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
Claims 1, 3, 5-6, 8-16, 18-23, and 25-29 are pending.
Objections and Rejections Withdrawn
The rejections to claims 2, 4, 7, 17, and 24 are moot in view of claim cancelation.
The objection to the Drawings are withdrawn in view of replacement Drawings.
The rejection of claims 1, 5, 8, and 10-16, 18-23, and 25-29 under 35 U.S.C. 112(b) are withdrawn in view of claim amendment.
The rejection of claims 1, 5, 8, and 10-16, and 18-23 under 35 U.S.C. 112(a) are withdrawn in view of claim amendment.
Objections and Rejections Necessitated by Amendment and Maintained.
Objections to the Claims
Claim 10 is objected to because of the following informalities:
Regarding instant claim 10, in line 1, “wherein anti-CD70 binding domain” is grammatically incorrect. The phrase should be exchanged with ---wherein the anti-CD70 binding domain---.
Appropriate correction is required.
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 3 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. Regarding option e) the VH of SEQ ID NO:958 is only 74.9% of SEQ ID NO:908. Regarding option i) the VH of SEQ ID NO:950 is only 83.8% of SEQ ID NO:900. Thus, the claim represents an expansion of scope of parental instant claim 1 that requires a 90% sequence identity. 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.
Claims 1, 5, 8, 10-16, 18, 21-23, 25, and 28-29 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.
Instant claims 1, 18, and 25 claim anti-CD70 binding domains comprising a VH region having at least 90% sequence identity and a VL region having at least 90% sequence identity to sequence defined VH and VL pairs, but the claimed anti-CD70 binding domains would allow changes to the HCDR and LCDR binding determinant regions of the VH and VL regions. The disclosure does not test mutations, additions, or deletions of the HCDR1-3 or LCDR1-3 for expression of the CAR or binding CD70. Claims 5, 8, 10-16, 21-23, and 28-29 are dependent on claims 1, 18, and 25 without narrowing the claims outside of changes to the HCDR and LCDR regions.
Instant claims 1, 18, and 25 claim an anti-CD70 binding domain comprising e) a VH of SEQ ID NO:908 and a VL SEQ ID NO:1032; and i) a VH of SEQ ID NO:900 and a VL of SEQ ID NO:1024, but the disclosure only tests an scFv of NK77.65 comprising a VH of SEQ ID NO:950 and a VL of SEQ ID NO:1024 and NK77.73 comprising a VH of SEQ ID NO:958 and a VL SEQ ID NO:1032. The disclosure does not test mixing of VH and VL regions. Claims 5, 8, 10-16, 21-23, and 28-29 are dependent on claims 1 and 25 and further include the mixed VH and VL pairs.
Scope of the claimed genus
Instant claims 1, 18, and 25 claim methods of treating a CD70-expressing cancer in a subject comprising administering to the subject a population of genetically engineered NK expressing an anti-CD70 chimeric antigen receptor CAR, but the claimed sequences of the VH and VL are only required to be 90% identical to the VH and VL sequences without requiring sequence defined HCDR1-3 and LCDR1-3 to be held constant.
Instant claims 1 and 25 claim methods of treating a CD70-expressing cancer in a subject comprising administering to the subject a population of genetically engineered NK expressing an anti-CD70 chimeric antigen receptor CAR, but options e) and i) allow an anti-CD70 binding domain comprising e) a VH of SEQ ID NO:908 and a VL SEQ ID NO:1032; and i) a VH of SEQ ID NO:900 and a VL of SEQ ID NO:1024, which were not tested. The disclosure only tests an scFv of NK77.65 comprising a VH of SEQ ID NO:950 and a VL of SEQ ID NO:1024 and NK77.73 comprising a VH of SEQ ID NO:958 and a VL SEQ ID NO:1032.
Summary of Species disclosed in the original specification
1)-2) The instant specification does not test CD70 binding and expression of a CAR in NK cells wherein the HCDR1-3 and LCDR1-3 are not 100% identical to the VH and VL in NK77.11, NK77.16, NK77.17, NK77.31, NK77.44, NK77.55, NK77.58, NK77.65, NK77.71, and NK77.73.
Fig. 50 shows NK cells comprising the VH and VL of anti-CD70 binding domain scFvs of:
NK77.71_CD70_DB04_D02(VH SEQ ID NO:956/VL SEQ ID NO:1030);
NK77.17_CD70_DB02_B06(VH SEQ ID NO:905/VL SEQ ID NO:979);
NK77.58_CD70_DB03_H08(VH SEQ ID NO:943/VL SEQ ID NO:1017);
NK77.11_CD70_DB02_A05(VH SEQ ID NO:899/VL SEQ ID NO:973);
NK77.16_CD70_DB02_A11(VH SEQ ID NO:904/VL SEQ ID NO:978);
NK77.44_CD70_DB03_B06(VH SEQ ID NO:929/VL SEQ ID NO:1003);
NK77.31_CD70_DB02_F08(VH SEQ ID NO:916/VL SEQ ID NO:990);
NK77.55_CD70_DB03_F12(VH SEQ ID NO:940/VL SEQ ID NO:1014);
NK77.65_CD70_DB04_B05(VH SEQ ID NO:950/VL SEQ ID NO:1024); and
NK77.73_CD70_DB04_D07(VH SEQ ID NO:958/VL SEQ ID NO:1032).
NK77.11, NK77.16, NK77.17, NK77.31, NK77.44, NK77.55, NK77.58, NK77.65, NK77.71, and NK77.73 were effectively expressed and effectively killed cancer cells in Fig. 59D. The instant specification does not show NK cells comprising the VH and VL of anti-CD70 binding domain scFvs comprising a VH of SEQ ID NO:908 and a VL of SEQ ID NO:1032 or a VH of SEQ ID NO:900 and a VL of SEQ ID NO:1024 are effectively expressed in NK cells, bind CD70, or kill cancer cells. The specification only shows a VH of SEQ ID NO:958 and a VL of SEQ ID NO:1032 or a VH of SEQ ID NO:950 and a VL of SEQ ID NO:1024 are effectively expressed in NK cells, bind CD70, or kill cancer cells.
Alignment of the Kabat defined CDRs of show the HCDR1-3 comparing VH SEQ ID NO:908 and SEQ ID NO:958 or VH SEQ ID NO:900 and SEQ ID NO:950 are not identical and have several changes within the binding determinant region.
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Thus, a VH of SEQ ID NO:908 and SEQ ID NO:958 are not considered exchangeable with the same VL and a VH of SEQ ID NO:900 and SEQ ID NO:950 are not considered exchangeable with the same VL.
The instant specification taught that CAR constructs were expressed in: 1) NK cells (Fig. 61D) and T cells (Fig 50E-F) . In a cytotoxicity assay, the tested NK constructs NK77.11, NK77.16, NK77.17, NK77.58, and NK77.71 in donor 512 NK cells all exhibited greater cytotoxicity at E:T ratios of either 1:2 or 1:4 against 786-O cells (Figures 61K-61L) or ACHN cells (Figures 61M-61N) relative to NK71 control and negative control (page 167, [00369]). The cytotoxicity of anti-CD70 CAR expressing NK cells against tumor cells with gene editing was further shown in Fig. 44A-C, 49H-49I, 55A-55M, 56A-56J. Figure 31A shows CAR expression levels an anti-CD70 CAR (NK71) on NK cells treated with CD70 gRNA, CD70 and CISH gRNAs, CD70 and NKG2A gRNAs, CD70 and TGFBR2 gRNAs.
State of the Relevant Art
1)-2) The prior art taught T cells expressing CD70-specific first- and second-generation CARs which utilized the CD70-binding domain of CD27 for target-cell recognition specifically lysed CD70-positive primary GB cells in vitro, and inhibited growth or induced complete tumor regression in xenograft and syngeneic GB models in mice. (Burger MC et al. CAR-Engineered NK Cells for the Treatment of Glioblastoma: Turning Innate Effectors Into Precision Tools for Cancer Immunotherapy. (Front Immunol. 2019 10:2683. doi: 10.3389/fimmu.2019.02683) page 6, left column, first paragraph). Further, Burger taught similar to T cells, specific recognition and elimination of cancer cells by NK cells can be markedly enhanced through expression of chimeric antigen receptors (CARs), which provides an opportunity to generate NK-cell therapeutics of defined specificity for cancer immunotherapy (abstract). The prior art has not taught a structure activity relationship that would allow less than 100% identity of a sequence defined HCDR1-3 and LCDR1-3 of the VH and VL of NK77.11, NK77.16, NK77.17, NK77.31, NK77.44, NK77.55, NK77.58, NK77.65, NK77.71, and NK77.73.
At the time of the filing of the instant application, it was well established in the art that the formation of an intact antigen-binding site in an antibody usually required the association of the complete heavy and light chain variable regions of a given antibody, each of which consists of three “complementarity determining regions” (“CDRs”) which provide the majority of the contact residues for the binding of the antibody to its target epitope. E.g., Almagro & Fransson, Frontiers in Bioscience 2008; 13:1619-33; (see Section 3 “Antibody Structure and the Antigen Binding Site” and Figure 1). While affinity maturation techniques can result in differences in the CDRs of the antibody compared to its parental antibody (page 3 “The IgG Molecule, second and third paragraphs), those techniques involve trial-and-error testing and the changes that maintain or improve affinity are not predictable a priori. E.g., id., (page 6 ending paragraph onto page 7). Chiu ML et al. (Antibodies 2019 8, 55, 1-80) taught the antigen binding of antibodies often results in conformational changes in the contact surface areas of both the antibody and the antigen (page 5, first paragraph). Thus, the prediction of CDR binding to the epitope is difficult to predict. Chiu further taught antibody modeling has been shown to be accurate for the framework region sequences, but CDR modeling requires further development and improvements (page 6, second paragraph). Prediction of the structure of HCDR3 could not be accurately produced when given the Fv structures without their CDR-H3s (page 6, second paragraph). Chiu taught the quality of antibody structure prediction, particularly regarding CDR-H3, remains inadequate, and the results of antibody–antigen docking are also disappointing (page 11, paragraph 2).
The prior art taught the antigen-binding properties of a CAR are defined by the antigen recognition domain, which usually consists of a single-chain variable fragment (scFv) (Stoiber S et al. (Cells 2019 8 472 doi:10.3390/cells8050472), page 3, last paragraph). Stoiber taught a crucial determinant of CAR functionality is the affinity of the scFv for its cognate antigen and work done by several groups suggests that there is a lower limit to CAR affinity, below which sufficient antigen recognition does not occur, resulting in suboptimal CAR T cell activation (page 4, second paragraph). Stoiber taught the fine-tuning of CAR affinity also encompasses the possibility to mitigate on-target off-tumor toxicities related to low-level antigen expression on normal tissue, while retaining sufficient effector functions to eradicate antigen-overexpressing malignant cells (page 4, third paragraph). Stoiber taught an attenuated response to normal cells is especially relevant in light of a previous report, where a patient died after CAR T cell therapy, likely due to recognition of lung epithelial cells expressing low levels of HER2/neu (page 4, third paragraph). Thus, alteration of antigen binding via changes to the HCDR1-3 and LCDR1-3 of the scFv in a CAR can cause unpredictable changes to CAR activity or toxicity.
Claims 1, 5, 8, 10-16, 18, 21-23, 25, and 28-29 are rejected under 35 U.S.C. 112(a) or 35 U.S.C. 112 (pre-AIA ), first paragraph, because the specification, while being enabling for: a method of treating a CD70-expressing cancer in a subject comprising administering to the subject a population of genetically engineered immune NK cells expressing an anti-CD70 CAR comprising:
NK77.71_CD70_DB04_D02(VH SEQ ID NO:956/VL SEQ ID NO:1030);
NK77.17_CD70_DB02_B06(VH SEQ ID NO:905/VL SEQ ID NO:979);
NK77.58_CD70_DB03_H08(VH SEQ ID NO:943/VL SEQ ID NO:1017);
NK77.11_CD70_DB02_A05(VH SEQ ID NO:899/VL SEQ ID NO:973);
NK77.73_CD70_DB04_D07(VH SEQ ID NO:958/VL SEQ ID NO:1032)
NK77.16_CD70_DB02_A11(VH SEQ ID NO:904/VL SEQ ID NO:978);
NK77.44_CD70_DB03_B06(VH SEQ ID NO:929/VL SEQ ID NO:1003);
NK77.31_CD70_DB02_F08(VH SEQ ID NO:916/VL SEQ ID NO:990);
NK77.65_CD70_DB04_B05(VH SEQ ID NO:950/VL SEQ ID NO:1024); and
NK77.55_CD70_DB03_F12(VH SEQ ID NO:940/VL SEQ ID NO:1014);
or a sequence defined HCDR1-3 and LCDR1-3 of a) to j) above as defined in instant Fig. 50B; and does not reasonably provide enablement for the method above with less than 100% identity of an anti-CD70 CAR comprising:
NK77.71_CD70_DB04_D02(VH SEQ ID NO:956/VL SEQ ID NO:1030);
NK77.17_CD70_DB02_B06(VH SEQ ID NO:905/VL SEQ ID NO:979);
NK77.58_CD70_DB03_H08(VH SEQ ID NO:943/VL SEQ ID NO:1017);
NK77.11_CD70_DB02_A05(VH SEQ ID NO:899/VL SEQ ID NO:973);
NK77.73_CD70_DB04_D07(VH SEQ ID NO:958/VL SEQ ID NO:1032)
NK77.16_CD70_DB02_A11(VH SEQ ID NO:904/VL SEQ ID NO:978);
NK77.44_CD70_DB03_B06(VH SEQ ID NO:929/VL SEQ ID NO:1003);
NK77.31_CD70_DB02_F08(VH SEQ ID NO:916/VL SEQ ID NO:990);
NK77.65_CD70_DB04_B05(VH SEQ ID NO:950/VL SEQ ID NO:1024); and
NK77.55_CD70_DB03_F12(VH SEQ ID NO:940/VL SEQ ID NO:1014);
or a less than 100% of a sequence defined HCDR1-3 and LCDR1-3 of a) to j) above as defined in instant Fig. 50B.
The specification does not enable any person skilled in the art to which it pertains, or with which it is most nearly connected, to make the invention commensurate in scope with these claims.
Instant claims 1, 18, and 25 claim anti-CD70 binding domains comprising a VH region having at least 90% sequence identity and a VL region having at least 90% sequence identity to sequence defined VH and VL pairs, but the claimed anti-CD70 binding domains would allow changes to the HCDR and LCDR binding determinant regions of the VH and VL regions. The disclosure does not test mutations, additions, or deletions of the HCDR1-3 or LCDR1-3 for expression of the CAR or binding CD70 and the prior art does not describe a structure activity relationship for changing the HCDR1-3 or LCDR1-3. Claims 5, 8, 10-16, 21-23, and 28-29 are dependent on claims 1, 18, and 25 without narrowing the claims outside of changes to the HCDR1-3 and LCDR1-3 regions.
Instant claims 1, 18, and 25 claim an anti-CD70 binding domain comprising e) a VH of SEQ ID NO:908 and a VL SEQ ID NO:1032; and i) a VH of SEQ ID NO:900 and a VL of SEQ ID NO:1024, but the disclosure only tests an scFv of NK77.65 comprising a VH of SEQ ID NO:950 and a VL of SEQ ID NO:1024 and NK77.73 comprising a VH of SEQ ID NO:958 and a VL SEQ ID NO:1032. The disclosure does not test mixing of VH and VL regions. Claims 5, 8, 10-16, 21-23, and 28-29 are dependent on claims 1 and 25 and further include the mixed VH and VL pairs.
There are many factors to be considered when determining whether there is sufficient evidence to support a determination that a disclosure does not satisfy the enablement requirement and whether any necessary experimentation is "undue." These
factors include, but are not limited to:
(A) The breadth of the claims;
(B) The nature of the invention;
(C) The state of the prior art;
(D) The level of one of ordinary skill;
(E) The level of predictability in the art;
(F) The amount of direction provided by the inventor;
(G) The existence of working examples; and
(H) The quantity of experimentation needed to make or use the invention based on the content of the disclosure.
Scope of the claimed genus and nature of the invention.
Instant claims 1, 18, and 25 claim methods of treating a CD70-expressing cancer in a subject comprising administering to the subject a population of genetically engineered NK expressing an anti-CD70 chimeric antigen receptor CAR, but the claimed sequences of the VH and VL are only required to be 90% identical to the VH and VL sequences without requiring sequence defined HCDR1-3 and LCDR1-3 to be held constant. Claims 5, 8, 10-16, 21-23, and 28-29 are dependent on claims 1, 18, and 25 without narrowing the claims outside of changes to the HCDR1-3 and LCDR1-3 regions.
Instant claims 1 and 25 claim methods of treating a CD70-expressing cancer in a subject comprising administering to the subject a population of genetically engineered NK expressing an anti-CD70 chimeric antigen receptor CAR, but options e) and i) allow an anti-CD70 binding domain comprising e) a VH of SEQ ID NO:908 and a VL SEQ ID NO:1032; and i) a VH of SEQ ID NO:900 and a VL of SEQ ID NO:1024, which were not tested. The disclosure only tests an scFv of NK77.65 comprising a VH of SEQ ID NO:950 and a VL of SEQ ID NO:1024 and NK77.73 comprising a VH of SEQ ID NO:958 and a VL SEQ ID NO:1032. Claims 5, 8, 10-16, and 28-29 are dependent on claims 1 and 25 and further include the mixed VH and VL pairs.
Summary of Species disclosed in the original specification; the amount of direction provided by the inventor, existence of working examples; and quality of experimentation needed to make or use the invention based on the content of the disclosure.
1)-2) The instant specification does not test CD70 binding and expression of a CAR in NK cells wherein the HCDR1-3 and LCDR1-3 are not 100% identical to the VH and VL in NK77.11, NK77.16, NK77.17, NK77.31, NK77.44, NK77.55, NK77.58, NK77.65, NK77.71, and NK77.73.
Fig. 50 shows NK cells comprising the VH and VL of anti-CD70 binding domain scFvs of:
NK77.71_CD70_DB04_D02(VH SEQ ID NO:956/VL SEQ ID NO:1030);
NK77.17_CD70_DB02_B06(VH SEQ ID NO:905/VL SEQ ID NO:979);
NK77.58_CD70_DB03_H08(VH SEQ ID NO:943/VL SEQ ID NO:1017);
NK77.11_CD70_DB02_A05(VH SEQ ID NO:899/VL SEQ ID NO:973);
NK77.16_CD70_DB02_A11(VH SEQ ID NO:904/VL SEQ ID NO:978);
NK77.44_CD70_DB03_B06(VH SEQ ID NO:929/VL SEQ ID NO:1003);
NK77.31_CD70_DB02_F08(VH SEQ ID NO:916/VL SEQ ID NO:990);
NK77.55_CD70_DB03_F12(VH SEQ ID NO:940/VL SEQ ID NO:1014);
NK77.65_CD70_DB04_B05(VH SEQ ID NO:950/VL SEQ ID NO:1024); and
NK77.73_CD70_DB04_D07(VH SEQ ID NO:958/VL SEQ ID NO:1032).
NK77.11, NK77.16, NK77.17, NK77.31, NK77.44, NK77.55, NK77.58, NK77.65, NK77.71, and NK77.73 were effectively expressed and effectively killed cancer cells in Fig. 59D. The instant specification does not show NK cells comprising the VH and VL of anti-CD70 binding domain scFvs comprising a VH of SEQ ID NO:908 and a VL of SEQ ID NO:1032 or a VH of SEQ ID NO:900 and a VL of SEQ ID NO:1024 are effectively expressed in NK cells, bind CD70, or kill cancer cells. The specification only shows a VH of SEQ ID NO:958 and a VL of SEQ ID NO:1032 or a VH of SEQ ID NO:950 and a VL of SEQ ID NO:1024 are effectively expressed in NK cells, bind CD70, or kill cancer cells.
Alignment of the Kabat defined CDRs of show the HCDR1-3 comparing VH SEQ ID NO:908 and SEQ ID NO:958 or VH SEQ ID NO:900 and SEQ ID NO:950 are not identical and have several changes within the binding determinant region.
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79
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86
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Thus, a VH of SEQ ID NO:908 and SEQ ID NO:958 are not considered exchangeable with the same VL and a VH of SEQ ID NO:900 and SEQ ID NO:950 are not considered exchangeable with the same VL.
The instant specification taught that CAR constructs were expressed in: 1) NK cells (Fig. 61D) and T cells (Fig 50E-F) . In a cytotoxicity assay, the tested NK constructs NK77.11, NK77.16, NK77.17, NK77.58, and NK77.71 in donor 512 NK cells all exhibited greater cytotoxicity at E:T ratios of either 1:2 or 1:4 against 786-O cells (Figures 61K-61L) or ACHN cells (Figures 61M-61N) relative to NK71 control and negative control (page 167, [00369]). The cytotoxicity of anti-CD70 CAR expressing NK cells against tumor cells with gene editing was further shown in Fig. 44A-C, 49H-49I, 55A-55M, 56A-56J. Figure 31A shows CAR expression levels an anti-CD70 CAR (NK71) on NK cells treated with CD70 gRNA, CD70 and CISH gRNAs, CD70 and NKG2A gRNAs, CD70 and TGFBR2 gRNAs.
State of the Relevant Art; level of one of ordinary skill; and level of predictability of the art.
1)-2) The prior art taught T cells expressing CD70-specific first- and second-generation CARs which utilized the CD70-binding domain of CD27 for target-cell recognition specifically lysed CD70-positive primary GB cells in vitro, and inhibited growth or induced complete tumor regression in xenograft and syngeneic GB models in mice. (Burger MC et al. CAR-Engineered NK Cells for the Treatment of Glioblastoma: Turning Innate Effectors Into Precision Tools for Cancer Immunotherapy. (Front Immunol. 2019 10:2683. doi: 10.3389/fimmu.2019.02683) page 6, left column, first paragraph). Further, Burger taught similar to T cells, specific recognition and elimination of cancer cells by NK cells can be markedly enhanced through expression of chimeric antigen receptors (CARs), which provides an opportunity to generate NK-cell therapeutics of defined specificity for cancer immunotherapy (abstract). The prior art has not taught a structure activity relationship that would allow less than 100% identity of a sequence defined HCDR1-3 and LCDR1-3 of the VH and VL of NK77.11, NK77.16, NK77.17, NK77.31, NK77.44, NK77.55, NK77.58, NK77.65, NK77.71, and NK77.73.
At the time of the filing of the instant application, it was well established in the art that the formation of an intact antigen-binding site in an antibody usually required the association of the complete heavy and light chain variable regions of a given antibody, each of which consists of three “complementarity determining regions” (“CDRs”) which provide the majority of the contact residues for the binding of the antibody to its target epitope. E.g., Almagro & Fransson, Frontiers in Bioscience 2008; 13:1619-33; (see Section 3 “Antibody Structure and the Antigen Binding Site” and Figure 1). While affinity maturation techniques can result in differences in the CDRs of the antibody compared to its parental antibody (page 3 “The IgG Molecule, second and third paragraphs), those techniques involve trial-and-error testing and the changes that maintain or improve affinity are not predictable a priori. E.g., id., (page 6 ending paragraph onto page 7). Chiu ML et al. (Antibodies 2019 8, 55, 1-80) taught the antigen binding of antibodies often results in conformational changes in the contact surface areas of both the antibody and the antigen (page 5, first paragraph). Thus, the prediction of CDR binding to the epitope is difficult to predict. Chiu further taught antibody modeling has been shown to be accurate for the framework region sequences, but CDR modeling requires further development and improvements (page 6, second paragraph). Prediction of the structure of HCDR3 could not be accurately produced when given the Fv structures without their CDR-H3s (page 6, second paragraph). Chiu taught the quality of antibody structure prediction, particularly regarding CDR-H3, remains inadequate, and the results of antibody–antigen docking are also disappointing (page 11, paragraph 2).
The prior art taught the antigen-binding properties of a CAR are defined by the antigen recognition domain, which usually consists of a single-chain variable fragment (scFv) (Stoiber S et al. (Cells 2019 8 472 doi:10.3390/cells8050472), page 3, last paragraph). Stoiber taught a crucial determinant of CAR functionality is the affinity of the scFv for its cognate antigen and work done by several groups suggests that there is a lower limit to CAR affinity, below which sufficient antigen recognition does not occur, resulting in suboptimal CAR T cell activation (page 4, second paragraph). Stoiber taught the fine-tuning of CAR affinity also encompasses the possibility to mitigate on-target off-tumor toxicities related to low-level antigen expression on normal tissue, while retaining sufficient effector functions to eradicate antigen-overexpressing malignant cells (page 4, third paragraph). Stoiber taught an attenuated response to normal cells is especially relevant in light of a previous report, where a patient died after CAR T cell therapy, likely due to recognition of lung epithelial cells expressing low levels of HER2/neu (page 4, third paragraph). Thus, alteration of antigen binding via changes to the HCDR1-3 and LCDR1-3 of the scFv in a CAR can cause unpredictable changes to CAR activity or toxicity.
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.
The provisional rejection of claims 1, 5, and 14-16 are on the ground of nonstatutory double patenting as being unpatentable over claims 111, 114, 118-119, 121-138 of copending Application No. 18/179,201 is maintained. Although the claims at issue are not identical, they are not patentably distinct from each other because:
Regarding instant claims 1, 5, and 14-16, ‘201 taught a method of treating a CD70-expressing cancer in a subject comprising administering a population of NK cells (instant claim 17 ) engineered to express a CAR comprising a binding domain that targets CD70, a transmembrane domain, and a cytotoxic signaling complex, wherein the binding domain that targets CD70 comprises a scFv (instant claim 10) comprising SEQ ID NO:52, which comprises a VH sequences of NYAIS; GIIPIFGTANYAQKFQG; and DHSAGTHHDAFDI which would be a Kabat defined CDR sequence identical to instant SEQ ID NO:956 and a VL sequences of RASQSIGNWLA; DASDLET; and QQSYTTPWT which would be a Kabat defined CDR sequence identical to instant SEQ ID NO:1030 (instant claims 1 and 3), wherein the VH and VL region of the scFv have at least a 90% sequence identity to a VH of instant SEQ ID NO:956 and a VL of instant SEQ ID NO:1030 (instant claim 5 ) wherein CD70 (instant claim 14 ), CIS (instant claim 15 ), and CBLB (instant claim 16 ) are genomically disrupted, which would be genetically editing to reduce the expression of the protein of the gene, in copending claims 119 and 111.
This is a provisional nonstatutory double patenting rejection because the patentably indistinct claims have not in fact been patented.
Response to Arguments
Applicant respectfully disagrees with the double patenting rejection in view of the '201 application, which is not a proper reference for nonstatutory, obviousness-type double patenting because it has a later filing date, and thus there is no improper time-wise extension of the term of any patent that issues from the pending application. Additionally, the Manual of Patent Examining and Procedure (MPEP) states, "If a provisional nonstatutory double patenting rejection is the only rejection remaining in an application having the earlier patent term filing date, the examiner should withdraw the rejection in the application having the earlier patent term filing date and permit that application to issue as a patent, thereby converting the provisional nonstatutory double patenting rejection in the other application into a nonstatutory double patenting rejection upon issuance of the patent." See Manual of Patent Examining and Procedure § 804.1.B.1.(b )(i). Accordingly, withdrawal of the rejection is respectfully requested.
In response, Applicant's arguments filed 7/31/2026 have been fully considered but they are not persuasive. While the Applicant is correct that the copending ‘201 application is later filed compared to the instant application, the provisional nonstatutory double patenting rejection is not the only rejection remaining in an application. Thus, the rejection is maintained.
The provisional rejection of claims 1, 5, 11-12, and 14-16 are provisionally rejected on the ground of nonstatutory double patenting as being unpatentable over claims 111, 114, 118-119, 121-137 of copending Application No. 18/179,201 is maintained.
The claims of copending ‘201 teach the limitations of claims 1, 5, and 14-16 for the reasons set forth above.
The claims of copending ‘201 did not teach a single embodiment of a method of treating cancer with NK CAR cells wherein the cells comprised a CD8alpha transmembrane domain, and a cytotoxic signaling complex comprising OX-40 and CD3zeta, but this is obvious in view of the claims of ‘201.
Regarding instant claims 11-12, ‘201 taught a population of NK cells engineered to express a CAR comprising a binding domain that targets CD70, a transmembrane domain, and a cytotoxic signaling complex, wherein the binding domain that targets CD70 comprises a scFv comprising SEQ ID NO:52, wherein CD70, CIS, and CBLB are genomically disrupted in copending claim 111 and further taught the NK CAR cells as comprising a CD8alpha transmembrane domain in copending claim 124, and a cytotoxic signaling complex comprising OX-40 and CD3zeta in copending claim 125. The claims of ‘201 further taught a population of NK cells engineered to express a CAR comprising a binding domain that targets CD70, a transmembrane domain, and a cytotoxic signaling complex, wherein the binding domain that targets CD70 comprises a scFv comprising SEQ ID NO:51, 52, or 53 wherein CD70, CIS, and CBLB are genomically disrupted in copending claims 111, 114, 118, and 121-127, and a method for generating CAR cells in immune cells in copending claims 129-137.
Regarding instant claims 11-12, it would have been obvious for a person having ordinary skill in the art to take the method of the above copending claims 119 and 111 for a method of treating a CD70-expressing cancer in a subject comprising administering a population of NK cells engineered to express a CAR comprising a binding domain that targets CD70, a transmembrane domain, and a cytotoxic signaling complex, wherein the binding domain that targets CD70 comprises a scFv comprising SEQ ID NO:52, wherein CD70, CIS, and CBLB are genomically disrupted – and:
include in the CAR a CD8alpha transmembrane domain as described in copending claim 124, and a cytotoxic signaling complex comprising OX-40 and CD3zeta as described in copending claim 125.
This is obvious with a reasonable expectation of success because: 1) ‘201 described the NK CAR cells as further comprising a CD8alpha transmembrane domain in copending claim 124, and a cytotoxic signaling complex comprising OX-40 and CD3zeta in copending claim 125. Further, NK CAR cells would require a transmembrane domain and cytotoxic signaling complex to functionally kill cancer cells. Thus, these regions would be expected to be functional wherein the scFv targets CD70 expressing cancer cells and the transmembrane domain and cytotoxic signaling complex to functionally kill cancer cells.
This is a provisional nonstatutory double patenting rejection.
Response to Arguments
Applicant respectfully disagrees with the double patenting rejection in view of the '201 application, which is not a proper reference for nonstatutory, obviousness-type double patenting because it has a later filing date, and thus there is no improper time-wise extension of the term of any patent that issues from the pending application. Additionally, the Manual of Patent Examining and Procedure (MPEP) states, "If a provisional nonstatutory double patenting rejection is the only rejection remaining in an application having the earlier patent term filing date, the examiner should withdraw the rejection in the application having the earlier patent term filing date and permit that application to issue as a patent, thereby converting the provisional nonstatutory double patenting rejection in the other application into a nonstatutory double patenting rejection upon issuance of the patent." See Manual of Patent Examining and Procedure § 804.1.B.1.(b )(i). Accordingly, withdrawal of the rejection is respectfully requested.
In response, Applicant's arguments filed 7/31/2026 have been fully considered but they are not persuasive. While the Applicant is correct that the copending ‘201 application is later filed compared to the instant application, the provisional nonstatutory double patenting rejection is not the only rejection remaining in an application. Thus, the rejection is maintained.
Allowable Subject Matter
Claims 6, 9, 19-20, 26-27 are objected to as being dependent upon a rejected base claim, but would be allowable is rewritten in independent form, including all of the limitations of the base claim and any intervening claims.
Conclusion
Claims 1, 3, 5, 8, 10-16, 18, 21-23, 25, and 28-29 are rejected.
Claims 6, 9, 19-20, 26-27 are objected to.
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 nonprovisional extension fee (37 CFR 1.17(a)) 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 mailing date of this final action.
Any inquiry concerning this communication or earlier communications from the examiner should be directed to JOHN J SKOKO III whose telephone number is (571)272-1107. The examiner can normally be reached M-F 8:30 - 5:00.
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/J.J.S./Examiner, Art Unit 1643
/Karen A. Canella/Primary Examiner, Art Unit 1643
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