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and the fee set forth in 37 CFR 1.17(e) has been timely paid, the finality of the previous Office action has been withdrawn pursuant to 37 CFR 1.114.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 May 30, 2026 has been entered. By way of this submission, Applicant has amended claim 1 and cancelled claim 6.
Claims 1-5, 7-10 and 16-32 are pending in the application. Claims 7-10 and 16-28 remain
withdrawn from consideration, pursuant to the Restriction Requirement mailed January 10, 2025.
Claims 1-5 and 29-32 are therefore under examination before the Office.
The rejections of record can be found in the previous Office action, dated December 31, 2025.
Response to Arguments
Applicant argues that the amendments to claim 1 have addressed the previous indefiniteness issue.
Applicant's arguments in view of the amendments to the claims have been considered fully but are not persuasive.
Clause b) of claim 1 recites: "fragmenting the first and second cancerous tissue samples into a first portion and a second portion and culturing said first portion". It is unclear which first portion is to be cultured, the first portion of the first cancerous tissue sample, the first portion of the second cancerous tissue sample, or both. Likewise, clause d) of claim 1 recites "subjecting the second portion of the cancerous tissue sample to sequencing". It is unclear which second portion is to be subjected to sequencing, the second portion of the first cancerous tissue sample, the second portion of the second cancerous tissue sample, or both.
The claim therefore remains indefinite due to the ambiguity as to which tissue sample portion is to be used in each step.
The rejection of claims 1-5 and 29-32 under 35 U.S.C 112(b) is therefore maintained.
Applicant argues that the cited references to Tran (US20170218042A1), Yelensky (WO2019050994A1), and Slanetz (WO2018005712A1) do not teach every aspect of the claims as amended; specifically, the references do not teach TCRVβ sequencing.
Applicant's arguments in view of the amendments to the claims have been considered fully but are not persuasive.
Tran teaches performing TCR-Vβ deep sequencing on genomic DNA isolated from tumor tissue (para. 0100).
Tran also teaches performing sequencing on the TCR-Vβ sequences of TILs that reacted in co-cultures of neoantigens (para. 0132).
The rejection of claims 1-2, 6, 29, and 31 under 35 U.S.C. 102 over Tran is withdrawn.
The rejection of claims 1-5, 29, and 31-32 under 35 U.S.C. 103 over Tran in view of Yelensky is maintained.
The rejection of claim 30 under 35 U.S.C. 103 over Tran in view of Yelensky and further in view of Slanetz is maintained.
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 1-5 and 29-32 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.
Clause b) of claim 1 recites: "fragmenting the first and second cancerous tissue samples into a first portion and a second portion and culturing said first portion". It is unclear which first portion is to be cultured, the first portion of the first cancerous tissue sample, the first portion of the second cancerous tissue sample, or both.
Likewise, clause d) of claim 1 recites "subjecting the second portion of the cancerous tissue sample to sequencing". It is unclear which second portion is to be subjected to sequencing, the second portion of the first cancerous tissue sample, the second portion of the second cancerous tissue sample, or both.
For the purpose of claim construction, any culturing or any sequencing of any sample is considered to read upon the claims.
The following is a quotation of 35 U.S.C. 112(d):
(d) REFERENCE IN DEPENDENT FORMS.—Subject to subsection (e), a claim in dependent form shall contain a reference to a claim previously set forth and then specify a further limitation of the subject matter claimed. A claim in dependent form shall be construed to incorporate by reference all the limitations of the claim to which it refers.
The following is a quotation of pre-AIA 35 U.S.C. 112, fourth paragraph:
Subject to the following paragraph [i.e., the fifth paragraph of pre-AIA 35 U.S.C. 112], a claim in dependent form shall contain a reference to a claim previously set forth and then specify a further limitation of the subject matter claimed. A claim in dependent form shall be construed to incorporate by reference all the limitations of the claim to which it refers.
Claim 2 is rejected under 35 U.S.C. 112(d) or pre-AIA 35 U.S.C. 112, 4th paragraph, as being of improper dependent form for failing to further limit the subject matter of the claim upon which it depends, or for failing to include all the limitations of the claim upon which it depends. This is a new grounds of rejection, necessitated by Applicant’s amendments to the claims.
Claim 2 recites that the "sequencing applied to the second portion of the tissue sample is whole exosome sequencing or RNA sequencing". This is broader than what is recited in claim 1, as claim 1 specifies that the sequencing is TCRVβ sequencing. TCRVβ sequencing only examines the sequences of the variable beta region of T-cell receptors, whereas whole exome sequencing examines the entire exome, and RNA sequencing examines all RNA in the transcriptome. Applicant's arguments in the response dated May 30, 2026 also state that TCRVβ sequencing is a completely different sequencing technique and provides entirely different information that whole genome sequencing. As such, claim 2 impermissibly broadens the scope of claim 1.
Applicant may cancel the claim(s), amend the claim(s) to place the claim(s) in proper dependent form, rewrite the claim(s) in independent form, or present a sufficient showing that the dependent claim(s) complies with the statutory requirements.
In the event the determination of the status of the application as subject to AIA 35 U.S.C. 102 and 103 (or as subject to pre-AIA 35 U.S.C. 102 and 103) is incorrect, any correction of the statutory basis (i.e., changing from AIA to pre-AIA ) for the rejection will not be considered a new ground of rejection if the prior art relied upon, and the rationale supporting the rejection, would be the same under either status.
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 1-6, 29, and 31-32 are rejected under 35 U.S.C. 103 as being unpatentable over Tran (US20170218042A1) in view of Yelensky (WO2019050994A1).
Tran teaches that “TILs for the patient’s first treatment were generated…” from “…resected tumors were minced into approximately 1-2 mm fragments and individual fragments were placed in wells of a 24-well plate containing 2 ml of complete media (CM) containing high dose IL-2” (para. 0082 and 0120). Tran also teaches that the patient “underwent a non-myeloablative lymphodepleting regimen composed of cyclophosphamide and fludarabine prior to receiving” a treatment of T cell immunotherapy (para. 0082). This indicates that sample was taken before the combination therapy of cyclophosphamide and fludarabine was administered, as Tran teaches that culturing the T cells takes several weeks.
Tran further teaches that tumors “were resected and used as a source for whole-exomic sequencing and generation of T cells for treatment,” and the identification of “somatic mutations identified by whole-exome sequencing” of a tumor sample (i.e., neoantigens) (para. 0106).
Tran further teaches performing TCR-Vβ deep sequencing on genomic DNA isolated from tumor tissue (para. 0100). Tran also teaches performing sequencing on the TCR-Vβ sequences of TILs that reacted in co-cultures of neoantigens (para. 0132).
Tran further teaches that neoantigen constructs were “co-culture[d] with TIL to determine whether any of the processed and presented mutated antigens were recognized by TIL… as demonstrated by up-regulation of the activation markers OX40 and 4-1BB” (para. 0109).
Tran also teaches that reactive TILs indicate that the putative neoantigen co-cultured with the TILs is a neoantigen (para. 0110-0114). Tran further teaches culturing peripheral blood T cells with cancer neoantigens, and selecting T cells that have antigenic specificity for said neoantigen (para. 0039-0040).
Tran further teaches that the cancer sample may be taken from a primary tumor (para. 0030), which is pertinent to claim 29.
Tran further teaches that the patient has lung cancer (para. 0076 and 0106), which is pertinent to claim 31.
Tran also teaches that such TILs are useful in treating cancer (e.g., para. 0145).
However, Tran does not teach non-small cell lung cancer or culturing T cells isolated from peripheral blood mononuclear cells with neoantigens.
Yelensky teaches a method of identifying T cells that can bind neoantigens by co-culturing the T-cells with one or more of the neoantigens in the subset under conditions that expand the T-cells (para. 00154), which is pertinent to claim 5.
Yelensky further teaches culturing peripheral blood mononuclear cells (PBMCs) with cancer neoantigens to expand neoantigen-reactive T-cells (para. 00475), which is pertinent to claim 3.
Yelensky further teaches selecting (i.e., isolating) T cells from a sample with magnetic-activated cell sorting (MACS) (para. 00557) or FACS sorting (para. 00563-00564), which is pertinent to claim 4.
Yelensky further teaches that cancers with a high mutational burden, such as non-small cell lung cancer (NSCLC), are particularly attractive targets of T-cell therapy based on tumor-specific neoantigens given the relatively greater likelihood of neoantigen generation (para. 0001), which is pertinent to claim 32.
It would have been prima facie obvious for a person of ordinary skill in the art as of the effective filing date to combine the teachings of Tran and Yelensky to arrive at the claimed invention. An ordinary artisan would have been motivated to do so, and have a reasonable expectation of success, since both Tran and Yelensky are both concerned with TIL therapies that target neoantigens. Methods of expanding neoantigen-specific TILs were known in the art, according to Tran. Yelensky teaches that PBMCs are also useful in the generation of neoantigen-specific TILs, especially for the treatment of non-small cell lung cancer due to the abundance of neoantigens. One of ordinary skill would be readily able to combine the PBMCs of Yelensky with the methods of Tran, with each component of the combination performing its known, usual function, and the combination would have yielded nothing more than predictable results.
Claim 31 is rejected under 35 U.S.C. 103 as being unpatentable over Tran (US20170218042A1) and Yelensky (WO2019050994A1) as applied to claim 1 above, and further in view of Slanetz (WO2018005712A1).
The teachings of Tran and Yelensky have been described supra. However, Tran does not teach a recurring tumor.
Slanetz teaches a method of making a composition useful in adoptive cell therapy enriched for T cells that are reactive to one or more target antigens, comprising obtaining an initial cell population comprising T-cells, stimulating the T-cells by exposing the cell population to one or more target antigens, and testing the cell population for antigen-specific reactivity (para. 0007). Slanetz further teaches that the antigen used may be a cancer neoantigen (para. 0014).
Slanetz further teaches that this method may be useful to generate neoantigens from primary and recurrent tumors (para. 0248).
It would have been prima facie obvious for a person of ordinary skill in the art as of the effective filing date to combine the teachings of Tran, Yelensky, and Slanetz to arrive at the claimed invention. An ordinary artisan would have been motivated to do so, and have a reasonable expectation of success, since all of Tran, Yelensky, and Slanetz are both concerned with TIL therapies that target neoantigens. Methods of expanding neoantigen-specific TILs were known in the art, according to Tran and Yelensky. Slanetz teaches that it is useful to use either primary or recurring tumors for the purpose of generating neoantigens that can be used to culture TILs. One of ordinary skill
would be readily able to combine the recurrent tumors of Slanetz with the methods of Tran and Yelensky, with each component of the combination performing its known, usual function, and the combination would have yielded nothing more than predictable results.
Conclusion
The prior art made of record and not relied upon is considered pertinent to applicant's disclosure. Pardoll (WO2018071796A2) teaches the use of next-generation sequencing of TCR-Vβ CDR3 regions to measure of antigen-specific T cell expansion in response to co-culture with cancer neoantigens (Example 1: pages 40-42, and Figure 1).
No claim is allowed.
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/PETER JOHANSEN/Examiner, Art Unit 1644
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