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 .
The Response of 5 Feb. 2026 has been entered.
Claims 1, 2, 6-8, 10-12, 20, 21 and 28-30 are currently pending.
Claims 1, 2, 6-8 and 10-12 are withdrawn as being drawn to a nonelected invention.
Claims 20, 21 and 28-30 are considered here with respect to the elected species of mass as the measured property, blood as the sample, T-cells as the immune cells, cytokines as the immune component, and CAR T-cells as the cell therapy.
Response to Arguments
Applicant's arguments filed 5 Feb. 2026 have been fully considered but they are not persuasive.
Applicant argues that the independent claim as amended "requires two mass measurements, i.e., one before and one after administration, with efficacy determined based on both" (Response, p. 5), and that the cited combination "does not yield a method of comparing mass measurements before and after cell therapy administration" (Response, p. 6). This is not persuasive because the features upon which applicant relies (i.e., determining efficacy based on mass measurements before and after administration and/or comparing mass measurements before and after administration) are not recited in the rejected claim(s). Although the claims are interpreted in light of the specification, limitations from the specification are not read into the claims. See In re Van Geuns, 988 F.2d 1181, 26 USPQ2d 1057 (Fed. Cir. 1993). The claims recite two measuring steps, one prior to administration and another after administering a cell therapy, along with a step of determining efficacy "based on said measuring step". As set forth in the 112(b) rejection below, the step of determining efficacy is construed herein such that the determination can be based on one or both of the measuring steps. The cited combination teaches steps of measuring T-cell activation before and after administration of a CAR T-cell therapy and use of such measurements to assess efficacy, and thus meets the limitations of the claims. This is nothing in the claims requiring use of both measurements together to determine efficacy, or requiring a comparison between the two measurements. Moreover, the cited combination renders obvious determining efficacy of a CAR T-cell therapy based on a pre-administration mass/T-cell activation measurement as well as based on a post-administration mass/T-cell activation measurement. Even if the claims were construed to require the efficacy determination to be based on both the pre-administration and post-administration measuring steps, there is nothing in the claims requiring that both of the measurements measure efficacy on the same basis (the determining step does not require any particular type of analysis, such as a comparison of the two determined masses to detect a change).
Applicant further argues that Cermak fails to teach use of SMR measurements before and after a cell therapy to assess efficacy, and that Darwoski fails to teach any mass measurements. This is not persuasive because one cannot show nonobviousness by attacking references individually where the rejections are based on combinations of references. See In re Keller, 642 F.2d 413, 208 USPQ 871 (CCPA 1981); In re Merck & Co., 800 F.2d 1091, 231 USPQ 375 (Fed. Cir. 1986). Darwoski teaches a method of assessing efficacy of a CAR T-cell therapy comprising measuring T-cell activation before and/or after CAR T-cell administration, and Cermak teaches that T-cell activation can be assessed by measuring mass using SMR. Thus, the cited combination as a whole renders the claims obvious.
Claim Rejections - 35 USC § 112(b)
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.
Claims 20, 21 and 28-30 are rejected under 35 U.S.C. 112(b) 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.
Claim 20 recites steps of "measuring mass of one or more immune cells or immune components prior to administration", "measuring mass of one or more immune cells or immune components after the administering step" and "determining efficacy of said cell therapy based on said measuring step." The recitation of "said measuring step" does not indicate which of the above measuring steps is being referred to, making the basis for the efficacy determination unclear. For purposes of applying prior art, the claims are construed such that the step of determining efficacy can be based on the pre-administration and/or the post-administration measuring step(s).
Claim 20 further recites "measuring mass of one or more immune cells or immune components prior to administration". However, the claim does not indicate what administration is being referred to, making the scope of the step unclear (it is unclear whether the step must occur prior to administering the cell therapy, prior to some other administering or prior to any administering).
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.
Claims 20 and 28-30 are rejected under 35 U.S.C. 103 as being unpatentable over the combination of Cermak et al., Nature biotechnology 34.10 (2016): 1052-1059 in view of US20210025894 to Darowski.
Regarding claims 20, 29 and 30, Cermak teaches a method of measuring the mass of one or more immune cells (T-cells) using a suspended microchannel resonator (SMR) device comprising a series of cantilevered resonators in fluid communication via a plurality of microfluidic channels (p. 1053-1055, under Device design; Device operation and data analysis; p. 1056, 1st and 2nd full ¶). Cermak teaches that the SMR measurements could be used to detect T-cell activation, both in isolated T-cells and in T-cells from a patient blood sample (p. 1056, 1st and 2nd full ¶). Cermak teaches that the SMR mass assay allows for rapid assessment of T-cell activation using unlabeled T-cells (withing 36 hours after activation), and also allows for detection on a single-cell level (e.g., allowing for identification of responsive cells within a heterogeneous population) (p. 1056, 2nd full ¶). Cermak teaches that the SMR assay could serve as a useful and more rapid alternative to established clinical methods for measuring T-cell activation (p. 1056, 2nd full ¶).
Claims 20 and 28-30 differ from Cermak in that: the mass measurement is used in a method for determining the efficacy of a CAR T-cell therapy, comprising measuring mass of one or T-cells prior to administration; administering CAR T-cells to a subject; measuring the mass of T-cells after said administering; and determining efficacy of the therapy based on one or more of the measuring steps (claim 20; CAR T-cell therapy = elected species of cell therapy)
Darowski teaches a method of assessing the efficacy of a CAR T-cell therapy by taking a sample (e.g., a blood sample) from a prospective patient and measuring the activation of therapeutic CAR T-cells in response to the sample, thereby indicating whether the CAR T-cells are responsive to antigens present in the sample and are thus likely to have therapeutic activity in the patient ([0006]-[0029]; [0103]; [0212]-[0216]; [0245]). Darowski further teaches that the method can further be carried out after the patient has received the CAR T-cell therapy to monitor the efficacy of the therapy by determining the presence of tumor cells/antigens responsive to the CAR T-cells in the patient sample ([0244]).
It would have been obvious to one of ordinary skill in the art at the time the invention was made to use the SMR-based method of Cermak for measuring T-cell activation to assess the efficacy of a CAR T-cell therapy (before and/or after administration) as taught by Darowski because it would have been obvious to combine prior art elements according to known methods to yield predictable results. One of ordinary skill would have been motivated to use the method of Cermak to assess the efficacy of a CAR T-cell therapy because Cermak teaches that the SMR assay is advantageous in that it allows for rapid assessment of T-cell activation on a single cell level without the need for labels or specially modified T-cells (such as the genetically modified reporter cells of Darowski). Using the method of Cermak to assess the efficacy of a CAR T-cell therapy as taught by Darowski would have led to predictable results with a reasonable expectation of success because the method of Darowski is based on the detection of T-cell activation and Cermak teaches that the SMR assay can detect T-cell activation in both isolated T-cells and blood samples such as that used by Darowski.
Regarding the recitation in claim 20 of measuring mass after administration and determining efficacy based on “said measuring step”, Darowski teaches that the method for assessing efficacy can be carried out prior to administration to determine whether the CAR T-cells are responsive to patient antigens and following administration to monitor the presence of antigens in the patient, and it would have been obvious to carry out any one or both assessments to assess the effectiveness of the therapy. The step of determining efficacy is construed herein such that the determination can be based on either or both of the measuring steps (see 112(b) rejection, above). Even if the claims were construed to require the efficacy determination to be based on both the pre-administration and post-administration measuring steps, there is nothing in the claims requiring that both of the measurements measure efficacy on the same basis (i.e. the determining step does not require any particular type of analysis, such as a comparison of the two determined masses).
Claim 21 is rejected under 35 U.S.C. 103 as being unpatentable over the combination of Cermak in view of Darowski, as applied to claims 20 and 28-30, further in view of Frey and Porter, Biology of Blood and Marrow Transplantation 25.4 (2019): e123-e127.
Claim 21 differs from the combination of Cermak in view of Darowski, as applied to claims 20 and 28-30, in that: said determining step comprises identifying the current presence or future risk of cytokine release syndrome in said subject.
Frey teaches that cytokine release syndrome (CRS) is a known side effect of CAR T-cell therapy, and that clinical signs of CRS correlate with T-cell activation (Abstract; INTRODUCTION).
It would have been obvious to one of ordinary skill in the art at the time the invention was made to use the method of Cermak in view of Darowski to assess efficacy of CAR T-cell therapy by measuring T-cell activation using an SMR-based mass assay wherein the SMR measurements are used to identify a risk of CRS because it would have been obvious to combine prior art elements according to known methods to yield predictable results. One of ordinary skill would have been motivated to use the results of the method of Cermak in view of Darowski to indicate a risk of CRS because Frey teaches that CRS is the most significant toxicity related to CAR T-cell therapy (Frey, Abstract). Using the results of the method of Cermak in view of Darowski to indicate a risk of CRS would have led to predictable results with a reasonable expectation of success because Frey teaches that CRS correlates with T-cell activation, and thus detecting T-cell activation using the method of Cermak in view of Darowski (before and/or after CAR T-cell administration) would provide an indicator of risk of CRS. It is noted that claim 21 does not require any specific measurement or any specific basis for identifying the risk of CRS. A finding that CAR T-cells are activated in response to a patient sample and thus likely to undergo activation upon administration would indicate a higher likelihood of activation-related side effects such as CRS relative to a negative finding, and it would have been obvious to use such results to identify risk of any activation-related side effects.
Double Patenting
The nonstatutory double patenting rejection is based on a judicially created doctrine grounded in public policy (a policy reflected in the statute) so as to prevent the unjustified or improper timewise extension of the “right to exclude” granted by a patent and to prevent possible harassment by multiple assignees. A nonstatutory double patenting rejection is appropriate where the conflicting claims are not identical, but at least one examined application claim is not patentably distinct from the reference claim(s) because the examined application claim is either anticipated by, or would have been obvious over, the reference claim(s). See, e.g., In re Berg, 140 F.3d 1428, 46 USPQ2d 1226 (Fed. Cir. 1998); In re Goodman, 11 F.3d 1046, 29 USPQ2d 2010 (Fed. Cir. 1993); In re Longi, 759 F.2d 887, 225 USPQ 645 (Fed. Cir. 1985); In re Van Ornum, 686 F.2d 937, 214 USPQ 761 (CCPA 1982); In re Vogel, 422 F.2d 438, 164 USPQ 619 (CCPA 1970); In re Thorington, 418 F.2d 528, 163 USPQ 644 (CCPA 1969).
A timely filed terminal disclaimer in compliance with 37 CFR 1.321(c) or 1.321(d) may be used to overcome an actual or provisional rejection based on nonstatutory double patenting provided the reference application or patent either is shown to be commonly owned with the examined application, or claims an invention made as a result of activities undertaken within the scope of a joint research agreement. See MPEP § 717.02 for applications subject to examination under the first inventor to file provisions of the AIA as explained in MPEP § 2159. See MPEP § 2146 et seq. for applications not subject to examination under the first inventor to file provisions of the AIA . A terminal disclaimer must be signed in compliance with 37 CFR 1.321(b).
The filing of a terminal disclaimer by itself is not a complete reply to a nonstatutory double patenting (NSDP) rejection. A complete reply requires that the terminal disclaimer be accompanied by a reply requesting reconsideration of the prior Office action. Even where the NSDP rejection is provisional the reply must be complete. See MPEP § 804, subsection I.B.1. For a reply to a non-final Office action, see 37 CFR 1.111(a). For a reply to final Office action, see 37 CFR 1.113(c). A request for reconsideration while not provided for in 37 CFR 1.113(c) may be filed after final for consideration. See MPEP §§ 706.07(e) and 714.13.
The USPTO Internet website contains terminal disclaimer forms which may be used. Please visit www.uspto.gov/patent/patents-forms. The actual filing date of the application in which the form is filed determines what form (e.g., PTO/SB/25, PTO/SB/26, PTO/AIA /25, or PTO/AIA /26) should be used. A web-based eTerminal Disclaimer may be filled out completely online using web-screens. An eTerminal Disclaimer that meets all requirements is auto-processed and approved immediately upon submission. For more information about eTerminal Disclaimers, refer to www.uspto.gov/patents/apply/applying-online/eterminal-disclaimer.
Claims 20, 21 and 28-30 are provisionally rejected on the ground of nonstatutory double patenting as being unpatentable over claims 19-21 of copending Application No. 19388956 (filed 13 Nov. 2025), optionally (in the case of claims 29-30) in view of Cermak (cited above).
Regarding instant claims 20, 21 and 28, the '956 claims teach a method for determining the efficacy of a cell therapy which can be CAR-T therapy, comprising administering a CAR-T cell therapy to a subject; measuring mass of one or more immune cells or immune components before (claim 20) and after (claim 19) said administering step; and determining efficacy of said CAR-T cell therapy based on said either of said measuring steps. Claim 21 further teaches that said determining step comprises identifying the current presence or future risk of cytokine release syndrome in said subject. Claims 20, 21 and 28 are thus anticipated by the '956 claims.
Instant claims 29 and 30 differ from the '956 claims in that the measuring step is carried out using a SMR (claim 29) which comprises a series of resonators and microfluidic channels (claim 30). Cermak teaches measuring the mass of T-cells using a SMR device comprising a series of cantilevered resonators in fluid communication via a plurality of microfluidic channels (p. 1053-1055, under Device design; Device operation and data analysis; p. 1056, 1st and 2nd full ¶), and it would have been obvious in view of Cermak to carry out the mass measurements of the '956 claims using such an SMR device (see also, 103 rejection above).
This is a provisional nonstatutory double patenting rejection.
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.
Any inquiry concerning this communication or earlier communications from the examiner should be directed to ROBERT J YAMASAKI whose telephone number is (571)270-5467. The examiner can normally be reached M-F 930-6 PST.
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/ROBERT J YAMASAKI/Primary Examiner, Art Unit 1657