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
Amendments
In the reply filed 01/07/2026, Applicant has amended claims 1, 16, 22-24 and 31, and added new claim 46.
Claim Status
Claims 1-2, 4, 6, 9, 11-12, 16, 19, 22-24, 28-31, 33-34 and 45-46 are pending.
Claims 28-31 and 33-34 have been withdrawn from further consideration pursuant to 37 CFR 1.142(b) as being drawn to non-elected inventions, there being no allowable generic or linking claim. Election was made without traverse in the reply filed on 05/28/2025.
Claims 1-2, 4, 6, 9, 11-12, 16, 19, 22-24 and 45-46 are considered on the merits.
Withdrawn Claim Objections
The prior objection to claims 1, 16 and 23 because of minor informalities is withdrawn in light of Applicant’s amendment to the claims.
Withdrawn Claim Rejections - 35 USC § 112(d)
The prior rejection of claim 22 under 35 U.S.C. 112(d) or pre-AIA 35 U.S.C. 112, 4th paragraph, as being of improper dependent form is withdrawn in light of Applicant’s amendment to the claim to recite the correct amino acid sequences.
Withdrawn Claim Rejections - 35 USC § 112(a)
(Written Description)
The prior rejection of claims 22 and 24 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112(a) or 35 U.S.C. 112 (pre-AIA ), first paragraph, as failing to comply with the written description requirement is withdrawn in light of Applicant’s amendment to remove the limitation the sequences having at least 90% sequence identity to SEQ ID NOs: 6, 7 or 8.
Claim Rejections - 35 USC § 103
The following is a quotation of 35 U.S.C. 103 which forms the basis for all obviousness rejections set forth in this Office action:
A patent for a claimed invention may not be obtained, notwithstanding that the claimed invention is not identically disclosed as set forth in section 102, if the differences between the claimed invention and the prior art are such that the claimed invention as a whole would have been obvious before the effective filing date of the claimed invention to a person having ordinary skill in the art to which the claimed invention pertains. Patentability shall not be negated by the manner in which the invention was made.
The factual inquiries for establishing a background for determining obviousness under 35 U.S.C. 103 are summarized as follows:
1. Determining the scope and contents of the prior art.
2. Ascertaining the differences between the prior art and the claims at issue.
3. Resolving the level of ordinary skill in the pertinent art.
4. Considering objective evidence present in the application indicating obviousness or nonobviousness.
This application currently names joint inventors. In considering patentability of the claims the examiner presumes that the subject matter of the various claims was commonly owned as of the effective filing date of the claimed invention(s) absent any evidence to the contrary. Applicant is advised of the obligation under 37 CFR 1.56 to point out the inventor and effective filing dates of each claim that was not commonly owned as of the effective filing date of the later invention in order for the examiner to consider the applicability of 35 U.S.C. 102(b)(2)(C) for any potential 35 U.S.C. 102(a)(2) prior art against the later invention.
Claims 1, 6, 9, 11, 12, 16, 19, 23 and 45-46 stand rejected under 35 U.S.C. 103 as being unpatentable over Campana et al., (US Patent No. 9,511,092. Prior art of record) in view of Pule et al., (US 2017/0066838. Prior art of record) and Fry et al., (WO 2018/213337. Prior art of record).
It is noted that the prior rejection of claims 1, 6, 9, 11, 12, 16, 19, 23 and 45 are maintained. The following rejection is merely modified to discuss the new claim 46. It is also noted that claim 22 is newly rejected as necessitated by amendments.
Claim 1 is directed to a polynucleotide construct comprising a first sequence encoding an NK activating receptor and a second sequence encoding an anti-GD2 scFv operably linked to the NK activating receptor.
Campana teaches a chimeric receptor comprising NKG2D, DAP10 and CD3 zeta, a polynucleotide encoding the chimeric receptor and the expressing of the chimeric receptor in activated NK cells (e.g., col. 2, para “Brief Summary”). Campana teaches NKG2D is a key receptor for NK cell activation (col. 1, lines 59-60), thus teaches NKG2D is an NK activating receptor. Thus, Campana teaches a polynucleotide construct comprising a first sequence encoding an NK activating receptor. Campana teaches NKG2D chimeric receptor engineered NK cells can be used for treating a cancer such as sarcoma (e.g., col. 6, para 2-3).
However, Campana is silent on a second sequence encoding an anti-GD2 scFv.
Pule teaches an anti-GD2 CAR that comprises an anti-GD2 scFv as antigen-binding domain (abstract, see e.g., Fig 1 and [0043-0044]). Pule teaches a nucleic acid sequence which encodes the CAR ([0060-0064]), a cytolytic immune cell, such as an NK cell comprising the CAR ([0065]) and a method of treating cancer, such as sarcoma, by administering the cell comprising the CAR (e.g., [0070] and [0141-0143]).
Therefore, it would have been obvious for one of ordinary skill in the art before the effective filing date of the claimed invention to have modified the NK cells engineered with a polynucleotide sequence encoding an NKG2D chimeric receptor for treating a cancer such as sarcoma disclosed by Campana, by combining a second sequence encoding an anti-GD2 CAR comprising an anti-GD2 scFv as taught by Pule with a reasonable expectation of success. Since Campana teaches NKG2D chimeric receptor engineered NK cells can be used for treating a cancer such as sarcoma (e.g., col. 6, para 2-3), and since Pule teaches NK cells comprising an anti-GD2 CAR can be used for treating a cancer such as sarcoma ([0065] and [0141-0143]), one of ordinary skill in the art would have had a reason to combine a sequence encoding an anti-GD2 CAR of Pule in the NK cells comprising an NKG2D chimeric receptor of Campana in order to treat cancer such as sarcoma.
Furthermore, MPEP 2144.06 states "It is prima facie obvious to combine two compositions each of which is taught by the prior art to be useful for the same purpose, in order to form a third composition to be used for the very same purpose.... [T]he idea of combining them flows logically from their having been individually taught in the prior art." In re Kerkhoven, 626 F.2d 846, 850, 205 USPQ 1069, 1072 (CCPA 1980) (citations omitted).
However, Campana and Pule do not specifically teach the two sequences encoding the NKG2D chimeric receptor and the anti-GD2 CAR are operably linked within a single polynucleotide construct.
Fry teaches a bicistronic CAR polynucleotide construct (abstract). Fry teaches the construct comprises a first CAR and a second CAR; wherein the first and second CARs are linked through a cleavable domain (e.g., [0005-0008] and see Fig 1). To compare different scenarios in combinatory therapy with two CARs (using anti-CD19 CAR and anti-CD22 CAR as an example) in treating cancer, Fry investigates (1) sequential infusion of anti-CD19-CAR T cells followed by anti-CD22 CART-cells or vice versa, but the sequential infusion does not prevent acute lymphoblastic leukemia (ALL) progression (see [0238]); (2) co-transducing both anti-CD19 and anti-CD22 CAR into the same T cell, however, co-transduction efficiency is consistently low, yielding only a quarter of the total T cell product expressing both CARs (see [0239]); (3) bivalent CARs with tandem sequencing of scFv in which two different scFv domains are tandemly coupled into a single CAR construct, but neither tandem CAR construct fully eradicates CD19posCD22pos ALL in vivo ([0240-0241]); (4) bivalent CARs with looping structure of two scFv domains ([0242-0244]), but even the optimal construct LoopCAR6 does not completely eradicate CD19neg and CD22neg leukemia ([0267]); (5) bicistronic CARs in which CD19 CAR and CD22 CAR become two separate fragments and are expressed as two CARs on the cell surface in an equal molar ([0268]), bicistronic CARs have very potent activity on clearing the leukemia and is superior to the bivalent CARs in reducing the CD19neg and CD22neg leukemia ([0273-0275]). Thus, Fry indicates that a bicistronic construct, i.e., a single polynucleotide construct comprising two CARs linked through a cleavable domain, is superior over other combinatory systems.
Therefore, it would have been obvious for one of ordinary skill in the art before the effective filing date of the claimed invention to have modified the combinatory CAR-NK therapy comprising an NKG2D CAR and an anti-GD2 CAR for treating a cancer such as sarcoma suggested by Campana in view of Pule, by choosing a bicistronic construct comprising a single polynucleotide construct comprising two CARs operably linked through a cleavable domain as taught by Fry with a reasonable expectation of success. Since Campana in view of Pule suggests a combinatory CAR-NK therapy for treating cancer, and since Fry investigates and teaches a bicistronic construct achieves an equal-molar expression of two CARs and has the superior therapeutic results (see [0268 and 0273-0275]), one of ordinary skill in the art would have had a reason to choose the bicistronic construct of Fry to express the two CARs of Campana in view of Pule in order to obtain an equal-molar expression of the two CARs and to obtain the superior therapeutic results.
With respect to claim 6 directed to the NK activating receptor comprising an extracellular ligand-binding domain comprising an NKG2D, as stated supra, Campana teaches the polynucleotide encoding “an extracellular ligand-binding domain comprising a Natural Killer Group 2 member D receptor (NKG2D)” (see e.g., col. 3, para 4).
With respect to claim 9 directed to the NK activating receptor comprising an extracellular ligand-binding domain comprising an NKG2D and the first sequence further encoding upregulated expression of the NKG2D as compared to expression of NKG2D in a wild-type NK cell, as stated supra, Campana teaches the polynucleotide encoding an extracellular ligand-binding domain comprising an NKG2D (see e.g., col. 3, para 4), and teaches the NKG2D chimeric receptor construct transduction results in an increase of NKG2D expression in NK cells compared to NKG2D expression in NK cells transduced with a Mock vector (equivalent to a wild-type NK cell) (see col. 53, result para 6.2.1 from line 37 and Fig 1B). Thus, Campana teaches the first sequence further encodes upregulated expression of the NKG2D compared to that in a wild-type NK cell.
With respect to claim 11 directed to the first sequence being expressed in a first CAR and the second sequence being expressed in a second CAR, as stated supra, Campana teaches a first sequence is expressed in an NKG2D chimeric receptor (equivalent to a first CAR, see e.g., col. 2, para “Brief Summary”) and Pule teaches the second sequence anti-GD2 scFv is expressed in an anti-GD2 CAR (equivalent to a second CAR, see e.g., abstract).
With respect to claim 12 directed to one of the first and second sequences encoding a signaling domain for promoting cytotoxic or cytolytic activity upon activation, and claim 16 directed to the signaling domain being DAP10 or CD3 zeta, Campana teaches the first sequence encodes a DAP10 and a CD3 zeta signaling domain (e.g., col. 2, para “Brief Summary”) and teaches “signal transduction occurs upon ligation via the phosphorylation of DAP10, which recruits downstream signaling effector molecules and, ultimately, cytotoxicity (col. 2, para 3). Thus, Campana teaches the first sequence encodes a signaling domain, such as a DAP10 and a CD3 zeta, for promoting cytotoxicity upon activation.
With respect to claim 19 directed to the first sequence further encoding a self-cleaving peptide, as stated supra, Campana, in view of Pule and Fry, suggests a bicistronic polynucleotide construct comprising a first sequence operably linked to a second sequence through a cleavable domain (equivalent to a self-cleaving peptide, see an exemplary P2A used in constructs #V5-V8 in Fry, Fig 1), thus suggests the first sequence further encodes a self-cleaving peptide.
With respect to claim 23 directed to an engineered cell expressing the polynucleotide construct of claim 1, as stated supra, Campana teaches an engineered NK cell that expresses the polynucleotide construct suggested by Campana in view of Pule and Fry (see Campana, col. 2, para “Brief Summary”).
With respect to claim 45 directed to the self-cleaving peptide being P2A, as stated supra, Fry teaches a cleavable domain (equivalent to a self-cleaving peptide) comprising a P2A (see [0071] and Constructs #V5-V8 in Fig 1).
With respect to new claim 46 directed to the polynucleotide construct of claim 1 in combination with a pharmacological autophagy inhibitor selected from a list including chloroquine, Applicant is reminded that claim scope is not limited by … claim language that does not limit a claim to a particular structure. See MPEP 2111.04 (I). In the instant case, the claimed combination with a pharmacological autophagy inhibitor does not limit the structure of the claimed polynucleotide construct. Thus this limitation does not provide any patentable weight in determining patentability of the claimed product. Accordingly, claim 46 is rejected in the same way as claim 1 as discussed above.
Hence, the claimed invention as a whole was prima facie obvious to a person of ordinary skill before the effective filing date of the claimed invention in the absence of evidence to the contrary.
Response to Traversal:
Applicant’s arguments filed on 01/07/2026 are acknowledged.
Applicant first argues that Claims 2 and 4 are allowable because they are not rejected under 35 U.S.C. §103 in the Office Action (referring to the Office action mailed on 07/08/2025) (Remarks, p. 12, section 1).
Applicant’s arguments have been fully considered but they are not persuasive. Applicant is referred to the prior Office action mailed on 07/08/2025, pages 18 – 21, in which Claims 2 and 4 are rejected under 35 U.S.C. 103 as being unpatentable over Campana et al., (US Patent No. 9,511,092) in view of Pule et al., (US 2017/0066838) and Fry et al., (WO 2018/213337), as applied to claim 1 above, and further in view of Hay et al., (US 2016/0129108) and Wang et al., (J Mol Med. 2018 August 1; 96: 903-913). Therefore, Claims 2 and 4 are rejected under 35 U.S.C. §103 in the prior Office Action.
Applicant further argues that the cited references provides no motivation to combine (Remarks, p. 12, section 2). Specifically, Applicant argues that (1) none of the cited references discloses or suggests the claimed single construct. The cited art at most teaches these features in isolation (p. 13, 1st full para). (2) the rejection fails to articulate any reasoned motivation to combine innate NK activation logic with tumor-specific antigen targeting as a unified strategy, nor does it establish a reasonable expectation that such an approach would overcome the dominant resistance mechanisms (p. 13, 2nd full para – p. 15).
Applicant’s arguments have been fully considered but they are not persuasive.
In response to the first argument that the cited art teaches the claimed features in isolation, Applicant is reminded that one cannot show nonobviousness by attacking references individually where the rejections are based on combinations of references. See In re Keller, 642 F.2d 413, 208 USPQ 871 (CCPA 1981); In re Merck & Co., 800 F.2d 1091, 231 USPQ 375 (Fed. Cir. 1986). In the instant case, the prior art Campana teaches a polynucleotide construct comprising the first claimed sequence encoding a NK activating receptor NKG2D (an NKG2D CAR in an NK cell). The only difference between Campana and the instant invention is that Campana is silent on a second sequence encoding an anti-GD2 CAR. Pule is cited to make obvious an anti-GD2 CAR to be combined in Campana’s NKG2D CAR-NK cells, and Fry is further cited to make obvious a single bicistronic construct to be chosen to arrange the two CARs of Campana and Pule in one single construct.
In response to the second argument that there is no motivation to combine the two CARs of Campana and Pule or there is no reasonable expectation of success, as stated supra, both Campana and Pule teach a CAR-NK cell (an NKG2D CAR-NK cell and an anti-GD2 CAR-NK cell) that can be used to treat cancers such as sarcoma (e.g., Campana col. 6, para 2-3 and Pule [0065] and [0141-0143]), one of ordinary skill in the art would have had a reason to combine the two CARs in NK cells to treat cancers such as sarcoma, because MPEP 2144.06 states "It is prima facie obvious to combine two compositions each of which is taught by the prior art to be useful for the same purpose, in order to form a third composition to be used for the very same purpose.... [T]he idea of combining them flows logically from their having been individually taught in the prior art." In re Kerkhoven, 626 F.2d 846, 850, 205 USPQ 1069, 1072 (CCPA 1980) (citations omitted). One of ordinary skill in the art would have had a reasonable expectation of success in treating cancers such as sarcoma using an NK cell expressing the two CARs since each of the CARs is taught by the prior art to be useful for treating cancers such as sarcoma (e.g., Campana col. 6, para 2-3 and Pule [0065] and [0141-0143]).
Furthermore, in regard to Applicant’s argument on combining distinct and non-overlapping paradigms (innate NK activation logic with tumor-specific antigen targeting) as a unified strategy, as a first matter, those purported distinct and non-overlapping paradigms both belong to the field of immunotherapy, more specifically, adoptive CAR-NK cell therapy. Thus, they are neither distinct nor non-overlapping. Additionally, combinatory therapeutic strategy is well-known to one of ordinary skill in the art, as evidenced by Campana who suggests that “a genetically engineered cell(s) described herein is administered to a subject in combination with one or more other therapies, e.g., anti-cancer agents, cytokines, cellular vaccines or anti-hormonal agents, to treat and/or manage cancer” (col. 28, para 2). Thus, one of ordinary skill would have had a reason to perform a combinatory therapy, by combining the anti-GD2 CAR taught by Pule with the NKG2D CAR taught by Campana.
Applicant finally argues that the present claims are directed to multifunctional engineered NK cell constructs designed to simultaneously target multiple clinically relevant pathways involved in tumor progression, including antigen escape, immunometabolic suppression, and impaired intratumoral NK cell function (p. 15-17).
Applicant’s arguments have been fully considered but they are not persuasive. As stated supra, Campana, Pule and Fry make obvious the claimed multifunctional engineered NK cell constructs.
In regard to new claim 46, Applicant argues that the cited art does not teach or reasonably suggest the use of the claimed construct together with autophagy inhibition to achieve the claimed combination (Remarks, p. 17-18).
Applicant’s arguments have been fully considered but they are not persuasive. As discussed above, the claimed combination with an autophagy inhibitor does not limit the structure of the claimed polynucleotide construct. Thus, this limitation does not provide any patentable weight in determining patentability of the claimed product. See MPEP 2111.04 (I).
Claims 2 and 4 stand rejected under 35 U.S.C. 103 as being unpatentable over Campana et al., (US Patent No. 9,511,092. Prior art of record) in view of Pule et al., (US 2017/0066838. Prior art of record) and Fry et al., (WO 2018/213337. Prior art of record), as applied to claim 1 above, and further in view of Hay et al., (US 2016/0129108. Prior art of record) and Wang et al., (J Mol Med. 2018 August 1; 96: 903-913. Prior art of record).
Claim 2 is directed to the polynucleotide construct further comprising a third sequence encoding a binding domain specific for an adenosine-producing cell surface protein and further comprising a cleavable linker. Claim 4 is directed to the binding domain comprising an antibody fragment specific for CD73.
However, Campana, Pule and Fry are silent on a third sequence encoding an antibody fragment specific for an adenosine-producing cell surface protein CD73.
Hay teaches an anti-CD73 antibody (e.g., MEDI9447) for reducing tumor-mediated immunosuppression (abstract). Hay teaches CD73 is anchored to the cell membrane and plays a role in conversion of extracellular 5'-AMP to adenosine ([0003]), thus teaches CD73 is an adenosine-producing cell surface protein in claims 2 and 4. Hay teaches CD73 generates an immunosuppressed environment by increasing adenosine levels, which promote the development and progression of cancer ([0004]). Hay teaches anti-CD73 antibody MEDI9447 can internalize CD73 on tumor cells (Example 4, [0344]) and inhibit conversion of AMP to adenosine in cancer cells in a dose-dependent manner (Example 5, [0349-0350] and Fig 3). Hay teaches anti-CD73 antibody can be used in treating cancer such as sarcoma (e.g., [0010]).
Wang summarizes adenosinergic signaling (e.g., through CD73) as a target for natural killer cell immunotherapy of cancer (abstract). Wang teaches “one human CD73 antibody has progressed to clinical trials, Medimmune’s MEDI9447” (the anti-CD73 antibody taught by Hay), and teaches anti-CD73 antibody inhibits tumor growth by recruitment of NK cells and enhances the lytic ability of NK cells against cancer cells by a combination of antibody-dependent cellular cytotoxicity (ADCC) as well as a reduction in the rate of adenosine accumulation due to inhibition of CD73 catalytic activity (p. 908, right col, para 3).
Therefore, it would have been obvious for one of ordinary skill in the art before the effective filing date of the claimed invention to have modified the NK cells engineered with the polynucleotide construct comprising an NKG2D CAR operably linked to an anti-GD2 CAR for treating cancer such as sarcoma suggested by Campana, Pule and Fry, by combining a third sequence encoding an anti-CD73 antibody taught by Hay with a reasonable expectation of success. Since Campana and Pule suggest an NK cell engineered with the polynucleotide construct comprising two CARs for treating cancer such as sarcoma (see above), and since Hay teaches an anti-CD73 antibody such as MEDI9447 can reduce tumor-mediated immunosuppression in a tumor environment by reducing adenosine in cancer cells (abstract, [0003-0004] and Example 5, [0349-0350]) and can be used in treating cancer such as sarcoma (e.g., [0010]), and since Wang summarizes an anti-CD73 antibody inhibits tumor growth by recruiting NK cells and enhancing the lytic ability of NK cells against cancer cells by a combination of ADCC as well as a reduction in adenosine accumulation (p. 908, right col, para 3), one of ordinary skill in the art would have had a reason to combine an anti-CD73 antibody of Hay with the NK cells engineered with two CARs of Campana, Pule and Fry in order to reduce immunosuppression and to enhance the cytolytic activity of NK cells for treating a cancer such as sarcoma.
In regard to combing the third sequence encoding an anti-CD73 antibody with the first and second sequences within a single polynucleotide construct that further comprises a cleavable linker, as stated supra, Fry teaches a bicistronic polynucleotide construct that may comprise multiple CARs (e.g., three) wherein each CAR is separated by a cleavable domain ([0052]). Thus, Fry provides a polynucleotide construct that may comprise a first sequence (encoding an NKG2D chimeric receptor of Campana), a second sequence (encoding an anti-GD2 CAR of Pule) and a third sequence (encoding an anti-CD73 antibody of Hay). As stated supra, Fry investigates different combinatory therapies and concludes that the bicistronic (or multicistronic) polynucleotide construct functions superior over other systems (see discussion above).
Therefore, it would have been obvious for one of ordinary skill in the art before the effective filing date of the claimed invention to have modified the combinatory CAR-NK therapy and anti-CD73 antibody for treating a cancer such as sarcoma suggested by Campana in view of Pule, Fry, Hay and Wang, by choosing a bicistronic (multicistronic) construct comprising a single polynucleotide construct comprising multiple sequences each operably linked through a cleavable domain as taught by Fry with a reasonable expectation of success. Since Fry investigates and teaches a bicistronic (multicistronic) construct achieves superior therapeutic results over other combinatory systems (see [0268 and 0273-0275]), one of ordinary skill in the art would have had a reason to choose the multicistronic construct of Fry to express the anti-CD73 antibody of Hay in the same single polynucleotide construct comprising the two CARs of Campana in view of Pule and Fry in order to obtain an equal expression of the sequences to achieve superior therapeutic results.
Hence, the claimed invention as a whole was prima facie obvious to a person of ordinary skill before the effective filing date of the claimed invention in the absence of evidence to the contrary.
Response to Traversal:
Applicant’s arguments filed on 01/07/2026 are acknowledged and have been discussed above.
Claim 22 is rejected under 35 U.S.C. 103 as being unpatentable over Campana et al., (US Patent No. 9,511,092. Prior art of record) in view of Pule et al., (US 2017/0066838. Prior art of record) and Fry et al., (WO 2018/213337. Prior art of record), as applied to claims 1 and 19 above, and further in view of Alignment 2 (sequence alignment between prior arts and instant sequences of SEQ ID NOs: 6-7, p. 1-8, attached as NPL) and De Palma et al., (US 2019/0062450 A1, published on 2019-02-28).
In regard to the first sequence encoding a first amino acid of SEQ ID NO: 6, as stated supra, Campana teaches a chimeric receptor comprising NKG2D, DAP10 and CD3 zeta (e.g., col. 2, para “Brief Summary”), wherein the CD3 zeta cytoplasmic domain comprises the amino acid sequence of SEQ ID NO: 10, the NKG2D receptor comprises the amino acid sequence of SEQ ID NO: 12 (Campana claim 8). Figure 1A (attached below) shows the structure of the NKG2D CAR arranged as CD3zeta-NKG2D-IRES-DAP10-FLAG tag (it is noted that Campana’s DAP10 contains a FLAG tag and DAP-FLAG has a sequence in Campana SEQ ID NO: 18).
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However, Campana uses an IRES site between the NKG2D and the DAP10, but is silent on a P2A site between the two domains.
As stated supra, Fry teaches a cleavable domain P2A (“GSGATNFSLLKQAGDVEENPGP”, Fry, SEQ ID NO: 44 in page 15).
Therefore, it would have been obvious for one of ordinary skill in the art before the effective filing date of the claimed invention to have substituted the IRES domain of Campana with the P2A cleavable domain taught by Fry with a reasonable expectation of success. Since Campana’s IRES domain and Fry’s P2A domain are for the same purpose (i.e., to produce two separate proteins from a single mRNA), these domains are art-recognized obvious equivalents to each other. Therefore, it would have been obvious for one of ordinary skill in the art to have substituted Fry’s P2A domain for Campana's IRES domain. See MPEP 2144.06. Thus, Campana, in view of Fry, make obvious an NKG2D CAR construct encoding a sequence of CD3zeta-NKG2D-P2A-DAP10-FLAG tag, i.e., Campana SEQ ID NOs: 10-12-P2A-18 (see alignment 2, p. 1-2) that is 100% identical to the instant SEQ ID NO: 6 (see alignment 2, p. 3-4).
In regard to the second sequence encoding a second amino acid that differs from SEQ ID NO: 7 by no more than five conservative amino acid substitutions, as stated supra, Pule teaches a polynucleotide construct encoding an anti-GD2 CAR. Pule teaches one of the anti-GD2 CARs has an antigen-binding domain scFv derived from the anti-GD2 14g2a clone antibody (which is a gold standard as it is used as a therapeutic antibody, see [0044]) and an intracellular signaling domain containing CD28-CD3 zeta (14g2a-28-Z, see Fig 14a second row, the intracellular domain of CD28-CD3z has a sequence of SEQ ID NO: 17 [0097]). Pule teaches the CAR has a transmembrane domain comprising the sequence shown as SEQ ID NO: 13 ([0094]), and a spacer sequence to connect the GD2-binding domain with the transmembrane domain, such as a human CD8 stalker with SEQ ID NO: 21 ([0108-0111]).
De Palma teaches an anti-GD2 chimeric receptor (“EVIR”) in which the 14G2a-based anti-GD2 scFv has an amino acid sequence of De Palma SEQ ID NO: 114 (e.g., [0116], [0144]).
Therefore, it would have been obvious for one of ordinary skill in the art before the effective filing date of the claimed invention to have chosen the 14G2a-based anti-GD2 scFv as suggested by Pule and taught by De Palma with a reasonable expectation of success. Since Pule suggests using the anti-GD2 14g2a clone antibody in the anti-GD2 CAR because it is a gold standard as it is used as a therapeutic antibody (see [0044]), and since De Palma reduces to practice the 14G2a-based anti-GD2 scFv (De Palma SEQ ID NO: 114, see e.g., [0116], [0144]), one of ordinary skill in the art would have had a reason to choose the 14g2a-based anti-GD2 scFv in the anti-GD2 CAR in order to take advantage of its therapeutic effect. Thus, Pule, in view of De Palma, make obvious an anti-GD2 CAR having the sequence of 14G2a-based anti-GD2 scFv - CD8 stalker-transmembrane domain - CD28-CD3z (i.e., De Palma SEQ ID NO: 114 - Pule SEQ ID NOs: 21-13 – 17 comprising 466 amino acids, see alignment 2, p. 5-6) that is 100% identical to the sequence of instant SEQ ID NO: 7 (469 amino acids), with only 3 amino acids indels (see alignment 2, p. 7-8).
Hence, the claimed invention as a whole was prima facie obvious to a person of ordinary skill before the effective filing date of the claimed invention in the absence of evidence to the contrary.
Response to Traversal:
Applicant’s arguments filed on 01/07/2026 are acknowledged and have been discussed above.
Allowable Subject Matter
Claim 24 is objected to as being dependent upon a rejected base claim, but would be allowable if rewritten in independent form including all of the limitations of the base claim and any intervening claims. Specifically, the prior art does not teach nor reasonably suggest an engineered cell or cell line expressing an amino acid sequence of SEQ ID NO: 8 or that differs from SEQ ID NO: 8 by no more than five conservative amino acid substitutions. It is noted that the amino acid sequence of SEQ ID NO: 8 comprises, in 5’ to 3’ order, an anti-CD73 antibody - an uPA protease cleavage site - anti-GD2 CAR - P2A cleavage site - NKG2D CAR.
Conclusion
Applicant's amendment necessitated the new ground(s) of rejection presented in this Office action. Accordingly, THIS ACTION IS MADE FINAL. See MPEP § 706.07(a). Applicant is reminded of the extension of time policy as set forth in 37 CFR 1.136(a).
A shortened statutory period for reply to this final action is set to expire THREE MONTHS from the mailing date of this action. In the event a first reply is filed within TWO MONTHS of the mailing date of this final action and the advisory action is not mailed until after the end of the THREE-MONTH shortened statutory period, then the shortened statutory period will expire on the date the advisory action is mailed, and any extension fee pursuant to 37 CFR 1.136(a) will be calculated from the mailing date of the advisory action. In no event, however, will the statutory period for reply expire later than SIX MONTHS from the date of this final action.
No claims are allowed.
Examiner Contact Information
Any inquiry concerning this communication or earlier communications from the examiner should be directed to Jianjian Zhu whose telephone number is (571)272-0956. The examiner can normally be reached M - F 8:30AM - 4PM (EST).
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/JIANJIAN ZHU/Examiner, Art Unit 1631
/JAMES D SCHULTZ/Supervisory Patent Examiner, Art Unit 1631
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