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 .
Continued Examination Under 37 CFR 1.114
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and the fee set forth in 37 CFR 1.17(e) has been timely paid, the finality of the previous Office action has been withdrawn pursuant to 37 CFR 1.114.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 filed on February 6, 2026 has been entered. By way of this submission, Applicant has amended claims 1 and 6 and cancelled claims 4-5 and 7-8.
Claims 1 and 6 are pending in the application and under examination before the Office.
The rejections of record can be found in the previous Office action, dated August 7, 2025.
Claim Rejections - 35 USC § 112
Claim 4 was previously rejected under 35 U.S.C. 112(d) or pre-AIA 35 U.S.C. 112, 4th paragraph, as being of improper dependent form for failing to further limit the subject matter of the claim upon which it depends, or for failing to include all the limitations of the claim upon which it depends.
Applicant's cancellation of claim 4 has rendered this rejection moot, and it is withdrawn.
Claim Rejections - 35 USC § 102
Claims 1 and 4-8 were previously rejected under 35 U.S.C. 102(a)(1) and (a)(2) as being anticipated by June (US20150202286A1, cited in IDS).
Applicant argues that June does not teach every limitation of the claims as amended; specifically, June does not teach a two-component assay comprising a disposable cartridge and a microfluidic analyzer.
Applicant's amendments to the claims have addressed this issue, and this rejection is hereby withdrawn.
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.
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.
The factual inquiries for establishing a background for determining obviousness under 35 U.S.C. 103 are summarized as follows:
1. Determining the scope and contents of the prior art.
2. Ascertaining the differences between the prior art and the claims at issue.
3. Resolving the level of ordinary skill in the pertinent art.
4. Considering objective evidence present in the application indicating obviousness or nonobviousness.
Claims 1 and 6 are rejected under 35 U.S.C. 103 as being unpatentable over June (US20150202286A1, cited in IDS) in view of Aldo (Am J Reprod Immunol 2016; 75: 678-693).
June teaches a method of treatment for cytokine release syndrome, comprising administering an inhibitor of IL-6 or an inhibitor of TNF-alpha after administration of CAR-T cells (para. 0155-0157). Specifically, "the second-line of therapy comprises compounds and methods for neutralizing the effects against the elevated cytokines resulting from the administration of the CART19 cells. In one embodiment, the neutralizing agents are capable of counteracting undesired concerted burst of cytokine expression/activity and, thus, are useful for the prevention, amelioration and treatment of CRS associated with CART19 therapy" (para. 0157).
June further teaches that such a method may be useful in reducing or avoiding an adverse effect associated with the administration of a cell genetically modified to express a CAR (para. 0012). More specifically, June teaches that CAR-T cells induce a cytokine releases syndrome that can be managed with the IL-6 antagonist tocilizumab (Example 2, para. 0164-170). June also teaches adverse effects associated with CAR-T toxicity may include encephalopathy (table 2). Applicant's specification at paragraph 24 states that encephalopathy is an example of a neurotoxicity. Therefore, June inherently teaches this aspect of the claims.
June also teaches a method of reducing or avoiding an adverse effect associated with the administration of a cell genetically modified to express a CAR, the method comprising monitoring the levels of a cytokine in a patient to determine the appropriate type of cytokine therapy to be administered to the patient and administering the appropriate cytokine therapy to the patient (claim 8).
June also teaches that cytokine levels may be monitored by detecting the protein level of the cytokine in a biological sample from the patient (para. 0010), and that an increase in the level of a cytokine identifies a type of cytokine inhibitory therapy to be administered to the patient (para. 0013). More specifically, June teaches measuring of serum cytokine levels in patients experiencing cytokine release, that all patients exhibited increased levels of IL-6 compared to a baseline control, and administration of tocilizumab, an anti-IL6R antibody, treated the disease (para. 0019-0020, 0022, 0115, 0197, and figures 1, 2, and 4).
June also teaches evaluation of a cytokine profile as part of the overall treatment (para. 0032), as well as evaluating differential levels of one or more cytokines to generate a cytokine profile in a patient post T cell infusion in order to determine the type of cytokine therapy to be applied to the patient for the purpose of regulating the cytokine level back to normal levels (para. 0097, also see para. 0112-113).
June further teaches the use of selective binding partners (e.g., an antibody) of the cytokine to identify the presence or determine the levels of the cytokine in a biological sample with an immunoassay, and that such methods are known in the art (para. 0103-0108). June incorporates by reference the publication "Using Antibodies: A Laboratory Manual" (para. 0103), which recites, among other methods, immunoassays such as Western blotting.
June further teaches that biological samples in which the cytokine can be detected include serum (para. 0102).
June further teaches that said serum be prepared from a whole blood sample (para. 0182).
However, June does not teach an immunoassay comprising a two-component assay comprising a disposable cartridge and a microfluidic analyzer.
Aldo describes Simple Plex: a multi-analyte, automated microfluidic immunoassay platform for the detection of human and mouse cytokines and chemokines (abstract). Aldo further teaches that the Simplex Plex system comprises a microfluidic analyzer and an assay kit that contains a disposable cartridge (page 679, left column, third paragraph).
Additionally, Applicant's specification at page 32 describes Simple Plex as "a two component assay that measures host-cell proteins (HCP) comprising a disposable cartridge and a microfluidic analyzer". Aldo therefore inherently teaches this aspect of claim 1.
Aldo further states that this system is useful for analysis of human serum samples for cytokines such as IL-6 and TNF-alpha (page 680, left column, third paragraph, and Table 1).
It would have been prima facie obvious for a person of ordinary skill in the art as of the effective filing date to combine the teachings of June and Aldo to arrive at the claimed invention. As June teaches, the use of measuring levels of cytokines may be useful to inform treatment choice and efficacy for cytokine releases syndrome as a result of CAR-T cell therapy. Likewise, Aldo teaches that the Simple Plex instrument is a useful way to measure cytokine levels from blood scrum. The Simple Plex instrument taught by Aldo therefore solves the problem of a rapid test for serum cytokines in order to perform the method taught by June. A skilled artisan could therefore use the instrument taught by Aldo to perform the method taught by June, which each component of the combination performing its known, typical function, yielding a predictable result.
Applicant argues that neither June nor Aldo teach every limitation of the claims as amended; specifically, the cited references do not teach that the claimed method can be performed with whole blood, bone marrow, or cerebrospinal fluid (CSF).
Applicant's arguments have been considered fully but are not found to be persuasive.
As stated above, June teaches that biological samples in which the cytokine can be detected include serum (para. 0102), and that said serum be prepared from a whole blood sample (para. 0182).
The only requirement in step a) of claims 1 and 6 is that the tissue sample is whole blood, bone marrow, or cerebrospinal fluid (CSF). There is nothing in the claims that excludes further steps, such as processing the whole blood sample into serum.
It is also noted that Applicant's experiments on page 30-32 also rely on serum that is obtained by processing whole blood.
This rejection is therefore maintained.
Conclusion
The prior art made of record and not relied upon is considered pertinent to applicant's disclosure. Garfall (WO2017040930A2, cited previously) teaches that IL-6 is elevated in profiles of patients with cytokine releases syndrome following CAR-T cell treatment, and the anti IL-6 antibody tocilizumab is useful for treating this condition (page 273, line 15 through page 274, line 9). Garfall also teaches detection of markers such as IL-6 in whole blood, serum, cerebrospinal fluid, and bone marrow (page 59, lines 5-13 and page 92, lines 1-5).
Hu (J Hematol Oncol. 2016 Aug 15;9(1):70, cited previously) teaches that patients may show increased levels of IL-6 and interferon-gamma in cerebrospinal fluid after CAR-T infusion (Figure 2c).
No claim is allowed.
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/PETER JOHANSEN/Examiner, Art Unit 1644