DETAILED ACTION
Response to Amendment
Applicant’s response to the office action filed on September 8, 2025 has been entered. The claims pending in this application are claims 1, 2, 5, 7, 13, 14, 21, and 22. The objection not reiterated from the previous office action is hereby withdrawn in view of applicant’s amendment filed on September 8, 2025. Claims 1, 2, 5, 7, 13, 14, 21, and 22 will be examined.
Claim Objections
Claim 1 is objected to because of the following informalities: (1) “from a subject” in line 2 should be “from a human subject”; and (2) “loading, within 3 hours to 36 hours of the step of obtaining the sample from the subject, the live cells individually” in the loading step should be “within 3 hours to 36 hours of the step of obtaining the sample from the human, loading the live cells individually after said exposing the living cells to a therapeutic agent”.
Claim 21 is objected to because of the following informality: “after exposing the living cells to a therapeutic agent” in the loading step should be “after said exposing the living cells to a therapeutic agent”. Note that applicant has not addressed the issue in claim 21 in the response filed on September 8, 2025.
Appropriate correction 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.
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, 2, 7, 13, 21, and 22 are rejected under 35 U.S.C. 103 as being unpatentable over Stevens et al., (Nature Biotechnology, 34, 1161-1167, 2016) in view of Manalis et al., (US 2009/0053749 A1, published on February 26, 2009).
Regarding claim 1, Stevens et al., teach the method for measuring a mass of a live cell, the method comprising: obtaining, from a mouse, a sample comprising the live cells (eg., a sample from mice by either cardiac bleed or cheek bleed) including the living cell; isolating the live cells from the sample (eg., cells isolated from the bloodstream of mice by either cardiac bleed or cheek bleed); exposing the live cells to a therapeutic agent (eg., a drug such as100 nM ponatinib); loading, within 3 hours to 36 hours of the step of obtaining the sample from the mouse (ie., after exposing to a drug for 14-20 hours), the live cells individually into an input channel of a measurement instrument comprising a suspended microchannel resonator (SMR); and flowing the live cell through the SMR to measure the mass of the live cell (ie., MAR) as recited in claim 1 (see pages 1161-1163 and 1165, Figure 4D and Supplementary Figure 9, and Online Methods).
Regarding claim 7, since the specification teaches that “mass measurement instruments
that use a suspended microchannel resonator (SMR) are capable of measuring mass, mass change, or MAR with a precision of at least about 0.01% of a cell mass” (see paragraph [0023] of US 2020/0224239 A1, which is US publication of this instant case), the SMR taught by Stevens et al., has an ability to measure the mass with a precision of at least about 0.01 % of a cell mass.
Regarding claim 21, Stevens et al., teach the method for measuring a mass of a live cell, the method comprising: obtaining a sample comprising the live cells (eg., a sample from mice by either cardiac bleed or cheek bleed) including the living cell; isolating the live cells from the sample (eg., cells isolated from the bloodstream of mice by either cardiac bleed or cheek bleed); exposing the live cells to a therapeutic agent (eg., a drug such as100 nM ponatinib); loading the live cells individually after said exposing the living cells to a therapeutic agent into an input channel of a measurement instrument comprising a suspended microchannel resonator (SMR) without first culturing the living cells (ie., only exposing with a drug); and flowing the live cell through the SMR to measure the mass of the live cell (ie., MAR) (see pages 1161-1163 and 1165, Figure 4D and Supplementary Figure 9, and Online Methods).
Stevens et al., do not disclose obtaining, from a human subject, a sample of human tissue or body fluids comprising the live cells including the living cell as recited in claim 1 wherein the sample is obtained from a human subject and the live cells include cancer cells as recited in claim 2, the live cells are obtained by a fine needle aspirate as recited in claim 13, and disclose obtaining a sample of human tissue or body fluids comprising the live cells including the living cell as recited in claim 21 wherein the sample is a biopsy sample as recited in claim 22.
Manalis et al., teach to detect changes in cell biomechanics in cells within a human sample using SMR wherein the sample is blood, urine, CSF, synovial fluid, and/or any other bodily fluid containing cells, fine needle aspirate or tissue samples processed to release individual cells from a tumor or a cancer (see paragraphs [0029], [0035], and [0039] to [0042]).
Therefore, it would have been prima facie obvious to one having ordinary skill in the art at the time the invention was made to have performed the methods recited in claims 1, 2, 13, 21, and 22 using a sample of human tissue or body fluid comprising the live cells from a tumor or a cancer including the living cell obtained by a fine needle aspirate wherein the sample is obtained from a human subject, the live cell include cancer cells, and the sample is a biopsy sample in view of the prior arts of Stevens et al., and Manalis et al.. One having ordinary skill in the art would have been motivated to do so because Manalis et al., teach to detect changes in cell biomechanics in cells within a human sample using SMR wherein the sample is blood, urine, CSF, synovial fluid, and/or any other bodily fluid containing cells, fine needle aspirate or tissue samples processed to release individual cells from a tumor or a cancer (see paragraphs [0029], [0035], and [0039] to [0042]) and the simple substitution of one kind of sample (ie., the sample from mice by either cardiac bleed or cheek bleed taught by Stevens et al.,) from another kind of sample (ie., the tissue or bodily fluid from a human obtained by a fine needle aspirate taught by Manalis et al.,) during the process of performing the methods recited in claims 1, 2, 13, 21, and 22, in the absence of convincing evidence to the contrary, would have been prima facie obvious to one having ordinary skill in the art at the time the invention was made because the sample from mice by either cardiac bleed or cheek bleed taught by Stevens et al., and the tissue or bodily fluid from a human obtained by a fine needle aspirate taught by Manalis et al., are used for the same purpose (ie., measuring single-cell mass by SMR). One having ordinary skill in the art at the time the invention was made would have a reasonable expectation of success to perform the methods recited in claims 1, 2, 13, 21, and 22 using the tissue or bodily fluid from a human obtained by a fine needle aspirate taught by Manalis et al., as a sample of claims 1 and 21 in view of the prior arts of Stevens et al., and Manalis et al., in order to measure a mass of a live cell from a human tissue or bodily fluid obtained by a fine needle aspirate.
Furthermore, the motivation to make the substitution cited above arises from the expectation that the prior art elements will perform their expected functions to achieve their expected results when combined for their common known purpose. Support for making the obviousness rejection comes from the M.P.E.P. at 2144.06, 2144.07 and 2144.09.
Also note that there is no invention involved in combining old elements is such a manner that these elements perform in combination the same function as set forth in the prior art without giving unobvious or unexpected results. In re Rose 220 F.2d. 459, 105 USPQ 237 (CCPA 1955).
Response to Arguments
In page 4, second paragraph bridging to page 6, second paragraph of applicant’s remarks, applicant argues that “[A]s an initial matter, claim | has been amended to clarify that the method comprises obtaining, from a subject, a sample of human tissue or body fluid comprising live cells and loading the live cells within 3 hours to 36 hours of the step of obtaining the sample from the subject. The Patent Office’s rejection of claim | appears to suggest a potential interpretation of ‘obtained’ that comprises obtaining the sample after exposing to a drug for 14-20 hours. (Office Action, p. 3.) However, contrary to the assertions of the Patent Office, Stevens teaches that such a sample was exposed to the drug in vitro, not from a subject as recited in independent claim 1. Nowhere does Stevens teach or make obvious loading the live cells within 3 hours to 36 hours of the step of obtaining the sample from the subject. For at least these reasons, independent claim 1 is patentable over Stevens. Independent claim 21 recites, inter alia, loading the live cells individually after exposing the live cells to a therapeutic agent into an input channel of a measurement instrument comprising a suspended microchannel resonator (SMR) without first culturing the live cells. The Patent Office supports its rejection of claim 21 by asserting that Stevens teaches ‘[O]btaining... tumor cells from the peripheral blood of mice... without culturing the live cells.’ However, the Patent Office’s interpretation of Stevens respectfully appears to be based on a mischaracterization of the reference, rather than the teachings of Stevens as a whole. While Stevens does describe ‘[Isolating] tumor cells from the peripheral blood of mice,’ (p. 1165 of Stevens), the methods of Stevens explains that ‘Splenocytes or blood samples were harvested... cells were isolated by sorting for CD19/GFP double-positive cells...sorted mouse leukemia cells were seeded at a density of 5 x 10°/mL and cultured...replicate cultures were dosed for 10 h with... imatinib... or ponatinib...” (Stevens, Online Methods section immediately following p. 1167.) That is to say, the portion of Stevens relied upon by the Patent Office describes a process that includes (i) an undisclosed amount of time required to sort cells obtained from a blood sample; (ii) additional time required for culturing and replicating cell cultures in vitro, and (iii) a period of at least 10 hours of drug exposure, prior to loading cells into an SMR. As such, nowhere does Stevens teach or make obvious a process that comprises loading a sample within 3 to 36 hours of obtaining it from a subject, nor does Stevens teach a way to modify the process to achieve such a result. Nor does stevens teach or make obvious a process that comprises loading live cells individually after exposing the live cells to a therapeutic agent into an input channel of a measurement instrument comprising a suspended microchannel resonator (SMR) without first culturing the live cells. One of ordinary skill in the art would not have had a reason, let alone any motivation, to load cells into an SMR without first culturing the cells, absent the teachings of the instant specification. Nowhere does Stevens show the slightest indication of recognition of the importance of the combination of features recited in at least claims 1 and 21. As such, it is respectfully believed that the only way a rejection of this claim, based on the art of record or any other art known to Applicant, can be sustained is on the premise of broad statements of the sort, replete in the art, that any component of any such device can perform any function, or modified to perform any function, so generalized and voluminous as to render unfair any rejection of the precise discovery/development of the distinctions recited in claims 1 and 21. Alternatively, or concurrently, such a rejection would appear to be based on impermissible hindsight where it is simply assumed that the components of the art relied upon might be modified such that the claimed components and functionality is included without any supporting disclosure in any reference. The Patent Office has not shown where Manalis cures the above-noted deficiencies of Stevens with respect to at least independent claims 1 and 21. The remaining claims rejected on this ground each depend, directly or indirectly, from independent claim | or 21 and are therefore patentable over Stevens and Manalis for at least these same µthe invention, as claimed”.
These arguments have been fully considered but they are not persuasive toward the
withdrawal of the rejection.
First, since the specification teaches that “mass measurement instruments that use a suspended microchannel resonator (SMR) are capable of measuring mass, mass change, or MAR with a precision of at least about 0.01% of a cell mass” (see paragraph [0023] of US 2020/0224239 A1, which is US publication of this instant case) and Stevens et al., teach that “[S]ingle-cell MAR data was then collected on both cheek bleed (~25 µl) and cardiac bleed (~500 µl) sample that were exposed to either DMSO to 100 nM ponatinib for 14-20 h in vitro” (see 1165, right column, last paragraph) and “[C]ells isolated from the bloodstream of mice by either cardiac or cheek bleed and treated with 100 nM ponatinib or DMSO for specific interval” (see page 1165, legend of Figure 4(d)), Stevens et al., disclose loading, within 3 hours to 36 hours of the step of obtaining the sample from the mouse (ie., 14-20 hours), the live cells individually into an input channel of a measurement instrument comprising a suspended microchannel resonator (SMR) as recited in claim 1 and loading the live cells individually after exposing the live cells to a therapeutic agent into an input channel of a measurement instrument comprising a suspended microchannel resonator (SMR) without first culturing the live cells as recited in claim 21, and applicant’s arguments “[N]owhere does Stevens teach or make obvious loading the live cells within 3 hours to 36 hours of the step of obtaining the sample from the subject” and “[N]or does stevens teach or make obvious a process that comprises loading live cells individually after exposing the live cells to a therapeutic agent into an input channel of a measurement instrument comprising a suspended microchannel resonator (SMR) without first culturing the live cells” are incorrect.
Second, although applicant argues that “such a rejection would appear to be based on impermissible hindsight where it is simply assumed that the components of the art relied upon might be modified such that the claimed components and functionality is included without any supporting disclosure in any reference”, it must be recognized that any judgment on obviousness is in a sense necessarily a reconstruction based upon hindsight reasoning. But so long as it takes into account only knowledge which was within the level of ordinary skill at the time the claimed invention was made, and does not include knowledge gleaned only from the applicant's disclosure, such a reconstruction is proper. See In re McLaughlin, 443 F.2d 1392, 170 USPQ 209 (CCPA 1971).
Claim 5 is rejected under 35 U.S.C. 103 as being unpatentable over Stevens et al., in view of Manalis et al., as applied to claims 1, 2, 7, 13, 21, and 22 above, and further in view of News (Using Cancer Cells’ Mass to Predict Treatment Response, published on November 24, 2016).
The teachings of Stevens et al., and Manalis et al., have been summarized previously, supra.
Stevens et al., and Manalis et al., do not disclose performing a nucleic acid sequencing assay on nucleic acids isolated from the live cells after the live cells have left the measurement instrument comprising the SMR in the living state as recited in claim 5.
News (Using Cancer Cells’ Mass to Predict Treatment Response) suggests that cells tested with the SMR can still be used for additional analyses, including sequencing (see last page).
Therefore, it would have been prima facie obvious to one having ordinary skill in the art at the time the invention was made to have performed the method recited in claim 5 by performing a nucleic acid sequencing assay on nucleic acids isolated from the live cells after the live cells have left the measurement instrument comprising the SMR in the living state and are lysed in view of the prior arts of Stevens et al., Manalis et al., and News (Using Cancer Cells’ Mass to Predict Treatment Response). One having ordinary skill in the art would have been motivated to do so because Stevens et al., have suggested that “[M]AR measurement within the SMR is not a terminal assay, as cells are kept viable throughout the measurement and thereby remain compatible with downstream analyses. Thus, a key advantage of MAR measurements is that cells can be studied downstream of the SMR using other single-cell assays, as we demonstrated by quantifying the tumorsphere-forming potential of GBM-PDCL cells after passage through the device (Supplementary Fig. 1). This ability will ultimately allow for correlations between single-cell changes in MAR, other functional outcomes and non-functional biomarkers (e.g. genetics, gene expression, chromatin modifications). Further studies are needed to assess the effects of passage through the SMR on aspects of tumor cell biology, including changes in the transcriptome, genome, and proteome. Previous studies have found that cellular and genomic properties of single cells can be measured using techniques such as RNA-sequencing and are well-preserved following exposure to microfluidic environments” (see page 1166, right column, third paragraph) while News (Using Cancer Cells’ Mass to Predict Treatment Response) suggests that cells tested with the SMR can still be used for additional analyses, including sequencing (see last page). One having ordinary skill in the art at the time the invention was made would have a reasonable expectation of success to perform the method recited in claim 5 by performing a nucleic acid sequencing assay on nucleic acids isolated from the live cells after the live cells have left the measurement instrument comprising the SMR in the living state and are lysed in view of the prior arts of Stevens et al., Manalis et al., and News (Using Cancer Cells’ Mass to Predict Treatment Response) in order to measure genomic properties of the single cells (ie., the individual live cells) taught by Manalis et al., by sequencing nucleic acids of the single cells and reuse the cells tested with the SMR for additional analyses such as sequencing nucleic acids from the cells tested with the SMR.
Response to Arguments
In page 6, third to fifth paragraphs of applicant’s remarks, applicant argues that “[I]ndependent claim 1 is patentable over Stevens in view of Manalis for at least the reasons explained above. News fails to cure the above-noted deficiencies of Stevens in view of Manalis. Claim 5 depends from independent claim 1. Accordingly, claim 5 is patentable over the asserted combination for at least these same reasons”.
These arguments have been fully considered but they are not persuasive toward the withdrawal of the rejection because Stevens et al., in view of Manalis et al., teach all limitations recited in claim 1 (see above Response to Arguments related to the Rejection Item No. 5).
Claim 14 is rejected under 35 U.S.C. 103 as being unpatentable over Stevens et al., in view of Manalis et al., as applied to claims 1, 2, 7, 13, 21, and 22 above, and further in view of Sudo et al., (US 2003/0149535 A1, published on August 7, 2003)
The teachings of Stevens et al., and Manalis et al., have been summarized previously, supra.
Stevens et al., and Manalis et al., do not disclose that the sample of human body fluid is from a pleural effusion as recited in claim 14.
Sudo et al., teach that representative examples of clinical samples include, but are not limited to, phlegm, blood, blood cell (e.g., leukocyte), tissue, or fine needle biopsy sample, urine, peritoneal effusion, pleural effusion or cells thereof (see paragraph [0041]).
Therefore, it would have been prima facie obvious to one having ordinary skill in the art at the time the invention was made to have performed the method recited in claim 14 using a sample of human body fluid from a pleural effusion in view of the prior arts of Stevens et al., Manalis et al., and Sudo et al.. One having ordinary skill in the art would have been motivated to do so because Manalis et al., teach to detect changes in cell biomechanics in cells within a human sample using SMR wherein the sample is blood, urine, CSF, synovial fluid, and/or any other bodily fluid containing cells, fine needle aspirate or tissue samples processed to release individual cells from a tumor or a cancer (see paragraphs [0029], [0035], and [0039] to [0042]) while Sudo et al., teach that representative examples of clinical samples include, but are not limited to, phlegm, blood, blood cell (e.g., leukocyte), tissue, or fine needle biopsy sample, urine, peritoneal effusion, pleural effusion or cells thereof (see paragraph [0041]), and the simple substitution of one kind of sample (ie., the tissue or bodily fluid from a human obtained by a fine needle aspirate taught by Manalis et al.,) from another kind of sample (ie., the pleural effusion taught by Sudo et al.,) during the process of performing the method recited in claim 1, in the absence of convincing evidence to the contrary, would have been prima facie obvious to one having ordinary skill in the art at the time the invention was made because the tissue or bodily fluid from a human obtained by a fine needle aspirate taught by Manalis et al., and the pleural effusion taught by Sudo et al., are capable of being used for the same purpose (ie., measuring single-cell mass by SMR). One having ordinary skill in the art at the time the invention was made would have a reasonable expectation of success to perform the method recited in claim 14 using the pleural effusion taught by Sudo et al., in view of the prior arts of Stevens et al., Manalis et al., and Sudo et al., in order to measure a mass of a live cell from a human pleural effusion.
Furthermore, the motivation to make the substitution cited above arises from the expectation that the prior art elements will perform their expected functions to achieve their expected results when combined for their common known purpose. Support for making the obviousness rejection comes from the M.P.E.P. at 2144.06, 2144.07 and 2144.09.
Also note that there is no invention involved in combining old elements is such a manner that these elements perform in combination the same function as set forth in the prior art without giving unobvious or unexpected results. In re Rose 220 F.2d. 459, 105 USPQ 237 (CCPA 1955).
Response to Arguments
In page 6, sixth to last paragraphs of applicant’s remarks, applicant argues that “[I]ndependent claim 1 is patentable over Stevens in view of Manalis for at least the reasons explained above. Sudo fails to cure the above-noted deficiencies of Stevens in view of Manalis. Claim 14 depends from independent claim 1. Accordingly, claim 14 is patentable over the asserted combination for at least these same reasons”.
These arguments have been fully considered but they are not persuasive toward the
withdrawal of the rejection because Stevens et al., in view of Manalis et al., teach all limitations recited in claim 1 (see above Response to Arguments related to the Rejection Item No. 5).
Conclusion
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.
No claim is allowed.
Papers related to this application may be submitted to Group 1600 by facsimile transmission. Papers should be faxed to Group 1600 via the PTO Fax Center. The faxing of such papers must conform with the notices published in the Official Gazette, 1096 OG 30 (November 15, 1988), 1156 OG 61 (November 16, 1993), and 1157 OG 94 (December 28, 1993)(See 37 CAR § 1.6(d)). The CM Fax Center number is (571)273-8300.
Any inquiry concerning this communication or earlier communications from the examiner should be directed to Frank Lu, Ph.D., whose telephone number is (571)272-0746. The examiner can normally be reached on Monday-Friday from 9 A.M. to 5 P.M.
If attempts to reach the examiner by telephone are unsuccessful, the examiner's supervisor, Dr. Anne Gussow, Ph.D., can be reached on (571)272-6047.
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/FRANK W LU/Primary Examiner, Art Unit 1683 November 6, 2025