (Slide 6). Mishima-ASH teaches analysis of CD45 also (Slide 6). Mishima-ASH teaches analysis of the CTC using probes including t(4:14), t(11:14), 13q14 and 17p13.1 (Slide 9). Mishima-ASH teaches whole exome sequence of CTC (Slide 11).
Therefore, it would have been prima facie obvious prior to the effective filing date of the claimed invention to have identified and selected CTC from multiple myeloma patients using the method Mishima in view of Van Dongen. Van Dongen teaches the methods using combination of antibodies can reach sensitivities of at least 10-4, even down to 10-5. Therefore, the ordinary artisan would have been motivated to have used the very sensitive method of Van Dongen to analyze circulating tumor cells for unique mutation in CTC. The prior art including Mishima, Mishima-ASH and Van Dongen teach isolating CTC using CD38, CD138, CD19 and CD45 prior to sequencing to identify genetic abnormalities including translocations and amplifications. The ordinary artisan would have been motivated to have isolated CTC using the known methods and further analyze the genetic material for abnormalities associated with multiple myeloma.
Claim(s) 64-65, 68-70, 72, 75-77, 81, 84-85, 87-92 is/are rejected under 35 U.S.C. 103 as being unpatentable over Vij et al. (Clinical Lymphoma, Myeloma & Leukemia, Vol. 14, No. 2, pages 131-139, April 2014) in view of Mishima et al. (Molecular analysis of circulating tumor cells identifies mutations that are distinct from those present in the bone marrow of patients with multiple Myeloma, Dana-Farber Cancer Institute, 2013 ASH Annual Meeting and Exposition, December 9th, 2013) and further in view of Van Dongen et al. (WO2013/187765, December 19, 2013).
Vij et al. teaches deep sequencing reveals myeloma cells in peripheral blood in a majority of multiple myeloma patients. Vij teaches a deep sequencing approach to detect and quantify myeloma cells in peripheral blood. Vij teaches a total of 60 peripheral blood samples were analyzed. Vij teaches flow cytometry and cell sorting of the cells using FACSAria (page 132, col. 2)(limitations of Claim 65, 81). The cells were CD38+ and CD45low. Genomic DNA and RNA was amplified using locus-specific primer sets designed to allow for the amplification of known alleles (page 132, col. 2). The assay used was LymphoSIGHT which is a next generation targeted deep sequencing method (limitations of Claim 75). Vij also teaches myeloma-derived sequences identified in BMMC or CD138+ cells were used as a target to assess the presence of minimal residual disease in peripheral blood samples (page 132, col. 2). Figure 1 illustrates cell-free samples were analyzed for detection of MM clones in plasma and serum (page 134, col. 1).
Vij does not teach selecting a CTC based on downregulation of CD19. Vij does not specify analyzing one of the recited genetic alterations.
However, Van Dongen teaches flow cytometric minimal residual myeloma (MM) using fluorochromes based on CD38, CD138, CD19 and CD45 (see page 8, (o) and (r)). Van Dongen teaches CD138, CD38, CD56, Cd19 are four “core markers” and CD45 is a preferred fifth marker (page 8). Thus, Van Dongen teaches isolating MM cells with CD45. Van Dongen teaches CD45 is under expressed in malignant plasma cells compared to normal plasma cells (page 20). Van Dongen teaches CD19 is underexpressed (usually negative) in malignant plasma cells compared to normal plasma cells (page 20).
Further, Mishima-ASH teaches analysis of circulating myeloma tumor cells to investigate cytogenetic abnormalities. Slide 5 provides the characteristics of patients including MGUS, SMM and MM patients. Mishima-ASH teaches CTC detection and sorting using blood and flow cytometry using CD38+, CD138+ and CD19- (Slide 6). Mishima-ASH teaches analysis of CD45 also (Slide 6). Mishima-ASH teaches analysis of the CTC using probes including t(4:14), t(11:14), 13q14 and 17p13.1 (Slide 9). Mishima-ASH teaches whole exome sequence of CTC (Slide 11). Mishima-ASH additionally teaches nonsynonymous SNP abnormalities (slide 14).
Therefore, it would have been prima facie obvious prior to the effective filing date of the claimed invention to have identified and selected CTC from multiple myeloma patients using the method of Van Dongen. Van Dongen teaches the methods using combination of antibodies can reach sensitivities of at least 10-4, even down to 10-5. Therefore, the ordinary artisan would have been motivated to have used the very sensitive method of Van Dongen to analyze circulating tumor cells for unique mutation in CTC, as taught by Chapman, that may provide mechanistic insight into myeloma cell dissemination and inform treatment strategies.
Claim(s) 67 is/are rejected under 35 U.S.C. 103 as being unpatentable over Mishima et al. (Blood, Vol. 122, No. 21, Abstract 533, October 21, 2013) in view of Mishima et al. (Molecular analysis of circulating tumor cells identifies mutations that are distinct from those present in the bone marrow of patients with multiple Myeloma, Dana-Farber Cancer Institute, 2013 ASH Annual Meeting and Exposition, December 9th, 2013) and further in view of Van Dongen et al. (WO2013/187765, December 19, 2013) as applied to Claims 64-65, 68, 70, 81, 84-85, 87-92 above and further in view of Einwallner et al. (J. of Immunological Methods, Vol. 390, pages 127-132, 2013).
Neither Mishima, Mishima-ASH nor Van Dongen teach lysing red blood cells followed by removal of proteins and other contaminants prior to the isolation of genetic material.
However, Einwallner teaches whole blood lysis has become a standard procedure to remove red cells prior to immunophenotypic analysis of leukocytes.
Therefore, it would have been prima facie obvious to have modified the flow cytometry method to include a red blood lysis step to purify the sample prior to genetic material analysis. The ordinary artisan would have been motivated to have performed the “standard procedure” to remove known contaminants from the sample.
Claim(s) 67, 73 is/are rejected under 35 U.S.C. 103 as being unpatentable over Vij et al. (Clinical Lymphoma, Myeloma & Leukemia, Vol. 14, No. 2, pages 131-139, April 2014) ) in view of Mishima et al. (Molecular analysis of circulating tumor cells identifies mutations that are distinct from those present in the bone marrow of patients with multiple Myeloma, Dana-Farber Cancer Institute, 2013 ASH Annual Meeting and Exposition, December 9th, 2013) and further in view of Van Dongen et al. (WO2013/187765, December 19, 2013) as applied to Claims 64-65, 68-70, 72, 75-77, 81, 84-85, 87-92 above in view of Einwallner et al. (J. of Immunological Methods, Vol. 390, pages 127-132, 2013).
Vij et al. teaches deep sequencing reveals myeloma cells in peripheral blood in a majority of multiple myeloma patients. Vij teaches a deep sequencing approach to detect and quantify myeloma cells in peripheral blood. Vij teaches a total of 60 peripheral blood samples were analyzed. Vij teaches flow cytometry and cell sorting of the cells using FlowJo (limitations of Claim 65). The cells were CD38+ (limitations of Claim 66). Genomic DNA and RNA was amplified using locus-specific primer sets designed to allow for the amplification of known alleles (page 132, col. 2). The assay used was LymphoSIGHT which is a next generation targeted deep sequencing method (limitations of Claim 75). Vij also teaches myeloma-derived sequences identified in BMMC or CD138+ cells were used as a target to assess the presence of minimal residual disease in peripheral blood samples (page 132, col. 2). Figure 1 illustrates cell-free samples were analyzed for detection of MM clones in plasma and serum.
Van Dongen teaches flow cytometric minimal residual myeloma (MM) using fluorochromes based on CD38, CD138, CD19 and CD45 (see page 8, (o) and (r)). Van Dongen teaches CD138, CD38, CD56, Cd19 are four “core markers” and CD45 is a preferred fifth marker (page 8). Thus, Van Dongen teaches isolating MM cells with CD45. Van Dongen teaches CD45 is underexpressed in malignant plasma cells compared to normal plasma cells (page 20).
Further, Chapman teaches significantly mutated genes include KRAS, NRAS and TP53 that were observed following whole exome sequencing.
Neither Mishima nor Van Dongen nor Chapman teach lysing red blood cells followed by removal of proteins and other contaminants prior to the isolation of genetic material.
However, Einwallner teaches whole blood lysis has become a standard procedure to remove red cells prior to immunophenotypic analysis of leukocytes.
Therefore, it would have been prima facie obvious to have modified the flow cytometry method to include a red blood lysis step to purify the sample prior to genetic material analysis. The ordinary artisan would have been motivated to have performed the “standard procedure” to remove known contaminants from the sample.
Conclusion
No claims allowable.
Pertinent prior art
Jeong et al. (Korean J. Hematol. Vol. 47, No. 4, pages 260-266, December 12, 2012) teaches simplified flow cytometric immunophenotyping panel for multiple meloma that uses CD19, CD138 (CD38) and CD45. Jeong teaches neoplastic plasma cells are CD45-; CD138+ and CD19- (see Figure 1).
Sata et al. (Experiential Hematology, Vol. 43, pages 374-381, January 13, 2015) teaches analysis cell-free DNA from the sera of patients with multiple myeloma (MM), a blood biopsy from a subject suffering from plasma cell dyscrasias.
Any inquiry concerning this communication or earlier communications from the examiner should be directed to JEANINE ANNE GOLDBERG whose telephone number is (571)272-0743. The examiner can normally be reached Monday-Friday 6am-3:30pm.
Examiner interviews are available via telephone, in-person, and video conferencing using a USPTO supplied web-based collaboration tool. To schedule an interview, applicant is encouraged to use the USPTO Automated Interview Request (AIR) at http://www.uspto.gov/interviewpractice.
If attempts to reach the examiner by telephone are unsuccessful, the examiner’s supervisor, Wu-Cheng (Winston) Shen can be reached on (571) 272-3157. The fax phone number for the organization where this application or proceeding is assigned is 571-273-8300.
Information regarding the status of published or unpublished applications may be obtained from Patent Center. Unpublished application information in Patent Center is available to registered users. To file and manage patent submissions in Patent Center, visit: https://patentcenter.uspto.gov. Visit https://www.uspto.gov/patents/apply/patent-center for more information about Patent Center and https://www.uspto.gov/patents/docx for information about filing in DOCX format. For additional questions, contact the Electronic Business Center (EBC) at 866-217-9197 (toll-free). If you would like assistance from a USPTO Customer Service Representative, call 800-786-9199 (IN USA OR CANADA) or 571-272-1000.
/JEANINE A GOLDBERG/Primary Examiner, Art Unit 1682 June 16, 2026
Prosecution Insights