DETAILED ACTION
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 .
Claim Status
Claims 1-17, 31, 34, and 36 have been cancelled and claims 18, 35, and 38 have been amended, as requested in the amendment filed on 03/17/2026. Following the amendment, claims 18-30, 32-33, 35, and 37-38 are pending in the instant application.
Claims 18-30, 32-33, 35, and 37-38 are under examination in the instant office action.
Information Disclosure Statement
The information disclosure statement (IDS) submitted on 03/17/2026 is in compliance with the provisions of 37 CFR 1.97. Accordingly, the information disclosure statement is being considered by the examiner.
Claim Rejections - 35 USC § 103 - Maintained
Claims 18-21, 32-33, 35, and 37-38 stand as rejected under 35 U.S.C. 103 as being unpatentable over WO 2018/073267 A1 (previously cited on PTO-892; herein after referred to as "Auiti") in view of non-patent literature by Kalos et. al., Leukemia, 2011, 3(95), 1-11 (previously cited on PTO-892; herein after referred to as "Kalos") and CN 110157680 A (previously cited on PTO-892; machine translation of the description previously provided; herein after referred to as "Huang").
Claims 22-30 stand as rejected under 35 U.S.C. 103 as being unpatentable over WO 2018/073267 A1 (previously cited on PTO-892; herein after referred to as "Auiti"), Kalos et. al., (previously cited on PTO-892; herein after referred to as "Kalos"), and CN 110157680 A (previously cited on PTO-892; machine translation of the description previously provided; herein after referred to as "Huang"), as applied to claims 18-21, 32-33, and 35 above, and in further view of non-patent literature by Finak et. al., Scientific Reports, 2016, 6, 1-11 (previously cited on PTO-892; herein after referred to as "Finak").
Response to Arguments
Applicant's arguments filed 0 (herein after referred to as “Remarks”) have been fully considered but they are not persuasive.
On Pages 7-14 of Remarks, Applicant argues the following regarding the claim rejections under 35 U.S.C. 103:
The amended claims are directed to characterizing CD3- impurities in a T cell immunotherapy product. Independent claims 18 and 38 have been amended to clarify that the claimed flow cytometry methods are for characterizing CD3-cellular impurities in a T cell immunotherapy product by identifying a subpopulation of cells within a population of cells using a defined antibody cocktail. Claim 35 has been amended to clarify that the modified population of cells that includes CAR T cells is formulated as a T cell immunotherapy product. Thus, as amended, the instant claims are directed to a fit-for-purpose, 2-8 color impurity panel used in a T cell product manufacturing setting to characterize CD3-impurities in a CAR-T (or other engineered T cell) product.
Aiuti is directed to broad hematopoietic immunophenotyping in bone marrow and peripheral blood for diagnostic purposes, using a 16-marker panel to distinguish >20 hematopoietic subtypes and to diagnose hematologic disorders such as primary immunodeficiencies and leukemias; Aiuti does not involve T cell immunotherapy products, CAR T cells, or CD3-impurity specifications.
Kalos investigates in vivo persistence, expansion, and anti-tumor efficacy of CD19-targeted CART cells in heavily pretreated CLL patients, using flow cytometry primarily to track CART19 cells and cytokine responses in patients post-infusion; Kalos does not teach flow-based impurity characterization of a T cell product prior to administration.
Huang is directed to improving CAR-T efficacy and persistence by adding dasatinib during in vitro culture to prevent terminal differentiation and exhaustion, again using flow cytometry to phenotype CAR-T cells (e.g., CD45RO/CD62L/PD1/TIM3/LAG3) and monitor CAR-T frequency in an ALL-NSG mouse model; Huang does not teach quantifying non-CD3 impurities in a CAR-T product, nor use of CD34/CD14-based impurity panels.
The rejection is missing is the inventive concept-to design and use a fit-for-purpose CD3-impurity panel (claims 18 and 38) and implemented as a lyophilized cocktail (claims 22-30) in the context of T cell product release testing-rather than patient diagnostics or CAR-T persistence biology; the rejections are based on hindsight reconstruction. The "characterizing CD3-impurities in a T cell immunotherapy product" limitation is neither taught nor obvious.
Dependent claims 22-30 recite specific structural limitations that define the lyophilized antibody cocktail and its performance characteristics, wherein none of the cited references discloses or suggests these particular combinations or ratios. Absent explicit teaching, arriving at the claimed compositions would require extensive experimentation and design choices, not routine optimization.
There is also no identified motivation for a person of ordinary skill to combine a complex diagnostic panel (Aiuti) with CAR-T persistence studies (Kalos) and in-vitro dasatinib treatment (Huang) to arrive at a manufacturing-grade CD3-impurity QC method.
The specification and Figures 2-6 provide data demonstrating that the claimed lyophilized panels produce staining results comparable to or better than liquid antibody cocktails (Figures 2A-2B, 3A), maintain stability and performance over at least 10 days at room temperature (Figure 3B, Table 16), exhibit high inter-assay precision (Figure 4), show robust specificity for CD34, CD19, and CD56 (Figure 5), and are robust to variation in incubation time (Figure 6). These results address long-felt and unmet needs in T cell product manufacturing for simple, robust, and standardized impurity assays that can be implemented across lots and sites without constant re-titration and re-optimization of multi-color flow panels. The cited references neither recognize this problem nor provide the claimed solution.
It is specifically noted that the above-presented arguments rely on the recitation of “characterizing CD3-impuities in a T cell immunotherapy product” in the amended claims. In response to applicant's arguments that the limitation “characterizing CD3-impuities in a T cell immunotherapy product” is neither taught nor obvious in view of the cited references, it is specifically noted that a recitation of the intended use of the claimed invention must result in a structural difference between the claimed invention and the prior art in order to patentably distinguish the claimed invention from the prior art. If the prior art structure is capable of performing the intended use, then it meets the claim. As such, the instantly claimed flow cytometry method is rendered obvious by the cited prior art, further detail is provided below, and as such the prior art structure is capable of performing the intended use, and therefore meets the claims even as amended.
With regard to the motivation to combine the cited prior art references, it is noted that there is no requirement that an “express, written motivation to combine must appear in prior art references before a finding of obviousness.” See Ruiz v. A.B. Chance Co., 357 F.3d 1270, 1276, 69 USPQ2d 1686, 1690 (Fed. Cir. 2004). While it is acknowledged that the context of the different references regarding flow cytometric panels and method differ, all of the reference still read on flow cytometry panels and flow cytometry methods. Auiti teaches methods for analysis of T cell sub-populations, wherein flow cytometry was utilized to isolate (i) T, NKT, NK and all CD19+ cells; (ii) mature B cells, Pre-B and Pro-B precursors; (iii) PMN, iPMN, monocytes and DCs; and (iv) erythroblasts and myeloblasts using separate sorting strategies. Auiti also discloses a kit for identifying, determining the relative frequency of and/or quantifying the number of cells within lymphoid cell subtypes wherein the kit comprises one or more fluorescently labelled antibodies which may be individually packaged and labelled or the one or more antibodies of the kit may be packaged as a mixture (i.e., antibody cocktail) wherein the mixture of antibodies may comprise two or more of said antibodies and more generally discloses antibodies capable of use in such methods/kits including fluorescently labeled antibodies against CD3, CD56, CD14, CD61/41, CD135, CD34, CD45RA (Biolegend) and CD33, CD66b, CD38, CD45, CD90, CD10, CD11c, CD19, CD7 and CD71 (i.e., a fluorescently labeled antibody cocktail). The methods of Auiti allow for the detection of up to 17 fluorescent signals and it is specifically noted by Auiti that a person skilled in the art is able to routinely prepare antibodies labelled with fluorochromes without undue experimentation; antibodies labelled with fluorochromes may be prepared according to any method known in the art and/or commercially available antibodies labelled with a fluorochrome may be employed for the present invention. Kalos is relied upon for its teaching of CAR-T cell manufacturing from a apheresis sample, administration of said CAR-T cells to a subject (i.e., the CAR-T cells are formulated as an immunotherapy product), and subsequently the use of polychromatic flow cytometry to perform detailed studies and further characterize the expression, phenotype, and function of CART19 cells; while the CAR-T cell analysis is performed post-infusion, Kalos demonstrates, generically, the use of flow cytometry in the analysis of CAR-T cells (i.e., an immunotherapy product). Huang is relied upon for teachings regarding the genetic modification of T cells (i.e., manufacturing CAR-T cells as an immunotherapy product) and detecting/analyzing said T cells using flow cytometry prior to administration to a subject. It would have been obvious to one of ordinary skill in the art to utilize a population of cells collected by apheresis (i.e., samples primarily comprising T cells), suggested by Kalos, and genetically modifying said T cells to produce a therapeutic population of T cells, as disclosed by Huang, and subsequently using flow cytometry for more specific T cell population/subpopulation analysis, as suggested by Huang, using the method rendered obvious by Auiti, which comprises contacting a population of cells (including T cells) with at least two fluorochrome-labeled antibodies (e.g., anti-CD34 and anti-CD14 antibodies) and analyzing the resultant mixture via flow cytometry to identify specific sub-populations. The method could be further modified such that the cell population comprising genetically modified cells and an identified subpopulation could then be administered to a subject for therapeutic purposes, as suggested by Huang and Kalos. One of ordinary skill in the art would have been motivated to arrive at a flow cytometric method that allows for analysis of T cell populations, including genetically modified T cell populations, and subpopulations thereof in order to (i) monitor genetically modified T cell production and identify subpopulations particularly beneficial for therapeutic applications, and./or (ii) monitor patient response to therapy (e.g., after administration of a genetically modified T cell population) or monitor a disease/condition with the motivation of monitoring therapeutic cell population production, identifying therapeutic populations/subpopulations, and administering said therapeutic populations/subpopulations for the treatment of a disease/condition which can subsequently be monitored for efficacy to facilitate more effective treatments.
With regard to the argument regarding the highly specific structural limitations that define the composition of the lyophilized cocktail and its performance characteristics, it is specifically noted that Auiti teaches that a person skilled in the art is able to routinely prepare antibodies labelled with fluorochromes without undue experimentation and provides exemplary fluorochromes and the excitation/emission wavelengths (see, for example, the Table on Page 28), and Auiti provides exemplary antibody panels for recognizing specific cellular subpopulations (see, for example, Figure 2A). Thus, it was within the level of ordinary skill in the art to (i) select antibodies (e.g., an antibody panel) specific each different target cellular subpopulation in order to separate/identify them specifically and (ii) to select a set of fluorochromes and label said antibodies with said fluorochromes.
With regard to the argument of impermissible hindsight, it is noted that “[a]ny judgement on obviousness is in a sense necessarily a reconstruction based on hindsight reasoning, but so long as it takes into account only knowledge which was within the level of ordinary skill in the art at the time the claimed invention was made and does not include knowledge gleaned only from applicant’s disclosure, such a reconstruction is proper.” In re McLaughlin 443 F.2d 1392, 1395, 170 USPQ 209, 212 (CCPA 1971). The claim rejection rely only on knowledge within the level of ordinary skill in the art, and teachings that were available at the time the instant invention was filed.
With regard to the arguments pertaining to the data of the instant specification, it is noted that the fact that the inventor has recognized another advantage which would flow naturally from following the suggestion of the prior art cannot be the basis for patentability when the differences would otherwise be obvious. See Ex parte Obiaya, 227 USPQ 58, 60 (Bd. Pat. App. & Inter. 1985). The prior art renders obvious the active method steps of the instant claims, and as such the results of performing said active steps would naturally flow from the suggestion of the prior art. Furthermore, evidence of unexpected properties may be in the form of a direct or indirect comparison of the claimed invention with the closest prior art which is commensurate in scope with the claims. See In re Boesch, 617 F.2d 272, 205 USPQ 215 (CCPA 1980) and MPEP § 716.02(d) - § 716.02(e). An affidavit or declaration under 37 CFR 1.132 must compare the claimed subject matter with the closest prior art to be effective to rebut a prima facie case of obviousness. In re Burckel, 592 F.2d 1175, 201 USPQ 67 (CCPA 1979). “A comparison of the claimed invention with the disclosure of each cited reference to determine the number of claim limitations in common with each reference, bearing in mind the relative importance of particular limitations, will usually yield the closest single prior art reference.” In re Merchant, 575 F.2d 865, 868, 197 USPQ 785, 787 (CCPA 1978) (emphasis in original). Where the comparison is not identical with the reference disclosure, deviations therefrom should be explained, In re Finley, 174 F.2d 130, 81 USPQ 383 (CCPA 1949), and if not explained should be noted and evaluated, and if significant, explanation should be required. In re Armstrong, 280 F.2d 132, 126 USPQ 281 (CCPA 1960) (deviations from example were inconsequential). See also MPEP 716.02e.
With regard to the argument regarding solving an unmet, long-felt need, it is noted that MPEP 716.04 makes clear that Applicant has not met the criteria for this argument. Establishing long-felt need requires objective evidence that an art recognized problem existed in the art for a long period of time without solution. The relevance of long-felt need and the failure of others to the issue of obviousness depends on several factors. First, the need must have been a persistent one that was recognized by those of ordinary skill in the art. In re Gershon, 372 F.2d 535, 539, 152 USPQ 602, 605 (CCPA 1967). Second, the long-felt need must not have been satisfied by another before the invention by applicant. Newell Companies v. Kenney Mfg. Co., 864 F.2d 757, 768, 9 USPQ2d 1417, 1426 (Fed. Cir. 1988) ("[O]nce another supplied the key element, there was no long-felt need or, indeed, a problem to be solved".)
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Third, the invention must in fact satisfy the long-felt need. In re Cavanagh, 436 F.2d 491, 168 USPQ 466 (CCPA 1971). The detection of various subpopulations of cells within a sample of cell, for example a sample of T cells/modified T cells, is established in the art, as provided by the teachings of the prior art of record.
In view of the above, the above-listed claim rejections under 35 U.S.C. 103 in view of the cited prior art references are deemed proper and are maintained.
Conclusion
Claims 18-30, 32-33, 35, and 37-38 are pending. Claims 18-30, 32-33, 35, and 37-38 are rejected. No claims are allowed.
THIS ACTION IS MADE FINAL. 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.
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/ALYSSA RAE STONEBRAKER/Examiner, Art Unit 1642
/SAMIRA J JEAN-LOUIS/Supervisory Patent Examiner, Art Unit 1642
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