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 .
Election/Restrictions
Applicant’s election of Group 1 (Claims 1, 2, 5, 9, 12-22, 24, and 31, drawn to an immune cell comprising a chimeric antigen receptor) in the reply filed on 05/12/2026 is acknowledged.
Applicant’s election of species: CD8α as the transmembrane domain recited in claim 22; and 4-1BB/CD137 as the intracellular signaling domain recited in claim 24 in the reply filed on 05/12/2026 is acknowledged. Because applicant did not distinctly and specifically point out the supposed errors in the restriction requirement, the election has been treated as an election without traverse (MPEP § 818.01(a)).
STATUS OF CLAIMS:
Claims 3-4, 6-7. 10-11, 23, 25-30, and 32-33 are canceled.
Claims 1-2, 5, 8-9, 12-22, 24, and 31 are pending and are under examination in this action.
Priority
Applicant’s claim for the benefit of a prior-filed application under 35 U.S.C. 119(e) or under 35 U.S.C. 120, 121, 365(c), or 386(c) is acknowledged.
Information Disclosure Statement
The information disclosure statement (IDS) submitted on 09/19/2022 is in compliance with the provisions of 37 CFR 1.97. Accordingly, the information disclosure statement is being considered by the examiner.
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 2, 5, and 9 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.
Each of claims 2, 5, and 9 recite “at least 80% identical to” the respective SEQ ID NOs: 10, 8, and 11 or 12.
Adequate written description support for a claimed genus may be provided by describing sufficient identifying characteristics, describing a representative number of species, actual reduction to practice, disclosure of drawings or structural chemical formulas, complete or partial structure, physical and/or chemical properties, functional characteristics when coupled with a known or disclosed correlation between function and structure and any working examples, method of making the claimed invention, level of skill and knowledge in the art as well as predictability in the art are other determinants that are used to analyze whether applicants had possession of the claimed genus. The present specification fails to meet these requirements for the following reasons.
The specification describes SEQ ID NO: 10 (required by claim 2) as a single light chain variable domain (VL) amino acid sequence, SEQ ID NO:8 as a single heavy chain variable domain (VH) amino acid sequence, and SEQ ID NOs: 11 and 12 as human interleukin-18 (IL-18) cytokine nucleotide sequence. However, the specification does not identify which amino acid residues within these protein and nucleic acid sequences are critical to maintaining their respective functions (i.e., binding to GPC3 for the variable domains, and binding to IL-18 receptors to drive pro-inflammatory immune signaling for IL-18), nor does it disclose what specific substitutions, deletions, or insertions are tolerated across the claimed ranges.
For variants that are “at least 80% identical,” a significant portion of the primary sequence can be modified. For the light and heavy chain variable domains (SEQ ID NOs: 10 and 8), which are 112 and 115 amino acids, respectively, an 80% identity threshold permits up to 23 amino acid changes for each sequence. For the human IL-18 sequences (SEQ ID NOs: 11 or 12), which are both 474 nucleotides, an 80% identity threshold permits up to 95 base changes. The specification provides no guidance, mutational analysis, or structure-function correlations indicating which 23 amino acids of the variable domains or which 95 nucleotides of IL-18 coding sequence can be altered, deleted, substituted, or inserted while still ensuring the resulting variants fold correctly and retain the required biological activity.
The status of the prior art indicates that both antibody antigen-binding domains and cytokine signaling molecules are highly structurally sensitive, where minor alterations at certain interface positions can cause a complete loss of function. With respect to the light and heavy chain variable domains, Hsu H, et al., (Structure,; 22, 22-34, published 2013) demonstrate the unpredictability of mutations at the interface sequences. Hsu teaches that while some residues in the intradomain hydrophobic core exhibit flexibility, the interdomain interface residues are conserved with high stringency and are “directly coupled with the antigen-binding site formed by the CDRs,” see introduction last paragraph. Hsu teaches that these residues are a critical determinant that “determine the relative configurations of the CDRs, resulting in diversity of the antigen-recognition capabilities of the CDRs,” see conclusions second to last paragraph. Consequently, allowing up to 23 unguided amino acid changes across VH or VL domains, encompasses a very large number of sequence permutations with unpredictably results. As demonstrated by Hsu, unguided variations directly jeopardize the spatial configuration of the CDR loops, which very well may result in non-functional or misfolded domains that lose their target affinity. Similarly, with respect to cytokine biology, mutations in certain regions if IL-18 can disrupt the structural interfaces. Tsutsumi N, et al., (Nat Commun.;5:5340, published 2014) teach “IL-18 forms a signaling complex with the IL-18 receptor α (Rα) and β (Rβ) chains at the plasma membrane, which induces multiple inflammatory cytokines,” and that mutations at “functional residues markedly decrease its binding affinity for IL-18Rα,” see abstract and introduction.
Therefore, the breadth of claims 2, 5, and 9 is not supported by the disclosure. The 80% identity requirement encompasses a large genus of potential variations to SEQ ID NOs: 8, 10, and 11 or 12, many of which would be expected to have a substantially altered function. Yet, the specification discloses only a single species for each sequence and fails to provide a representative number of working examples of “functional variants” within the 80% to 995 identity range that retain the required functions. Since the specification lacks structure-function correlation, such as mutational scanning, one of ordinary skill in the art cannot visualize functional variants from non-functional variants across the claimed identity ranges.
Claims 22 and 24 are rejected on the basis that it contains an improper Markush grouping of alternatives. See In re Harnisch, 631 F.2d 716, 721-22 (CCPA 1980) and Ex parte Hozumi, 3 USPQ2d 1059, 1060 (Bd. Pat. App. & Int. 1984). A Markush grouping is proper if the alternatives defined by the Markush group (i.e., alternatives from which a selection is to be made in the context of a combination or process, or alternative chemical compounds as a whole) share a “single structural similarity” and a common use. A Markush grouping meets these requirements in two situations. First, a Markush grouping is proper if the alternatives are all members of the same recognized physical or chemical class or the same art-recognized class, and are disclosed in the specification or known in the art to be functionally equivalent and have a common use. Second, where a Markush grouping describes alternative chemical compounds, whether by words or chemical formulas, and the alternatives do not belong to a recognized class as set forth above, the members of the Markush grouping may be considered to share a “single structural similarity” and common use where the alternatives share both a substantial structural feature and a common use that flows from the substantial structural feature. See MPEP § 2117.
The Markush grouping of a protein selected from the group consisting of: 4-1BB/CD137, an activating NK cell receptor, an immunoglobulin protein, B7-H3, BAFFR, BLAME (SLAMF8), BTLA, CD100 (SEMA4D), CD103, CD160 (BY55), CD18, CD19, CD19a, CD2, CD247, CD27, CD276 (B7-H3), CD28, CD29, CD3 delta, CD3 epsilon, CD3 gamma, CD3 zeta, CD30, CD4, CD40, CD49a, CD49D, CD49f, CD69, CD7, CD84, CD8, CD8 alpha, CD8 beta, CD96 (Tactile), CDl1a,CDi1b, CD1c, CD11d, CDS, CEACAM1, CRT AM, cytokine receptor, DAP-10,DNAM1 (CD226), Fc gamma receptor, GADS, GITR, HVEM (LIGHTR), IA4, ICAM-1, Ig alpha (CD79a), IL-2R beta, IL-2R gamma, IL-7R alpha, inducible T cell costimulator (ICOS), an integrin, ITGA4, ITGA6, ITGAD, ITGAE, ITGAL, ITGAM, ITGAX, ITGB2, ITGB7, ITGB1, KIRDS2, LAT, LFA-1, a ligand that specifically binds with CD83, LIGHT, LTBR, Ly9 (CD229), lymphocyte function-associated antigen-1 (LFA-1), an MHC class 1 molecule, NKG2C, NKG2D, NKp30, NKp44, NKp46, NKp80 (KLRF1), OX-40, PAG/Cbp, programmed death-1 (PD-1), PSGL1, SELPLG (CD162), a Signaling Lymphocytic Activation Molecule (a SLAM protein), SLAM (SLAMF 1), SLAMF4 (CD244), SLAMF6 (NTB-A), SLAMF7, SLP-76, a TNF receptor protein, TNFR2, TNFSF14, a Toll ligand receptor, TRANCE/RANKL, VLAI, and VLA-6, is improper because the alternatives defined by the Markush grouping do not share both a single structural similarity and a common use for the following reasons: the alternatives do not all belong to or share a recognized structural or chemical class. The grouping spans proteins of fundamentally disparate structural classes and biological functions, for example co-stimulatory receptors (4-1BB/CD137, CD28, OX-40, ICOS), inhibitory/checkpoint receptors (PD-1, BTLA), adhesion molecules and integriins (LFA-1, ICAM-1, ITGA4, ITGA6, etc), cytokine receptors (IL-2R beta, IL-2R gamma, etc), NK cell receptors (NKG2C, NKG2D, etc), TNF receptor superfamily members (TNFR2, TNFSF14, etc), signaling scaffold proteins (LAT, GADS, etc), Fc receptors ( Fc gamma receptor), immunoglobulin superfamily members (MHC class 1 molecule, etc), SLAM family receptors (SLAM/SLAMF1, etc), CD3 complex components (CD3 delta, etc), and various other surface proteins with distinct structural architectures. The proteins belong to distinct structural families, and therefore cannot be said to share a common structural or chemical feature.
To overcome this rejection, Applicant may set forth each alternative (or grouping of patentably indistinct alternatives) within an improper Markush grouping in a series of independent or dependent claims and/or present convincing arguments that the group members recited in the alternative within a single claim in fact share a single structural similarity as well as a common use.
Claim Rejections - 35 USC § 103
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.
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 1-2, 5, 8-9, 12, 15-22, 24, and 31 are rejected under 35 U.S.C. 103 as being unpatentable over Heczey A. et al., (WO2019210293A1) in view of Chmielewski M, et al., (Cell Rep.;21(11):3205-3219, published 2017) and Im D-S. et al., (US20030143203A1).
Regarding claims 1-2, 5, and 19-21, Heczey teaches “ immunotherapy harnesses the body’s ability to fight cancer, and while the treatment of B-cell malignancies using CAR T cells has yielded robust complete remission induction rates, treatment of solid tumors with CAR T cells has yielded only modest antitumor responses so far,” see [0003]. Thus, Heczey teaches a solution: “T cells that express a GPC3-targeting chimeric antigen receptor (CAR) and one or more compositions that enhance the efficacy of the GPC3-targeting T cells, such as one, two, or more cytokines, including interleukins,” see [0006]. Heczey further teaches “the interleukin is two or more of IL-7, IL-2, IL-12, IL-15, IL-21, and IL-18,” see claim 1. Heczey further teaches that when “the T cells have increased expression of IL-7, IL-2, IL-12, IL-15, IL-21, and/or IL-18,” … “this increased expression induces enhanced antitumor properties of the modified T cells,” see [0049]. Heczey further teaches specific combinations including “IL-15 and IL-18; and IL-21 and IL-18,” see [0055]. Heczey further teaches that “the cytokine may be expressed from the cell from a recombinant vector,” see [0056], and that “the CAR and the cytokine(s) are delivered into the T cells on the same vector,” see [0070]. Heczey demonstrates this approach with a retroviral construct encoding GPC3-CAR with IL-5 and IL-21, see [0111] and FIG. 1A. A person of ordinary skill in the art would understand this same retroviral transgene delivery approach applies equally to IL-18, which Heczey names as an alternative for co-expression.
Heczey further teaches CAR is expressed in human cells, including human T cells, and the targeting of GPC3-positive cancers,” see [0062]. Heczey further teaches “an example of a GPC3 human nucleotide sequence is L47125 in GenBank® (with corresponding protein sequence in AAA98132 of GenBank®),” see [0064]. Thus, Heczey teaches the antigen binding domain is human/humanized such that it binds human GPC3. Heczey further teaches “the GPC3-specific CAR comprises an scFv that comprises an amino acid sequence that is at least 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99%, or 100% identical to the sequence of SEQ ID NO:1,” see [0007], which is scFvGC33 having the amino acid sequence of: Underlined Leader; Bold scFv MDWIWRILFLVGAATGAHSQVQLQQSGAELVRPGASVKLSCKASGYTFTDYEMHWVKQTPVHGLKWIGALDPKTGDTAYSQKFKGKATLTADKSSSTAYMELRSLTSEDSAVYYCTRFYSYTYWGQGTLVTVSAGGGGSGGGGSGGGGSDVVMTQTPLSLPVSLGDQASISCRSSQSLVHSNGNTYLHWYLQKPGQSPKLLIYKVSNRFSGVPDRFSGSGSGTDFTLKISRVEAEDLGVYFCSQNTHVPPTFGSGTKLEIK (SEQ ID NO:1),” see [0065].
This amino acid sequence of scFv for human GPC3 above comprises SEQ ID NOs: 1-6 recited in instant claim 1 with 100% identity, SEQ ID NO: 10 recited in instant claim 2 with 93.2% identity, and SEQ ID NO: 8 recited in instant claim 5 with 88.1% identity. See respective alignments below:
SEQ ID NO: 1
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SEQ ID NO: 2
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SEQ ID NO: 3
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SEQ ID NO: 4
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SEQ ID NO: 5
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SEQ ID NO: 6
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SEQ ID NO: 8
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SEQ ID NO: 10
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Thus, the 100% identity threshold for SEQ ID NOs: 1-6 in instant claim 1 and the greater than or equal to 80% identity threshold recited in instant claims 2 and 5 are satisfied.
Regarding claim 8, Heczey teaches interleukin (including IL-18) in human CAR-T cells for human cancer therapy; thus, the IL-18 is necessarily human IL-18 as would be understood by a person having ordinary skill in the art, see [0062] and claim 1.
Regarding claim 22, Heczey teaches “the CAR may include one or more transmembrane domains, such as one selected from the group consisting of CD3-zeta, CD28, CD8 alpha, CD4, and a combination thereof,” see [0008].
Regarding claim 24, Heczey teaches intracellular signaling domain comprises an intracellular signaling domain from a protein selected from the group consisting of: “CD28, 4-1BB, OX40, DAP10, DAP12, CD27, ICOS, or a combination thereof,” see [0008] and [0010].
Heczey does not explicitly teach wherein the human interleukin-18 comprises a sequence that is at least 80% identical to SEQ ID NO: 11 or 12, wherein the exogenous nucleic acid further comprises a promoter operably linked to the sequence encoding interleukin-18, wherein the promoter is a constitutive promoter, wherein the promoter is an inducible promoter, wherein the promoter is an NFAT promoter, and wherein the cell secretes IL-18.
Chmielewski teaches CAR T cells with constitutive or inducible release of IL-18, see FIG. 2 title and FIG. 2B, pg. 3209. Chmielewski further teaches a constitutive CMV promoter and an NFAT/IL-2 inducible promoter operatively linked to an exogenous nucleotide sequence encoding IL-18, see FIG. 2B and pg. 3208, and provided below for convenience:
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Chmielewski further teaches “to deposit IL-18 in the targeted tumor tissue while avoiding systemic T cell activation, anti-CEA CAR T cells were engineered with an inducible IL-18 (iIL-18) expression cassette under control of the nuclear factor of activated T cells (NFAT)-IL2 minimal promoter (Figure 2B). The use of such an expression construct means that IL-18 is released by the engineered T cells following CAR engagement of antigens, with the 18-kD mature form of IL-18,” see pg. 3207 column 2. Chmielewski provides a graphical abstract depicting IL-18 secretion, reproduced below:
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Thus, Chmielewski teaches that the engineered T cells release “the 18-Kd mature form of IL-18,” which is the processed, secreted form of IL-18, see page 3207. A person having ordinary skill in the art would understand that secretion of the mature IL-18 form necessarily requires a secretion signal sequence, either the native IL-18 pro-peptide signal or a heterologous signal.
Chmielewski further teaches that “CAR T Cells with inducible release of IL-18 induced regression of advanced tumors,” see pg. 3209 column 2 and 3210 column 1. Chmielewski further teaches that “only mice treated with iIL-18 anti-CEA CAR T cells completely eliminated established lung cancer in an advanced stage of the disease and remained tumor-free over the course of the observation time,” see pg. 3213 column 1. Thus, Chmielewski teaches “production of IL-18 in the tumor tissue by CAR T cells improved the overall survival of mice with a large tumor burden,” see pg. 3213 column 1.
While both Heczey and Chmielewski teach CAR T cells with an exogenous IL-18 cassette, neither explicitly provide the nucleic acid sequence for human IL-18.
Im teaches the nucleotide sequence for human IL-18, and provides SEQ ID NO: 1, which aligns with 100% identity to the human IL-18 nucleotide represented by SEQ ID NO: 11 in instant claim 9. See alignment score provided below:
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It would have been obvious to a person having ordinary skill in the art (PHOSITA) before the effective filing date to modify the GPC3 CAR T cell of Heczey such that the exogenous (i.e., recombinant) interleukin co-expressed with the GPC3-CAR is IL-18, operatively linked to the CMV constitutive or the NFAT inducible promoter as taught by Chmielewski, to drive tumor-localized release of IL-18. It would have further been obvious for a PHOSITA to use the human IL-18 sequence as taught by Im.
A PHOSITA would have been motivated to do so because: (1) Heczey expressly teaches IL-18 as a named alternative interleukin for co-expression with GPC3-CAR T cells and explicitly identities IL-18 cytokine combinations as preferred embodiments, providing direct motivation to select IL-18; (2) Chmielewski demonstrates the IL-18 specifically, among the available cytokines, improves CAR T cells such that they become capable of eliminating advanced solid tumors; and (3) both references share the same therapeutic objective of overcoming T Cell exhaustion and limited persistence in the solid tumor microenvironment. Thus, a PHOSITA would look to combine their teachings.
A PHOSITA would have had a reasonable expectation of success because: (1) Heczey already demonstrated functional GPC3 CAR T cells secreting recombinant (i.e., exogenous) interleukins, establishing the technical feasibility of the platform; (2) Chmielewski demonstrates that NFAT inducible promoter driving IL-18 expression functions in CAR T cells and produces secreted, biologically active IL-18; and (3) substituting IL-18 for IL-15/IL-21 in Heczey’s established CAR T cell represents routine molecular biology requiring only the swap of one cytokine coding sequence for another within an already validated system with predictable results.
Claims 13-14 are rejected under 35 U.S.C. 103 as being unpatentable over Heczey A. et al., (WO2019210293A1) in view of Chmielewski M, et al., (Cell Rep.;21(11):3205-3219, published 2017) and Im D-S. et al., (US20030143203A1) as applied to claims 1-2, 5, 8-9, 12, 15-22, 24, and 31 above, and further in view of Ma Y. et al., (US20190255108A1).
The teachings of Heczey, Chmielewski, and Im are incorporated herein from the 103 rejection above, and all limitations not discussed below are taught by the first rejection combination.
While Chmielewski teaches the sequence encoding interleukin-18 further includes a sequence encoding a secretion signal sequence, neither Heczey, Chmielewski, or Im explicitly teach replacing the IL-18 secretion signal with the IL-2 secretion signal and wherein the IL-2 secretion signal sequence comprises a sequence of SEQ ID NO: 13 or 14.
Ma teaches CAR T cells comprising an exogenous nucleic acid comprising a sequence encoding interleukin-18, wherein the sequence encoding interleukin-18 further includes a sequence encoding a secretion signal sequence, the secretion signal sequence is an interleukin-2 secretion signal sequence, and the interleukin-2 secretion signal sequence comprises a sequence of SEQ ID NO: 13 or 14. Specifically, Ma teaches “the IL-18 signal peptide is replaced with IL-2 signal peptide for a better secretion of IL-18 and anchoring on the cell surface,” see [0139]. Ma further teaches the IL-18 anchor sequence (i.e., IL-18 where the IL-18 signal peptide is replaced with IL-2 signal peptide) is designated as SEQ ID NO. 13, which comprises amino acid sequence for IL-2 signal peptide that corresponds with 100% identity to the nucleic acid sequences of SEQ ID NOs: 13 or 14 of the instant case that encode for the IL-2 secretion signal,” see [0682]. See alignments below:
SEQ ID NO: 13
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It would have been obvious to a person having ordinary skill in the art (PHOSITA) before the effective filing date to replace the native IL-18 secretion signal sequence in the IL-18 expression construct of the combination of Heczey and Chmielewski with the IL-2 secretion signal sequence as taught by Ma.
A PHOSITA would have been motivated to do so because Ma explicitly teaches that replacing the native IL-18 signal peptide with the IL-2 signal peptide results in “better secretion of IL-18 and anchoring on the cell surface,” providing a direct motivation to make this specific substitution. Signal peptide optimization to improve cytokine secretion efficiency is a well-recognized goal in the art, and the IL-2 signal peptide was a known, high-efficiency secretion signal used in CAR T constructs as demonstrated by Ma.
A PHOSITA would have had a reasonable expectation of success because Ma demonstrates that CAR T cells engineered with the IL-2 signal peptide fused to IL-18 successfully secrete IL-18, confirming that the substitution achieves its intended purpose with a predictable result. The IL-2 signal peptide sequence used by Ma is identical to that of SEQ ID NOs: 13 and 14 of the instant application; thus, establishing the exact sequence to incorporate with predictable results.
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, 5, 8-9, 12-22, 24, and 31 are provisionally rejected on the ground of nonstatutory double patenting as being unpatentable over claims 1-6, 12-13, 15-20, 23-30, 36-37, 39-40, 42-47, and 55-56 of copending Application No. 17/622-503 in view of Heczey A. et al., (WO2019210293A1), Chmielewski M, et al., (Cell Rep.;21(11):3205-3219, published 2017) and Im D-S. et al (US20030143203A1) as applied to claims 1-2, 5, 8-9, 12, 15-22, 24, and 31, and further in view of Ma Y. et al., (US20190255108A1) as applied to claims 13-14.
The copending application claims an immune cell comprising a GPC3-targeting CAR wherein the antigen-binding domain is an scFv comprising a heavy-chain variable region consisting of an amino acid sequence of SEQ ID No: 16 and a light-chain variable region consisting of an amino acid sequence of SEQ ID No: 15, a transmembrane domain, and an intracellular domain comprising a costimulatory endodomain of SEQ ID NO: 4, and an intracellular domain from CD3ζ, see claims 1 and 25. The copending application further claims the transmembrane domain options, costimulatory endodomain specifics, humanized antigen-binding domain, signal peptide, nucleic acid, and engineered immune cell embodiments corresponding to instant claims 2, 5, 12, 15-22, and 24, see copending claims 2-6, 12-13, 15-20, 23-30, 36-37, 39-40, and 42-47.
The instant application claims an immune cell comprising a GPC3-targeting CAR with specific CDR sequences (SEQ ID NOs: 1-6) for the antigen binding domain, a transmembrane domain, an intracellular signaling domain, and an exogenous nucleic acid encoding IL-18, optionally with a secretion signal sequence, promoter, and additional structural features as recited in the dependent claims.
The claims of the instant application differ from those of the copending application primarily in: (1) the recitation of specific CDR sequence (SEQ ID NOs: 1-6) and heavy and light SEQ ID NOs: 8 and 10, respectively; and (2) the additional requirement of an exogenous nucleic acid sequence encoding IL-18. These differences do not render the claims patentably distinct for the following reasons:
Regarding difference (1), the antigen-binding domain sequences of the copending application and the instant application are not patentably distinct, they are in fact directed to the same GPC3-vinding scFv. Specifically, SEQ ID NO: 16 of the copending application, which defines the heavy-chain variable region of the GPC3-targeting scFv, aligns with 100% identity to SEQ ID NO: 8 of the instant application (which also comprises SEQ ID NOs: 4-6), and SEQ ID NO: 15 of the copending application , which defines the light-chain variable region, aligns with 100% identity to SEQ ID NO: 10 (which also comprises SEQ ID NOs: 1-3) of the instant application. See respective alignments provided below:
US-17-906-722-10 vs US-17-622-503-15
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US-17-906-722-8 vs US-17-622-503-16
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Furthermore, the CDR sequences of instant claim 1 (SEQ ID NOs: 1-6) are encompassed within the variable domain sequences of SEQ ID NOs: 15-16 of the copending application, as the CDRs are constituent subsequences of the variable domains. Thus, any immune cell satisfying the variable chain limitations of the copending application’s claim 1 also satisfies the CDR limitation s of the instant application’s claim 1. The claims are therefore directed to the identical GCP3-targeting scFv antigen-binding domain and differ only in the level of sequence ID numbers assigned to the binding domain.
Regarding difference (2), as established in the 103 rejection above, Heczey expressly teaches co-expression of IL-18 with a GPC3-targeting CAR as a preferred embodiment, see Heczey teachings above, and Chmielewski teaches the specific construct design for constitutive and inducible IL-18 expression in CAR T cells including the NFAT promoter and IL-18 native secretion signal, see Chmielewski teaching in 103 above. It would have been obvious to a PHOSITA to combine the GPC3-CAR immune cell if the copending application with the IL-18 co-expression construct of Chmielewski, as Heczey itself provides the direct motivation to do so by naming IL-18 as a preferred interleukin for co-expression with the GPC3-CAR T cell. Regarding the IL-2 secretion signal of instant claims 13-14, Ma teaches replacement of the native IL-18 signal peptide with the IL-2 signal peptide for better secretion, as set forth in the 103 rejection above of claims 13-14 above, the teachings and rational are incorporated herein by reference.
The rational for the motivation to combine and reasonable expectation of success is the same as set forth in the 103 rejections of claim s 1-2, 5, 8-9, 12, 13-22, 24, and 31, which are incorporated herein by reference in their entirety.
This is a provisional nonstatutory double patenting rejection.
Claims 1-2, 5, 8-9, 12-22, 24, and 31 are rejected on the ground of nonstatutory double patenting as being unpatentable over claims 1-6 of U.S. Patent No. US12630597B2 in view of Heczey A. et al., (WO2019210293A1), Chmielewski M, et al., (Cell Rep.;21(11):3205-3219, published 2017) and Im D-S. et al (US20030143203A1) as applied to claims 1-2, 5, 8-9, 12, 15-22, 24, and 31, and further in view of Ma Y. et al., (US20190255108A1) as applied to claims 13-14.
The claims of US12630597B2 are directed to the same GPC3-targeting CAR immune cell platform as the claims of the copending Application No. 17/622, 503 addressed in the provisional nonstatutory double patenting rejection above, and share the same sequence identity relationships with the instant application. Specifically, the variable domain sequences SEQ ID NOs: 8 and 10 of US12630597B2 are identical to those of SEQ ID NOs: 8 and 10 of the instant case and SEQ ID NOs: 15 and 16 of the copending application, and the CDR sequences SEQ ID NOs: 1-6 of US12630597B2 claim 2 are identical to those of instant claim 1. The analysis of claim overlap, sequence identity, and the single material difference between the instant claims and claims of US12630597B2, namely the additional IL-18 co-expression requirement of the instant application, is therefore the same as set forth in the provisional nonstatutory double patenting rejection above over Application No. 17/622,503, which is incorporated herein by reference in its entirety.
The distinction between this rejection and the provisional nonstatutory double patenting rejection above is that US12630597B2 has already issued, and thus this rejection is not a provisional NSDP. The prior art references, claim mapping , motivation to combine, and reasonable expectation of success are identical to those set forth above and are incorporated herein by reference.
Conclusion
No claims are allowed.
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/COREY LANE BRETZ/Patent Examiner, 1635
/RAM R SHUKLA/Supervisory Patent Examiner, Art Unit 1635
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