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 67-86 are pending in the instant application and are under consideration.
Objections and Rejections Withdrawn
The objection to claim 69 is withdrawn in view of claim amendment.
The rejections to claims 69 and 86 under 35 USC §112(b) are withdrawn in view of claim amendment.
The rejections to claim 68 under 35 USC §112(d) is withdrawn in view of
claim amendment.
The rejections to claims 71, 73, and 76 under 35 USC §112(d) are withdrawn in view of the claimed ASTR 90% sequence comprising HCDR1-3 and LCDR1-3 not present in the VH of instant SEQ ID NO: 119 and VL of instant SEQ ID NO: 122.
The rejections to claims 68-75 and 77-86 under 35 USC §112(a) are withdrawn in view of the CDR mutations being detailed in the specification wherein the HCDR3 mutation of Y or E is specified as Y109V in VH SEQ ID NO:119 (page 103, [0343]) and wherein the LCDR2 mutation of Y or E is specified as Y055E in VH SEQ ID NO:122 (page 103, [0344]).
The rejections to claims 67-86 under nonstatutory double patenting are withdrawn in view of claim amendment.
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 67-86 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.
Claim 76 claims a nucleic acid encoding a CAR comprising an ASTR that binds to the same epitope as an antibody or a single-chain variable antibody fragment comprising the antibody heavy chain variable region of SEQ ID NO: 119 and the antibody light chain variable region of SEQ ID NO: 122. Thus, the claimed nucleic acid encoding a CAR comprises an ASTR that binds to the same epitope as another antibody, but the prediction of CDR binding to the epitope is unpredictable to the prior art. Further, the instant specification does not teach a structure activity relationship for what CDR residues of the ASTR can be altered that: 1) increases; 2) decreases; or 3) does not change, binding to the HER2 binding epitope which binds an ASTR comprising a VH of instant SEQ ID NO:119 and a VL of instant SEQ ID NO:122.
Claim 67 claims a nucleic acid encoding a CAR comprising an ASTR, wherein: A) amino acid 11 of SEQ ID NO: 133 is V of HCDR3; and B) amino acid 6 of SEQ ID NO: 135 is E of LCDR2, but these variations of the CDR region were not tested to determine binding of HER2 to an ASTR. Further, the instant specification does not teach a structure activity relationship for what CDR residues of the ASTR can be altered that: 1) increases; 2) decreases; or 3) does not change, binding to HER2. Claims 68-86 are also rejected because the claims depend on claim 67 without narrowing the claims outside of an ASTR, wherein: A) amino acid 11 of SEQ ID NO: 133 is V of HCDR3; and B) amino acid 6 of SEQ ID NO: 135 is E of LCDR2.
Scope of the claimed genus
Claim 76 claims a nucleic acid encoding a CAR for binding HER2 comprising a ASTR that binds HER2, a transmembrane domain, and an intracellular activating domain, wherein the ASTR binds to the same epitope of HER2 as an antibody or a single-chain variable antibody fragment comprising the antibody heavy chain variable region of SEQ ID NO: 119 and the antibody light chain variable region of SEQ ID NO: 122. Thus, the claimed nucleic acid encoding a CAR comprises an ASTR that binds to the same epitope as another antibody.
Claim 67 claims a nucleic acid encoding a CAR for binding HER2 comprising a ASTR that binds HER2, a transmembrane domain, and an intracellular activating domain, wherein the ASTR comprises: A) amino acid 11 of SEQ ID NO: 133 is V of HCDR3; and B) amino acid 6 of SEQ ID NO: 135 is E of LCDR2, but these variations of the CDR region were not tested to determine binding of HER2 for the claimed ASTR comprising a VH of HCDR1-3 of SEQ ID NO:131, 137, and 133 and a VL of LCDR1-3 of SEQ ID NO:142, 135, and 143, wherein the combination of X1, X2, X3, and X4 is, respectively: a) K, R, A, and H; b) K, E, A, and H; c) R, R, D, and H; d) K, E, D, and H; e) R, R, A, and D; f) R R, D, and D; g) K, R, D, and D; h) K, E, D, and D; i) R, R, A, and E; j) K, E, A, and E; k) K, RD, and E; or l) K, E, D, and E. Claims 68-86 are also rejected because the claims depend on claim 67 without narrowing the claims outside of an ASTR, wherein: A) amino acid 11 of SEQ ID NO: 133 is V of HCDR3; and B) amino acid 6 of SEQ ID NO: 135 is E of LCDR2.
Summary of Species Disclosed
Fig. 1 tested binding of instant antibodies: Fig 1A - VH-wt/VL-wt (BM); VH-R050K/VL-wt; VH-R059ENL-wt; VH-wt/VL-A032D; VH-wt/VL-H091D; VH-wt/VL-H091E; and in FIG. 1B - VH-wt/VL-wt (BM); VH-N028W /VL-A032D; VH-Y052K/VLA032D; VH-Y052D/VL-A032D; VH-N055ANL-A032D; VH-G056K/VL-A032D; VH-T058D/VLA032D; VH-A1063NL-A032D; and VH-Sl 19ENL-A032D. The HER2 recombinant protein tested in the ELISA assay in Fig. 1 comprised the entire HER2 protein, not only the epitope of HER2 that binds trastuzumab. Further, the instant specification does not teach a structure activity relationship for what CDR residues of the ASTR can be altered that: 1) increases; 2) decreases; or 3) does not change, binding to the HER2 binding epitope which binds an ASTR comprising a VH of instant SEQ ID NO:119 and a VL of instant SEQ ID NO:122.
The instant specification does not test any species of an antibody wherein the ASTR comprises: A) amino acid 11 of SEQ ID NO: 133 is V for HCDR3; and B) amino acid 6 of SEQ ID NO: 135 is E for LCDR2, for the claimed ASTR comprising a VH of HCDR1-3 of SEQ ID NO:131, 137, and 133 and a VL of LCDR1-3 of SEQ ID NO:142, 135, and 143, wherein the combination of X1, X2, X3, and X4 is, respectively: a) K, R, A, and H; b) K, E, A, and H; c) R, R, D, and H; d) K, E, D, and H; e) R R A, and D; f) R R, D, and D; g) K, R, D, and D; h) K, E, D, and D; i) R, R, A, and E; j) K, E, A, and E; k) K, RD, and E; or l) K, E, D, and E.
State of the Relevant Art
The ASTR comprising a VH of instant SEQ ID NO:119 and a VL of instant SEQ ID NO:122 comprises the amino acid sequence of trastuzumab. Moon SK et al. (Molecules and Cells 2016 39(3) 217-228) taught trastuzumab
is the humanized monoclonal antibody hu4D5 that binds to extracellular domain
IV of the HER2 receptor (page 217, right column, second paragraph). Moon taught construction of scFv libraries via random mutagenesis of several residues of CDR-H3 and -L3 of hu4D5 (abstract). Moon taught binding energy calculation and molecular modeling suggest that the substitution of residues of CDR-H3 to W98, F100c, A101 and L102 could stabilize binding of the antibody to HER2 and there could be direct hydrophobic interactions between the aromatic ring of W98 and the aliphatic group of I613 within HER2 domain IV as well as the heavy and light chain hydrophobic interactions by residues F100c, A101 and L102 of CDR-H3 (abstract). Moon taught CDR mutations led to results contrary to expectations, wherein the HER2-binding affinity of A058, which was substituted with W98, F100c, A101, and L102 in CDR-H3 (identical to AH06) and had 3 residues substituted with Q93, A96 and S97 in CDR-L3, was reduced to half that of hu4D5 (page 225, right column, third paragraph). Thus, mutations within the CDR of trastuzumab lead to unpredictable results in HER2 target binding. Further, alterations within the CDR would lead to unpredictable changes in epitope binding.
It is well established in the art that the formation of an intact antigen-binding site in an antibody usually requires the association of the complete heavy and light chain variable regions of a given antibody, each of which comprises three CDRs (or hypervariable regions) which provide the majority of the contact residues for the binding of the antibody to its target epitope. E.g., Almagro et. al., Front. Immunol. 2018; 8:1751 (see Section “The IgG Molecule” in paragraph 1 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).
Conclusion
Regarding claim 76, the Applicant does not have written description for a genus of species of nucleic acids encoding a CAR comprising an ASTR that binds to the same epitope as an antibody or a single-chain variable antibody fragment comprising the antibody heavy chain variable region of SEQ ID NO: 119 and the antibody light chain variable region of SEQ ID NO: 122. The prediction of CDR binding to the epitope is unpredictable and a structure activity relationship is not disclosed for what antibodies can or cannot bind to the same epitope as an antibody or a single-chain variable antibody fragment comprising the antibody heavy chain variable region of SEQ ID NO: 119 and the antibody light chain variable region of SEQ ID NO: 122.
Regarding claim 67, the Applicant does not have written description for a genus of species of nucleic acids encoding a CAR comprising an ASTR, wherein: A) amino acid 11 of SEQ ID NO: 133 is V of HCDR3; and B) amino acid 6 of SEQ ID NO: 135 is E of LCDR2. These variations of the CDR region were not tested to determine binding of HER2 to an ASTR and the instant specification does not teach a structure activity relationship for what CDR residues of the ASTR can be altered that: 1) increases; 2) decreases; or 3) does not change, binding to HER2. Claims 68-86 are also rejected because the claims depend on claim 67 without narrowing the claims outside of an ASTR, wherein: A) amino acid 11 of SEQ ID NO: 133 is V of HCDR3; and B) amino acid 6 of SEQ ID NO: 135 is E of LCDR2. Claims 68-86 are also rejected because the claims depend on claim 67 without narrowing the claims outside of an ASTR, wherein: A) amino acid 11 of SEQ ID NO: 133 is V of HCDR3; and B) amino acid 6 of SEQ ID NO: 135 is E of LCDR2.
Claims 67-86 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: 1) a CAR comprising an ASTR, wherein: A) amino acid 11 of SEQ ID NO: 133 is Y of HCDR3; and B) amino acid 6 of SEQ ID NO: 135 is Y of LCDR2, does not reasonably provide enablement for 1) a CAR comprising an ASTR, wherein: A) amino acid 11 of SEQ ID NO: 133 is V of HCDR3; and B) amino acid 6 of SEQ ID NO: 135 is E of LCDR2. The specification does not enable any person skilled in the art to which it pertains, or with which it is most nearly connected, to use the invention commensurate in scope with these claims.
Claim 67 claims a nucleic acid encoding a CAR comprising an ASTR, wherein: A) amino acid 11 of SEQ ID NO: 133 is V of HCDR3; and B) amino acid 6 of SEQ ID NO: 135 is E of LCDR2, but these variations of the CDR region were not tested to determine binding of HER2 to an ASTR. Further, the instant specification and prior art does not teach a structure activity relationship for what CDR residues of the claimed ASTR can be altered that: 1) increases; 2) decreases; or 3) does not change, binding to HER2. Claims 68-86 are also rejected because the claims depend on claim 67 without narrowing the claims outside of an ASTR, wherein: A) amino acid 11 of SEQ ID NO: 133 is V of HCDR3; and B) amino acid 6 of SEQ ID NO: 135 is E of LCDR2.
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.
Claim 67 claims a nucleic acid encoding a CAR for binding HER2 comprising a ASTR that binds HER2, a transmembrane domain, and an intracellular activating domain, wherein the ASTR comprises: A) amino acid 11 of SEQ ID NO: 133 is V of HCDR3; and B) amino acid 6 of SEQ ID NO: 135 is E of LCDR2, but these variations of the CDR region were not tested to determine binding of HER2 for the claimed ASTR comprising a VH of HCDR1-3 of SEQ ID NO:131, 137, and 133 and a VL of LCDR1-3 of SEQ ID NO:142, 135, and 143, wherein the combination of X1, X2, X3, and X4 is, respectively: a) K, R, A, and H; b) K, E, A, and H; c) R, R, D, and H; d) K, E, D, and H; e) R R A, and D; f) R R, D, and D; g) K, R, D, and D; h) K, E, D, and D; i) R, R, A, and E; j) K, E, A, and E; k) K, RD, and E; or l) K, E, D, and E. Claims 68-86 are also rejected because the claims depend on claim 67 without narrowing the claims outside of an ASTR, wherein: A) amino acid 11 of SEQ ID NO: 133 is V of HCDR3; and B) amino acid 6 of SEQ ID NO: 135 is E of LCDR2.
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.
The instant specification does not test any species of an antibody wherein the ASTR comprises: A) amino acid 11 of SEQ ID NO: 133 is V for HCDR3; and B) amino acid 6 of SEQ ID NO: 135 is E for LCDR2, for the claimed ASTR comprising a VH of HCDR1-3 of SEQ ID NO:131, 137, and 133 and a VL of LCDR1-3 of SEQ ID NO:142, 135, and 143, wherein the combination of X1, X2, X3, and X4 is, respectively: a) K, R, A, and H; b) K, E, A, and H; c) R, R, D, and H; d) K, E, D, and H; e) R R A, and D; f) R R, D, and D; g) K, R, D, and D; h) K, E, D, and D; i) R, R, A, and E; j) K, E, A, and E; k) K, RD, and E; or l) K, E, D, and E.
Fig. 1 tested binding of instant antibodies: Fig 1A - VH-wt/VL-wt (BM); VH-R050K/VL-wt; VH-R059ENL-wt; VH-wt/VL-A032D; VH-wt/VL-H091D; VH-wt/VL-H091E; and in FIG. 1B - VH-wt/VL-wt (BM); VH-N028W /VL-A032D; VH-Y052K/VLA032D; VH-Y052D/VL-A032D; VH-N055ANL-A032D; VH-G056K/VL-A032D; VH-T058D/VLA032D; VH-A1063NL-A032D; and VH-Sl 19ENL-A032D. The HER2 recombinant protein tested in the ELISA assay in Fig. 1 comprised the entire HER2 protein, not only the epitope of HER2 that binds trastuzumab. Further, the instant specification does not teach a structure activity relationship for what CDR residues of the ASTR can be altered that: 1) increases; 2) decreases; or 3) does not change, binding to the HER2 binding epitope which binds an ASTR comprising a VH of instant SEQ ID NO:119 and a VL of instant SEQ ID NO:122.
State of the Relevant Art; level of one of ordinary skill; and level of predictability of the art.
The ASTR comprising a VH of instant SEQ ID NO:119 and a VL of instant SEQ ID NO:122 comprises the amino acid sequence of trastuzumab. Moon SK et al. (Molecules and Cells 2016 39(3) 217-228) taught trastuzumab
is the humanized monoclonal antibody hu4D5 that binds to extracellular domain
IV of the HER2 receptor (page 217, right column, second paragraph). Moon taught construction of scFv libraries via random mutagenesis of several residues of CDR-H3 and -L3 of hu4D5 (abstract). Moon taught binding energy calculation and molecular modeling suggest that the substitution of residues of CDR-H3 to W98, F100c, A101 and L102 could stabilize binding of the antibody to HER2 and there could be direct hydrophobic interactions between the aromatic ring of W98 and the aliphatic group of I613 within HER2 domain IV as well as the heavy and light chain hydrophobic interactions by residues F100c, A101 and L102 of CDR-H3 (abstract). Moon taught CDR mutations led to results contrary to expectations, wherein the HER2-binding affinity of A058, which was substituted with W98, F100c, A101, and L102 in CDR-H3 (identical to AH06) and had 3 residues substituted with Q93, A96 and S97 in CDR-L3, was reduced to half that of hu4D5 (page 225, right column, third paragraph). Thus, mutations within the CDR of trastuzumab lead to unpredictable results in HER2 target binding.
It is well established in the art that the formation of an intact antigen-binding site in an antibody usually requires the association of the complete heavy and light chain variable regions of a given antibody, each of which comprises three CDRs (or hypervariable regions) which provide the majority of the contact residues for the binding of the antibody to its target epitope. E.g., Almagro et. al., Front. Immunol. 2018; 8:1751 (see Section “The IgG Molecule” in paragraph 1 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).
Conclusion
Regarding claim 67, the Applicant does not have enablement for a genus of species of nucleic acids encoding the claimed CAR comprising an ASTR, wherein: A) amino acid 11 of SEQ ID NO: 133 is V of HCDR3; and B) amino acid 6 of SEQ ID NO: 135 is E of LCDR2. These variations of the CDR region were not tested to determine binding of HER2 to the claimed ASTR and the instant specification and prior art does not teach a structure activity relationship for what CDR residues of the claimed ASTR can be altered that: 1) increases; 2) decreases; or 3) does not change, binding to HER2. Claims 68-86 are also rejected because the claims depend on claim 67 without narrowing the claims outside of an ASTR, wherein: A) amino acid 11 of SEQ ID NO: 133 is V of HCDR3; and B) amino acid 6 of SEQ ID NO: 135 is E of LCDR2.
Claim 76 is rejected under 35 U.S.C. 112(a) or 35 U.S.C. 112 (pre-AIA ), first paragraph, as failing to comply with the enablement requirement. The claim(s) contains subject matter which was not described in the specification in such a way as to enable one skilled in the art to which it pertains, or with which it is most nearly connected, to make and/or use the invention.
Claim 76 claims a nucleic acid encoding a CAR comprising an ASTR that binds to the same epitope as an antibody or a single-chain variable antibody fragment comprising the antibody heavy chain variable region of SEQ ID NO: 119 and the antibody light chain variable region of SEQ ID NO: 122. Thus, the claimed nucleic acid encoding a CAR comprises an ASTR that binds to the same epitope as another antibody, but the prediction of CDR binding to the epitope is unpredictable to the prior art. Further, the instant specification and prior art does not teach a structure activity relationship for what CDR residues of the claimed ASTR can be altered that: 1) increases; 2) decreases; or 3) does not change, binding to the HER2 binding epitope which binds an ASTR comprising a VH of instant SEQ ID NO:119 and a VL of instant SEQ ID NO:122.
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.
Claim 76 claims a nucleic acid encoding a CAR for binding HER2 comprising a ASTR that binds HER2, a transmembrane domain, and an intracellular activating domain, wherein the ASTR binds to the same epitope of HER2 as an antibody or a single-chain variable antibody fragment comprising the antibody heavy chain variable region of SEQ ID NO: 119 and the antibody light chain variable region of SEQ ID NO: 122. Thus, the claimed nucleic acid encoding a CAR comprises an ASTR that binds to the same epitope as another antibody.
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.
Fig. 1 tested binding of instant antibodies: Fig 1A - VH-wt/VL-wt (BM); VH-R050K/VL-wt; VH-R059ENL-wt; VH-wt/VL-A032D; VH-wt/VL-H091D; VH-wt/VL-H091E; and in FIG. 1B - VH-wt/VL-wt (BM); VH-N028W /VL-A032D; VH-Y052K/VLA032D; VH-Y052D/VL-A032D; VH-N055ANL-A032D; VH-G056K/VL-A032D; VH-T058D/VLA032D; VH-A1063NL-A032D; and VH-Sl 19ENL-A032D. The HER2 recombinant protein tested in the ELISA assay in Fig. 1 comprised the entire HER2 protein, not only the epitope of HER2 that binds trastuzumab. Further, the instant specification does not teach a structure activity relationship for what CDR residues of the ASTR can be altered that: 1) increases; 2) decreases; or 3) does not change, binding to the HER2 binding epitope which binds an ASTR comprising a VH of instant SEQ ID NO:119 and a VL of instant SEQ ID NO:122.
State of the Relevant Art; level of one of ordinary skill; and level of predictability of the art.
The ASTR comprising a VH of instant SEQ ID NO:119 and a VL of instant SEQ ID NO:122 comprises the amino acid sequence of trastuzumab. Moon SK et al. (Molecules and Cells 2016 39(3) 217-228) taught trastuzumab
is the humanized monoclonal antibody hu4D5 that binds to extracellular domain
IV of the HER2 receptor (page 217, right column, second paragraph). Moon taught construction of scFv libraries via random mutagenesis of several residues of CDR-H3 and -L3 of hu4D5 (abstract). Moon taught binding energy calculation and molecular modeling suggest that the substitution of residues of CDR-H3 to W98, F100c, A101 and L102 could stabilize binding of the antibody to HER2 and there could be direct hydrophobic interactions between the aromatic ring of W98 and the aliphatic group of I613 within HER2 domain IV as well as the heavy and light chain hydrophobic interactions by residues F100c, A101 and L102 of CDR-H3 (abstract). Moon taught CDR mutations led to results contrary to expectations, wherein the HER2-binding affinity of A058, which was substituted with W98, F100c, A101, and L102 in CDR-H3 (identical to AH06) and had 3 residues substituted with Q93, A96 and S97 in CDR-L3, was reduced to half that of hu4D5 (page 225, right column, third paragraph). Thus, mutations within the CDR of trastuzumab lead to unpredictable results in HER2 target binding. Further, alterations within the CDR would lead to unpredictable changes in epitope binding.
It is well established in the art that the formation of an intact antigen-binding site in an antibody usually requires the association of the complete heavy and light chain variable regions of a given antibody, each of which comprises three CDRs (or hypervariable regions) which provide the majority of the contact residues for the binding of the antibody to its target epitope. E.g., Almagro et. al., Front. Immunol. 2018; 8:1751 (see Section “The IgG Molecule” in paragraph 1 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).
Conclusion
Regarding claim 76, the Applicant does not have enablement for a genus of species of nucleic acids encoding a CAR comprising an ASTR that binds to the same epitope as an antibody or a single-chain variable antibody fragment comprising the antibody heavy chain variable region of SEQ ID NO: 119 and the antibody light chain variable region of SEQ ID NO: 122. The prediction of CDR binding to the epitope is unpredictable and a structure activity relationship is not disclosed for what antibodies can or cannot bind to the same epitope as an antibody or a single-chain variable antibody fragment comprising the antibody heavy chain variable region of SEQ ID NO: 119 and the antibody light chain variable region of SEQ ID NO: 122.
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.
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Claims 67-75, 77-81, and 83-85 are provisionally rejected on the ground of nonstatutory double patenting as being unpatentable over claims 1-19 and 43-68 of copending Application No. 17/759,195 in view of Sun M et al. (Breast Cancer Res. 2014 Jun 11;16(3):R61 reference of record) and US 20160207989 (Short J et al. reference of record) and evidenced by Cheng LS et al. (Cell Research 2003 13, 35–48 reference of record).
‘195 claim 1 taught an antibody or antibody fragment that specifically binds HER2, wherein the antibody fragment comprises:
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‘195 claim 12 taught an antibody fragment comprising a heavy chain variable region of SEQ ID NO:33 and a light chain variable region of SEQ ID NO:31, wherein the VH sequence comprises GFNIKDTYIH; RIYPTNGYTRYADSVKG; and WGGDGFYAMDY, and the VL sequence comprises RASQDVNTAVA; SASFLYS; and QQDYTTPPT. ‘195 claim 9 taught an antibody fragment comprising a VH of SEQ ID NO:27 and a VL of SEQ ID NO:31. ‘195 claim 43 taught The antibody or antibody fragment of claim 1, wherein the antibody or antibody fragment has a ratio of binding affinity to the HER2 protein at a pH in a tumor microenvironment to a binding affinity to the HER2 protein at a different pH in a non-tumor microenvironment of at least about 1.5:1 ‘195 claim 51 taught the antibody or antigen binding fragment of copending claim 1 in a composition with a pharmaceutically acceptable carrier, wherein claims 52-57 taught further combinations with the composition. ‘195 claim 58 taught a method of treating cancer by administering the antibody fragment of claim 1 to a patient with cancer. ‘195 claims 2, 8 taught a bispecific antibody of HER2 and CD3. ‘195 claims 3-7 further narrowed the claimed X variables of CDRs in the HER2 antibody or antigen binding fragment of ‘195 claim 1, while claims 44-50 taught conjugates. ‘195 claims 9-11 and 13-19 taught sequences of a HER2 antibody or antigen binding fragment.
The claims of ‘195 did not teach a chimeric antigen receptor for binding HER2, but this is obvious in view of Sun and Short.
Sun taught construction of a pSin lentiviral vector plasmid, which has an operably linked promoter active in T cells for expression of a chimeric antigen receptor of an anti-HER2 scFvA21 which includes a VH and VL domain with a spacer and a CD8 hinge as a stalk, CD28 transmembrane domain, CD28 co-stimulatory intracellular domain, and a CD3Z signaling domain (Fig. 1), wherein T cells transduced with the plasmid express the CAR and kill HER2+ tumor cells in vitro (Fig. 4) and wherein a composition was administered via injection in a delivery suspension in vivo (Fig. 5). Cheng evidenced that the HER2 targeting scFvA21 antigen binding fragment contains a linker of (Gly4Ser)4 (page 36, last paragraph) and an orientation of VL-linker-VH (page 39, right column, first paragraph).
Short taught a CAR comprising an ASTR, extracellular spacer domain, transmembrane domain, co-stimulatory domain, and an intracellular signaling domain (Fig. 1). Short taught CAR-T Cells with a conditionally active scFv antibody against target antigen ROR2 (page 40, paragraph 381), wherein scFv-116101, was used to construct CAR molecules for producing CAR-T cells (116101 CAR-T), wherein the CAR-T cells with the scFv antibody targeting target antigen ROR2 on the Daudi cells (116101 CAR-T) induced significant cell death for the Daudi cells as shown by the higher dead/live cell ratio in FIG. 11A. (page 40, paragraph 382) and INFgamma and IL cytokine levels were elevated after binding of CAR-T cells containing a conditionally active scFv antibody against target antigen ROR2 with Rajib
cells and Daudi cells both of which express target antigen ROR2 (page 40, paragraph 385 and Fig. 13A-13B).
Regarding instant claims 67-75, 77-81, and 83-85, it would have been obvious for a person having ordinary skill in the art to take the antibody of ‘195 claim 12 comprising a heavy chain variable region of SEQ ID NO:33 and a light chain variable region of SEQ ID NO:31, wherein the VH sequence comprises GFNIKDTYIH; RIYPTNGYTRYADSVKG; and WGGDGFYAMDY, and the VL sequence comprises RASQDVNTAVA; SASFLYS; and QQDYTTPPT– and:
Exchange the nucleic acid coding for the VH and VL in the scFv CAR T cells in a delivery suspension for in vivo administration of Sun with the nucleic acid encoding the VH and VL of ‘195 T cells in a pSin lentiviral vector with a promoter encoding for a CAR comprising of an anti-HER2 scFv with a CD8 hinge as a stalk, CD28 transmembrane domain, CD28 co-stimulatory intracellular domain, and a CD3Z signaling domain.
This is obvious with a reasonable expectation of success because: 1a) ‘195 taught a HER2 antibody Sun taught that the scFv HER2 antibodies in the scFv formats were effective against cancer cells; 1b) ‘195 claim 43 taught antibody fragments comprising the CDR as conditionally active, and 1c) Short taught conditionally active CAR cells where effective. Further, the HER2 targeting antibody of ‘195 would be expected to target HER2 in cancer cells and be effective.
This would produce a delivery suspension for in vivo administration of modified T cells (instant claim 70) with a pSin lentiviral vector which has an operably linked promoter active in T cells for expression of a chimeric antigen receptor (instant claim 69) that encodes for a CAR comprising of an anti-HER2 scFv (instant claim 77) wherein the VH sequence comprises GFNIKDTYIH; RIYPTNGYTRYADSVKG; and WGGDGFYAMDY, and the VL sequence comprises RASQDVNTAVA; SASFLYS; and QQDYTTPPT (instant claim 78) and the linker separating the VH and VL contains a sequence of (Gly4Ser)4, which has an identical sequence to instant SEQ ID NO:152 (instant claims 79-80), in the orientation of VL-linker-VH (instant claim 81), with a CD8 hinge as a stalk domain, CD28 transmembrane domain, CD28 co-stimulatory intracellular domain, and a CD3Z signaling domain (instant claims 83-85), wherein the X1-X4 CDR variables would be R, R, A, and D respectively (instant claim 71). This meets the limitations of instant claims 67-68. Further, this would naturally produce a CAR that is conditionally active having increased CAR activity at a pH of 6.7 compared to a pH of 7.4 as evidenced by X4-08 in Fig. 3A (instant claim 72). This also meets the limitations of at least 90% identical to instant SEQ ID NO:119
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(instant claim 74) and 90% identical to instant SEQ ID NO:122
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(instant claim 73 and 75).
This is a provisional nonstatutory double patenting rejection.
Response to Arguments
Applicant respectfully requests that the Examiner hold the provisional double patenting rejections in abeyance until such time as the claims at issue are deemed otherwise allowable.
Applicant's arguments filed 10/31/2025 have been fully considered but they are not persuasive. Applicant requests that the double patenting rejection over co-pending application 17/759,195 be held in abeyance (Remarks p. 10). A request to hold a rejection in abeyance is not a proper response to a rejection. Rather, a request to hold a matter in abeyance may only be made in response to an OBJECTION or REQUIREMENTS AS TO FORM (see 37 CFR 1.111(b) and MPEP §714.02). The double patenting rejection is above.
Claims 67-75 and 77-85 are provisionally rejected on the ground of nonstatutory double patenting as being unpatentable over claims 1-19 and 43-68 of copending Application No. 17/759,195 in view of Sun M et al. (Breast Cancer Res. 2014 Jun 11;16(3):R61 reference of record) and US 20160207989 (Short J et al. reference of record) and Ahmad ZA et al. Clin Dev Immunol. 2012 2012:980250 reference of record).
The claims of the ‘195 patent in view of Sun and Short teach the limitations of claims 67-75, 77-81, and 83-85 for the reasons set forth above.
‘195, Sun, and Short are discussed above.
‘195 is silent to the orientation of a scFv of VH-linker-VL or VL-linker-VH, but both are obvious in view of Ahmad.
Ahmad taught in the scFv (single-chain fragment variable) construction, the order of the domains can be either VH-linker-VL or VL-linker-VH and both orientations have been applied (page 3, left column, last paragraph). Ahmad taught most of the scFv (single-chain fragment variable) are constructed in a VH-linker-VL orientation (page 3, left column, last paragraph).
Regarding instant claim 82, it would have been obvious for a person having ordinary skill in the art to take the delivery suspension for in vivo administration of modified T cells that encodes for a CAR comprising of an anti-HER2 scFv wherein the VH sequence comprises GFNIKDTYIH; RIYPTNGYTRYADSVKG; and WGGDGFYAMDY, and the VL sequence comprises RASQDVNTAVA; SASFLYS; and QQDYTTPPT and the linker separating the VH and VL contains a sequence of (Gly4Ser)4 in the orientation of VL-linker-VH above – and: 1) exchange the order of the VH and VL fragment from VL-linker-VH to VH-linker-VL.
This is obvious because Ahmad taught the order of the domains of scFv antibodies can be either VH-linker-VL or VL-linker-VH and both orientations have been applied and most of the scFv (single-chain fragment variable) are constructed in a VH-linker-VL orientation.
There is a reasonable expectation of success because the scFv in the CAR would still be expected to bind its target HER2.
This is a provisional nonstatutory double patenting rejection.
Response to Arguments
Applicant respectfully requests that the Examiner hold the provisional double patenting rejections in abeyance until such time as the claims at issue are deemed otherwise allowable.
Applicant's arguments filed 10/31/2025 have been fully considered but they are not persuasive. Applicant requests that the double patenting rejection over co-pending application 17/759,195 be held in abeyance (Remarks p. 10). A request to hold a rejection in abeyance is not a proper response to a rejection. Rather, a request to hold a matter in abeyance may only be made in response to an OBJECTION or REQUIREMENTS AS TO FORM (see 37 CFR 1.111(b) and MPEP §714.02). The double patenting rejection is above.
Claims 67-75, 77-81, and 83-86 are provisionally rejected on the ground of nonstatutory double patenting as being unpatentable over claims 1-19 and 43-68 of copending Application No. 17/759,195 in view of Sun M et al. (Breast Cancer Res. 2014 Jun 11;16(3):R61 reference of record) and US 20160207989 (Short J et al. reference of record) and Turtle CJ et al. (Sci Transl Med. 2016 Sep 7;8(355):355ra116 reference of record).
The claims of the ‘195 patent in view of Sun and Short teach the limitations of claims 67-75, 77-81, and 83-85 for the reasons set forth above.
‘195, Sun, and Short are discussed above.
‘195 is silent to inclusion of a recognition domain recognized by a regulatory approved antibody, but this is obvious in view of Turtle CJ et al.
Turtle taught T cells were transduced with a lentiviral vector that encoded the CD19 CAR and a truncated cell surface human epidermal growth factor receptor (EGFRt), which enabled identification of transduced cells by flow cytometry using the anti-EGFR monoclonal antibody, cetuximab (page 2, right column, paragraph 3) and Fig. 3 showed that it was clinically effective at tracking CAR-T cells in patients.
Regarding instant claim 86, it would have been obvious for a person having ordinary skill in the art to take the delivery suspension for in vivo administration of modified T cells that encodes for a CAR comprising of an anti-HER2 scFv wherein the VH sequence comprises GFNIKDTYIH; RIYPTNGYTRYADSVKG; and WGGDGFYAMDY, and the VL sequence comprises RASQDVNTAVA; SASFLYS; and QQDYTTPPT above – and: 1) further include a recognition domain wherein the recognition domain is recognized by cetuximab an approved EGFR antibody.
This is obvious with a reasonable expectation of success because: 1) Turtle taught T cells transduced with a lentiviral vector that encoded the CD19 CAR and a truncated cell surface human epidermal growth factor receptor (EGFRt) enabled identification of transduced cells by flow cytometry using the anti-EGFR monoclonal antibody, cetuximab and was clinically effective at tracking CAR-T cells in patients. Thus, including a truncated cell surface human epidermal growth factor receptor (EGFRt) would allow for tracking of the CAR-T cells in vivo.
This is a provisional nonstatutory double patenting rejection.
Response to Arguments
Applicant respectfully requests that the Examiner hold the provisional double patenting rejections in abeyance until such time as the claims at issue are deemed otherwise allowable.
Applicant's arguments filed 10/31/2025 have been fully considered but they are not persuasive. Applicant requests that the double patenting rejection over co-pending application 17/759,195 be held in abeyance (Remarks p. 10). A request to hold a rejection in abeyance is not a proper response to a rejection. Rather, a request to hold a matter in abeyance may only be made in response to an OBJECTION or REQUIREMENTS AS TO FORM (see 37 CFR 1.111(b) and MPEP §714.02). The double patenting rejection is above.
Conclusion
Claims 67-86 are rejected.
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.
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/J.J.S./Examiner, Art Unit 1643
/Karen A. Canella/Primary Examiner, Art Unit 1643