DETAILED ACTION
This action is in reply to papers filed 02/17/2026.
This is a second non-final action. The previous office action has been vacated. Applicant’s arguments, as they pertain to the rejections in the instant Office Action, are addressed after the rejections.
Claims 1-11 are pending and examined herein. Claims 12-16 are cancelled.
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 .
Election/Restrictions
Applicant elected with traverse of Group I, drawn to claims 1-11, in the reply filed on 08/25/2025. As set forth in the Office Action mailed 11/17/2025, the requirement was still deemed proper and was therefore made FINAL. Claims 17-19 are withdrawn from consideration as being drawn to a non-elected invention.
Priority
The instant application is a 371 of PCT/US2021/012444 filed 01/07/2021, which claims benefit of US provisional application 62/957,939 filed 01/07/2020.
Claim Objections
Claim 1 is objected to because of the following informalities: Claim 1 recites the acronym “TCR” in line 2 of step (e). Because this is the first time this acronym is recited in the claims, the acronym should be defined in the claim as “T cell receptor (TCR).” Appropriate correction is required.
Claim Interpretation
Claims 1 and 3, drawn to a method of producing an isolated population of T cells, recite the preamble “for adoptive cell therapy” (lines 1-2 and 20 of claim 1; lines 3-4 of claim 3). The preamble does not impose additional limitations to the method of claim 1 or 3, and therefore is not given patentable weight. See MPEP 2111.02(II).
Claim 3 is drawn to the method of claim 2, further comprising transducing naïve PBMCs with the sequence of the alpha-chain and beta-chain pair of the TCR. It is unclear whether this step falls within steps (a)-(f) of claim 1, or whether this is a parallel step to produce a population of PBMC that is distinct from the population of T cells produced in step (f) of claim 1. The latter interpretation is used for the purposes of examination.
Claim 1 recites the limitation “screening the CD4-CD8- (double negative) T cells” in step (e). The term “screening” is not defined in the specification. In the absence of a definition, the broadest reasonable interpretation of the term “cellular screening” used in the art, which includes different strategies ranging from reporter gene technology to protein fragment complementation assays (Wei, Biophysics Reports, 2021, 7(6): 504-516 at page 505, col 2, para 2), is used for the purposes of examination.
Claim Rejections - 35 USC § 112(d)
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.
Claims 3 and 8-11 are 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.
Claim 3, which depends from claim 2, which in turn depends from claim 1, recites the limitation “transducing naïve peripheral mononuclear cells (PBMC)” (lines 1-2). PBMCs are not recited in the method of claims 1 or 2. Furthermore, “the sequence of the alpha-chain and beta-chain of the TCR” (lines 2-3) is an element of claims 1 and 2, but not the end result. Claims 8-11 depend from claim 3, and are therefore included in the rejection. 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.
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.
Claim(s) 1-2 and 4-7 are rejected under 35 U.S.C. 103 as being unpatentable over Nakauchi (US 2021/0032595 A1), as evidenced by Balch (Archives of Surgery, 1990, 125(2): 200-205), Reiser (Journal of Immunology Research, 2016(1): 8941260), and BIORAD (“High -Throughput Screening for Flow Cytometry,” 2023).
Regarding claims 1-2 and 5: Nakauchi teaches obtaining T cells from a human suffering from a malignant tumor, infection, or autoimmune disease (para 103) (claim 1a), and isolating the T cells by using known procedures, including flow cytometry using an antibody directed to a cell surface marker, including anti-CD4 and anti-CD8 antibodies, and a cell sorter, or by using the secretion of cytokines or the expression of functional molecules as an indicator (para 50-51, 106, 130-135) (claim 1b). Biorad shows that the use of flow cytometry is a type of screening (p 2, para 2) (claim 1e). Nakauchi teaches culturing the separated T cells to produce T cell-induced pluripotent stem cells (T-iPS) (para 113-121) (claim 1c). Nakauchi teaches culturing and differentiating the T-iPS cells into CD4/C8 double negative cells (para 134-135) (claim 1d), wherein the culturing medium comprises IL-7, IL-2, and/or IL-15 (para 128) (claim 5).
Nakauchi teaches an experimental example comprising differentiating the T-iPS cells into CD4/CD8 double negative (DN) cells (para 127-135, 189-191; Comparative Example B1, para 270-286; Fig 49) (claim 1, step d). Nakauchi teaches using flow cytometry using an anti-TCRαβ antibody, an anti-CD3 antibody, an anti-CD4 antibody, and an anti-CD8 antibody, to determine whether or not T cell receptor (TCR) is expressed on the cellular surface of the resulting CD4/CD8 DN cells (para 135; Example B1; Fig 49) (claim 1, step e).
Nakauchi teaches stimulating the TCR of the T-iPS-derived double negative cells to produce double negative and CD8 single-positive T cells having the same pattern of the TCR gene as in their originating human T cells (para 136-147) (claim 1f). Nakauchi teaches sequencing the genomic DNA of the differentiated T cells to detect the TCR gene rearrangement pattern (para 153) (claim 2). Nakauchi teaches isolating the differentiated T cells using flow cytometry directed to a cell surface marker, such as CD4 or CD8 (para 154) (claim 1e). Nakauchi further teaches examining TCRαβ gene rearrangement using multiplex PCR (para 265-268) (claim 1e, claim 2).
With respect to the order of steps in claim 1, it is noted that the courts have held that any order of performing process steps is prima facie obvious in the absence of new or unexpected results (In re Gibson, 39 F.2d 975, 5 USPQ 230 (CCPA 1930); Ex parte Rubin, 128 USPQ 440 (Bd. App. 1959)). See MPEP §2144.04 (IV)(C). Therefore, the claimed order of steps is an obvious variant of the steps of the cited prior art.
Regarding claim 4: Nakauchi is silent as to the T cells being tumor infiltrating lymphocytes (TIL). However, Nakauchi teaches that the T cell can be obtained from a human suffering from a malignant tumor (para 103), and that the T cell can be isolated from a lesion site tissue (para 106).
Balch shows the presence of TILs in 120 samples of human cancers, including melanoma, renal cell carcinoma, breast cancer, sarcoma, and colon cancer (Abstract). Therefore, the T cells isolated from a lesion site tissue from a patient with malignant tumor would contain TILs.
Regarding claims 6-7: Nakauchi is silent as to the antigen of interest being a cancer antigen. However, Nakauchi teaches sequencing the TCR-alpha and TCR-beta mRNAs in the differentiated CD8 single-positive cell lines produced according to the above method (para 298). The rearrangement patterns of the TCR genes in the differentiated T cells were identical to those exhibited by their originating CD8 T-cell clone H25-4 (para 298). H25-4 T cells are cytotoxic T cells (CTLs) (para 66, 105).
Reiser shows that CD8+ cytotoxic lymphocytes, including tumor-infiltrating lymphocytes, recognize tumor antigens (Abstract). Therefore, the TCR alpha-chain and beta-chain pair of the differentiated T cells taught in Nakauchi would have antigenic specificity for a cancer antigen.
Claim(s) 1-3 and 8-11 are rejected under 35 U.S.C. 103 as being unpatentable over Nakauchi (US 2021/0032595 A1), in view of Yang (Journal of Immunotherapy, 2008, 31(9): 830-839).
The teachings of Nakauchi are set forth above. Nakauchi renders obvious claims 1 and 2.
Nakauchi does not teach transducing naïve peripheral blood mononuclear cells (PBMC) with the sequence of the alpha-chain and beta-chain pair of the TCR to provide an isolated population of cells.
Yang teaches the use of lentiviral vectors (claims 8-10) harboring specific anti-tumor T-cell receptor (TCR) to transduce peripheral blood lymphocytes (PBL), which are a type of PBMC (claims 3, 11) (Abstract). Yang teaches that spinoculation in the presence of protamine sulfate represents the most efficient and economical approach to transduce a large number of PBLs (Abstract). TCR- transduced PBLs mediated specific anti-tumor activities including IFN-γ release and cell lysis (Abstract).
It would have been prima facie obvious to a person of ordinary skill in the art before the effective filing date of the invention to have modified the method of Nakauchi by transducing naïve PBLs with the sequence of the alpha-chain and beta-chain pair of the TCR to provide an isolated population of cells, as taught in Yang. One of ordinary skill in the art would have been motivated to make this modification because Yang teaches that transduction of PBLs with lentiviral vectors harboring specific anti-tumor TCRs allows for the establishment of clinical-scale lentiviral transduction of PBL (Abstract). One of ordinary skill in the art would have had a reasonable expectation of successfully making this modification because Nakauchi teaches obtaining sequences encoding the alpha-chain and beta-chain pair of the TCR, and Yang teaches that PBLs, which are PBMCs, can be transduced with lentiviral vectors harboring TCR sequences.
Response to Arguments
Regarding rejections of claims 1-11 under 35 U.S.C. 103
Applicant argues: The Office Action alleges that Nakauchi (paragraph [0154]) teaches isolating the differentiated T cells using flow cytometry directed to a cell surface marker, such as CD4 or CD8, and that T cells having a desired antigen specificity can be purified using an MHC tetramer to which the desired antigen has been attached. The Office appears to characterize these teachings as the "screening" of part (e) of claim 1. This is incorrect.
Paragraph [0154] of Nakauchi does not teach screening the CD4-CD8- (double negative) T cells to identify one or more CD4-CD8- (double negative) T cells that comprise a TCR alpha-chain and beta-chain pair having antigenic specificity for an antigen of interest, as claimed. Rather, the cells being subjected to flow cytometry or purification using an MHC tetramer in paragraph [0154] of Nakauchi are already differentiated past the DN stage. The targeting of CD4 or CD8 (i.e., in the singular) in paragraph [0154] of Nakauchi indicates that these are single positive (not double negative) cells undergoing flow cytometry or purification using an MHC tetramer in Nakauchi.
In response: The Applicant’s arguments have been fully considered, but are not persuasive. As set forth in the body of the rejection above, Nakauchi teaches in paragraph [0135] that “Whether or not T cell receptor (TCR) is expressed on the cellular surface of the resulting CD4/CD8 DN cells can be assessed by flow cytometry using an anti-TCRαβ antibody, an anti-CD3 antibody, an anti-CD4 antibody, and an anti-CD8 antibody.” Thus, the teachings of Nakauchi does not preclude the identification of CD4-CD8- (double negative) T cells.
Applicant argues: One of ordinary skill in the art would understand that the term "screening" in part (e) of claim 1 means "testing" the DN cells for the function of "antigenic specificity for an antigen of interest." An Example of such screening is described in Example 4 of the present application.
Nakauchi fails to teach screening (namely, testing) the CD4-CD8- (double negative) T cells to identify one or more CD4-CD8- (DN) T cells that comprise a TCR alpha-chain and beta-chain pair having antigenic specificity for an antigen of interest, as claimed. Nakauchi only discloses testing the function of redifferentiated CD8 SP cells (see Nakauchi, example B2). Nor would there have been any rationale for one of ordinary skill in the art to modify the method of Nakauchi to screen CD4-CD8- (double negative) T cells for a TCR alpha-chain and beta-chain pair having antigenic specificity for an antigen of interest, as claimed.
In response: The Applicant’s arguments have been fully considered, but are not persuasive. “Screening” is not defined in the instant specification. Therefore, the broadest reasonable interpretation of the limitation “screening” includes the use of flow cytometry to assess whether or not TCR is expressed on the cellular surface of the resulting CD4/CD8 DN cells, as taught in Nakauchi (para 135). In the absence of a definition, “screening” is not limited to “testing the DN cells for the function of antigenic specificity for an antigen of interest,” as asserted by the Applicant.
Applicant argues: The inventors of the present application showed that TIL-iPSC-derived double negative T cells show a higher affinity to target peptides than other iPSC-derived T cells
previously generated (double positive or CDS single positive T cells) (see Example 3 of the present application and paragraph [0018]). The inventors have shown, for the first time, that the generation of TIL-iPSC and their further functional validation in double negative T cell stage can serve to develop an improved screening method to find tumor-antigen specific TCRs from bulk populations of TILs (specification, paragraph [0018]).
In response: The Applicant’s arguments have been fully considered, but are not persuasive. In response to applicant's argument that the references fail to show certain features of the invention, it is noted that the features upon which applicant relies (i.e., that TIL-iPSC-derived double negative T cells show a higher affinity to target peptides than other iPSC-derived T cells previously generated) are not recited in the rejected claim(s). Although the claims are interpreted in light of the specification, limitations from the specification are not read into the claims. See In re Van Geuns, 988 F.2d 1181, 26 USPQ2d 1057 (Fed. Cir. 1993).
Applicant argues: Balch, Reiser, and Yang fail to make up for the deficiencies of Nakauchi. Balch, Reiser, and Yang also fail to teach screening the CD4-CD8- (double negative) T cells to
identify one or more CD4-CD8- (DN) T cells that comprise a TCR alpha-chain and beta-chain pair having antigenic specificity for an antigen of interest, as claimed.
In response: The Applicant’s arguments have been fully considered, but are not persuasive. As set forth in the body of the rejections above, Balch, Reiser, and Yang are not upon for teachings regarding screening the CD4-CD8- (double negative) T cells to identify one or more CD4-CD8- (DN) T cells that comprise a TCR alpha-chain and beta-chain pair having antigenic specificity for an antigen of interest.
Conclusion
Any inquiry concerning this communication or earlier communications from the examiner should be directed to Risa Takenaka whose telephone number is (571)272-0149. The examiner can normally be reached M-F, 12-7 EST.
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/RISA TAKENAKA/Examiner, Art Unit 1632
/TITILAYO MOLOYE/Primary Examiner, Art Unit 1632
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