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 .
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and the fee set forth in 37 CFR 1.17(e) has been timely paid, the finality of the previous Office action has been withdrawn pursuant to 37 CFR 1.114.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 5 March 2026 has been entered.
Response to Amendment/Argument
The Applicants reply filed 5 March 2026 is acknowledged. No claims are amended (see formal matters, below).
Formal Matters
The Examiner notes that the instant claim set filed 5 March 2026 is improperly annotated because it is marked as amended, but the amendments that are marked were entered in the claim set filed after final on 28 July 2025. The Examiner entered the claims after final as described in the PTOL-303 dated 8/5/2025 and therefore claims 1 and 5 are improperly marked as “Currently Amended” (See MPEP CFR 1.121).
Claim Status
Claims 1-5, 15-17 are pending. Claims 5 and 15-17 are withdrawn as previously described. Claims 1-4 are under examination in the instant office action.
Withdrawal of Objections
The objection to claim 1 is withdrawn in view of the amendments to the claims.
Priority- New
The Examiner notes that the instant Application is a 371 of PCT/US2020/035272 filed 5/29/2020, which claims benefit of provisional App. No. 62854228 filed 5/29/2019. However, the examiner notes that there is no support in the provisional application for an “aged immune effector cell”. Accordingly, the instant claims have been examined with an effective filing date of the 371, 29 May 2020.
Nucleotide and/or Amino Acid Sequence Disclosures- Maintained
REQUIREMENTS FOR PATENT APPLICATIONS CONTAINING NUCLEOTIDE AND/OR AMINO ACID SEQUENCE DISCLOSURES
Items 1) and 2) provide general guidance related to requirements for sequence disclosures.
37 CFR 1.821(c) requires that patent applications which contain disclosures of nucleotide and/or amino acid sequences that fall within the definitions of 37 CFR 1.821(a) must contain a "Sequence Listing," as a separate part of the disclosure, which presents the nucleotide and/or amino acid sequences and associated information using the symbols and format in accordance with the requirements of 37 CFR 1.821 - 1.825. This "Sequence Listing" part of the disclosure may be submitted:
In accordance with 37 CFR 1.821(c)(1) via the USPTO patent electronic filing system (see Section I.1 of the Legal Framework for Patent Electronic System (https://www.uspto.gov/PatentLegalFramework), hereinafter "Legal Framework") as an ASCII text file, together with an incorporation-by-reference of the material in the ASCII text file in a separate paragraph of the specification as required by 37 CFR 1.823(b)(1) identifying:
the name of the ASCII text file;
ii) the date of creation; and
iii) the size of the ASCII text file in bytes;
In accordance with 37 CFR 1.821(c)(1) on read-only optical disc(s) as permitted by 37 CFR 1.52(e)(1)(ii), labeled according to 37 CFR 1.52(e)(5), with an incorporation-by-reference of the material in the ASCII text file according to 37 CFR 1.52(e)(8) and 37 CFR 1.823(b)(1) in a separate paragraph of the specification identifying:
the name of the ASCII text file;
the date of creation; and
the size of the ASCII text file in bytes;
In accordance with 37 CFR 1.821(c)(2) via the USPTO patent electronic filing system as a PDF file (not recommended); or
In accordance with 37 CFR 1.821(c)(3) on physical sheets of paper (not recommended).
When a “Sequence Listing” has been submitted as a PDF file as in 1(c) above (37 CFR 1.821(c)(2)) or on physical sheets of paper as in 1(d) above (37 CFR 1.821(c)(3)), 37 CFR 1.821(e)(1) requires a computer readable form (CRF) of the “Sequence Listing” in accordance with the requirements of 37 CFR 1.824.
If the "Sequence Listing" required by 37 CFR 1.821(c) is filed via the USPTO patent electronic filing system as a PDF, then 37 CFR 1.821(e)(1)(ii) or 1.821(e)(2)(ii) requires submission of a statement that the "Sequence Listing" content of the PDF copy and the CRF copy (the ASCII text file copy) are identical.
If the "Sequence Listing" required by 37 CFR 1.821(c) is filed on paper or read-only optical disc, then 37 CFR 1.821(e)(1)(ii) or 1.821(e)(2)(ii) requires submission of a statement that the "Sequence Listing" content of the paper or read-only optical disc copy and the CRF are identical.
Specific deficiencies and the required response to this Office Action are as follows:
The enumerated sequence called “SFG DN cMyb-P2A-h1928z” in the specification para. [173] is identified as SEQ ID NO: 6, but the SEQ ID NO: 6 in the sequence listing does not match the identity of the sequence enumerated in para. [0173].
Specification- Maintained
The disclosure is objected to because of the following informalities: human c-Myb SEQ ID NO: 3 [0012] contains sequences (residues 201-498) from the dominant negative transcription factor, Drosophila engrailed, and is not wild-type human c-Myb. See the alignment from BLAST below:
engrailed protein [Drosophila melanogaster]
Sequence ID: AAA65478.1Length: 552Number of Matches: 1
Range 1: 1 to 298GenPeptGraphicsNext MatchPrevious Match
Query 201 MALEDRCSPQSAPSPITLQMQHLHHQQQQQQQQQQQMQHLHQLQQLQQLHQQQLAAGVFH 260
MALEDRCSPQSAPSPITLQMQHLHHQQQQQQQQQQQMQHLHQLQQLQQLHQQQLAAGVFH
Sbjct 1 MALEDRCSPQSAPSPITLQMQHLHHQQQQQQQQQQQMQHLHQLQQLQQLHQQQLAAGVFH 60
Query 261 HPAMAFDAAAAAAAAAAAAAAHAHAAALQQRLSGSGSPASCSTPASSTPLTIKEEESDSV 320
HPAMAFDAAAAAAAAAAAAAAHAHAAALQQRLSGSGSPASCSTPASSTPLTIKEEESDSV
Sbjct 61 HPAMAFDAAAAAAAAAAAAAAHAHAAALQQRLSGSGSPASCSTPASSTPLTIKEEESDSV 120
Query 321 IGDMSFHNQTHTTNEEEEAEEDDDIDVDVDDTSAGGRLPPPAHQQQSTAKPSLAFSISNI 380
IGDMSFHNQTHTTNEEEEAEEDDDIDVDVDDTSAGGRLPPPAHQQQSTAKPSLAFSISNI
Sbjct 121 IGDMSFHNQTHTTNEEEEAEEDDDIDVDVDDTSAGGRLPPPAHQQQSTAKPSLAFSISNI 180
Query 381 LSDRFGDVQKPGKSIENQASIFRPFEANRSQTATPSAFTRVDLLEFSRQQQAAAAAATAA 440
LSDRFGDVQKPGKSIENQASIFRPFEANRSQTATPSAFTRVDLLEFSRQQQAAAAAATAA
Sbjct 181 LSDRFGDVQKPGKSIENQASIFRPFEANRSQTATPSAFTRVDLLEFSRQQQAAAAAATAA 240
Query 441 MMLERANFLNCFNPAAYPRIHEEIVQSRLRRSAANAVIPPPMSSKMSDANPEKSALGS 498
MMLERANFLNCFNPAAYPRIHEEIVQSRLRRSAANAVIPPPMSSKMSDANPEKSALGS
Sbjct 241 MMLERANFLNCFNPAAYPRIHEEIVQSRLRRSAANAVIPPPMSSKMSDANPEKSALGS 298
2. The enumerated sequence called “SFG DN cMyb-P2A-h1928z” in the specification para. [173] is identified as SEQ ID NO: 6, but the SEQ ID NO: 6 in the sequence listing does not match the identity of the sequence enumerated in para. [0173].
Appropriate correction is required.
Response to arguments
Applicant has not addressed the objections to the specification in the Remarks dated 3/5/2026; the objections are maintained.
Claim Rejections - 35 USC § 103- Maintained
The following is a quotation of 35 U.S.C. 103 which forms the basis for all obviousness rejections set forth in this Office action:
A patent for a claimed invention may not be obtained, notwithstanding that the claimed invention is not identically disclosed as set forth in section 102, if the differences between the claimed invention and the prior art are such that the claimed invention as a whole would have been obvious before the effective filing date of the claimed invention to a person having ordinary skill in the art to which the claimed invention pertains. Patentability shall not be negated by the manner in which the invention was made.
The factual inquiries for establishing a background for determining obviousness under 35 U.S.C. 103 are summarized as follows:
1. Determining the scope and contents of the prior art.
2. Ascertaining the differences between the prior art and the claims at issue.
3. Resolving the level of ordinary skill in the pertinent art.
4. Considering objective evidence present in the application indicating obviousness or nonobviousness.
Claims 1 and 3 are rejected under 35 U.S.C. 103 as being unpatentable over Gacerez AT, Sentman CL. T-bet promotes potent antitumor activity of CD4+ CAR T cells. Cancer Gene Ther. 2018 Jun;25(5-6):117-128. doi: 10.1038/s41417-018-0012-7. Epub 2018 Mar 7. PMID: 29515240; PMCID: PMC6021366 (Of Record, 892 dated 1/13/2025) and Liu X, Tang Z, Zhang Y, Hu J, Li D, Zang G, Yu Y. Lentivirally overexpressed T-bet regulates T-helper cell lineage commitment in chronic hepatitis B patients. Mol Med Rep. 2012 Aug;6(2):361-6. doi: 10.3892/mmr.2012.905. Epub 2012 May 8. PMID: 22580570 (cited in IDS dated 11/29/2021 NPL No: 2) as evidenced by Scott CS, et. al. Patterns of membrane TcR alpha beta and TcR gamma delta chain expression by normal blood CD4+CD8-, CD4-CD8+, CD4-CD8dim+ and CD4-CD8- lymphocytes. Immunology. 1990 Jul;70(3):351-6. PMID: 2143170; PMCID: PMC1384165 (Of Record, 892 1/13/2025) and Human T-bet Protein Geneseq AAB51013 published 07 December 2000 (Of Record, 892 1/13/2025).
Gacerez et. al. teaches “B7H6-specific CAR was combined with different variants of T-bet, a transcription factor that acts as the master regulator to induce a Th1 phenotype in CD4+ T cells, to create more effective CAR T cells. Skewing CD4+ CAR T cells into a Th1 improved CAR T cell functional activity while promoting a robust proinflammatory response against B7H6-expressing tumors. The expression of T-bet with the B7H6-specific CAR in CD4+ T cells conferred higher expression of the CAR, elevated secretion of Th1 and proinflammatory cytokines, and improved cellular cytotoxicity against B7H6-expressing tumor cells. In vivo, CD4+ T cells co-expressing a B7H6-specific CAR and T-bet improved the survival of RMA-B7H6 lymphoma-bearing mice. Thus, CD4+ CAR T cells with increased T-bet expression have the potential to modify the tumor microenvironment and the immune response to better treat solid and hematologic cancers” (Abstract). Gacerez et. al. teaches that overexpression of T-bet with a B7H6 CAR in a CD4+ CAR-T cell increases the anti-tumor activity and survival of a mouse model of lymphoma (Figure 5, “Discussion” paragraph 4).
Gacerez et. al. does not teach that the recombinant immune effector cells is an aged immune effector cell derived from a human donor at least 40 years old, wherein the aged immune effector cell is selected from the group consisting of an alpha-beta T cell, a gamma-delta T cell, and a regulatory T cell.
Liu et. al. teaches a recombinant aged T cell immune effector cell genetically modified to express recombinant T-bet: “The aim of this study was to investigate the effect of T-bet overexpression on Th cell differentiation and the possible mechanism in chronic hepatitis B patients. CD4+ T cells from the peripheral blood [were used…] to generate a recombinant lentiviral vector pGC-FU-T-bet” (Abstract). Liu et. al. teaches that their patient were “45 CHB patients (31 males and 14 females; average age, 38.0±12.1 years; 34 with positive HBeAg, 11 with negative HBeAg; average ALT, 227.1±163.3 IU/l)” (Patients and methods section, page 361), which teaches aged immune effector cells. Regarding claim 14, 38.0±12.1 years is a distribution with a standard deviation which would encompass patients greater than 40 years old. Regarding claim 3, as evidenced by Human T-bet Protein Geneseq AAB51013 published 07 December 2000, human T-bet is 100% is identical to instant SEQ ID NO: 1. As evidenced by Scott CS, Richards SJ, Roberts BE. Patterns of membrane TcR alpha beta and TcR gamma delta chain expression by normal blood CD4+CD8-, CD4-CD8+, CD4-CD8dim+ and CD4-CD8- lymphocytes. Immunology. 1990 Jul;70(3):351-6. PMID: 2143170; PMCID: PMC1384165, “Normal CD4+CD8- lymphocytes were almost invariably (greater than 99%) TcR alpha beta+, whereas lymphocytes expressing membrane CD8, which could be further subdivided according to differences in fluorescent staining intensity into CD3+CD4-CD8+, CD3+CD4-CD8dim+ and CD3-CD4-CD8dim+ components, were characterized by distinct differences in patterns of TcR chain expression” (Abstract), demonstrating that the CD4+ T cells of Liu et. al. would have included alpha-beta T cells. Additionally, Liu et. al. teach that “Persistent HBV infection is characterized by a weak adaptive immune response, considered to be due to inefficient CD4+ T cell priming early in the infection and subsequent development of a quantitatively and qualitatively ineffective CD8 cytotoxic T-lymphocyte (CTL) response. The HBV-specific CTL response plays a fundamental role in viral clearance and pathogenesis of liver disease. The peripheral blood CTL response in chronically infected patients is weak and narrowly focused” (page 363, column 1 paragraph 2- column 2 paragraph 1); “Lentiviral introduction of T-bet into peripheral blood CD4+ T cells is a likely candidate for regulating the Th1/Th2 immune response” (page 364, column 2 paragraph 2); and “T-bet overexpression may be immunostimulatory for Th1 type responses mediated by HLX1, which have important implications for enhancing weak immunity in CHB patients” (page 365, column 1 paragraph 3).
It would have been obvious for a person of ordinary skill in the art, before the effective filing date, to apply the overexpression of T-bet in aged T cells as taught by Liu et. al. to the overexpression of T-bet in T-cells expressing a CAR polypeptide (CAR-T cells) as taught by Gacerez et. al., resulting in an aged CAR-T cell overexpressing T-bet with improved anti-tumor and cytokine activity as taught by Gacerez et. al to benefit from the reprogramming of T cells to a Th1 phenotype for improved T cell anti-tumor or anti-viral activity as taught by Liu et. al. and Gacerez et. al. This would have a predictable effect because the overexpression of T-bet in both the anti-viral T cells of Liu and the anti-tumor T cells of Gacerez is providing the same role of increasing T cell cytotoxicity and function; further, an artisan would expect based on the teachings of Liu et. al. that T-bet overexpression would be particularly efficacious at boosting T-cell function through commitment to a Th1 lineage in any population of T cells that may be senescent, weak, or exhausted, and therefore it would have a predictable effect of making a more effective CAR-T cell, for example an autologous CAR-T cell from a cancer patient who is older than age 40.
Claims 2 and 4 are rejected under 35 U.S.C. 103 as being unpatentable over Gacerez et. al. Cancer Gene Ther. 2018 Jun;25(5-6):117-128. doi: 10.1038/s41417-018-0012-7. Epub 2018 Mar 7. (Of Record, 892 dated 1/13/2025) and Liu X, et. al. Mol Med Rep. 2012 Aug;6(2):361-6. doi: 10.3892/mmr.2012.905. Epub 2012 May 8 (cited in IDS dated 11/29/2021 NPL No: 2) as evidenced by Scott et. al. (892 1/13/2025)and Geneseq T-bet (892 1/13/2025) as applied to claim 1 above, and further in view of Gruarin, P., et. al., 2019. Eomesodermin controls a unique differentiation program in human IL‐10 and IFN‐γ coproducing regulatory T cells. European journal of immunology, 49(1), pp.96-111 (published 29 November 2018) (PTO-892 6/9/2025) as evidenced by Uniprot “EOMES_HUMAN” O95936 (PTO-892 6/9/2025).
The teachings of Gacerez et. al. and Liu et. al. in regards to claims 1 are in the 103 rejection above.
Gacerez et. al. in view of Liu et. al. does not teach the immune effector cells are further modified to express Eomes, wherein Eomes comprises SEQ ID NO: 2. This deficiency is resolved by Gruarin, P., et. al.
Gruarin et. al. teaches a subset of IL-10 producing regulatory T cells (“Tr1”), and particularly that “Eomes+ Tr1-like cells are effector cells of a unique GzmK-expressing CD4+ T-cell subset. Gruarin particularly teaches that Eomes induction by expression with a lentiviral vector encoding full-length human Eomes was sufficient to increase IFNγ production, decrease CD40L expression, increase GzmK, and increase degranulation (Fig. 5B). Gruarin et. al. states, “IFN-γ production was also induced by Eomes (Fig 5B) or by IL-12 (data not shown), and to a lesser degree by IL-27. Importantly, Eomes significantly inhibited CD40L expression and cooperated with IL-27 to efficiently downregulate CD40L (Fig. 5B), while IL-12 was inefficient (data not shown). In addition, Eomes was sufficient to induce high levels of GzmK, while IL-27 (Fig. 5B) and IL-12 (data not shown) alone induced only low levels. Eomes had also a weak positive effect on GzmB, but GzmB expression was low unless IL-12 was added (Supporting Information Fig. 5B). Finally, Eomes-expressing CD4+ T cells also degranulated (Fig. 5B). Overall, these results show that Eomes regulates the expression of several effector molecules that are characteristic for in vivo occurring Tr1-like cells, and is sufficient to induce IFN-γ and GzmK. In addition, Eomes promoted a switch from CD40L to IL-10 in cooperation with IL-27” (“Eomes regulates Tr1 effector molecules jointly with IL-27” p. 102 col. 2-p. 104 para. 1). As evidenced by Uniprot “EOMES_HUMAN”, full-length human EOMES is identical to instant SEQ ID NO: 2 (see Uniprot alignment, .rup, of SEQ ID NO: 2, Result 1). Lastly, Gruarin et. al. teaches “IL-27 failed to induce Eomes in human T cells, suggesting that it induces Eomes+ Tr1-like cells from Eomes_ Th1 precursors rather than from naïve T cells” (Discussion, p. 107 Col. 2).
It would have been obvious for a person of ordinary skill in the art, before the effective filing date, to add the overexpression of EOMES as described Gruarin et. al. to further modify the aged immune effector cells of Gacerez et. al. and Liu et. al. in order to benefit from the increased effector cell activity of Tr1-like EOMES+ effector cells as taught by Gruarin et. al. This would have a predictable effect because Gruarin describes that Th1 lineage cells (which are induced by T-bet as taught by Gacerez and Liu et. al.) can be driven towards this phenotype by EOMES lentiviral overexpression, and an artisan would expect that Eomes and T-bet co-overexpression would lead to the induction of the Tr-1 like effector cells as taught by Gruarin. An artisan would modulate and further modify the transcriptional profile of the genetically modified T cells as desired by a combination of genetic modifications such as overexpression of transcription factors and culture conditions (e.g. cytokines) to achieve the type of T-cell phenotype desired.
Claim 2 is rejected under 35 U.S.C. 103 as being unpatentable over Gacerez et. al. Cancer Gene Ther. 2018 Jun;25(5-6):117-128. doi: 10.1038/s41417-018-0012-7. Epub 2018 Mar 7. (Of Record, 892 dated 1/13/2025) and Liu X, et. al. Mol Med Rep. 2012 Aug;6(2):361-6. doi: 10.3892/mmr.2012.905. Epub 2012 May 8 (cited in IDS dated 11/29/2021 NPL No: 2) as evidenced by Scott et. al. (PTO-892 1/3/2025) and Geneseq T-bet (PTO-892 1/3/2025) as applied to claim 1 above, and further in view of WO2017035251 to Gautam et. al. published 02 March 2017 (PTO-892 1/3/2025).
The teachings of Gacerez et. al. in view of Liu et. al. in regards to claim 1 are in the 103 rejection above.
Gacerez et. al. in view of Liu et. al. does not teach the immune effector cells are further modified to express c-Myb. This deficiency is resolved by Gautam et. al.
Gautam et. al. teach a “T cell has been modified to express a transcription factor at a level that is higher than the level of the transcription factor expressed by a T cell that has not been modified to express the transcription factor, wherein the transcription factor is V-Myb Avian Myeloblastosis Viral Oncogene Homolog (c-Myb), a functional variant of c-Myb, or a functional fragment of c-Myb” (See Abstract, [0032]). Gautam et. al. teaches that c-Myb overexpression in T cells results in “an increase of any one or more of in vivo proliferation, survival, persistence, anti-tumor activity, and antiviral activity as compared to T cells that have not been modified to overexpress c-Myb (e.g., T cells that lack the vector)” [0033]. Example 3 shows that c-Myb increases T cell proliferation ([0114-0117], Figure 2); Example 4 shows that c-Myb increases the number of cells with a central memory phenotype ([0118-0121], Figure 2).
It would have been obvious for a person of ordinary skill in the art, before the effective filing date, to add the overexpression of c-Myb as described Gautam et. al. to further modify the aged immune effector cells of Liu et. al. in order to benefit from the increased proliferation and central memory phenotype as described by Gautam et. al. This would have a predictable effect because Gautam describes how c-Myb overexpression drives T cells to a less effector-like phenotype, which is typical in aged or exhausted cells; therefore, the same benefit would be expected to be conferred to the T-bet expressing cells of Liu et. al.
Response to Declaration
The 132 declaration filed 5 March 2026 has been fully considered. The declaration is insufficient to overcome the 103 rejection of record for the following reasons:
The declaration demonstrates that the frequency of CD4+ CAR-T cells decreases in a population of aged CAR-T cells. It is unclear how many donors were tested or the age of the CAR-T cell donor(s), or even if the cells are aged mouse cells as used in the specification (See e.g. Example 3 [0174]; “aged B6 derived conventional CAR T cells”) or aged cells from a human donor. Therefore, it is not understood from the instant experiment what variability can be expected from “old” vs. “young” in any aged effector cell that is an alpha-beta, gamma-delta, or regulatory T cell from a human donor at least 40 years old. The declaration further states “The following data demonstrate that T-bet expression increases the proportion of CD4+ T cells within the aged CAR+ population, partially restoring the CD4+ compartment relative to aged conventional CAR-T cells” (Declaration p. 1). The Declaration does not address how this data is unexpected over the teachings of the prior art. As described in the 103 rejection above, Gacerez teaches that Tbet regulates Th1-phenotype in CD4+ CAR-T cells and “The expression of T-bet with the B7H6-specific CAR in CD4+ T cells conferred higher expression of the CAR, elevated secretion of Th1 and proinflammatory cytokines, and improved cellular cytotoxicity against B7H6-expressing tumor cells”. Liu et. al. also teaches that in situations with a weak T cell response, in particular chronic hepatitis B, this is due to the weak Th1 response in CD4+ T cells, and that overexpression of T-bet can restore this response. A person of ordinary skill in the art would have expected all of the features taught by Gacerez and Liu to apply to T cells from a donor above age 40. The Examiner notes that, additionally, the loss of both CD4+ T cell number and function during aging was well described in the prior art before the instant filing date. For example, Lefebvre JS, Haynes L. Aging of the CD4 T Cell Compartment. Open Longev Sci. 2012 Jan 1;6:83-91 teaches “The dwindling of the CD4+ T cell population is an important characteristic of aging” (Introduction ¶3) and that CD4+ T cells show a preferential differentiation to Th17 compared to Th1/Th2 effector subsets (Table 1).
MPEP §2145 teaches “Evidence pertaining to secondary considerations must be taken into account whenever it has been properly presented; however, it does not necessarily control the obviousness conclusion. See, e.g., Pfizer, Inc. v. Apotex, Inc., 480 F.3d 1348, 1372, 82 USPQ2d 1321, 1339 (Fed. Cir. 2007) ("the record establish[ed] such a strong case of obviousness" that allegedly unexpectedly superior results were ultimately insufficient to overcome obviousness conclusion); Leapfrog Enterprises Inc. v. Fisher-Price Inc., 485 F.3d 1157, 1162, 82 USPQ2d 1687, 1692 (Fed. Cir. 2007) ("given the strength of the prima facie obviousness showing, the evidence on secondary considerations was inadequate to overcome a final conclusion" of obviousness) […] Office personnel should weigh all relevant evidence of record in order to determine whether the claims would have been obvious based on a preponderance (more likely than not) standard, and then explain their conclusions. See MPEP § 716 - § 716.10 for additional information pertaining to the evaluation of rebuttal evidence submitted under 37 CFR 1.132”.
Thus, upon careful consideration of all of the evidence in the case, as stated in the 103 rejection above, it would have been obvious to an person of ordinary skill in the art based to combine Gacerez in view of Liu as described above to arrive at a recombinant immune effector cell genetically modified to co-express a chimeric antigen receptor (CAR) and recombinant T-bet, wherein the recombinant immune effector cell is an aged immune effector cell derived from a human donor at least 40 years old, and wherein the aged immune effector cell is selected from the group of an alpha-beta T cell, a gamma-delta T cell, and a regulatory T cell in order to benefit from the increased Th1 activity and increase cytotoxicity in T-cells with CD4+ activity defects as taught by both Liu and Gacerez. This would have a reasonable expectation as described above of success because both Liu and Gacerez teach overexpression of T-bet in human T-cells with loss or weakness in function for example in chronic hepatitis B in patients that are above 40 years old as explicitly recited by Liu. There is no teaching in Gacerez or Liu that would lead a person of ordinary skill in the art away from overexpressing recombinant T-bet in T-cells from a patient above 40 years old. As described in the declaration, T-bet overexpression partially restores the number of CD4+ T cells in one aged T cell population; this technical effect would naturally follow from the teachings of Gacerez and Liu. Thus, even if this particular effect is not explicitly stated in either Gacerez or Liu, the result is not surprising or outside of the scope of what a person of ordinary skill in the art would have reasonably expected at the time of filing. Therefore, the declaration is insufficient and the instant 103 rejection is maintained.
Response to Arguments
Applicant states that “under Graham V. John Deere Co., secondary considerations (objective indicia) such as unexpected results must be considered as part of the obviousness analysis. They are not optional; they are integral to the § 103 determination […] Thus, although the prior art need not suggest the same advantage to establish a prima facie case, once the Applicant demonstrates that the claimed invention achieves an unexpected technical effect, the legal conclusion of obviousness can no longer stand unless the Examiner proves that the result would nevertheless have been predictable to a POSITA” (Remarks 3/5/2026 p. 4).
This is not a correct summary of how secondary considerations are applied to the determination of obviousness by the Examiner. First, MPEP §2145 states “once a prima facie case of obviousness is made by the USPTO through citation of references, the burden is on the applicant to produce contrary evidence”. Thus, the burden is on the Applicant to provide sufficient evidence such that upon consideration, the totality of the evidence shows that the invention as claimed would not have been obvious. Additionally, MPEP §2145 states “Consideration of rebuttal evidence and arguments requires Office personnel to weigh the proffered evidence and arguments. Id.; see also In re Alton, 76 F.3d 1168, 1174-75, 37 USPQ2d 1578, 1582-83 (Fed. Cir. 1996). Office personnel should avoid giving no weight to evidence submitted by applicant, except in rare circumstances. However, to be entitled to substantial weight, the applicant should establish a nexus between the rebuttal evidence and the claimed invention, i.e., objective evidence of nonobviousness must be attributable to the claimed invention”. Thus, if the technical effect is indeed surprising, the scope of what has been shown to be unexpectedly much match the breadth of the claims. Lastly, “Office personnel should weigh all relevant evidence of record in order to determine whether the claims would have been obvious based on a preponderance (more likely than not) standard, and then explain their conclusions” (MPEP §2145).
Applicant argues that, based on the Davila Declaration, “The combination of Garcerez and Liu do not teach that an aged immune effector CD4+ CAR-T cell expressing T-bet can increase CD4: CD8 ratios and improve cytotoxicity with a reasonable expectation of success. Instead, Applicants’ discovery represents an unexpected, and therefore non-obvious, result”; “Gacerez does not teach or suggest that T-bet will reverse the intrinsic defects of aged immune effector cells (e.g. at least 40 years old), such as terminal differentiation and loss of central memory cells […] Liu does not overcome this deficiency of Gacerez. The patients in Liu were 38 + 12.1 years old and therefore at least 40 years old, However, Liu did not teach or suggest that T-bet overcame the intrinsic defects of aged immune effector cells. Instead, Liu merely showed that T-bet regulates Th cell lineage commitment in chronic hepatitis B (CHB) patients”.
This is not persuasive. First, in response to applicants’ arguments against the references individually, one cannot show nonobviousness by attacking references individually where the rejections are based on combinations of references. See In re Keller, 642 F.2d 413, 208 USPQ 871 (CCPA 1981); In re Merck & Co., 800 F.2d 1091, 231 USPQ 375 (Fed. Cir. 1986). As described in the 103 rejection above, Gacerez teaches that “The expression of T-bet with the B7H6-specific CAR in CD4+ T cells conferred higher expression of the CAR, elevated secretion of Th1 and proinflammatory cytokines, and improved cellular cytotoxicity against B7H6-expressing tumor cells”. The Examiner would like to note that, although Gacerez does not explicitly recite an aged T-cell, a person of ordinary skill in the art would certainly not expect from the teachings of Gacerez that this improvement in T cell function would apply only to young T cells. In particular, improvement of T cell immunotherapy requires increased T-cell function across populations that have the diseases treated by T cell immunotherapy. CAR-T cell therapies have yet to experience significant success in the allogeneic CAR-T cell space. By necessity, then, any CAR-T cell therapy for an adult is likely to be a CAR-T cell therapy in an aged T cell as defined by the applicant. For example, Robbins, et. al. JNCI: Journal of the National Cancer Institute, Volume 107, Issue 3, March 2015 (Of record, 892 6/9/2025) teaches that the median age at diagnosis for many cancers, including blood cancers such as Hodgkin’s lymphoma, is above the age of 40 (See Table 1). Therefore, any effort to improve CAR-T cell function would have, predictably, been an effort at improving aged T cell function. Liu et. al. is merely the strongest explicit evidence that T-bet has a similar function of driving a T cell towards a Th1 phenotype, even if that cell is obtained from a donor over the age of 40. Thus, considering the totality of the evidence, Liu et. al. overcomes the deficiency of Gacerez because, although Gacerez fails to explicitly recite a T cell from a human over the age of 40, a person of ordinary skill in the art would read the explicit teaching of Liu et. al. of recombinant Tbet expression in a human T cell over the age of 40 and understand that the improved functions in these CD4 T cells must necessarily overcome any age related deficits in these CD4+ T cells from 40 year old human patients in order to show the efficacy of increased cytotoxic activity against chronic hepatitis B. A person of ordinary skill in the art, at the time of filing, would only be interested in the CD4/CD8 ratio or the Th1/Th2 and Th17 phenotypes of the T cells to the extent that it informative to the end result, which is a more effective T-cell population at killing a disease target (such as a tumor or a virally-infected cell). The rebalancing of the CD4/CD8 ratio as described by the Applicant would naturally follow from the overexpression of recombinant Tbet in aged T cells as suggested by both Gacerez and Liu in view of the state of the art around the function of T cell immunotherapy and the fact that the target human patient population would naturally include patients over the age of 40. The result the Applicant describes, although not expressly described by Gacerez and Liu, would be entirely within the scope of expected results of a person of ordinary skill in the art (POSITA) at the time of filing because the POSITA would expect that the more effective CD4+ T cells as described by both Gacerez and Liu must be healthier and more active, both things that correlate with persistence and proliferation of T cells and therefore would result in more CD4 T cells. The rebalancing of the CD4/CD8 ratio is an intermediate mechanism between the expression of T-bet and the goal of a POSITA of creating a more effective genetically engineered T cell population.
Thus, 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).
Additionally, en arguendo, the Examiner notes that even if the rebalancing of CD4:CD8 ratio in aged T cells was unexpected, there is not sufficient nexus between the claimed invention and the unexpected result. Although it is not explicitly stated, it appears that this result is from Black 6 mice as in the specification (Example 3). There is no evidence that any given population of T cells isolated from a patient over 40 years old exhibits the particular characteristics of senescence as shown. A human that is 40 and is otherwise healthy may have T cells with completely different cytotoxic properties and activities (such as Th1 phenotype and CD4:CD8) compared to a 60-year-old cancer patient. There is no evidence that 40 years is the age at which this T cell phenotype is prevalent. There is no evidence of record of which T cell population (alpha-beta, gamma-delta, Treg, CD4, or CD8) expressing Tbet contributes the most to this mechanism of rebalancing as described by applicant. Therefore, even if en arguendo, the reversal of senescence in T cells was surprising as alleged by the applicant, this would not be persuasive because the Applicant is arguing a result for which the is no nexus between the result and the composition broadly recited in the claims.
Overall, the totality of the evidence suggests that the invention as claimed was obvious to a person of ordinary skill in the art at the time of filing as described and therefore the 103 rejection above is maintained.
Regarding the arguments over Gacerez and Liu in view of Gruarin, Applicant argues that Gruarin does not overcome the deficiencies of Gacerez and Liu (Remarks 3/5/2026 p. 5-6). This is not persuasive as described above.
Regarding the arguments regarding Gacerez and Liu in view of Gautam (Remarks p. 6, paragraph 2), Applicant argues that Gruarin does not overcome the deficiencies of Gacerez and Liu (Remarks 3/5/2026 p. 5-6). This is not persuasive as described above.
Conclusion
No claims are allowed.
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/KATHLEEN CUNNINGCHEN/Examiner, Art Unit 1646
/GREGORY S EMCH/Supervisory Patent Examiner, Art Unit 1678
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