DETAILED ACTION
CONTINUED EXAMINATION UNDER 37 CFR 1.114 AFTER FINAL REJECTION
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and the fee set forth in 37 CFR 1.17(e) has been timely paid, the finality of the previous Office action has been withdrawn pursuant to 37 CFR 1.114.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 of RCE and the amendment filed on May 11, 2026 have been entered. The claims pending in this application are claims 1, 2, 5, 7, 13, 14, 21, and 22. Objection not reiterated from the previous office action is hereby withdrawn in view of applicant’s amendment filed on May 11, 2026. Claims 1, 2, 5, 7, 13, 14, 21, and 22 will be examined.
Claim Objections
Claim 1 is objected to because of the following informality: “loading, within 3 hours to 36 hours of the step of obtaining the sample from the subject, the live cells that were obtained from the human subject individually” in the loading step should be “within 3 hours to 36 hours of the obtaining step, loading the live cells that are obtained from the human subject individually after said exposing the living cells to a therapeutic agent”.
Claim 21 is objected to because of the following informalities: (1) “that were obtained from the human subject” should be “that are obtained from the human subject”; and (2) “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 (2) in claim 21 in the response filed on May 11, 2026.
Appropriate correction is required.
Response to Arguments
In page 5, third to last paragraphs of applicant’s remarks, applicant argues that “[T]he claim is not unclear as written-the claim includes a step of exposing the live cells to a therapeutic agent and it additionally includes a loading step. There is no logical requirement exposure to the therapeutic agent must happen first. In fact, in some instances it is desirable for exposure to the therapeutic agent to happen during or after loading, so that cumulative effects of the therapeutic agents on cells can be measured. For example, the Patent Office is directed towards p. 2 of the specification as originally filed, discussing how cancer cells that are responding favorably to a therapeutic may exhibit loss of mass during detection of mass accumulation. If the Patent Office wishes to object to the breadth of the claims on other grounds, Applicant requests that those grounds be stated and explained. But the language of the claims is not unclear as written”.
These arguments have been fully considered but they are not persuasive toward the
withdrawal of the objection. Although applicant argues that “[T]here is no logical requirement exposure to the therapeutic agent must happen first. In fact, in some instances it is desirable for exposure to the therapeutic agent to happen during or after loading, so that cumulative effects of the therapeutic agents on cells can be measured”, claim 1 or 21 clearly indicates that the loading step is happened after the exposing step. Furthermore, since the loading step is happened after the exposing step in claim 1 or 23, the examiner suggests to change the phrase “after exposing the living cells to a therapeutic agent” in claim 1 or 21 to “after said exposing the living cells to a therapeutic agent” or “after the exposing step”.
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 of mouse body fluid 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 that are obtained from the mouse individually into an input channel of a measurement instrument comprising a suspended microchannel resonator (SMR) without first exposing the live cells to culturing conditions (ie., only exposing with a drug); 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 of mouse body fluid 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 that are obtained from the sample of mouse body fluid 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 exposing the live cells to culturing conditions (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 and 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 6, first paragraph bridging to page 7, second paragraph of applicant’s remarks, applicant argues that “as discussed in the Interview, the cited portions of Stevens relate to cells that were exposed to culturing conditions (e.g., cells that were seeded and cultured at 37 °C in a humidified 5% CO2 incubator).2 The cited portions of Stevens relate to cells that were harvested, stained, sorted, seeded, and exposed to culture conditions, prior to being exposed to a drug, and this progression would have been understood by the person of ordinary skill reading Stevens. Moreover, instant amendments to claims 1 and 21 clarify that the cells are not first exposed to culturing conditions during performance of the method. Nothing in Stevens teaches or suggests that one of ordinary skill in the art could have avoided the use of culturing conditions for the reasons discussed above. Manalis fails to cure the above-noted deficiencies of Manalis. For at least these reasons, independent claims 1 and 21 are patentable over Stevens and Manalis. The remaining claims rejected on this ground each depend, directly or indirectly, from one of independent claims 1 and 21 and are therefore patentable over Stevens and Manalis for at least these same reasons. It is also not conceded that one of ordinary skill in the art would have been
motivated to modify Stevens or Manalis in the manner asserted by the Patent Office, or that such modifications would result in the invention, as claimed”.
These arguments have been fully considered but they are not persuasive toward the
withdrawal of the rejection. 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 that are obtained from the mouse individually into an input channel of a measurement instrument comprising a suspended microchannel resonator (SMR) without first exposing the live cells to culturing conditions (ie., only exposing with a drug) as recited in claim 1 and loading the live cells that are obtained from the sample of mouse body fluid 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 exposing the live cells to culturing conditions (ie., only exposing with a drug) as recited in claim 21, and applicant’s arguments “[T]he cited portions of Stevens relate to cells that were harvested, stained, sorted, seeded, and exposed to culture conditions, prior to being exposed to a drug, and this progression would have been understood by the person of ordinary skill reading Stevens” are incorrect.
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 7, third to sixth paragraphs of applicant’s remarks, applicant argues that “[C]laim 1 is patentable over Stevens and Manalis for at least the reasons explained above. News does not cure the deficiencies of Stevens and Manalis. News only reports a device that can detect minuscule changes in cell mass and may allow researchers to predict how cancer cells will respond to drug treatment" and that the device is an SMR. News, 1st paragraph and 1st Figure. However, just like Stevens and Manalis, News does not teach or motivate the method of claim 1 as currently amended which recites, in part, ‘...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) within a period of about 3 hours to about 36 hours of the sample being obtained and without first exposing the live cells to culturing conditions…’ The remaining claims rejected on this ground each depend, directly or indirectly, from independent claims 1 and 21 and are therefore patentable over Stevens, Manalis, and News for at least these same reasons. It is also not conceded that one of ordinary skill in the art would have been motivated to modify Stevens, Manalis, or News in the manner asserted by the Patent Office, or that such modifications would result in the invention, as claimed”.
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 7, seventh paragraph bridging to page 8, third paragraphs of applicant’s remarks, applicant argues that “[C]laim 1 is patentable over Stevens and Manalis for at least the reasons explained above. Sudo does not cure the deficiencies of Stevens and Manalis. Sudo only reports ‘…a method for correcting data variations caused by tissues and cells other than the targeted tissues in the measurement of tissues and cellular nucleic acids (DNA, mRNA, RNA)’. Sudo, paragraph 0009. However, just like Stevens, Manalis, and News, Sudo does not teach or motivate the method of claim 1 as currently amended which recites, in part, ‘…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) within a period of about 3 hours to about 36 hours of the sample being obtained and without first exposing the live cells to culturing conditions…’ The remaining claims rejected on this ground each depend, directly or indirectly, from one of independent claims 1 and 21 and are therefore patentable over Stevens, Manalis, and Sudo for at least these same reasons. It is also not conceded that one of ordinary skill in the art would have been motivated to modify Stevens, Manalis, or Sudo in the manner asserted by the Patent Office, or that such modifications would result in the invention, as claimed”.
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
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
July 10, 2026
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