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 .
Application Status
The reply to the Requirements for Restriction and Election of Species mailed on November 6, 2025 has been entered. Applicant’s election without traverse of the invention of Group I in the reply filed December 11, 2025 is acknowledged. Applicant’s election without traverse of the species of RFX5 as the endogenous gene that regulates MHC class I expression, TRAC as the endogenous gene that regulates MHC class II expression, CRISPR/Cas9 as the gene editing method, and an anti-CD19 CAR having the amino acid sequence of SEQ ID NO: 26, in the reply filed December 11, 2025 is also acknowledged.
Applicant submits that claims 1-2, 9, 11, and 14 read on the elected invention and species.
Claims 1-2, 9, 11, 14, 16-17, 22, 24-25, 27-28, 31-32, and 34-35 are pending. Claims 3, 5, 8, and 15 have been canceled. Claim 1 and 14 are amended. Claims 16-17, 22, 24-25, 27-28, 31-32, and 34-35 are withdrawn from further consideration pursuant to 37 CFR 1.142(b) as being drawn to a nonelected invention, there being no allowable generic or linking claim. Claims 1-2, 9, 11, and 14 are under examination herein.
It is noted that a Power of Attorney is not on record for the instant application. Applicant is encouraged to file a Power of Attorney in the event that the Examiner needs to communicate with an authorized representative for the Applicant during the prosecution of the case.
Claim Rejections - 35 USC § 112(b)
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, 9, 11, and 14 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 recites the limitation “…wherein the endogenous gene of B2M (Beta-2-microglobulin) in the T cell is not engineered” in lines 6-7. There is insufficient antecedent basis for this limitation in the claim. The preamble of the claim more generically recites “an isolated human immune cell”, but not “a T cell”, to which this limitation may refer.
Claims 9, 11, and 14, which depend from claim 1 and do not remedy this deficiency, are similarly rejected.
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.
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.
Claim 2 recites the immune cell of claim 1, wherein the immune cell is a T cell or a natural killer (NK) cell. However, as noted in the 35 U.S.C. § 112(b) rejection above, claim 1 appears to recite that the immune cell is a T cell (lines 6-7). Under the condition that the immune cell is an NK cell, claim 2 fails to include all of the limitations of the previous claim since the previous claim sets forth that the immune cell is a T cell. Under the condition that the immune cell is a T cell, claim 2 fails to further limit the previous claim.
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 § 112(a)
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.
Claim 11 is 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.
“[T]he purpose of the written description requirement is to ‘ensure that the scope of the right to exclude, as set forth in the claims, does not overreach the scope of the inventor’s contribution to the field of art as described in the patent specification.’” Ariad Pharm., Inc. v. Eli Lilly & Co., 598 F.3d 1336, 1353-54 (Fed. Cir. 2010) (en banc) (quoting Univ. of Rochester v. G.D. Searle & Co., 358 F.3d 916, 920 (Fed. Cir. 2004)). To satisfy the written description requirement, the specification must describe the claimed invention in sufficient detail that one skilled in the art can reasonably conclude that the inventor had possession of the claimed invention. Vas-Cath, Inc. v. Mahurkar, 935 F.2d 1555, 1562-63, 19 USPQ2d 1111 (Fed. Cir. 1991).
MPEP § 2163 states that the written description requirement for a claimed genus may be satisfied through sufficient description of a representative number of species by actual reduction to practice, or it may be satisfied by the disclosure of relevant, identifying characteristics, i.e., structure or other physical and/or chemical properties, by functional characteristics coupled with a known or disclosed correlation between function and structure, or by a combination of such identifying characteristics, sufficient to show the applicant was in possession of the claimed genus. “Functional” terminology may be used “when the art has established a correlation between structure and function” but “merely drawing a fence around the outer limits of a purported genus is not an adequate substitute for describing a variety of materials constituting the genus and showing one has invented a genus and not just a species. Ariad Pharmaceuticals Inc. v. Eli Lilly & Co., 598 F3d 1336, 94 USPQ2d 1161, 1171 (Fed Cir. 2010).
For a claim to a genus, a generic statement that defines a genus of substances by only their functional activity does not provide an adequate written description of the genus. Reagents of the University of California v. Eli Lilly, 43 USPQ2d 1398 (CAFC 1997). “[A] sufficient description of a genus . . . requires the disclosure of either a representative number of species falling within the scope of the genus or structural features common to the members of the genus so that one of skill in the art can ‘visualize or recognize’ the members of the genus.” Ariad, 598 F.3d at 1350 (quoting Eli Lilly, 119 F.3d at 1568-69). A “representative number of species” means that those species that are adequately described are representative of the entire genus. AbbVie Deutschland GMBH v. Janssen Biotech, 111 USPQ2d 1780, 1790 (Fed. Cir. 2014). Thus, when there is substantial variation within the genus, one must describe a sufficient variety of species to reflect the variation within the genus to provide a "representative number” of species. The “structural features common to the members of the genus” needed for one of skill in the art to ‘visualize or recognize’ the members of the genus takes into account the state of the art at the time of the invention. For example, the Federal Circuit has found that possession of a mouse antibody heavy and light chain variable regions provides a structural "stepping stone" to the corresponding chimeric antibody, but not to human antibodies. Centocor Ortho Biotech Inc. v. Abbott Labs., 97 USPQ2d 1870, 1875 (Fed. Cir. 2011).
The claimed invention. The nature and scope of the claimed invention at issue is an isolated human immune cell engineered to have an exogenous polynucleotide encoding a CAR, wherein said CAR comprises “a sequence having 90% sequence identity to SEQ ID NO:26-27, 65-76 or 78-83” as recited in claim 11. (Pursuant to the species election requirement, the species comprising the amino acid sequence of SEQ ID NO: 26 is focused upon herein.) The present claim fails to satisfy the written description requirement because these limitations allow for 10% variability within the structure (amino acid sequence) of the claimed CAR construct, including within structural portions responsible for conferring its antigen-binding properties. This modification would be expected to impact the antigen-binding function of the protein based on the state of the prior art and the teachings of the present disclosure.
State of the prior art. The broad goal of cancer immunotherapy is to enhance the immune response against tumor cells. As taught by Harris (Trends in Pharmacological Sciences (2016) 37(3): 220-230), adoptive T cell therapies such as T cell receptors (TCRs) and chimeric antigen receptors (CARs) have great potential for harnessing the tumor-killing properties of T cells through genetic engineering (Abstract). CAR-based adoptive T cell therapies have shown great promise and have gained the interest of biotechnology and pharmaceutical companies (Abstract; Introduction, first paragraph). Harris teaches that CARs are synthetic constructs typically comprising a single-chain antibody fragment (scFv, VH-linker-VL, or VL-linker-VH), an extracellular stalk (hinge) region, a transmembrane domain, and one or more intracellular signaling domains (page 223, “Chimeric Antigen Receptor: Structure and Signaling”). The scFv enables the CAR to respond to cell surface antigens independent of MHC. Per Harris, “The hinge region of a CAR typically comprises either immunoglobulin-like CH2-CH3 (Fc) domains from the constant region of immunoglobulin G (IgG) or the spacer domain from either CD4 or CD8.” Lengthening or shortening the extracellular domain can optimize activity of an individual CAR (page 223). Various transmembrane regions incorporated into CARs include CD3 zeta, CD28, OX40, and others (pages 223-224). The intracellular signaling domains of a CAR are derived from CD3 zeta and a co-stimulatory molecule (typically CD28 or 4-1BB) (Figure 1). Harris teaches that these intracellular signaling domains have received the most attention in terms of their impact on T cell activity, T cell persistence, and efficacy. Second-generation CARs comprising co-stimulatory signaling components in concert with CD3 zeta have shown improved clinical efficacy and persistence (page 224).
The scFv comprises antibody heavy- and light-chain variable fragments, connected by a long flexible peptide linker, that form the antigen-binding domain of the CAR construct. Wu (Expert Opinion on Biological Therapy (2016) 16(12): 1469-1478) teaches that the small size of scFvs allow them to penetrate more rapidly and evenly to tumor and other tissues in comparison to full-size antibodies. However, scFvs also have notable disadvantages, including aggregation, poor expression, instability, and tendency to dimerize (page 1470, Section 2). Wu discloses, “For CAR T cells, extracellular scFv antibodies represent the dominant immunogenic components. While [monoclonal antibodies] can be classified as murine, chimeric, humanized, and fully humans mAbs, CARs can similarly be classified into three types based on the origin of their scFv moieties: murine scFv-based, humanized scFv-based, and fully human scFv-based CARs” (page 1471, Section 3 introduction). For conventional monoclonal antibodies, the structural element that correlates with the function of antigen binding is its complementarity determining regions (CDRs). As discussed by Sela-Culang (Frontiers in Immunology (2013) 4: 302), “A major focus in analyzing the structural basis for [antigen] recognition has been in identifying the exact boundaries of the CDRs in a given [antibody]. It is a common practice to identify paratopes through the identification of CDRs” (page 3, left column, “CDRs Identification”). CAR scFvs likewise comprise CDRs (e.g., Figure 1, Wu) that are critical for
imparting its antigen recognition properties.
CARs with specificity for CD19, and their expression in immune cells (e.g., engineered immune cells), have previously been described in the art. See, for example, Zhang (WO 2019/076149 A1; cited in IDS), Perez (WO 2020/123691 A2; cited in IDS), Shang (WO 2021/136263 A1; cited in IDS), and Zhou (WO 2022/095802 A1; cited in IDS).
Scope of species disclosed in original specification. With respect to CARs targeting CD19 and/or CD20, the specification discloses CARs having the amino acid sequence of SEQ ID NO: 26 or SEQ ID NO: 27 (e.g., ¶ 0012). Exemplary CD20- and CD19-binding sequences, including bicistronic anti-CD20/anti-CD19 CAR sequences, are summarized in Table 3 (pages 30-37). The Examples disclose the production of allogeneic (MHC-mismatched) CAR-T cells via transduction of healthy donor T cells with CD19/CD20 bicistronic CARs followed by electroporation of zinc-finger nucleases (ZFNs) targeting TRAC and RFX5 (e.g., Example 1). These engineered CAR-T cells had similar manufacturability and CAR functionality to B2M KO CAR-T cells (e.g., Example 1, Tables 7-9). The working examples do not identify the specific amino acid sequence(s) of the tested CD19/CD20 CARs, nor which residues which may be modified to achieve 10% sequence variability while retaining the ability to bind to CD19 and/or CD20.
MPEP § 2163 states that a “representative number of species” means that the species which are adequately described are representative of the entire genus. Thus, when there is substantial variation within the genus, one must describe a sufficient variety of species to reflect the variation within the genus. In the absence of a representative number of species, the written description requirement for a claimed genus may be satisfied by disclosure of relevant, identifying characteristics; i.e., structure or other physical and/or chemical properties, by functional characteristics coupled with a known or disclosed correlation between function and structure, or by a combination of such identifying characteristics, sufficient to show the applicant was in possession of the claimed genus.
As set forth above, the specification sets forth very few species of anti-CD19/anti-CD20 CAR constructs, and offers no guidance with respect to which residues within these constructs may be altered while retaining their required functional qualities. Accordingly, the specification only possesses adequate written description for CAR constructs which have a complete structure (i.e., those having 100% sequence identity to the amino acid sequences of SEQ ID NO: 26 or SEQ ID NO: 27) that would be expected to correlate with the instantly claimed function of binding to CD19. As presently claimed, the CAR construct having 90% sequence identity to the amino acid sequence of SEQ ID NO: 26 may lack the basic structural features (i.e., heavy chain variable region (VH) and light chain variable region (VL) CDRs) in the scFv) which are required to confer CD19 binding.
Conclusion. For all of the reasons presented above, one of skill in the art would not know which of the countless other CD19-binding CARs encompassed by the highly general structural requirements of the claims would also possess the required functional activity. Given the lack of shared structural properties that provide the claimed binding activity, the limited number of species described, and the fact that the species that were described cannot be considered representative of the broad genus, the Applicant did not possess the full genus of CD19-binding CARs as broadly claimed at the time the application was filed.
Claim Rejections - 35 USC § 102
The following is a quotation of the appropriate paragraphs of 35 U.S.C. 102 that form the basis for the rejections under this section made in this Office action:
A person shall be entitled to a patent unless –
(a)(2) the claimed invention was described in a patent issued under section 151, or in an application for patent published or deemed published under section 122(b), in which the patent or application, as the case may be, names another inventor and was effectively filed before the effective filing date of the claimed invention.
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.
Claims 1-2 and 9 are rejected under 35 U.S.C. 102(a)(2) as being anticipated by Zhou (WO 2022/095802 A1; earliest priority date: November 3, 2020; original cited in IDS; machine translation attached; hereafter “Zhou ‘802”).
Zhou ‘802 discloses engineered immune cells expressing a chimeric antigen receptor (CAR) comprising an anti-CD7 antigen-binding domain in which the expression of endogenous CD7, at least one TCR/CD3 gene, and at least one MHC-II related gene is suppressed or silenced, which are useful for treating diseases associated with CD7 expression (e.g., Abstract). Regarding claims 1-2, Zhou ‘802 describes engineered immune cells (e.g., T cells and NK cells) that express an anti-CD7 CAR and have suppressed or silenced expression of endogenous CD7, TRAC, and RFX5 (e.g., Summary of the Invention, ¶ 0007-0021; Invention details, ¶ 0051-0063; claims 1-11). Suppressing or silencing endogenous TCR/CD3 genes (e.g., TRAC) reduces risk of graft-versus-host disease (GVHD), while inhibiting or silencing the expression of endogenous MHC-II related genes (e.g., RFX5) in the CAR-T cells of the invention minimizes killing of the exogenous CAR-T cells by the patient’s endogenous CD4+CD7 T cells (e.g., Invention details, ¶ 0053-0060). Zhou ‘802 further states that in one embodiment, endogenous B2M in the CAR-T cells of the invention is functional (e.g., Invention Details, ¶ 0060). Regarding claim 9, the antigen-binding domain of the CAR may comprise an antibody targeting a second antigen such as CD19 (e.g., Summary of the Invention, ¶ 0010; claims 4-5).
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.
Claims 1 and 14 are rejected under 35 U.S.C. 103 as being unpatentable over Zhou ‘802 (WO 2022/095802 A1; supra) as applied to claims 1-2 and 9 above, and further in view of Liu (Cell Research (2017) 27: 154-157).
The teachings of Zhou ‘802 are described in the 35 U.S.C. § 102 rejection above. In addition, although Zhou ‘802 further teaches that methods for inhibiting or silencing genes in the engineered immune cells of the invention include Cas enzymes in the CRISPR system (e.g., Invention details, ¶ 0063; Detailed Implementation/Examples, ¶ 0123, 0148), Zhou ‘802 does not expressly state that endogenous RFX5 and/or TRAC are silenced or suppressed using the CRISPR/Cas9 system.
Liu teaches that adopting an allogeneic adoptive transfer strategy using CAR-T cells derived from healthy patients would make CAR-T therapy more universally accessible, but that eliminating αβ-TCR (to avoid GVHD) and human leukocyte antigens class I (HLA-Is) (to minimize immunogenicity) is necessary to make this strategy effective (page 154). Liu previously demonstrated that up to five genes can be disrupted simultaneously in mouse embryonic stem cells using CRISPR-Cas9 (page 154). Following up on these findings, Liu investigated whether CRISPR/Cas9 gene editing could be applied to perform multiplex gene editing in anti-CD19 CAR-T cells by testing double-knockout (DKO) of B2M and TRAC or triple-knockout (TKO) of B2M, TRAC, and PD-1 (e.g., pages 154 and 156). Liu discloses that DKO CAR-T cells could be enriched with a purity of 95% or higher and showed loss of expression of TCR and HLA-I on the cell surface (pages 156-157). TKO CAR-T cells showed more variable levels of purity upon enrichment (57-90%) (page 156). Liu further discloses that DKO and TKO CAR-T cells demonstrated equivalent or superior anti-tumor activity relative to standard CAR-T cells in vitro and in vivo (page 157). Liu concludes that “These data indicate that CAR-T cells with both TCR and HLA-I eliminated from the cell surface maintained CD19-specific antitumor function, and CRISPR-Cas9-mediated multiplex gene editing did not compromise their potency relative to standard CD19 CAR-T cells” (page 157).
In view of the further teachings of Liu, it would have been obvious to one of ordinary skill in the art, before the filing date of the instantly claimed invention, to use CRISPR/Cas9-mediated gene editing to suppress or silence TRAC and RFX5 expression in the engineered immune cells described by Zhou ‘802. The skilled artisan would have been motivated to do so because Liu teaches that the CRISPR-Cas9 platform is capable of disrupting expression of several genes simultaneously, and multi-gene silencing/disruption is desired for the engineered immune cells of Zhou ‘802. Liu further notes that avoiding GVHD and minimizing immunogenicity, which are achieved by the engineered immune cells taught by Zhou ‘802, is desirable for allogeneic adoptive cell therapy. There would have been a reasonable expectation of success because Liu provides a proof-of-concept that the expression of at least two or three TCR/CD3- and/or HLA-I-related genes may be silenced or suppressed in a CAR-T cell while retaining or even improving its anti-tumor activity.
Claims 1-2, 9, and 14 are rejected under 35 U.S.C. 103 as being unpatentable over Zhou (WO 2022/012591 A1; published January 20, 2022; original cited in IDS; machine translation attached; hereafter “Zhou ‘591”) in view of Kim (Nature Biotechnology (2017) 35(8): 722-723) and Zhou ‘802 (WO 2022/095802 A1; supra).
Zhou ‘591 describes engineered immune cells in which the expression of at least one MHC-related gene (e.g., RFX5 or B2M), at least one NK activating receptor binding molecule, and at least one TCR/CD3 gene (e.g., TRAC) are suppressed or silenced, wherein said cells also express a chimeric antigen receptor that binds to a target selected from CD19, CD20, and others, “and any combination thereof” (e.g., Abstract; Invention Summary, ¶ 0006-0019; claims 1-13), pertinent to claims 1 and 9. Relevant to claim 2, Zhou ‘591 teaches that the immune cells are T cells or NK cells (e.g., ¶ 0019-0020; claims 13-14). Relevant to claim 14, Zhou ‘591 discloses that CRISPR/Cas9 was used to generate T cells having reduced expression of B2M, RFX5, and TRAC according to the invention, for which the NK cell killing effect was inhibited (e.g., Detailed Implementation/Examples, ¶ 0114-0119; Figure 3). Zhou ‘591 acknowledges that “since MHC molecules are key molecules for NK cells to recognize ‘autologous cells’, the complete inactivation of MHC class I molecules such as B2M will cause NK cells to regard the reinfused engineered immune cells as ‘foreign’ and kill them, ultimately affecting the survival and persistence of the reinfused cells, and thus affecting the treatment effect” (machine translation, ¶ 0004).
However, Zhou ‘591 does not expressly teach an embodiment in which expression of endogenous B2M is not engineered or otherwise altered in the engineered immune cell.
Kim discusses strategies for engineering pluripotent stem cells (PSCs), which have the ability to differentiate into any cell type, to avoid immune detection and rejection (page 722). Kim teaches that cell surface expression of MHC-I molecules requires association with B2M (page 722). Kim further teaches that while donor PSC lines deficient in B2M expression have the disadvantage of remaining susceptible to lysis by host NK cells, this effect can be overcome by engineering forced expression of HLA-E at the locus of a disrupted B2M gene (page 722; Figure 1).
However, Kim also notes that while lack of MHC class I expression may be beneficial for preventing rejection or recurrence of autoimmune or genetic diseases, there may also be some unintended consequences – for example, the development of immunologic “blind spots” where reservoirs of viral infection or tumors could go undetected (page 722). Kim also notes that other non-classic MHC-I or MHC-I-like molecules require B2M for their expression, and knocking out B2M can lead to unforeseen deleterious effects (page 723).
Based on the teachings of Kim, it would have been obvious to one of ordinary skill in the art, before the filing date of the instantly claimed invention, to modify the engineered CAR-T cells described by Zhou ‘591 such that B2M is not suppressed. The skilled artisan would have been motivated to do so because Zhou ‘591 and Kim both set forth that suppression of B2M expression in allogeneic cells results in increased host NK cell-mediated elimination, and furthermore, Kim also sets forth that B2M expression is required for the expression of other classic MHC-I or MHC-I-like molecules and that knocking out B2m can lead to unforeseen deleterious effects. There would have been a reasonable expectation of success because Zhou ‘802 sets forth a proof-of-concept of an engineered CAR-T cell in which expression of RFX5 and TRAC are inactivated or deficient, while retaining endogenous B2M expression.
Claims 1 and 11 are rejected under 35 U.S.C. 103 as being unpatentable over Zhou ‘591 (WO 2022/012591 A1; supra) in view of Kim (Nature Biotechnology (2017) 35(8): 722-723; supra) and Zhou ‘802 (WO 2022/095802 A1; supra) as applied to claims 1-2, 9, and 14 above, further in view of Perez (US 2020/0246382 A1; cited in IDS).
The teachings of Zhou ‘591 are recited in the 35 U.S.C. § 103 rejection above. While Zhou ‘591 does teach that the engineered immune cells of the invention may comprise a CAR against CD19 and/or CD20, Zhou ‘591 does not teach that said engineered immune cells express a CAR comprising the amino acid sequence of instant SEQ ID NO: 26.
The teachings of Kim and Zhou ‘802 are recited in the 35 U.S.C. § 102 and 103 rejections above.
Perez discloses CARs and TCRs comprising one or more antigen binding motifs, including against CD19 and CD20 (e.g., Abstract). In an exemplary embodiment, Perez discloses an anti-CD20/anti-CD19 bicistronic CAR having the amino acid sequence of SEQ ID NO: 292 (which shares 100% sequence identity to instant SEQ ID NO: 26) (e.g., ¶ 0183; Example 21 at ¶ 0361). Perez teaches that the anti-CD20/anti-CD19 bicistronic CAR constructs of the invention are well-tolerated and elicit anti-tumor activity (e.g., Example 10 at ¶ 0327-0330).
Considered together, it would have been obvious to one of ordinary skill in the art, before the filing date of the instantly claimed invention, to substitute into the engineered immune cell described by Zhou ‘591 an anti-CD20/anti-CD19 bicistronic CAR such as that taught by Perez. The skilled artisan would have been motivated to do so because the bicistronic CAR constructs taught by Perez (e.g., the CAR construct comprising the amino acid sequence of SEQ ID NO: 292) are well tolerated and show anti-tumor activity. There would have been a reasonable expectation of success because the CAR constructs described by Zhou ‘591 and Perez are functional equivalents (i.e., capable of binding CD19 and/or CD20) and possess utility for the same purpose (i.e., treating a CD19- and/or CD20-expressing tumor).
Double Patenting
The nonstatutory double patenting rejection is based on a judicially created doctrine grounded in public policy (a policy reflected in the statute) so as to prevent the unjustified or improper timewise extension of the “right to exclude” granted by a patent and to prevent possible harassment by multiple assignees. A nonstatutory double patenting rejection is appropriate where the conflicting claims are not identical, but at least one examined application claim is not patentably distinct from the reference claim(s) because the examined application claim is either anticipated by, or would have been obvious over, the reference claim(s). See, e.g., In re Berg, 140 F.3d 1428, 46 USPQ2d 1226 (Fed. Cir. 1998); In re Goodman, 11 F.3d 1046, 29 USPQ2d 2010 (Fed. Cir. 1993); In re Longi, 759 F.2d 887, 225 USPQ 645 (Fed. Cir. 1985); In re Van Ornum, 686 F.2d 937, 214 USPQ 761 (CCPA 1982); In re Vogel, 422 F.2d 438, 164 USPQ 619 (CCPA 1970); In re Thorington, 418 F.2d 528, 163 USPQ 644 (CCPA 1969).
A timely filed terminal disclaimer in compliance with 37 CFR 1.321(c) or 1.321(d) may be used to overcome an actual or provisional rejection based on nonstatutory double patenting provided the reference application or patent either is shown to be commonly owned with the examined application, or claims an invention made as a result of activities undertaken within the scope of a joint research agreement. See MPEP § 717.02 for applications subject to examination under the first inventor to file provisions of the AIA as explained in MPEP § 2159. See MPEP § 2146 et seq. for applications not subject to examination under the first inventor to file provisions of the AIA . A terminal disclaimer must be signed in compliance with 37 CFR 1.321(b).
The filing of a terminal disclaimer by itself is not a complete reply to a nonstatutory double patenting (NSDP) rejection. A complete reply requires that the terminal disclaimer be accompanied by a reply requesting reconsideration of the prior Office action. Even where the NSDP rejection is provisional the reply must be complete. See MPEP § 804, subsection I.B.1. For a reply to a non-final Office action, see 37 CFR 1.111(a). For a reply to final Office action, see 37 CFR 1.113(c). A request for reconsideration while not provided for in 37 CFR 1.113(c) may be filed after final for consideration. See MPEP §§ 706.07(e) and 714.13.
The USPTO Internet website contains terminal disclaimer forms which may be used. Please visit www.uspto.gov/patent/patents-forms. The actual filing date of the application in which the form is filed determines what form (e.g., PTO/SB/25, PTO/SB/26, PTO/AIA /25, or PTO/AIA /26) should be used. A web-based eTerminal Disclaimer may be filled out completely online using web-screens. An eTerminal Disclaimer that meets all requirements is auto-processed and approved immediately upon submission. For more information about eTerminal Disclaimers, refer to www.uspto.gov/patents/apply/applying-online/eterminal-disclaimer.
Claims 1-2, 9, and 11 are provisionally rejected on the ground of nonstatutory double patenting as being unpatentable over claims 1, 10, 19, 24, 27, 34, 43, 52, 57, 60, 65, 67-71, 74, 76-77, and 82 of co-pending Application No. 18/639,066 (reference application). Although the claims at issue are not identical, they are not patentably distinct from each other because the co-pending claims anticipate the instantly claimed invention.
The co-pending reference application recites an isolated immune cell (human T cell or NK cell) engineered to have lower or eliminated activity or expression of RFX5 and TRAC, and further expressing an anti-CD19 CAR comprising the amino acid sequence of SEQ ID NO: 26 (which shares 100% sequence identity to instant SEQ ID NO: 26), wherein endogenous B2M expression is not engineered or altered (e.g., co-pending claims 71, 74, 76-77, and 82), thereby anticipating claims 1-2, 9, and 11.
This is a provisional nonstatutory double patenting rejection because the patentably indistinct claims have not in fact been patented.
Claims 1 and 14 are provisionally rejected on the ground of nonstatutory double patenting as being unpatentable over claims 1, 10, 19, 24, 27, 34, 43, 52, 57, 60, 65, 67-71, 74, 76-77, and 82 of co-pending Application No. 18/639,066 (reference application) as applied to claims 1-2, 9, and 11 above, further in view of Liu (Cell Research (2017) 27: 154-157; supra).
The teachings of the co-pending reference application are described in the non-statutory double patenting rejection above.
However, the co-pending reference application does not expressly state that endogenous RFX5 and/or TRAC activity or expression are silenced or suppressed using the CRISPR/Cas9 system.
The teachings of Liu are summarized in the 35 U.S.C. § 103 rejection above.
In view of the further teachings of Liu, it would have been obvious to one of ordinary skill in the art, before the filing date of the instantly claimed invention, to use CRISPR/Cas9-mediated gene editing to suppress or silence TRAC and RFX5 expression in the engineered immune cells claimed in the co-pending reference application. The skilled artisan would have been motivated to do so because Liu teaches that the CRISPR-Cas9 platform is capable of disrupting expression of several genes simultaneously, and multi-gene silencing/disruption is desired for the engineered immune cells of the co-pending reference application. Liu further notes that avoiding GVHD and minimizing immunogenicity, which would be achieved by the engineered immune cells claimed in the co-pending reference application, is desirable for allogeneic adoptive cell therapy. There would have been a reasonable expectation of success because Liu provides a proof-of-concept that the expression of at least two or three TCR/CD3- and/or HLA-I-related genes may be silenced or suppressed in a CAR-T cell while retaining or even improving its anti-tumor activity.
This is a provisional nonstatutory double patenting rejection.
Conclusion
No claims are allowed.
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/ELIZABETH A SHUPE/Examiner, Art Unit 1643
/Brad Duffy/Primary Examiner, Art Unit 1643