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
The text of those sections of Title 35, U.S. Code not included in this action can be found in a prior Office action.
This Action is in response to the papers filed on August 18, 2025 for a Request for Continued Examination. 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and the fee set forth in 37 CFR 1.17(e) has been timely paid, the finality of the previous Office action has been withdrawn pursuant to 37 CFR 1.114.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 August 18, 2025 has been entered.
Pursuant to the amendment filed on August 18, 2025, claims 46- 50 and 54-66 are currently pending. Claims 46, 56-59, and 64 have been amended and claim 66 is newly filed in Applicant' s amendment filed on August 18, 2025. No claims have been cancelled in the amendment.
Applicant's election without traverse of Group II, claims 46 – 50, drawn to a method of producing an antigen specific immunoresponsive cell; and the election of Species without traverse as follows:
Species (A): the election of group II has rendered the species election A moot;
Species (B1): an endogenous locus (claim 48); and
Species (B2): a TRAC locus (claim 48), and
Species (C): the election of group II has rendered the species election C moot, in the reply filed February 21, 2024 was previously acknowledged.
Claims 49, 50, and 65 were previously withdrawn as being directed to a non-elected species, withdrawn from further consideration pursuant to 37 CFR 1.142(b) as being drawn to a non-elected species, there being no allowable generic or linking claim.
The restriction requirement between Groups I-IV as set forth in the Office Action dated October 13, 2023 was previously made FINAL in the Office Action dated April 18, 2024, and still deemed proper. The claims will be examined insofar as they read on the elected species.
Therefore, claims 46–48, 54–64, and 66 currently under examination to which the following grounds of rejection are applicable.
Priority
The instant application filed August 11, 2020, is a CONTINUATION of PCT/US/19/17525, filed on February 11, 2019, which claims benefit to PROVISIONAL application 62/629,072, filed February 11, 2018.
The instant application has the following child applications: DIVISIONAL Application 17/075,142 filed on October 20, 2020, now issued patent, US 11,229,669, issued January 25, 2022; CONTINUATION Application 17/505,515 filed on October 19, 2021, now issued patent, US 12,036,244, issued July 16, 2024.
Information Disclosure Statement
The information disclosure statements (IDS) submitted on April 18, 2022, April 20, 2025, and July 17, 2025 were filed. The submissions are in compliance with the provisions of 37 CFR 1.97. Accordingly, the information disclosure statements are being considered by the examiner.
Response to Arguments
Withdrawn Objections/Rejections in response to Applicants’ arguments or amendments:
Claim Objections
In view of Applicants’ amendment to the claims dated August 18, 2025, wherein claims 58 and 59 have been amended, the objection to claims 58-61 are withdrawn.
Claim Rejections - 35 USC § 103
In view of Applicants’ amendment to the claims dated August 18, 2025, wherein claims 46, 56-59, and 64 have been amended, the rejection to claims 46 – 48, 54 – 60, and 62 – 64 rejected under 35 U.S.C. 103 as being unpatentable over Zhao et al. in view of Larvor et al., have been withdrawn. The rejections have been withdrawn in view of the amendments of the claims, wherein claim 46 further specifies the structure of the vector comprising a nucleic acid molecule encoding a recombinant T cell receptor (TCR), wherein the recombinant TCR comprises either groups (i) and (ii). These groups include two different antigen binding groups in different order for which the prior art references do not teach.
After searching the prior art in view of the amendments to the claims, and in view of the recent Remarks, the prior art does not teach the entirety of claim 46. Hale et al. (Molecular therapy Methods & clinical development 4 (2017): 192-203) teaches using homology-directed recombination (HDR) for engineering TCR, in which the TRAC locus was targeted for the insertion of a second generation CD19 CAR via megaTAL nuclease and AAV donor template . However, in doing so TCR-negative CAR T cells are produced in which the cells are generally CD3 negative (Fig. 3; abstract). The reference is different in that the structure of the antigen binding sites are different despite the integration of a CAR into the TRAC locus, wherein the instant application utilizes the TCR alpha and beta constant chains in combination with CAR heavy and light chains while maintaining CD3 expression.
MacLeod et al. (Molecular Therapy 25.4 (2017): 949-961) is similar to Hale by targeting the TRAC locus with a CD19 CAR, but differs with an engineered, site specific endonuclease based on the I-CreI homing endonuclease from Chlamydomonas reinhardtii and AAV donor template (p 2, col 2). The outcome was eliminated expression of the endogenous TCR, with expression of the CAR transgene (abstract). The reference is different from the instant application in the process of engineering, the structure of the engineered TCR/CAR, and the outcomes of eliminating expression of the TCR.
Applicants’ arguments are moot in view of the withdrawn rejection.
New Grounds of Rejection:
Claim Rejections - 35 USC § 112
The following is a quotation of the first paragraph of 35 U.S.C. 112(a):
(a) IN GENERAL.—The specification shall contain a written description of the invention, and of the manner and process of making and using it, in such full, clear, concise, and exact terms as to enable any person skilled in the art to which it pertains, or with which it is most nearly connected, to make and use the same, and shall set forth the best mode contemplated by the inventor or joint inventor of carrying out the invention.
The following is a quotation of the first paragraph of pre-AIA 35 U.S.C. 112:
The specification shall contain a written description of the invention, and of the manner and process of making and using it, in such full, clear, concise, and exact terms as to enable any person skilled in the art to which it pertains, or with which it is most nearly connected, to make and use the same, and shall set forth the best mode contemplated by the inventor of carrying out his invention.
Claims 46-48, 54-64, and 66 are rejected under 35 U.S.C. 112(a) or 35 U.S.C. 112 (pre-AIA ), first paragraph, as failing to comply with the written description requirement.
The claim(s) contains subject matter which was not described in the specification in such a way as to reasonably convey to one skilled in the relevant art that the inventor or a joint inventor, or for applications subject to pre-AIA 35 U.S.C. 112, the inventor(s), at the time the application was filed, had possession of the claimed invention.
The MPEP states that the purpose of the written description requirement is to ensure that
the inventor had possession, as of the filing date of the application, of the specific subject matter later claimed by him. The courts have stated:
“To fulfill the written description requirement, a patent specification must describe an invention and do so in sufficient detail that one skilled in the art can clearly conclude that “the inventor invented the claimed invention.” Lockwood v. American Airlines, Inc., 107 F.3d 1565, 1572, 41 USPQ2d 1961, 1966 (Fed. Cir. 1997); In re Gostelli, 872 F.2d 1008, 1012, 10 USPQ2d 1614, 1618 (Fed. Cir. 1989) (“[T]he description must clearly allow persons of ordinary skill in the art to recognize that [the inventor] invented what is claimed.”). Thus, an applicant complies with the written description requirement “by describing the invention, with all its claimed limitations, not that which makes it obvious,” and by using “such descriptive means as words, structures, figures, diagrams, formulas, etc., that set forth the claimed invention.” Lockwood, 107 F.3d at 1572, 41 USPQ2d at 1966.” Regents of the University of California v. Eli Lilly & Co., 43 USPQ2d 1398.
Further, for a broad generic claim, the specification must provide adequate written description to identify the genus of the claim. In Regents of the University of California v. Eli Lilly & Co. the court stated:
“A written description of an invention involving a chemical genus, like a description of a chemical species, ‘requires a precise definition, such as by structure, formula, [or] chemical name,’ of the claimed subject matter sufficient to distinguish it from other materials.” Fiers, 984 F.2d at 1171, 25 USPQ2d 1601; In re Smythe, 480 F.2d 1376, 1383, 178 USPQ 279, 284985 (CCPA 1973) (“In other cases, particularly but not necessarily, chemical cases, where there is unpredictability in performance of certain species or subcombinations other than those specifically enumerated, one skilled in the art may be found not to have been placed in possession of a genus ...”) Regents of the University of California v. Eli Lilly & Co., 43 USPQ2d 1398.
The MPEP further states that if a biomolecule is described only by a functional characteristic, without any disclosed correlation between function and structure of the sequence, it is “not sufficient characteristic for written description purposes, even when accompanied by a method of obtaining the claimed sequence.” MPEP § 2163. The MPEP does state that for a generic claim the genus can be adequately described if the disclosure presents a sufficient number of representative species that encompass the genus. MPEP § 2163. If the genus has a substantial variance, the disclosure must describe a sufficient variety of species to reflect the variation within that genus. See MPEP § 2163. Although the MPEP does not define what constitute a sufficient number of representative species, the courts have indicated what do not constitute a representative number of species to adequately describe a broad generic. In Gostelli, the courts determined that the disclosure of two chemical compounds within a subgenus did not describe that subgenus. In re Gostelli, 872, F.2d at 1012, 10 USPQ2d at 1618.
The MPEP lists factors that can be used to determine if sufficient evidence of possession has been furnished in the disclosure of the Application. These include “level of skill and knowledge in the art, partial structure, physical and/or chemical properties, functional characteristics alone or coupled with a known or disclosed correlation between structure and function, and the method of making the claimed invention. Disclosure of any combination of such identifying characteristics that distinguish the claimed invention from other materials and would lead one of skill in the art to the conclusion that the applicant was in possession of the claimed species is sufficient.” MPEP § 2163. While all of the factors have been considered, a sufficient amount for a prima facie case are discussed below.
Claim 46 is directed to a method for producing an antigen-specific immunoresponsive cell, the method comprising transducing an immunoresponsive cell with a vector comprising a nucleic acid molecule encoding a recombinant T cell receptor (TCR), wherein the recombinant TCR comprises
(i) a first antigen-binding chain comprising an antigen-binding fragment of a heavy chain variable region (VH) of an antibody and a T cell receptor a chain constant (TRAC) polypeptide, and a second antigen-binding chain comprising an antigen-binding fragment of a light chain variable region (VL,) of the antibody and a T cell receptor B chain constant (TRBC) polypeptide; or ,
(ii) a first antigen-binding chain comprising an antigen-binding fragment of a heavy chain variable region (VH) of an antibody and a T cell receptor B chain constant (TRBC) polypeptide, and a second antigen-binding chain comprising an antigen-binding fragment of a light chain variable region (VL) of the antibody, and a T cell receptor a chain constant (TRAC) polypeptide; wherein the first and the second antigen-binding chains bind to an antigen; and thereby obtaining the antigen-specific immunoresponsive cell.
Claims 47, 48 and 54 further specify that gene locus that is modified in in which it is endogenous to the cell (claim 47), and more specific gene loci within the endogenous cell of which the TRAC locus and TRBC locus are included (claim 48, 54). Claims 55-57, and 67 further specify the immunoresponsive cell across different cell types, of which the cell is limited to a T cell in claim 57. Claims 62 and 63 further specify the vector as a viral vector (claim 62) and more specifically a retroviral vector (claim 63). Claim 64 specifies how the endogenous TCR is modified, by stating “disrupting or abolishing endogenous expression of a TCR comprising a native TCR α chain and/or a native TCR β chain, thereby preventing mispairing between the recombinant TCR and a native α chain and/or a native TCR β chain in the immunoresponsive cell.
In analyzing whether the written description requirement is met, it is first determined whether a representative number of species have been described by their complete structure. Next, it is determined whether a representative number of species have been sufficiently described by other relevant identifying characteristics.
Teachings within the Specification:
In view of the cell type(s) to be engineered, the vector(s) used, the gene editing technology(s) employed, and locus/loci that are targeted for engineering, the Specification states the following:
Cell-type: The immunoresponsive cell is selected from the group consisting of a T cell, a cytotoxic T lymphocyte (CTL), a regulatory T cell, a Natural Killer T (NKT) cell, a human embryonic stem cell, and a pluripotent stem cell from which lymphoid cells may be differentiated, and in certain embodiments, the immunoresponsive cell is autologous (p 5). The entirety of the Figures depict gene targeting as occurring in T cells.
Gene Editing & Vectors: The Figures depict gene targeting being conducted with CRISPR-Cas9 and a retrovirus vector, specifically an AAV vector, e.g. AAV6 (Figures 1A, 4A, 6A, and 10A). “Recombinant receptors can also be derived or obtained using transposases or targeted nucleases (e.g. Zinc finger nucleases, meganucleases, or TALE nucleases, CRISPR).” (p 56). Sections 4 and 6 describe using different vectors and editing technologies, respectively, to obtain modified TCRs.
Targets/Loci: The gene cassette is inserted in an endogenous gene locus that are a CD3δ locus, a CD3ε locus, a CD247locus, a B2Mlocus, a TRAC locus, a TRBC locus, a TRDC locus and/or a TRGC locus, and further limited to a TRAC locus and/or a TRBC locus (p 2, 5). Section 6 describes gene editing methods, and more specifically in section 6.1 particular T cell receptor loci for targeting. “In certain embodiments, the CRISPR system targets exon 1 of a human TRAC locus. In certain embodiments, the CRISPR system comprises a guide RNA (gRNA) that targets exon 1 of a human TRAC locus” (p 59).
Working Examples:
The working examples, i.e. Examples 1 & 2, begin on page 73, and are reflected in the Figures, i.e. Fig. 1A-10C. Example 1: “Targeting T cells with endogenous non-HLA restricted T cell
receptor/CD3 complexes” describes using CRISPR-Cas9 targeting of the TRAC locus in exon 1 in which the gene cassette is expressed from the endogenous TCR α promoter with concomitant disruption of the TCR alpha gene expression, leading to lack of TCR expression at the cell surface, stating “CAR gene targeting at the TRAC locus was accomplished through homologous recombination (HR) by using a site-specific nuclease (e.g. CRISPR/Cas9) and an AAV donor template.” The obtained HLA-Independent TCR-based Chimeric Antigen Receptor (i.e., HIT-CAR, FvTCR or HI-TCR) is schematically represented in Fig. 1A in addition to Fig. 1B depicting integration in the TRAC locus via CRISPR-Cas with an AAV donor template. Fig. 2A depicts the process of producing the HIT-CARs, for which the claims are directed to, have a yield of 65% of T cells with these vectors with activity being maintained in vitro and in vivo as seen in Fig. 2B. Fig. 3A-3E describe different targets other than the CD19 target, wherein Fig. 3B have examples of targeting the TRAC and TRBC loci. Example 1 further describes that TCR gene editing has applications in T-iPS- derived T cell, stating “T-iPS cells are pluripotent stem cells obtained through reprogramming of peripheral T lymphocytes. These T-iPS cells therefore contain a rearranged T-cell receptor, either an αβ or a γδ TCR, which can be modified using gene-editing technologies.”
The working examples point to only support with CRISPR-Cas editing that targets the TRAC locus or TRBC locus with an AAV vector within T cells.
Prior Art:
In reference to using different gene editing technologies, the prior art is extensive in a diversity of approaches. Maeder et al. describes technologies like zinc finger nucleases (ZFNs), transcription activator-like effector (TALE)-nucleases (TALENs), meganucleases, and CRISPR/Cas for providing different mechanisms of gene editing via homology directed repair, of which the instant application is directed, and nonhomologous end-joining (NHEJ), which is error-prone and often results in insertions and/or deletions (indels) at the site of the break (Fig. 1, 2). The review further explores each nuclease; and describes how each are targeted nucleases “cleaving the DNA in a site-specific manner while mitigating, or ideally preventing, collateral damage to the rest of the genome”. (p 434). Furthermore, the delivery of the gene editing technology used different approaches, wherein “For many applications, viral vectors are still the optimal vehicle to maximize the efficiency of delivery while minimizing cytotoxicity. In particular, lentiviral vectors have been optimized for highly efficient transduction of T cells and HSCs; however these vectors also integrate into the genome and stably express their transgene cargo. In order to take advantage of the efficiency of lentiviral transduction while limiting the duration of nuclease expression in target cells, integrase-deficient lentiviral vectors have been used to transiently deliver genome-editing tools to target cells” (p 434). Furthermore, lentiviral vector are limited by packaging constraints of ~4.8 kb of DNA, and in view of nucleases TALENs and Cas9 are often restricted, and subsequently requiring multiple vectors for delivery of machinery/constructs. The review highlights that a large pool of gene editing technologies wherein nucleases are restricted to cleaving the DNA in a site-specific manner, and based on size of the constructs for delivery.
In view of modifying TCR, as described above in the withdrawn rejections section, the majority of the TCR editing studies have employed gene knockouts of different loci other than the TRAC and/or TRBC loci. Wherein the TRAC locus is edited, it was done with different nucleases than the instant CRSIPR-Cas9, yet led to gene silencing/knockout. MacLeod states, “Gene editing of T cells to eliminate TCR expression has been reported using site-specific endonucleases, including TALENs, Mega-TALs, zinc-finger nucleases (ZFNs), and CRISPR/Cas9. (p 949, col 2). MacLeod et al. teaches an engineered, site specific endonuclease based on the I-CreI homing endonuclease from Chlamydomonas reinhardtii to enable editing of the TRAC gene, specifically a single-chain variant of I-CreI, called TRC1-2, that recognizes a 22-base pair (bp) sequence in exon 1 of the TRAC gene (Figure 1A) (p 950, col 2). The outcome was obtaining an anti-CD19 CAR T cells that do not express the endogenous TCR.
Hale et al. teaches using HDR via megaTAL nuclease with lentiviral delivery to produce TCR-negative anti-CD19 CAR (abstract). The instant application describes the targeting of the TRAC locus exon 1, to edit the TCRα chain wherein the construct inserted to be driven by the TCRα promoter is the TRAC-HIT-CAR construct as seen in Figure 1B. This construct includes a variable heavy chain connected to a T cell receptor β constant chain, and a variable light chain that is connected to a T cell receptor α constant chain after insertion. Therefore, the endogenous TCR is disrupted as it is modified, yet remains expressed. The structure is depicted in the “Hybrid (HIT)- CAR” of Fig. 1A.
Conclusion:
The disclosure does not support the scope encompassed by the method as it should include the relevant gene editing technology employed for HR, i.e. CRISPR-Cas, the vector delivered with the nucelase and/or construct, i.e. AAV, the cell-type engineered, and importantly, the locus targeted with the engineered nucleic acid molecule encoding a recombinant T cell receptor (TCR) as recited in claim 46 that is supported in Fig. 1A, B and Example 1.
Conclusion
Claims 46-48, 54-64, and 66 are rejected. No claims are allowed.
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/MICHAEL ANGELO RIGA/Examiner, Art Unit 1634
/TERESA E KNIGHT/Primary Examiner, Art Unit 1634