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 .
The text of those sections of Title 35, U.S. Code not included in this action can be found in a prior Office action.
This action is in response to the papers filed on 08/27/2026. Claims 1-5, 7, 9, 12, 15, 18, 25, 33, 38, 40, 42, 50, 53, 55, 57, and 59 are currently pending as per claims filed on 08/27/2026. Claims 38, 50, and 59 have been amended by Applicants’ amendment filed on 08/27/2026. No claims have been cancelled, and no new claims have been added.
Applicant’s election without traverse of Group I, claims 1, 4, 5, 7, 9, 12, 15, 18, 25, 33, 38, 40, 42, 50, 53, 55, 57, and 59. Claims 2 and 3 are withdrawn from further consideration by Applicants pursuant to 37 CFR 1.142(b), as being drawn to a nonelected species in the reply filed on 03/20/2026 was previously acknowledged. The restriction requirement was previously made final.
The examiner has previously rejoined claims 38 and 40 as examination.
Therefore, claims 1, 4, 5, 7, 9, 12, 15, 18, 25, 33, 38, 40, 42, 50, 53, 55, 57, and 59 are under examination to which the following grounds of rejection are applicable. Claim 1 is an independent claim.
Priority
The instant application claims domestic benefit to US provisional patent
application number 63/368,550 filed on 07/15/2022. Thus, the earliest possible priority
for the instant application is 07/15/2022.
Information Disclosure Statement
The information disclosure statement (IDS) submitted on 08/27/2026 was filed before the mailing date of the current office action. The submission is in compliance with the provisions of 37 CFR 1.97. Accordingly, the information disclosure statement is being considered by the examiner.
Withdrawn objections/rejection in response to Applicants’ arguments or
Amendment
Claim Objections
In view of Applicant’s amendments of claims 38 and 40 which now spell out STEAP2, VL-CDR and VH-CDR, the claim amendment has been withdrawn.
In view of Applicant’s amendments of claim 50 which now spell out TCM and TSCM, the claim amendment has been withdrawn.
In view of Applicant’s amendments of claim 59 which now spell out mpH/min, the claim amendment has been withdrawn.
Maintained and/or modified rejections in response to Applicants’ arguments or
Amendment
Claim Interpretation
Claim 18 recites the units “U/mL” and “IU/mL”. The specification fails to define what “U” and “IU” indicate. The examiner interprets U/mL to mean “units/mL” and can be broadly read as any unit of measurement. The examiner interprets IU/m to mean “international units/mL”, wherein “international units” is defined as a standardized measure of biological activity.
Claim Rejections - 35 USC § 103
Claim(s) 1, 4, 5, 7, 9, 12, 15, 18, 25, 33, 38, 40, 42, 50, 53, 55, 57, and 59 remain rejected under 35 U.S.C. 103 as being unpatentable over Alizadeh et al (WO 2018102761 A1; as cited in Office Action filed 04/27/2026), and further in view of Aftab et al (WO 2020055862 A1; as cited in Office Action filed 04/27/2026), Bosco et al (US Patent Application Pub 20230192803; as cited in IDS), Gilbreth et al (WO 2021126672 A1; as cited in Office Action filed 04/27/2026), Millipore Sigma (Successful Transduction Using Lentivirus, pages 1-7, downloaded 4/15/2026; as cited in Office Action filed 04/27/2026), and Moody et al (WO 2021214270 A1; as cited in IDS).
The applied Gilbreth reference has a common inventor with the instant application. Based upon the earlier effectively filed date of the reference, it constitutes prior art under 35 U.S.C. 102(a)(1). The publication date for Gilbreth is 24 June 2021 (35 U.S.C. 102(a)(1). The earliest effective filing date of the instant application is July 15, 2022.
The applied Bosco reference has a common inventor with the instant application
Based upon the earlier effectively filed date of the reference, it constitutes prior art under 35 U.S.C. 102(a)(2). The publication date for Bosco is 22 June 2023 and the earliest filing date is 15 October 2021. The earliest effective filing date of the instant application is July 15, 2022.
The applied Moody reference has a common inventor with the instant application
Based upon the earlier effectively filed date of the reference, it constitutes prior art under 35 U.S.C. 102(a)(2). The publication date for Bosco 28 October 2021. The earliest effective filing date of the instant application is July 15, 2022.
This rejection under 35 U.S.C. 102(a)(2) might be overcome by: (1) a showing under 37 CFR 1.130(a) that the subject matter disclosed in the reference was obtained directly or indirectly from the inventor or a joint inventor of this application and is thus not prior art in accordance with 35 U.S.C. 102(b)(2)(A); (2) a showing under 37 CFR 1.130(b) of a prior public disclosure under 35 U.S.C. 102(b)(2)(B) if the same invention is not being claimed; or (3) a statement pursuant to 35 U.S.C. 102(b)(2)(C) establishing that, not later than the effective filing date of the claimed invention, the subject matter disclosed in the reference and the claimed invention were either owned by the same person or subject to an obligation of assignment to the same person or subject to a joint research agreement.
Regarding claim 1, Alizadeh teaches a method for expanding T cells in culture media, wherein:
the culture media comprises optionally added IL-21 (para 0010);
a method for introducing a vector, e.g. a lentiviral vector, expressing a T cell receptor (e.g., a CAR) into a population of T cells that have been activated and the expanding the cells in said culture media (para 0010);
that the CAR can be produced by any means known in the art, preferably recombinant DNA techniques, and nucleic acid encoding regions of the chimeric receptor can be prepared, inserted into an expression vector, and used to transform a cell line such as T lymphocytes (para 0035),
and the collection of prepared cells described above for injection into mice engrafted with Raji tumor cells,
rendering obvious:
(b) culturing the T cells in a culture media that comprises human interleukin 21 (IL-2 1);
(c) activating the T cells
(d) transducing the T cells with a vector comprising a nucleic acid encoding a chimeric antigen receptor (CAR) or a T-Cell Receptor (TCR) to produce CAR-T cells or T-cell Receptor (TCR) cells;
(e) culturing the CAR-T cells in a medium;
And (f) harvesting the CAR-T cells or T-cell Receptor (TCR) cells.
Alizadeh does not teach (a) isolating CD3+ T cells from a sample and that the T cells of steps (b), (c), and (d) are CD3+.
Aftab teaches manufacturing processes for antigen-stimulated T cells that express CARs and “the process may comprise an initial T-cell enrichment step, wherein CD3+ T cells are enriched/purified from a more heterogeneous mixture of cells (e.g., from whole blood, from PBMCs, and the like); stimulated to recognize and respond to pre- selected antigens (e.g., viral antigens or other tumor/disease-associated antigens, etc.); and transduced with one or more CAR constructs. (page 6, detailed description, line 26-30).
It would have been prima facie obvious to one of ordinary skill, in the art at the time of the effective filing date, to modify the teachings of a method for expanding a population of T cells comprising culturing T cells in media with IL-21, activating cells, transducing with a vector encoding a CAR, and culturing and harvesting the CAR-T cells from Alizadeh with the teachings of isolating CD3+ T cells from a more heterogeneous mixture of cells at step (a) and then subsequently activating and transducing with a CAR-vector to respond to pre- selected antigens from Aftab to have a method for expanding a population of T cells that are enriched for CD3+ cells. One would be motivated to do so to increase efficiency of the methods process such that only CD3+ cells of interested are subjected to expansion. Since isolating, expanding, and culturing of CD3+ cells is known in the art, one would have a reasonable expectation of success.
Regarding claim 4, the teachings of Alizadeh and Aftab render obvious claim 1. Moreover, Alizadeh teaches the culture media comprises optionally added IL-21 (para 0010).
Regarding claim 5, the teachings of Alizadeh and Aftab render obvious claim 1. Moreover, Alizadeh teaches a method for introducing a vector, e.g. a lentiviral vector, expressing a T cell receptor (e.g., a CAR) into a population of T cells that have been activated and the expanding the cells in said culture media (para 0010);
culture media comprises optionally added IL-21 (para 0010), rendering transducing the CD3*I cells with a vector comprising a nucleic acid encoding a CAR to produce CAR-T cells.
Regarding claim 7, the teachings of Alizadeh and Aftab render obvious claim 1. Moreover, Alizadeh teaches “cultures are then maintained at 37°C, 5% CO2 with addition of X-Vivol5 10% FCS as required to keep cell density between 3x105 and 2x106 viable cells/mL, rendering obvious wherein from about l x106 to about 1 x 109 CD3+T cells are cultured in the culture media in (b).
Regarding claim 9, the teachings of Alizadeh and Aftab render obvious claim 1 and 7. Moreover, Alizadeh teaches culturing the population of human T cells for at least one day in a culture medium (page 23-24, claim 1 (b) – claim 15), rendering obvious wherein the CD3+ T cells in (c) are cultured for about one day or about two days.
Regarding claim 12, the teachings of Alizadeh and Aftab render obvious claim 1, 7, and 9. Moreover, Alizadeh teaches the activating step comprises exposing the cells to an anti-CD3 antibody and an anti-CD28 antibody (para 0011), rendering obvious wherein the CD3+ T cells in (c) are activated with an anti-CD3 antibody or CD3-binding fragment thereof, and an anti-CD28 antibody or a CD28-binding fragment thereof.
Regarding claim 15, the teachings of Alizadeh and Aftab render obvious claim 1, 7, 9, and 12. Moreover, Alizadeh teaches wherein the population of cells is cultured in the culture medium for at least five days and less than 40 days, rendering obvious wherein the CAR-T cells or TCR cells are cultured in (e) from about four to about six days.
Regarding claim 18, the teachings of Alizadeh and Aftab render obvious claim 1, 7, 9, 12, and 15. Moreover, Alizadeh teaches “all exogenously added interleukins other than IL-15 (e.g., IL-7, IL-21, IL-4 and IL-9) are present at less than 10 ng/ml (less than 8 ng/ml, less than 6 ng/ml, less than 5 ng/ml, 3 ng/ml or even less than 1 ng/ml) and exogenously added IL-2 is present at less than 50 U/ml (less than 40 U/ml, less than 30 U/ml, less than 20 U/ml, less than 10 U/ml, less than 5 U/ml or even less than 1 U/ml) (para 0003), rendering obvious wherein the concentration of human IL-21 is from about 0.01 U/mL to about 0.3 U/mL, and the concentration of human IL-2 is from about 5 IU/mL to about 100 IU/mL absent any evidence to the contrary.
Moreover, in relation to the claimed concentration of human IL-21 and human IL-2 in claim 18, With respect to modification of the variables in claims 8-12, it has long been settled to be no more than routine experimentation for one of ordinary skill in the art to discover an optimum value of a result effective variable. "[W]here the general conditions of a claim are disclosed in the prior art, it is not inventive to discover the optimum of workable ranges by routine experimentation." Aller, 220 F.2d 454, 456, 105 USPQ 233, 235-236 (C.C.P.A. 1955). "No invention is involved in discovering optimum ranges of a process by routine experimentation." Id. at 458, 105 USPQ at 236-237. The "discovery of an optimum value of a result effective variable in a known process is ordinarily within the skill of the art." Boesch, 617 F.2d 272, 276, 205 USPQ 215, 218-219 (C.C.P.A. 1980). Since the prior art teaches exogenously added IL-2 and IL-21 in culture for transfection and proliferation of CD3+ T cells, absent unexpected results, it would have been obvious for one of ordinary skill to discover the optimum workable ranges of the methods disclosed by the prior art by normal optimization procedures known in the biotech art.
Further, Applicant is reminded that differences in concentration or temperature will not support the patentability of subject matter encompassed by the prior art unless there is evidence indicating such concentration or temperature is critical. "[W]here the general conditions of a claim are disclosed in the prior art, it is not inventive to discover the optimum or workable ranges by routine experimentation." In re Aller, 220 F.2d 454, 456, 105 USPQ 233, 235 (CCPA 1955) (Claimed process which was performed at a temperature between 40°C and 80°C and an acid concentration between 25% and 70% was held to be prima facie obvious over a reference process which differed from the claims only in that the reference process was performed at a temperature of 100°C and an acid concentration of 10%.); see also Peterson, 315 F.3d at 1330, 65 USPQ2d at 1382 ("The normal desire of scientists or artisans to improve upon what is already generally known provides the motivation to determine where in a disclosed set of percentage ranges is the optimum combination of percentages.") See MPEP 2144.05 II. A.
Regarding claim 25, the teachings of Alizadeh and Aftab render obvious claim 1, 7, 9, 12, 15, and 18. However, the combined teachings do not teach the lentivirus is added at a multiplicity of infection (MOI of about 0.25 to about 20.
Millipore Sigma teaches “It is highly recommended that for each new cell type to be transduced, a range of MOI be tested” and “For most cell types, a range of 0.1 - 10 MOI is suitable.” (page 2, Recommendations and steps to optimize your experiment setup).
It would have been prima facie obvious to one of ordinary skill, in the art at the time of the effective filing date, to modify the teachings of a method for expanding a population of CD3+ T cells comprising culturing T cells in media with IL-21, activating cells, transducing with a vector encoding a CAR, and culturing and harvesting the CAR-T cells from Alizadeh and Aftab with the teachings of testing and optimizing the MOI to be between 0.1 and 10 from Millipore Sigma to use a range of 0.1 and 10 MOI for lentivirus transduction in the instantly claimed methods . One would be motivated to do so to efficiently transduce the cells with the optimal level of CAR lentivirus and, since lentivirus transduction in T cells is known in the art, one would have a reasonable expectation of success.
Regarding claim 33, the teachings of Alizadeh, Aftab, and Millipore Sigma render obvious claim 1, 7, 9, 12, 15, 18, and 25. Moreover, Alizadeh teaches the population of cells is cultured for a period of time sufficient to expand the population less than 100-fold (claim 21, page 24), rendering obvious herein the CAR-T cells or TCR cells are expanded from at least about 1 fold to about 5 fold during (e).
Regarding claim 38, the teachings of Alizadeh and Aftab render obvious claim 1. However, the combined teachings do not teach the CAR encodes an antigen-binding domain that binds to STEAP2 and wherein the antigen-binding domain comprises the amino acid sequences recited in (a), (b), (c), (d), or (e).
Bosco teaches a polynucleotide encoding a CAR comprising an antigen-binding domain that binds to STEAP2 and wherein the antigen-binding domain comprises a VL-CDR1 comprising SEQ ID: 1 having 100% similarity to SEQ ID NO: 1 of instant application claim 38 (a), VL-CDR2 comprising SEQ ID: 2 having 100% similarity to SEQ ID NO: 2 of instant application claim 38 (a), VL-CDR3 comprising SEQ ID: 3 having 100% similarity to SEQ ID NO: 3 of instant application claim 38 (a), VH-CDR1 comprising SEQ ID: 4 having 100% similarity to SEQ ID NO: 4 of instant application claim 38 (a), VH-CDR2 comprising SEQ ID: 5 having 100% similarity to SEQ ID NO: 5 of instant application claim 38 (a), and VH-CDR3 comprising SEQ ID: 6 having 100% similarity to SEQ ID NO: 6 of instant application claim 38 (a) (para 0010). Therefore, SEQ ID: 1-6 of Bosco renders obvious SEQ ID: 1-6 of the instant application, respectively. See sequence alignment below.
Qy = instant application sequence, Db = Bosco sequence
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SEQ ID NO: 1 Instant Application vs SEQ ID NO: 1 Bosco Reference
SEQ ID NO: 2 Instant Application vs SEQ ID NO: 2 Bosco Reference
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SEQ ID NO: 3 Instant Application vs SEQ ID NO: 3 Bosco Reference
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218
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SEQ ID NO: 4 Instant Application vs SEQ ID NO: 4 Bosco Reference
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SEQ ID NO: 5 Instant Application vs SEQ ID NO: 5 Bosco Reference
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SEQ ID NO: 6 Instant Application vs SEQ ID NO: 6 Bosco Reference
Regarding claim 40, the teachings of Alizadeh and Aftab render obvious claim 1. However, the combined teachings do not teach the CAR encodes an antigen-binding domain that binds to GPC3 and wherein the antigen-binding domain comprises a VH and VL comprising the amino acid sequences recited.
Gilbreth teaches a polynucleotide encoding a CAR comprising an antigen-binding domain that binds to GPC3 and wherein the antigen-binding domain comprises a VL-CDR1 comprising SEQ ID: 40 having 100% similarity to SEQ ID NO: 115 of instant application claim 40, VL-CDR2 comprising SEQ ID: 41 having 100% similarity to SEQ ID NO: 116 of instant application claim 40, VL-CDR3 comprising SEQ ID: 42 having 100% similarity to SEQ ID NO: 117 of instant application claim 40, VH-CDR1 comprising SEQ ID: 37 having 100% similarity to SEQ ID NO: 112 of instant application claim 40, VH-CDR2 comprising SEQ ID: 38 having 100% similarity to SEQ ID NO: 113 of instant application claim 40, and VH-CDR3 comprising SEQ ID: 39 having 100% similarity to SEQ ID NO: 114 of instant application claim 40. Therefore, SEQ ID: 37-42 of Bosco renders obvious SEQ ID: 112-117 of the instant application. See sequence alignment below.
Qy = instant application sequence, Db = Gilbreth sequence
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SEQ ID NO: 112 Instant Application vs SEQ ID NO: 37 Gilbreth Reference
SEQ ID NO: 113 Instant Application vs SEQ ID NO: 38 Gilbreth Reference
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SEQ ID NO: 114 Instant Application vs SEQ ID NO: 39 Gilbreth Reference
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SEQ ID NO: 115 Instant Application vs SEQ ID NO: 40 Gilbreth Reference
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SEQ ID NO: 116 Instant Application vs SEQ ID NO: 41 Gilbreth Reference
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SEQ ID NO: 117 Instant Application vs SEQ ID NO: 42 Gilbreth Reference
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Regarding claim 42, the teachings of Alizadeh and Aftab render obvious claim 1. However, the combined teachings do not teach the nucleic acid also encodes an armoring molecule and wherein the armoring molecule comprises a dominant-negative TGFβ receptor type 2 (TGFβRIIDN).
Moody teaches methods for using CAR-T cells to treat cancer and “an isolated nucleic acid sequence encoding (a) a chimeric antigen receptor (CAR), wherein the CAR comprises an antigen-binding domain specific for a cell surface antigen; and (b) an armoring molecule, wherein the armoring molecule counters immunosuppression of a cell in a tumor microenvironment when expressed on a surface of the cell” (para 0011). Moody also teaches “a TGFβRIIDN armoring molecule expressed on a surface of the cell.” (para 0012).
It would have been prima facie obvious to one of ordinary skill, in the art at the time of the effective filing date, to modify the teachings of a method for expanding a population of CD3+ T cells comprising culturing T cells in media with IL-21, activating cells, transducing with a vector encoding a CAR, and culturing and harvesting the CAR-T cells from Alizadeh and Aftab with the teachings of an armoring molecule, specifically being TGFβRIIDN, being expressed on the surface of a CAR-T cell to generate a nucleic acid that encodes a CAR and also encodes the armoring molecule TGFβRIIDN. One would be motivated to do so to counter immunosuppression of a cell in a tumor microenvironment and by having both the CAR and armoring molecule sequence on the same nucleic acid construct, it would eliminate the needing to use two constructs/molecules and, instead, increase efficiency of expression by only using one construct with both CAR and armoring molecule sequences.
Regarding claim 50, the teachings of Alizadeh and Aftab render obvious claim 1. Moreover, Alizadeh teaches “a population of T cells expressing a CAR and comprising central memory T cells; memory stem T cells, and naive T cells (TCM/SCM/N CAR expressing cells)” (claim 38, page 26), “wherein greater than 40% of the TCM/SCM/N CAR expressing cells are CD45RA+” (claim 39, page 26), cells cultured in IL21 have 7 +/- 5% CCR7+ cells (Example 7, para 0057, page 18; Figure 7A and B), and “the High IL-15/Low IL-2 culture conditions (i.e. optionally with IL-21) described herein result in a higher proportion of desirable CD45RA+ CD45RO- T cells (para 005).
Regarding the recitations of “ wherein from about 15% to about 50% of the CAR-T cells” (claim 50), “wherein more than 50% of the CAR-T cells express a chimeric antigen receptor” (claim 53) “wherein more than 50% of the CAR-T cells express CD8” (claim 55), “wherein the CAR-T cells or TCR cells have an oxygen consumption rate (OCR) above I00pmol/min” (claim 57), and “wherein the CAR-T cells or TCR cells have an extracellular acidification rate (ECAR) above 30mpH/min” (claim 59), do not provide an active step, and appears to be an inherent effect of the methodology of claim 1. The discovery of a new use for an old structure based on unknown properties of the structure might be patentable to the discoverer as a process of using. In re Hack, 245 F.2d 246, 248, 114 USPQ 161, 163 (CCPA 1957). However, when the claim recites using an old composition or structure and the "use" is directed to a result or property of that composition or structure, then the claim is anticipated. In re May, 574 F.2d 1082, 1090, 197 USPQ 601, 607 (CCPA 1978) and In re Tomlinson, 363 F.2d 928, 150 USPQ 623 (CCPA 1966). See M.P.E.P. § 2112.02.
Response to Applicant’s arguments as they apply to rejection of claims 1, 4, 5, 7, 9, 12, 15, 18, 25, 33, 38, 40, 42, 50, 53, 55, 57, and 59 under 35 USC § 103
Applicant’s arguments filed 08/27/2026 have been fully considered but not persuasive.
Applicant asserts that 1) Alizadeh teaches “little or no exogenously added IL-21” thus teaches culture conditions which avoid or minimize IL-21 exposure and does not disclose the claimed concentration ranges for IL-21 and does not disclose support for routine optimization; 2) Millipore does not identify the claimed range for MOI value as a preferred range for the specific processes and relies on hindsight reasoning; 3) the Office has not provided evidence showing the cited methods necessarily produce the characteristics of the cell population as recited in claims 33, 50, 53, 55, 57, and 59; 4) The claims 38 and 40 are directed to a specific process for producing engineered T cells and the recited CAR and TCR serve as a component, whereas the cited Bosco and Gilbreth art disclose specific CAR sequences and claims 38 and 40 are not seeking protection for the sequences per se; and 5) Claim 42 is not directed to a TGFBRIIDN composition, CAR or nucleic acid, but rather is directed to a method for producing engineered T cells which uses a vector which encodes a molecule comprising TGFBRIIDN.
Regarding argument 1), Examiner submits that Alizadeh indeed teaches a method for expanding T cells and, despite teaching that the medium can be absent of IL-21, the method does teach that the medium for culturing cells does contain IL-21 (Summary, para 003), which ultimately reads on claim 1 of the instant application.
The prior art’s mere disclosure of more than one alternative does not constitute a teaching away from the claimed invention because such disclosure does not criticize, discredit, or otherwise discourage the solution claimed in the patent application. See In re Fulton, 391 F.3d 1195, 73 USPQ2d 1411 (2004).
A reference may be relied upon for all that it would have reasonably suggested to one having ordinary skill the art, including nonpreferred embodiments. Merck & Co. v. Biocraft Laboratories, 874 F.2d 804, 10 USPQ2d 1843 (Fed. Cir.), cert. denied, 493 U.S. 975 (1989). Nonpreferred embodiments constitute prior art. Disclosed examples and preferred embodiments do not constitute a teaching away from a broader disclosure or nonpreferred embodiments. In re Susi, 440 F.2d 442, 169 USPQ 423 (CCPA 1971). "A known or obvious composition does not become patentable simply because it has been described as somewhat inferior to some other product for the same use." In re Gurley, 27 F.3d 551, 554, 31 USPQ2d 1130, 1132 (Fed. Cir. 1994). See M.P.E.P. §2123.
Furthermore, Alizadeh indeed teaches the concentration of IL-21 in the medium being less than 10 ng/mL and even less than 1 ng/mL (Summary, para 003) and, based on use of the units U/mL in the instant application, these units are can be interpreted to be any unit, thus one could optimize starting from the ranges provided by Alizadeh to determine the appropriate concentration needed for T cell expansion. Hence, Alizadeh indeed renders obvious claim 1.
Regarding argument 2), Examiner submits that Millipore indeed teaches methods for successful transduction using lentiviruses and provides recommendations for optimizing experiment set-up, including determining Multiplicity of Infection (MOI) and that “For most cell types, a range of 0.1 - 10 MOI is suitable” (page 3, first para; as recited in non-final office action), hence Millipore indeed teaches the limitations recited in claim 25 which requires the vector to be a lentivirus and MOI of about 0.25 to about 20 and that this MOI can further be optimized depending on cell type/application. In response to applicant's argument that the examiner's conclusion of obviousness is based upon improper hindsight reasoning, 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).
Regarding argument 3), Examiner submits that the characteristics recited (claims 33, 50, 53, 55, 57, and 59) would indeed inherently be present in the CAR-T cells of TCR cells due to the claimed methodology of expanding and culturing the CAR-T or TCR cells as recited in claim 1. As the combined teaching of Alizadeh, Aftab and the cited references render obvious the steps of claim 1, there is no reason to believe that the properties of the claimed CAR-T cells of TCR cells would differ from the CAR-T cells of TCR cells rendered obvious by Alizadeh, Aftab and the cited references. See M.P.E.P. § 2112.02. Hence the combined teaching of Alizadeh, Aftab and the cited references indeed reads on the characteristics recited in claims 33, 50, 53, 55, 57, and 59.
Regarding argument 4), Examiner submits that it is the combination of Bosco and Gilbreth with the methods taught by Alizadeh that read on claim 38 and 40 and that obviousness may be established by combining or modifying the teachings of the prior art to produce the claimed invention where there is some teaching, suggestion, or motivation to do so found either in the references themselves or in the knowledge generally available to one of ordinary skill in the art. See In re Fine, 837 F.2d 1071, 5 USPQ2d 1596 (Fed. Cir. 1988), In re Jones, 958 F.2d 347, 21 USPQ2d 1941 (Fed. Cir. 1992), and KSR International Co. v. Teleflex, Inc., 550 U.S. 398, 82 USPQ2d 1385 (2007). In this case, the STAP2-binding sequences were taught by Bosco with 100% sequence identity to SEQ ID NOs: 1-6 and Bosco teaches the STEAP2-binding sequence is a polynucleotide sequence which can be comprised by a host cell for production of CAR-T cells. Similarly, Gilbreth teaches the GPC3-binding sequences with 100% sequence identity to SEQ ID NOs: 112-117 and Gilbreth teaches the GPC3-binding sequence is a polynucleotide sequence which can be comprised by a host cell for production of CAR-T cells. Therefore, while Boscoe and Gilbreth are directed to the sequences for CARs (STEAP2-binding and GPC3-binding), they each teach that the respective sequences would be comprised by a host cell for CAR-T cell purposes. Thus the instant claims, which are directed to a method of expanding T cells which comprise the STEAP2-binding and GPC3-binding CARs, is rendered obvious by the combined teachings of the known sequences for STEAP2- and GPC3-binding from Bosco and Gilbreth with the methods teachings of Alizadeh and therefore would arrive at the instantly claimed invention.
Regarding argument 5), Examiner similarly submits that it is the combination of Moody with the methods taught by Alizadeh that read on claim 42 and that obviousness may be established by combining or modifying the teachings of the prior art to produce the claimed invention where there is some teaching, suggestion, or motivation to do so found either in the references themselves or in the knowledge generally available to one of ordinary skill in the art. In this case, Moody teaches a TGFβRIIDN armoring molecule expressed on a surface of the cell in CAR-T cells since the armoring molecule it can counter immunosuppression of a cell in a tumor microenvironment (para 0011-0012). Thus, it would be obvious to combine with the methods teachings of Alizadeh to arrive at an instantly claimed method to generate and expand CAR-T cells which have the ability to counter immunosuppression in a tumor microenvironment. Thus, the combined teachings of Alizadeh and Moody render obvious the instantly claimed invention.
Obviousness Type Double Patenting
Claims 1, 4, 5, 7, 9, 12, 15, 18, 25, 33, 38, 40, 42, 50, 53, 55, 57, and 59 remain rejected on the ground of nonstatutory double patenting as being unpatentable over claims 1 and 13 of copending Application No. 17/271,430 as per claims filed on 12/23/2025 (Now US Patent 12/630,604; date of patent May 19, 2026 ), in view Aftab et al (WO 2020055862 A1; as cited in Office Action filed 04/27/2026). Although the claims at issue are not identical, they are not patentably distinct from each other because the instant claims are obvious over the cited claims of.
Claim 1 of US Patent ‘604 is directed to:
A method of making a population of cells that express a chimeric antigen receptor (CAR), the method comprising:
contacting a population of cells with an agent that stimulates a CD3/TCR complex and/or an agent that stimulates a costimulatory molecule on the surface of the cells;
contacting the population of cells with a nucleic acid molecule encoding the CAR, thereby providing a population of cells comprising the nucleic acid molecule; and
harvesting the population of cells for storage or administration; wherein step (ii) is performed together with step (i) or less than 18 hours after the beginning of step (i), and step (iii) is performed no later than 48 hours after the beginning of step (i).
Claim 13 further limits claim 1 by reciting “wherein: (a) steps (i) and/or (ii) are performed in cell media comprising IL-2, IL-15, IL-7, IL-21, IL-6, hetIL-15 (IL15/sIL15Ra), IL-6/IL-6Ra, a LSD1 inhibitor, a MALT1 inhibitor, or a combination thereof; (b) steps (i) and/or (ii) are performed in serum-free media comprising IL-2, IL-15, IL-7, IL-21, IL-6, hetIL-15 (IL15/sIL15Ra), IL-6/IL-6Ra, a LSD1 inhibitor, a MALT1 inhibitor, or a combination thereof.
Claim 1 of the invention is directed to:
A method of expanding a population of T cells comprising:
(a) isolating CD3+ T cells from a sample;
(b) culturing the CD3+ T cells in a culture media that comprises human interleukin 21 (IL-2 1);
(c) activating the CD3+ T cells;
(d) transducing the CD3+ T cells with a vector comprising a nucleic acid encoding a chimeric antigen receptor (CAR) or a T-Cell Receptor (TCR) to produce CAR-T cells or T-cell Receptor (TCR) cells;
(e) culturing the CAR- T cells in a medium; and
(f) harvesting the CAR-T cells or T-cell Receptor (TCR) cells.
The instant application differs from claims 1 and 13 by requiring isolation of CD3+ T cells from a sample.
However, at the time the invention was made, Aftab teaches that manufacturing processes for antigen-stimulated T cells that express CARs and “the process may comprise an initial T-cell enrichment step, wherein CD3+ T cells are enriched/purified from a more heterogeneous mixture of cells (e.g., from whole blood, from PBMCs, and the like); stimulated to recognize and respond to pre- selected antigens (e.g., viral antigens or other tumor/disease-associated antigens, etc.); and transduced with one or more CAR constructs. (page 6, detailed description, line 26-30).
Therefore, in view of the teachings of Aftab for enriching CD3+ T cells for subsequent activation and transduction of a CAR nucleic acid, it would have been prima facie obvious to one of ordinary skill to modify the instantly claimed method to include a step of isolating CD3+ T cells as taught by Aftab to enrich for the cell type/population of interest (CD3+) for subsequent activation and CAR nucleic acid transduction. One would have been motivated to maximize the number of cells subsequently used to generate CAR-T cells or T cell receptors.
It is noted that claim 1 of ‘604 recites the steps: wherein step (ii) is performed together with step (i) or less than 18 hours after the beginning of step (i), and step (iii) is performed no later than 48 hours after the beginning of step (i) (i.e. the activation of the cells occurs simultaneously with contacting the cells with a nucleic acid molecule or occurs less than 18 hours after the beginning of activation and harvesting is performed no later than 48 hours after the beginning of step cell activation). While the instant claims do not explicitly recite these steps, the claims are broad and could comprise activating the CD3+ T cells (step (c) of instant application) and then less than 18 hours after the beginning of step (c), hence the US Patent ‘604 is a species of the genus of timings that may occur in Claim 1 of the instant application. Therefore, the order of contacting the cells with the nucleic acid and timing of harvesting as taught by US Patent ‘604 supports a prima facie case of obviousness for the claimed invention.
Response to Applicant’s arguments as they apply to rejection of claims 1, 4, 5, 7, 9, 12, 15, 18, 25, 33, 38, 40, 42, 50, 53, 55, 57, and 59 under Provisional Rejection, Obviousness Type Double Patenting
Applicants’ arguments filed 08/27/2026 have been fully considered but not persuasive.
Applicant asserts that the presently claimed subject matter is directed to a manufacturing workflow that begins with isolated CD3+ cells with defined culture conditions and parameters to generate a cell product with specific attributes and are not directed to CAR constructs, antibodies, or binding domains themselves. Applicants argue that “The present claims require a defined sequence of manufacturing steps, including isolation of CD3+ T cells, culture in media comprising IL-21, cellular activation, transduction with a nucleic acid encoding a CAR or TCR, expansion under defined conditions, and harvesting of the resulting engineered cell population. ”(page 11 of the remarks)
Examiner submits that the US Patent ‘604 indeed recites methods claims for the production of CAR-T cells (claim 1 of ‘604: “A method of making a population of cells that express a CAR” and dependent claim 7: (a) the naïve cells are naïve T cells) and not necessarily to CAR constructs, antibodies, or binding domains themselves. When combined with the teachings of Aftab for starting with isolated CD3+ cells to have a homogenous population of cells to start, Aftab and ‘604 read on claim 1 of the instant application. Moreover, claim 13 of ‘604 further limits claim 1 by reciting the culture medium includes IL-21 as recited in claim 1 of the instant application. Hence, collectively US Patent ‘604 combined with Aftab indeed claims a manufacturing workflow to generate cell populations with the claimed phenotypic attributes as a result of the instantly claimed methodology.
Conclusion
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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/JULIANA IRENE CANDELARIA/ Examiner, Art Unit 1634
/MARIA G LEAVITT/ Supervisory Patent Examiner, Art Unit 1634
