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 August 21, 2025. Currently, claims 64-65, 67-73, 75-77, 81-82, 84, 85 are pending. All arguments have been thoroughly reviewed but are deemed non-persuasive for the reasons which follow.
This action is made FINAL.
Any objections and rejections not reiterated below are hereby withdrawn.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.
Priority
This application
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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 r 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.
The applicant is reminded that the reply to this requirement must be made with candor and good faith under 37 CFR 1.56. Where the applicant does not have or cannot readily obtain an item of required information, a statement that the item is unknown or cannot be readily obtained may be accepted as a complete reply to the requirement for that item.
This requirement is an attachment of the enclosed Office action. A complete reply to the enclosed Office action must include a complete reply to this requirement. The time period for reply to this requirement coincides with the time period for reply to the enclosed Office action.
Claim Objections
Applicant is advised that should claim 71 be found allowable, claim 84 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 84 now requires whole exome sequencing, as does Claim 71.
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, 70-71, 81-82, 84-85 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 Van Dongen et al. (WO2013/187765, December 19, 2013) and Chapman et al. (Nature, Vol. 471, pages 467-472, March 2011).
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.
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+.
The DNA was extracted from sorted cells. Following collecting a CTC sample DNA was sequences to analyzing somatic mutation using whole exome sequencing (limitations of Claim 71). 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.
Mishima does not teach selecting a CTC based on downregulation of CD45. Mishima does not specify the somatic mutations or CTC specific mutations characterized and sequenced. The examiner has required additional information under the Request for Information above.
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, Chapman teaches significantly mutated genes include KRAS, NRAS and TP53 that were observed following whole exome sequencing.
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, such as those taught by Chapman, that may provide mechanistic insight into myeloma cell dissemination and inform treatment strategies.
Claim(s) 64-65, 68-70, 72, 75-77, 81 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 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, Chapman teaches significantly mutated genes include KRAS, NRAS and TP53 that were observed following whole exome sequencing.
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 Van Dongen et al. (WO2013/187765, December 19, 2013) as applied to Claims 64-65, 68-70, 72, 75-77, 81 above in view of Einwallner et al. (J. of Immunological Methods, Vol. 390, pages 127-132, 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. Mishima teaches “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+. The DNA was extracted from sorted cells. Following collecting a CTC sample DNA was sequences to analyzing somatic mutation using whole exome sequencing (limitations of Claim 71). 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.
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 calls 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 Van Dongen et al. (WO2013/187765, December 19, 2013) as applied to Claims 64-65, 68-70, 72, 75-77, 79, 81 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 calls 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.
Applicant's amendment necessitated the new ground(s) of rejection presented in this Office action. Accordingly, THIS ACTION IS MADE FINAL. See MPEP § 706.07(a). Applicant is reminded of the extension of time policy as set forth in 37 CFR 1.136(a).
A shortened statutory period for reply to this final action is set to expire THREE MONTHS from the mailing date of this action. In the event a first reply is filed within TWO MONTHS of the mailing date of this final action and the advisory action is not mailed until after the end of the THREE-MONTH shortened statutory period, then the shortened statutory period will expire on the date the advisory action is mailed, and any nonprovisional extension fee (37 CFR 1.17(a)) pursuant to 37 CFR 1.136(a) will be calculated from the mailing date of the advisory action. In no event, however, will the statutory period for reply expire later than SIX MONTHS from the mailing date of this final action.
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.
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/JEANINE A GOLDBERG/Primary Examiner, Art Unit 1682 October 14, 2025