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 .
Amendments
In the reply filed 07/25/2025, Applicant has amended claims 1-3, 9, 15, 16, 20, 21, 28, 31, 38, 46, 65, 67, 68, 77, 80, 83, 115 and 117.
Claim Status
Claims 1-4, 6, 9, 12-13, 15-16, 18, 20-21, 26, 28, 31, 38, 40, 46-47, 49, 55-56, 59, 64-65, 67-69, 72, 77-78, 80, 83, and 113-118 are pending.
Claims 116 and 118 have been withdrawn from further consideration pursuant to 37 CFR 1.142(b) as being drawn to non-elected species, there being no allowable generic or linking claim. Election was made without traverse in the reply filed on 10/09/2024.
Claims 1-4, 6, 9, 12-13, 15-16, 18, 20-21, 26, 28, 31, 38, 40, 46-47, 49, 55-56, 59, 64-65, 67-69, 72, 77-78, 80, 83, 113-115 and 117 are considered on the merits.
Information Disclosure Statement
The information disclosure statement (IDS) submitted on 07/25/2025 is in compliance with the provisions of 37 CFR 1.97. Accordingly, the information disclosure statement is being considered by the examiner. The corresponding signed and initialed PTO form 1449 has been mailed with this action.
Withdrawn Specification Objections
The prior objection to specification because of an embedded hyperlink and/or other form of browser-executable code has been withdrawn in light of Applicant’s amendment.
Withdrawn Claim Objection
The prior objection to claims 1-3, 9, 15-16, 20-21, 28, 31, 38, 46, 65, 67-68, 80, 83, 115 and 117 because of the minor informalities has been withdrawn in light of Applicant’s amendments.
New Claim Objection
Claims 2, 28 and 31 are objected to because of the following informalities:
Claim 2 c, line 5, recite “reactive to peptides presented on the APCs”. It should be changed to “reactive to the peptides presented on the APCs”.
Claim 28, line 2, recites “the T Cells”, which should be changed to “the T cells”.
Claim 31 c, line 7, recites “reactive peptides presented on the dendritic cells”. It should be changed to “reactive to the peptides presented on the dendritic cells”.
Furthermore, amendments to instant claim 31 c have not been properly submitted. 37 C.F.R. 1.121. Manner of making amendments in application; Section (1)(ii) The full text of any replacement paragraph with markings to show all the changes relative to the previous version of the paragraph. The text of any added subject matter must be shown by underlining the added text. Instant claim 31 is amended to recite a wherein clause at the end of claim 31 c that is not underlined.
Appropriate correction is required.
Withdrawn Claim Rejections - 35 USC § 112
The prior rejection of claims 31, 38, 67-68 and 77 under 35 U.S.C. 112(b) or 35 U.S.C. 112 (pre-AIA ), second paragraph, as being indefinite has been withdrawn in light of Applicant’s amendments.
New Claim Rejections - 35 USC § 112
The following is a quotation of 35 U.S.C. 112(b):
(b) CONCLUSION.—The specification shall conclude with one or more claims particularly pointing out and distinctly claiming the subject matter which the inventor or a joint inventor regards as the invention.
The following is a quotation of 35 U.S.C. 112 (pre-AIA ), second paragraph:
The specification shall conclude with one or more claims particularly pointing out and distinctly claiming the subject matter which the applicant regards as his invention.
Claims 1, 3-4, 6, 9, 12-13, 15-16, 18, 20-21, 26, 28, 38, 40, 46-47, 49, 55-56, 59, 64-65, 67-69, 72, 77-78, 80, 83, 113-115 and 117 are rejected under 35 U.S.C. 112(b) or 35 U.S.C. 112 (pre-AIA ), second paragraph, as being indefinite for failing to particularly point out and distinctly claim the subject matter which the inventor or a joint inventor (or for applications subject to pre-AIA 35 U.S.C. 112, the applicant), regards as the invention.
Claim 1 d, end of line 1, recites “the endogenous TCRs that are reactive to the peptides presented on the APCs”. There is insufficient antecedent basis for this limitation because the preamble recites “the T cells express a T cell receptor (TCR) that recognizes an antigen on the surface of a target cell”, and step c recites “a third population of cells containing T cells reactive to the peptides presented on the APCs”. Thus, claim 1 is silent on endogenous TCRs that are reactive to the peptides presented on the APCs. Claims 3-4, 6, 9, 12-13, 15-16, 18, 20-21, 26, 28, 38, 40, 46-47, 49, 55-56, 59, 64-65, 67-69, 72, 77-78, 80, 83, 113-115 and 117 are rejected as being dependent from claim 1 but not resolving the ambiguity.
Maintained Claim Rejections - 35 USC § 102
Claims 1-4, 6, 9, 12-13, 15, 18, 20, 26, 28, 38, 40, 46-47, 49, 56, 59, 65, 67-69, 72, 77-78, 80, 83, 114-115 and 117 stand rejected under 35 U.S.C. 102 (a)(1) as being anticipated by Parkhurst et al., (Clin Cancer Res. 2017; 23(10): 2491-505. Cited in IDS 04/27/2022) as evidenced by Gros et al., (J Clin Invest. 2014;124(5):2246-2259. Cited in IDS 04/27/2022) for the reason set forth in the Office action mailed on 01/28/2025.
Response to Traversal:
Applicant’s arguments filed on 07/25/2025 are acknowledged.
Applicant argues that (1) the teachings of Gros primarily relate to laboratory analysis of TILs and not preparation of TILs for therapy and treatment to a patient; (2) Gros does not disclose a first and second expansion as recited in the claims (Remarks, p. 16-17).
Applicant’s arguments have been fully considered but they are not persuasive.
In response to Applicant’s first argument that Gros relates to laboratory analysis of TILs but not preparation for therapy (Remarks, p. 16-17), the claim interpretation in prior Office action (p. 9-10) is recited below:
“It is noted that the limitation “for use in a therapeutic cell composition” is directed to an intended use. MPEP 2111.02 II states “If the body of a claim fully and intrinsically sets forth all of the limitations of the claimed invention, and the preamble merely states, for example, the purpose or intended use of the invention, rather than any distinct definition of any of the claimed invention' s limitations, then the preamble is not considered a limitation and is of no significance to claim construction”. Thus, the limitation “for use in a therapeutic cell composition” is reasonably interpreted as the T cells being capable of performing the intended use in a therapeutic cell composition as recited in the preambles. Since Parkhurst teaches adoptive transfer of tumor-infiltrating lymphocytes can mediate regression of metastatic melanoma and can target tumor-specific mutations (p. 2491, end of left col – beginning of right col), the stimulated and expanded tumor-infiltrating lymphocytes taught by Parkhurst are capable of performing the intended use in a therapeutic cell composition as recited in the preambles of claims 1 and 2.”
Therefore, Parkhurst, evidenced by Gros, discloses a method for manufacturing T cells, wherein the T cells express a TCR that recognizes an antigen on the surface of a target cell, and the T cells are capable of performing the intended use in a therapeutic cell composition.
In response to Applicant’s second argument that Gros does not disclose a first and second expansion as recited in the claims (Remarks, p. 16-17), Applicant is reminded that the 102 rejection in the prior Office action is based on Parkhurst et al., as evidenced by Gros et al.. Specifically, Parkhurst teaches a method of manufacturing T cells from tumor biopsies, starting with steps that “T cells from FrTu digests were isolated and expanded as described previously (25)” (p. 2492, right col, para “Isolation of TIL populations”) in which the reference #25 is Gros et al. Thus, Gros evidences steps of isolating (instant step a) and expanding (i.e., a first expansion in instant step b) in claims 1-2 (see prior Office action, p. 10-11). Parkhurst further teaches the method comprises additional steps of co-culturing with APCs (instant step c in claims 1-2), separating APCs from T cells (instant step d of claim 2), sorting cells based on upregulation markers (instant step d of claim 1 and step e of claim 2), and another expansion of the sorted cells (i.e., a second expansion in instant step e of claim 1 and step f of claim 2) (see prior Office action, p. 11-13). Accordingly, Parkhurst, as evidenced by Gros, disclose a first and second expansion as recited in the claims.
Maintained Claim Rejections - 35 USC § 103
Claims 16, 21 and 31 stand rejected under 35 U.S.C. 103 as being unpatentable over Parkhurst et al., (Clin Cancer Res. 2017; 23(10): 2491-505. Cited in IDS 04/27/2022) as evidenced by Gros et al., (J Clin Invest. 2014;124(5):2246-2259. Cited in IDS 04/27/2022), and in view of Liu et al., (J Immunother. 2003; 26(3): 190-201. Prior art of record) for the reason set forth in the Office action mailed on 01/28/2025.
Claims 47, 49 and 64 stand rejected under 35 U.S.C. 103 as being unpatentable over Parkhurst et al., (Clin Cancer Res. 2017; 23(10): 2491-505. Cited in IDS 04/27/2022) as evidenced by Gros et al., (J Clin Invest. 2014;124(5):2246-2259. Cited in IDS 04/27/2022) for the reason set forth in the Office action mailed on 01/28/2025.
Claims 47 and 55 stand rejected under 35 U.S.C. 103 as being unpatentable over Parkhurst et al., (Clin Cancer Res. 2017; 23(10): 2491-505. Cited in IDS 04/27/2022) as evidenced by Gros et al., (J Clin Invest. 2014;124(5):2246-2259. Cited in IDS 04/27/2022), and in view of Gros et al., (J Clin Invest. 2014;124(5):2246-2259. Cited in IDS 04/27/2022) for the reason set forth in the Office action mailed on 01/28/2025.
Claim 113 stands rejected under 35 U.S.C. 103 as being unpatentable over Parkhurst et al., (supra) as evidenced by Gros et al., (supra), and in view of Jin et al., (J Immunother. 2012;35:283-292. Cited in IDS 10/09/2024) and Bajgain et al., (Molecular Therapy - Methods & Clinical Development. 2014; 1: 14015, p. 1-9. Prior art of record) for the reason set forth in the Office action mailed on 01/28/2025.
Response to Traversal:
Applicant’s arguments filed on 07/25/2025 are acknowledged.
Applicant argues that (1) Parkhurst relates to a method for isolating TCRs using isolated neo-antigen reactive T cells as a source to sequence reactive TCRs - not to a method for manufacturing T cells for use in a therapeutic composition, and Gros also is interested in assessing the TCR repertoire of TILs (Remarks, p. 19-20).
Applicant’s argument has been fully considered but is not persuasive. Applicant is referred to the response to 102 rejection as discussed above.
Applicant argues that (2) Both Parkhurst and Gros directly select T cells based on certain markers (e.g. PD-1 or costimulatory markers) from tumor fragments. Unlike Parkhurst or Gros, the instant methods do not include selecting for certain subsets of cells directly from the tumor but rather involve an expansion of T cells outside of the tumor microenvironment prior to enrichment of reactive T cells following their co-culture with APCs, and selection for tumor reactive T cells after expansion and enrichment (Remarks, p. 20, para 1).
Applicant’s argument has been fully considered but is not persuasive.
Applicant is reminded that the step (a) of the instant independent claim 1, claim 2 and claim 31 recites “processing a biological sample containing a population of T lymphocyte cells obtained from a donor subject that has a tumor to produce a first population of T lymphocyte cells”. Thus, the claims clearly encompass selecting T cells from tumor fragments in order “to produce a first population of T lymphocyte cells”. As stated in prior Office action, Gros evidences a step of processing a tumor biopsy to select CD3+CD8+ T cells (prior Office action, p. 10-11 and 21), thus evidences step (a) in the independent claims.
Gros further evidences that the T cells are expanded by T-cell stimulating agents such as anti-CD3 antibody and recombinant human IL-2 for 14-15 days (i.e., the second population of activated T cells), and Parkhurst teaches co-culturing the second population of T cells with APCs (i.e., dendritic cells) that present one or more non-native peptides on a MHC (e.g., HLA-A*0201 or HLA-B*0702) (i.e., the third population of cells containing reactive T cells), and then selecting for tumor reactive T cells based on upregulation markers (such as CD137) after expansion and enrichment (prior Office action, p. 10-12 and 21-23).
Applicant argues that (3) the process is able to enrich for neoantigen reactive T cells with a resulting broad tumor specific TCR diversity and FIG. 24D demonstrates that cell populations contain CD4 and CD8 cells, indicating that class I and class II reactive cells were present in the enriched population (Remarks, p. 20).
Applicant’s argument has been fully considered but is not persuasive.
Parkhurst teaches a method for manufacturing T cells from tumor biopsies of cancer patients and identifies 27 TCRs from 6 patients that recognize 14 neoantigens expressed by autologous tumor cells (see abstract). Thus, the method of Parkhurst is able to enrich for neoantigen reactive T cells with a resulting broad tumor specific TCR diversity, the same as the claimed process.
In regard to cell populations contain both class I and class II reactive CD4 and CD8 cells, as stated supra, Parkhurst, evidenced by Gros, teaches isolating CD8+ T cells. Furthermore, Parkhurst teaches while this study is focused on identifying class I HLA-restricted TCRs from mutation-reactive CD8+ T cells, “tumor-reactive CD4+ T cells have been shown to play a significant role in mediating tumor regression in both animal models and patients. Therefore, in the future, we will also attempt to isolate class II HLA–reactive TCRs for use in gene therapy protocols”, and acknowledges “CD134 (OX40) is more robustly expressed on activated CD4+ T cells than CD137. CD134 is transiently expressed on CD4+ T cells upon antigen stimulation and can be used as a marker to sort mutation-reactive T cells. After stimulation of TILs with DCs electroporated with IVT RNAs or pulsed with long peptides containing mutations, it seems likely we will be able to isolate mutation-reactive class II restricted TCRs from CD137- or CD134-sorted CD4+ T cells” (p. 2503, last full para) (see prior Office action, p. 26). Thus, the method of Parkhurst is able to enrich for both class I and class II reactive CD4 and CD8 cells, the same as the claimed process.
Therefore, the claimed process works as expected as taught by Parkhurst evidenced by Gros.
Applicant argues that (4) in order to arrive at the claimed invention, the skilled person would have to redesign the method of Parkhurst or Gros that requires omitting steps taught in both Parkhurst and Gros to remove the steps of directly [selecting] cells from the tumor using cell surface markers (e.g. PD-1, LAG-3 and TIM-3, 4-lBB (CD 137) or others) and also adding an additional expansion step after selecting cells from a co-culture with peptide loaded APCs. There is absolutely no reason why the skilled person would do this, and certainly no teaching that would provide the skilled person with a reasonable expectation that doing so would result in a method for producing a therapeutic T cell composition (Remarks, p. 20-21).
Applicant’s argument has been fully considered but is not persuasive.
In regard to omitting steps of directly [selecting] cells from the tumor using cell surface markers, as discussed above, the instant claims clearly encompass selecting T cells from the tumor in order “to produce a first population of T lymphocyte cells”. Thus, there is no need to omit steps taught in both Parkhurst and Gros to remove the steps of directly selecting T cells from the tumor.
In regard to adding an additional expansion step after selecting cells from a co-culture with peptide loaded APCs, as stated in prior Office action (see p. 13 and p. 24), Parkhurst teaches sorted T cells (i.e., the fourth population of selected cells) were expanded in media containing anti-CD3 antibody and recombinant human IL2 for 2-3 weeks (p. 2493, left col, last para – right col, 1st para). Thus, Parkhurst has already taught an additional expansion step after selecting cells from a co-culture with peptide loaded APCs and there is no need to add this step.
In regard to no teaching or a reasonable expectation that would result in a method for producing a therapeutic T cell composition, as stated in prior Office action (e.g., p. 9-10) and discussed above, the limitation “for use as a therapeutic cell composition” is reasonably interpreted as the T cells being capable of performing the intended use in a therapeutic cell composition. Since Parkhurst teaches adoptive transfer of tumor-infiltrating lymphocytes can mediate regression of metastatic melanoma and can target tumor-specific mutations (p. 2491, end of left col – beginning of right col), Parkhurst, evidenced by Gros, discloses a method for manufacturing T cells that are capable of performing the intended use in a therapeutic cell composition.
In summary, Applicant’s arguments are not persuasive and thus the prior rejections have been maintained.
Maintained Provisional Double Patenting Rejections
Claims 1-4, 6, 9, 12-13, 15-16, 18, 20-21, 31, 46-47, 49, 55-56, 59, 67-69, 72, 77, 80, 83, 113-115 and 117 stand provisionally rejected on the ground of nonstatutory double patenting as being unpatentable over claims 1-2, 29-32, 34, 36-38, 48-49, 58, 63, 65, 67-69, 71, 74, 76, 78, 82, 86, 89-90, 101-102, 104, 113-114, 123, 129, 134, 137, and 158-159 of copending Application No. 17/599,446 (‘446).
Claims 1-2, 6, 9, 12-13, 15-16, 18, 20-21, 28, 31, 38, 40, 46-47, 49, 55-56, 59, 67-69, 72, 77, 80, 83, 113-115 and 117 stand provisionally rejected on the ground of nonstatutory double patenting as being unpatentable over claims 1, 7-8, 13, 15, 20, 23, 25, 39, 43, 49, 51-52, 55-57, 69, 79-80, 86-88, 94, 102, 104, 106-107, 109, 118-119, 127, 138-139 and 142 of copending Application No. 17/780,497 (‘497).
Response to Traversal:
Applicant’s arguments filed on 07/25/2025 are acknowledged.
Applicant requests that the provisional double patenting rejections be held in abeyance until allowable subject matter is identified (Remarks, p. 22).
This is not found persuasive therefore the rejections are maintained. Applicant is reminded that a complete response to a nonstatutory double patenting (NSDP) rejection is either a reply by applicant showing that the claims subject to the rejection are patentably distinct from the reference claims, or the filing of a terminal disclaimer. Such a response is required even when the nonstatutory double patenting rejection is provisional. See MPEP 804.I.B.1.
Conclusion
Applicant's amendment necessitated the new ground(s) of rejection presented in this Office action. Accordingly, THIS ACTION IS MADE FINAL. See MPEP § 706.07(a). 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 extension fee 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 date of this final action.
No claims are allowed.
Examiner Contact Information
Any inquiry concerning this communication or earlier communications from the examiner should be directed to Jianjian Zhu whose telephone number is (571)272-0956. The examiner can normally be reached M - F 8:30AM - 4PM (EST).
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If attempts to reach the examiner by telephone are unsuccessful, the examiner’s supervisor, James Douglas (Doug) Schultz can be reached on (571) 272-0763. The fax phone number for the organization where this application or proceeding is assigned is 571-273-8300.
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/JIANJIAN ZHU/Examiner, Art Unit 1631
/LAURA SCHUBERG/Primary Examiner, Art Unit 1631