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 .
DETAILED ACTION
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and the fee set forth in 37 CFR 1.17(e) has been timely paid, the finality of the previous Office action has been withdrawn pursuant to 37 CFR 1.114.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 12/01/2025 has been entered.
Applicant's response filed on 12/01/2025 has been received and entered into the case.
Claim Status
Claims 1-25 are pending.
Claims 22-25 have been withdrawn from further consideration pursuant to 37 CFR 1.142(b) as being drawn to a nonelected invention, there being no allowable linking claim. Election was made without traverse in the reply filed 08/19/2024.
Claims 1-21 are considered on the merits.
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.
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 1-5 and 7-21 are rejected under 35 U.S.C. 103 as being unpatentable over Pegram et al (Blood. 2012; 119(18): 4133-4141. Cited in IDS 07/24/2023) in view of Jiang et al (WO2018205343A1, effectively filed on 05/12/2017, cited in IDS 07/24/2023), Bourgeois et al., (Eur. J. Immunol. 2009. 39: 1046-1055. Cited in IDS 07/24/2023) and Qin et al., (Oncotarget. 2016;7(38):61069-61080. Prior art of record).
With respect to claim 1, Pegram teaches a method of lengthening survival of an immune competent mouse tumor model by injecting a population of genetically modified T cells (abstract, see e.g., Fig 3E), thus teaches the preamble of claim 1. Pegram teaches the T cells (19mz/IL-12+) are modified to comprise an antigen-recognizing receptor that binds to an antigen CD19 (i.e., CD19 CAR, see Fig 3A), thus teaches claim 1 (a). Pegram teaches the T cells (19mz/IL-12+) further comprises an exogenous cytokine IL-12 (see Fig 3A), thus contemplates an exogenous interleukin expressed in the CAR-T cell. Pegram teaches the mouse tumor models are C57BL6 (mCD19-/- hCD19+/-) mice, which are immune competent (p. 4134, right col, section “Mice and in vivo model” and last para).
However, Pegram is silent on co-expressing an exogenous IL-33 in the CAR-T cells in claim 1 (b), nor teach the IL-33 being secreted in claim 2, being expressed from a vector in claim 3, comprising a heterologous signal sequence in claim 4, a CD8 leader sequence in claim 5, comprising the amino acid sequence of SEQ ID NO: 4 in claim 7, or the exogenous IL-33 enhancing immune response or increasing cytokine IFN-γ production in claims 19-20.
Jiang teaches a cancer treatment method comprising injecting CAR-T cells to tumor patients (p. 4, 4th para from bottom). Jiang teaches a chimeric antigen receptor T cell expressing a tumor antigen-targeting CAR and human Interleukin-33 (IL-33) (Page 2, 3rd paragraph from the bottom), thus teaches an immunoresponsive cell comprising an antigen-recognizing receptor (i.e., a CAR) and an exogenous IL-33 from human in claim 1. Jiang teaches the IL-33 is expressed and secreted to outside of the cell membrane (p.2, last sentence), thus teaches claim 2. Jiang teaches construction of a fusion of chimeric antigen receptor targeted to a tumor antigen and Interleukin-33 expression vector (p. 3, 3rd para from bottom), thus teaches the CAR and the IL-33 are expressed from a vector in claim 3. Jiang teaches the amino acid sequence of human secreted IL-33 in the expression vector, shown as Jiang’s SEQ ID NO: 20 (see page 14), in which the amino-terminal amino acids 1-21 is a CD8a leader sequence, and the amino acids 22-180 represent the human IL-33 sequence, which is 100% identical to the amino acid sequence of instant SEQ ID NO: 4 (see below), thus teaches the IL-33 comprises a heterologous signal sequence, i.e., a CD8a leader sequence, at the amino-terminus in claims 4-5, and comprises the amino acid sequence of SEQ ID NO: 4 in claim 7.
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With respect to claims 19 and 20 directed to the IL-33 enhancing an immune response or increasing cytokine IFN-γ production, it must be noted that these wherein clauses do not recite an active step in the claimed method, but only the results of the injecting step of the CAR-IL-33 T cells as taught by Jiang. MPEP 2111.04 I states a whereby clause (or a wherein clause) “in a method claim is not given weight when it simply expresses the intended result of a process step positively recited.” Therefore, these wherein clauses do not provide any patentable weight in determining patentability of the claimed method. Nonetheless, Jiang teaches CEA.CAR.IL-33-T cells are more effective in killing tumor cells compared to CEA.CAR-T cells (Fig 4 and p. 5, line 6) and teaches IL-33 promotes secretion of IFN-γ by CD8+ T cells and NK cells enhancing their effector functions (p. 5, para 3 from bottom), thus teaches claims 19-20.
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Additionally, Bourgeois teaches IL-33 directly interacts with invariant NKT and NK cells to induce IFN-γ production and teaches “in combination with the pro-inflammatory cytokine IL-12, IL-33 enhanced IFN-γ production by both iNKT and NK cells” and “IL-33 can contribute as a co-stimulatory factor to innate cellular immune responses” (abstract, e.g., see p. 1049, right col, para 1 and Fig 8B (attached) for a remarkable 250-fold increase of IFN-γ production by NK cells treated with IL-33 in combination with IL-12).
Qin teaches coadministration of antigen-specific TCR-T cells together with exogenous IL-33 in treating leukemia (e.g., abstract). Qin first teaches exogenous IL-33 treatment alone leads to delayed leukemia development and improved overall survival (p. 61070, “Results” section, subsections 1 and 2), and further teaches that exogenous IL-33 reverses antigen-specific antileukemia CD8+ T cell dysfunction and overcomes peripheral T cell tolerance through promoting antigen-specific CD8+ T cell proliferation and function (e.g., see p. 61070, last subsection and p. 61071, right col, subsection). Additionally, Qin teaches IL-33 promotes dendritic cell (DC) maturation and activation in favor of its cross presentation ability to evoke a vigorous anti-leukemia immune response (abstract and p. 61072).
Therefore, it would have been obvious for one of ordinary skill in the art before the effective filing date of the claimed invention to have modified the method of lengthening survival of a tumor model by injecting CD19-CAR T cells co-expressing an exogenous IL-12 disclosed by Pegram, by combining co-expressing an exogenous IL-33 with the claimed features in the CAR T cells as taught by Jiang with a reasonable expectation of success. Since Pegram contemplates co-expressing exogenous interleukins in the CAR-T cell, since Jiang teaches CAR T cells expressing secretive IL-33 are more effective in killing tumor cells (Fig 4 and p. 5, line 6) and IL-33 enhances secretion of IFN-γ by CD8+ T cells and NK cells in the tumor microenvironment to enhance their effector functions (p. 5, para 3 from bottom), since Bourgeois teaches IL-33 in combination with IL-12 enhances IFN-γ production by both iNKT and NK cells (e.g., see Fig 8B attached for a 250-fold increase) and contributes as a co-stimulatory factor to innate cellular immune responses (abstract), and since Qin teaches IL-33 promotes antigen-specific T cell proliferation and function and promotes dendritic cell (DC) maturation and activation (p. 61071-61072), one of ordinary skill in the art would have had a reason to combine an exogenous IL-33 as suggested by Jiang, Bourgeois and Qin in the CAR-IL-12 T cells of Pegram in order to improve the tumoricidal effect as suggested by Jiang, to enhance IFN-γ production by both iNKT and NK cells in combination with IL-12 suggested by Bourgeois, and to promote antigen-specific T cell proliferation and function and dendritic cell (DC) maturation and activation as suggested by Qin.
In regard to the limitation the subject is immune-competent, as a first matter, Jiang does teach using the CEA.CAR.IL-33-T cells in an NSG mouse model (p. 20, para 3-4), which is an immunodeficient mouse line. However, one of ordinary skill in the art would have immediately expected that the reason to use an immunodeficient mouse line is to avoid rejection because Jiang constructs a xenograft model of human cancer cell line (“LoVo”, p. 20, para 3-4) in mice treated with CAR-IL-33 engineered human T cell line (“Jurkat”, p. 20, para 1). Jiang specifically teaches IL-33 promotes secretion of IFN-γ by CD8+ T cells and NK cells and enhances their effector functions (p. 5, para 3 from bottom). Thus, Jiang implicitly teaches the CAR-IL-33 T cells can be used in immune-competent subjects, i.e., subjects with immune effector cells such as CD8+ T cells and NK cells. Furthermore, Pegram teaches injecting the CAR T cells co-expressing exogenous IL-12 to treat an immuno-competent mouse tumor model (grafted with mouse cancer cell line EL4 and mouse T cells, see p. 4134, “Methods” section), and Qin teaches coadministration of TCR-T cells together with exogenous IL-33 to treat an immuno-competent mouse tumor model (grafted with mouse AML cell line C1498 and mouse T cells, see p. 61077, right col). Thus, one of ordinary skill in the art would have had a reasonable expectation of success in injecting the CAR-T cells co-expressing exogenous IL-12 and IL-33, as suggested by Pegram in view of Jiang, Bourgeois and Qin, to treat an immuno-competent subject.
With respect to claim 3 directed to the antigen-recognizing receptor being expressed from a vector, Pegram teaches the CAR is expressed from a vector (Fig 3A).
With respect to claims 8 and 9 directed to a tumor antigen, and claims 10 and 11 directed to the tumor antigen being CD19, as stated supra, Pegram teaches the CAR targets the tumor antigen CD19 (see e.g., Fig 3).
With respect to claims 12 and 13 directed to the immunoresponsive cell being a T cell, and claim 14 directed to the T cell being a cytotoxic T lymphocyte, Pegram teaches the CAR-T cells co-expressing interleukins include CD8+ cytotoxic T cells (see Fig 4A) that can lyse tumor cells (Fig 4D).
With respect to claims 15 and 16 directed to a CAR, claim 17 directed to the structure of the CAR and claim 18 directed to the intracellular signaling of the CAR not comprising a co-stimulatory signaling region, Pegram teaches a CAR (see e.g., Fig 3A) and the CAR comprises an extracellular CD19 scFv antigen-binding domain, a CD8 transmembrane domain and a intracellular signaling CD3ζ chain domain (see e.g. Fig 3A and p. 4134, left col, para “Generation of retroviral constructs”), and the intracellular signaling domain of the CAR does not comprise a co-stimulatory signaling region (see Fig 3A). Thus, Pegram teaches claims 15-18.
With respect to claim 21 directed to the subject not receiving preconditioning chemotherapy prior to the administration of the cells, Pegram teaches the CAR-T cells co-expressing IL-12 are able to safely eradicate established disease in the absence of prior conditioning (abstract, p. 4136, left col, last para – right col, para 1-2, see Fig 3), thus teaches the subject did not receive preconditioning chemotherapy prior to the administration of the cells.
Hence, the claimed invention as a whole was prima facie obvious to a person of ordinary skill before the effective filing date of the claimed invention in the absence of evidence to the contrary.
Response to Traversal:
Applicant’s arguments and exhibits A-C filed on 12/01/2025 are acknowledged.
Applicant argues that (1) both IL-33 and IL-2 exert their effects via overlapping signaling transduction pathways, including signaling via MAP kinase, ERK, and MEK. See, e.g., Griesenauer and Paczesny 2017 ("Exhibit A) and Liao et al., 2015 ("Exhibit B"), and (2) one of skill would understand that various effector functions of IL-33 are mediated specifically through IL-2 by reciting Exhibit A as follows:
IL-33-activated murine DCs have recently been shown to be
required for in vitro and in vivo expansion of ST2+ Tregs through
DC IL-2 production (104), which could be used for therapeutic
benefit against inflammatory diseases through expansion of Tregs
both in vitro and in vivo.
Thus, one of skill would not reasonably predict that IL-33 function is wholly independent of the presence or absence of IL-2, and would not have a reasonable expectation of success in simply applying the IL-33 of Jiang, to the cells of Pegram, where IL-2 signaling is known to be abrogated (Remarks, p. 6-7).
Applicant’s arguments and Exhibit A-B are fully considered but they are not persuasive.
As a first matter, Applicant is reminded that the listing of references in the specification is not a proper information disclosure statement. 37 CFR 1.98(b) requires a list of all patents, publications, or other information submitted for consideration by the Office, and MPEP § 609.04(a) states, "the list may not be incorporated into the specification but must be submitted in a separate paper."
Furthermore, regarding (1) the overlapping signaling pathways shared by IL-33 and IL-2, one of ordinary skill in the art would have immediately expected that merely sharing signaling pathways could not lead to the assumption that IL-33 functions upstream of IL-2, in other words, IL-33 function is completely abolished in the absence of IL-2.
Additionally, regarding (2) various effector functions of IL-33 are mediated specifically through IL-2 as supported by recitation from Exhibit A above, it is noted that the recitation from Exhibit A above is referring to reference 104, i.e., Matta et al., (J Immunology, 2014, 193: 4010-4020), who teaches IL-33 stimulates dendritic cells (DC) to produce IL-2 (see p. 4012, right col, section “IL-33 stimulates IL-2 production by CD11c+ DC”) and this IL-2 produced by DC is necessary for IL-33 mediated proliferation of ST2+ Treg (see p. 4013 using IL-2-/- DC). Thus, Matta teaches one function of IL-33 is mediated through IL-2 produced by DC (not T cells). Therefore, the teaching of Matta (and the Exhibit A) would not dissuade one of ordinary skill in the art from combining IL-33 to the T cells of Pegram, even if they are IL-2 absent.
Finally, as stated supra, prior art Qin teaches exogenous IL-33 treatment alone leads to delayed leukemia development and improved overall survival (p. 61070, “Results” section, subsections 1 and 2). Thus, even if IL-33 function is completely abolished in the T cells of Pegram due to their absence of IL-2 (which examiner does not concede), merely producing and releasing exogenous IL-33 alone, by the T cells of Pegram, would lead to delayed leukemia development and improved overall survival as suggested by Qin. Additionally, Bourgeois teaches “in combination with the pro-inflammatory cytokine IL-12, IL-33 enhanced IFN-γ production by both iNKT and NK cells” (e.g., see p. 1049, right col, para 1 and Fig 8B (attached) for a 250-fold increase of IFN-γ production by NK cells treated with IL-33 in combination with IL-12). Thus, one of ordinary skill in the art would have immediately expected that the CAR-T cells expressing and releasing IL-12 and IL-33, as suggested by Pegram and Jiang, would enhance IFN-γ production by both iNKT and NK cells of the treated subject that contributes to tumor elimination (Pegram, abstract).
In summary, one of ordinary skill in the art would have had a reasonable expectation of success in combining the IL-33 of Jiang to the T cells of Pegram, to obtain production and secretion of IL-12 and IL-33, to result in enhanced IFN-γ production by iNKT and NK cells and to achieve delayed cancer development and improved survival as suggested by Bourgeois and Qin.
Claims 4-6 are rejected under 35 U.S.C. 103 as being unpatentable over Pegram et al (Blood. 2012; 119(18): 4133-4141. Cited in IDS 07/24/2023) in view of Jiang et al (WO2018205343A1, effectively filed on 05/12/2017, cited in IDS 07/24/2023), Bourgeois et al., (Eur. J. Immunol. 2009. 39: 1046-1055. Cited in IDS 07/24/2023) and Qin et al., (Oncotarget. 2016;7(38):61069-61080. Prior art of record), as applied to claim 1 above, and further in view of Suzuki et al (J. Leukoc. Biol. 2001, 69: 531-537. Cited in IDS 07/24/2023).
Claims 4-6 are directed to the exogenous IL-33 comprising a heterologous signal sequence at the amino-terminus that is an IL-2 signal sequence.
However, Pegram, Jiang, Bourgeois and Qin are silent on an IL-2 signal sequence at the amino-terminus of the IL-33 polypeptide.
Suzuki teaches a method of treating prostate cancer comprising administering to a mouse cancer model NK cells expressing highly secretable IL-15 (abstract). Suzuki teaches the exogenous IL-15 comprises a chimeric IL-2 signal peptide in place of its own signal peptide (i.e., at the amino-terminus of IL-15) because cytokine IL-2 is easily secreted (page 533, right col, para 1), and teaches that this chimeric IL-15 with a heterologous IL-2 signal peptide is a “highly secretable form” that enables transfected cells “successfully secreted abundant bioactive IL-15 protein” (abstract, and p. 532, left col, para 1).
Therefore, it would have been obvious for one of ordinary skill in the art before the effective filing date of the claimed invention to have modified the method of lengthening survival of a mouse tumor model by injecting CD19-CAR T cells co-expressing exogenous IL-12 and IL-33 suggested by Pegram in view of Jiang, Bourgeois and Qin, by substituting the signal sequence at the amino-terminus of the IL-33 polypeptide with an IL-2 signal sequence as taught by Suzuki with a reasonable expectation of success. Since Suzuki teaches the heterologous IL-2 signal sequence enhances protein secretion and results in a highly secretable form of chimeric protein (abstract, and p. 532, left col, para 1), one of ordinary skill in the art would have had a reason to substitute with an IL-2 signal sequence taught by Suzuki in the IL-33 polypeptide of Pegram in view of Jiang, Bourgeois and Qin in order to enhance the secretion of IL-33 from the CAR-T cells into the tumor microenvironment to enhance the immune response (Jiang, p. 5, para 2-3 from the bottom).
Hence, the claimed invention as a whole was prima facie obvious to a person of ordinary skill before the effective filing date of the claimed invention in the absence of evidence to the contrary.
Response to Traversal:
Applicant’s arguments and exhibits A-C filed on 12/01/2025 are acknowledged and have been discussed above.
Double Patenting Rejections
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 USPTO Internet website contains terminal disclaimer forms which may be used. Please visit www.uspto.gov/patent/patents-forms. The 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/process/file/efs/guidance/eTD-info-I.jsp.
Claims 1-21 are rejected on the ground of nonstatutory double patenting as being unpatentable over claims 1-23 of US Patent No. 11,766,474 (‘474) in view of Jiang et al (WO2018205343A1, effectively filed on 05/12/2017, cited in IDS 07/24/2023) and Qin et al., (Oncotarget. 2016;7(38):61069-61080. Prior art of record). Although the claims at issue are not identical, they are not patentably distinct from each other.
Claims 1-23 of ‘474 are directed to a method of reducing tumor burden in a subject comprising administering to the subject an effective amount of immunoresponsive cells (claim 22), wherein the immunoresponsive cells comprises an exogenous antigen-recognizing receptor and an exogenous IL-36 (claim 1), the antigen being a tumor antigen (claim 2), the antigen-recognizing receptor being a CAR (claims 4 and 14) and being expressed from a vector (claim 5), the cell being a T cell (claims 6-7), a cytotoxic T lymphocyte (claim 8), the tumor antigen being CD19 (claims 9-10), the IL-36 comprising a heterologous signal sequence (claim 11), which is a CD8 leader sequence of an IL-2 signal sequence (claims 12-13), wherein the CAR comprises an extracellular antigen-binding domain, a transmembrane domain and an intracellular signaling domain (claim 15) and the intracellular signaling of the CAR does not comprise a co-stimulatory signaling region (claim 16), and the subject did not receive preconditioning chemotherapy prior to the administration of the cells (i.e., the subject is immuno-competent, claim 23).
However, the patented claims do not recite an exogenous IL-33 in the immunoresponsive cells.
Jiang teaches a cancer treatment method comprising the steps of the chimeric antigen receptor of T cells being administered to tumor patients (p. 4, 4th para from bottom). Jiang teaches “a chimeric antigen receptor T cell expressing a tumor antigen-targeting CAR and Interleukin-33 (IL-33)”(Page 2, 3rd paragraph from the bottom), thus teaches the immunoresponsive cell comprises an antigen-recognizing receptor (i.e., a CAR) and an exogenous IL-33 in instant claim 1. Jiang teaches the IL-33 is expressed and secreted to outside of the cell membrane (p.2, last sentence), thus teaches instant claim 2. Jiang teaches construction of a fusion of chimeric antigen receptor targeted to a tumor antigen and Interleukin-33 expression vector (p. 3, 3rd para from bottom), thus teaches the CAR and the IL-33 are expressed from a vector in instant claim 3. Jiang teaches the amino acid sequence of human secreted IL-33 in the expression vector, shown as Jiang’s SEQ ID NO: 20 (see page 14), in which the amino-terminal amino acids 1-21 is a CD8a leader sequence, and the amino acids 22-180 represent the human IL-33 sequence, which is 100% identical to the amino acid sequence of instant SEQ ID NO: 4 (see above), thus teaches the IL-33 comprises a heterologous signal sequence, i.e., a CD8a leader sequence, at the amino-terminus in instant claims 4-5, and comprises the amino acid sequence of SEQ ID NO: 4 in instant claim 7. It must be noted that these wherein clauses in instant claims 19-20 do not recite an active step in the claimed method, but only the results of the administration step of the CAR-IL-33 T cells as taught by Jiang. Therefore, these wherein clauses do not provide any patentable weight in determining patentability of the claimed method. See MPEP 2111.04 I. Nonetheless, Jiang teaches CEA.CAR.IL-33-T cells are more effective in killing tumor cells compared to CEA.CAR-T cells (Fig 4 and p. 5, line 6) and teaches IL-33 enhances secretion of IFN-γ by CD8+ T cells and NK cells and enhances their effector functions (p. 5, para 3 from bottom), thus teaches instant claims 19-20.
Qin teaches coadministration of antigen-specific TCR-T cells together with exogenous IL-33 in treating leukemia (e.g., abstract). Qin first teaches exogenous IL-33 treatment alone leads to delayed leukemia development and improved overall survival (p. 61070, “Results” section, subsections 1 and 2), and further teaches that exogenous IL-33 overcomes peripheral T cell tolerance through promoting antigen-specific CD8+ T cell proliferation and function (e.g., see p. 61070, last subsection and p. 61071, right col, subsection). Additionally, Qin teaches IL-33 promotes dendritic cell (DC) maturation and activation in favor of its cross presentation ability to evoke a vigorous anti-leukemia immune response (abstract and p. 61072).
Therefore, it would have been obvious for one of ordinary skill in the art before the effective filing date of the claimed invention to have modified the method of reducing tumor burden comprising administering an effective amount of immunoresponsive cells co-expressing an exogenous IL-36 recited in the patented claims of ‘474, by combining co-expressing an exogenous IL-33 with the claimed features in the immunoresponsive cells as taught by Jiang with a reasonable expectation of success. Since patented claims recite co-expressing exogenous interleukins in the CAR-T cell in reducing tumor burden, since Jiang teaches CAR T cells expressing secretive IL-33 are more effective in killing tumor cells (Fig 4 and p. 5, line 6) and IL-33 enhances secretion of IFN-γ by CD8+ T cells and NK cells in the tumor microenvironment to enhance their effector functions (p. 5, para 3 from bottom), and since Qin teaches IL-33 promotes antigen-specific T cell proliferation and function and promotes dendritic cell (DC) maturation and activation (p. 61071-61072), one of ordinary skill in the art would have had a reason to combine an exogenous IL-33 as suggested by Jiang and Qin in the immunoresponsive cells comprising an antigen-recognizing receptor and an exogenous IL-36 recited in the patented claims in order to improve the tumoricidal effect and to enhance secretion of anti-tumor cytokines by CD8+ T cells and NK cells as suggested by Jiang and to promote antigen-specific T cell proliferation and function and dendritic cell (DC) maturation and activation as suggested by Qin.
Furthermore, since patented claims recite administering the immunoresponsive cells co-expressing an exogenous IL-36 to treat a cancer subject that did not receive prior preconditioning chemotherapy (i.e., the subject is immuno-competent, see reference claim 23), one of ordinary skill in the art would have had a reasonable expectation of success in injecting the immunoresponsive cells co-expressing exogenous IL-36 and IL-33 to treat the immuno-competent cancer subject.
Additionally, one of ordinary skill in the art would have chosen an IL-2 signal sequence as recited in claim 13 of ‘474 in the IL-33 polypeptide since the patented claim has recited the use of an IL-2 signal sequence in the exogenous interleukins.
Since the instant application claims are obvious over cited patent claims, in view of Jiang and Qin, said claims are not patentably distinct.
Response to Traversal:
Applicant’s arguments and exhibits A-C filed on 12/01/2025 are acknowledged.
Applicant argues that (1) one of skill in the art would not expect that expression of multiple cytokines would elicit the same response in CAR-T cells as the expression of the cytokines individually, (2) Exhibit C indicates that a potential limitation of cytokine-armored CART cells is the uncontrolled secretion of cytokines and possible toxicities due to the pleiotropic effects of cytokines on multiple immune cells. Thus, one of skill in the art would not be motivated with the requisite expectation of success to simply stack multiple cytokines as suggested, nor would one of skill be able to predict the efficacy and safety of such an approach (Remarks, p. 8).
Applicant’s argument and Exhibit C have been fully considered but they are not persuasive.
In regard to Argument (1) on the multiple cytokines to elicit response in CAR-T cells, prior art Qin teaches exogenous IL-33 treatment alone leads to delayed leukemia development and improved overall survival (p. 61070, “Results” section, subsections 1 and 2). Thus, merely producing and releasing exogenous IL-33 alone, by the CAR-T cells of patent claims in view of Jiang, would lead to delayed leukemia development and improved overall survival as suggested by Qin.
In regard to Argument (2) Exhibit C indicating a potential limitation of cytokine-armored CART cells, it is noted that Exhibit C focuses on IL-6 that has been implicated on the development of cytokine release syndrome and further discusses that IL-36 armored CAR-T cells induces elevated IL-6 but does not induce weight loss or acute toxicity (p. 13 of Exhibit C). In other words, the potential limitation does not dissuade authors of Exhibit C from adding IL-36 to the CAR-T cells. Similarly, this limitation would not dissuade one of ordinary skill in the art from adding IL-33 to the CAR-T cells as well.
In summary, one of skill in the art would have been motivated with the requisite expectation of success to combine IL-33 as suggested by Jiang and Qin to the CAR-IL-36 T cells of patent claims in order to produce and release IL-33 to achieve enhanced secretion of IFN-γ by CD8+ T cells and NK cells as suggested by Jiang and to achieve delayed cancer development and improved survival as suggested by Qin with a reasonable expectation of success.
Maintained Provisional Double Patenting Rejections
Claims 1, 3, 8-10, 12-17 and 19-21 stand provisionally rejected on the ground of nonstatutory double patenting as being unpatentable over copending claims 1, 15-27 and 33-35 of US Application No. 17/693,060 (‘060) in view of Qin et al., (Oncotarget. 2016; 7(38): 61069-61080. Prior art of record). Although the claims at issue are not identical, they are not patentably distinct from each other.
Copending claims 1, 15-27 and 33-35 of ‘060 recite a method of reducing tumor burden, or lengthening survival or treating a tumor in a subject (claims 33-35), comprising administering an effective amount of the cell of claim 21, which comprises an antigen-recognizing receptor of claim 1 comprising an extracellular antigen-binding domain, a transmembrane domain and an intracellular signaling domain (claims 1 and 15-17), the cell comprises an exogenous polypeptide of the cytokine (claim 24), the cytokine is IL-33 (claim 25), the antigen-recognizing receptor is a CAR or TCR (claims 18-19) and is expressed from a vector (claim 20), wherein the cell constitutively expresses the antigen-recognizing receptor (claim 22), the cell is engineered to express a cytokine (claim 23), the cell is an immunoresponsive cell, a T cell, or a cytotoxic T lymphocyte (claim 26), the cell is a pluripotent stem cell (claim 27).
However, copending claims do not specifically recite the subject being immuno-competent.
Qin teaches a method of reducing tumor burden in an immuno-competent mouse tumor model (i.e., C57BL/6 mice intravenously injected murine acute myeloid leukemia cell lines C1498.GFP and C1498.SIY, see p. 61077, right col, para “Tumor challenge and treatment”) by systemic administration of IL-33 and adoptive transfer of antigen-specific T cells (i.e., SIY-specific 2C TCR transgenic CD8+ T cells) without prior preconditioning chemotherapy (see abstract, p. 61071, last para, and end of p. 61077-p. 61078, 1st para, see Fig 4). Qin teaches exogenous IL-33 promotes antigen-specific CD8+ T cell proliferation and function after adoptive transfer (abstract, see Fig 4).
Therefore, it would have been obvious for one of ordinary skill in the art before the effective filing date of the claimed invention to have modified the method of reducing tumor burden in a subject by administering an effective amount of immunoresponsive cells comprising an antigen-recognizing receptor and exogenous IL-33 recited in the copending claims, by choosing an immuno-competent subject as suggested by Qin with a reasonable expectation of success. Since Qin teaches the combination of exogenous IL-33 and antigen-specific T cells is effective in reducing tumor burden in an immuno-competent subject because exogenous IL-33 promotes antigen-specific CD8+ T cell proliferation and function after adoptive transfer (abstract, see Fig 4), one of ordinary skill in the art would have had a reason to choose the immuno-competent subject in the method of copending application in order to skip the preconditioning chemotherapy to avoid the toxic effect of chemotherapy and to expand the population of eligible patients.
Since the instant application claims are obvious over cited application claims, in view of Qin, said claims are not patentably distinct.
This is a provisional nonstatutory double patenting rejection because the patentably indistinct claims in the copending application have not in fact been patented.
Claims 1, 3, 8-10, 12-17 and 19-21 stand provisionally rejected on the ground of nonstatutory double patenting as being unpatentable over copending claims 1, 8-16, 22-24 and 28-32 of US Application No. 18/476,870 (‘870) in view of Qin et al., (Oncotarget. 2016; 7(38): 61069-61080. Prior art of record). Although the claims at issue are not identical, they are not patentably distinct from each other.
Copending claims 1, 8-16, 22-24 and 28-32 of ‘870 recite a method of reducing tumor burden, or lengthening survival or treating a tumor in a subject (claims 28-32), comprising administering an effective amount of the immunoresponsive cell of claim 12, which comprises an antigen-recognizing receptor of claim 1 comprising an extracellular antigen-binding domain, a transmembrane domain and an intracellular signaling domain (claims 1 and 8-10), the cell is engineered to express a cytokine IL-33 (claim 15) and the cell comprises an exogenous IL-33 (claim 16), the antigen-recognizing receptor is a CAR or TCR (claim 11) and is expressed from a vector (claims 22-24), wherein the cell constitutively expresses the antigen-recognizing receptor (claim 13), the immunoresponsive cell is a T cell, a cytotoxic T lymphocyte or a pluripotent stem cell (claim 14).
However, copending claims do not specifically recite the subject being immuno-competent.
Qin teaches a method of reducing tumor burden in an immuno-competent mouse tumor model (i.e., C57BL/6 mice intravenously injected murine acute myeloid leukemia cell lines C1498.GFP and C1498.SIY, see p. 61077, right col, para “Tumor challenge and treatment”) by systemic administration of IL-33 and adoptive transfer of antigen-specific T cells (i.e., SIY-specific 2C TCR transgenic CD8+ T cells) without prior preconditioning chemotherapy (see abstract, p. 61071, last para, and end of p. 61077-p. 61078, 1st para, see Fig 4). Qin teaches exogenous IL-33 promotes antigen-specific CD8+ T cell proliferation and function after adoptive transfer (abstract, see Fig 4).
Therefore, it would have been obvious for one of ordinary skill in the art before the effective filing date of the claimed invention to have modified the method of reducing tumor burden in a subject by administering an effective amount of immunoresponsive cells comprising an antigen-recognizing receptor and exogenous IL-33 recited in the copending claims, by choosing an immuno-competent subject as suggested by Qin with a reasonable expectation of success. Since Qin teaches the combination of exogenous IL-33 and antigen-specific T cells is effective in reducing tumor burden in an immuno-competent subject because exogenous IL-33 promotes antigen-specific CD8+ T cell proliferation and function after adoptive transfer (abstract, see Fig 4), one of ordinary skill in the art would have had a reason to choose the immuno-competent subject in the method of copending application in order to skip the preconditioning chemotherapy to avoid the toxic effect of chemotherapy and to expand the population of eligible patients.
Since the instant application claims are obvious over cited application claims, in view of Qin, said claims are not patentably distinct.
This is a provisional nonstatutory double patenting rejection because the patentably indistinct claims in the copending application have not in fact been patented.
Response to Traversal:
Applicant’s arguments and exhibits A-C filed on 12/01/2025 are acknowledged.
Applicant argues that both the '060 application and the '870 application have earliest nonprovisional priority dates that are subsequent to the earliest non-provisional priority date claimed by the instant application, and such later filed and later expiring applications cannot serve as reference claims against the claims of the instant application (Remarks, p. 9).
Applicant’s arguments have been fully considered but they are not persuasive. Applicant is reminded that this provisional nonstatutory double patenting rejection is not the only rejection remaining in the instant application. See MPEP 804.I.B.1 (b) (i).
Conclusion
No claims are allowed.
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/JIANJIAN ZHU/Examiner, Art Unit 1631
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