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
This action is in response to the papers filed October 29, 2025.
Election/Restrictions
Applicant’s reply filed 10/29/2025 to the Requirement for Restriction/Election mailed 07/30/2025 is acknowledged.
Applicant elected without traverse the invention of Group 1, drawn to a method of treating multiple myeloma in a subject in need thereof, and the antigen-binding domain according to SEQ ID NO: 114.
Please note that the elected antigen-binding domain according to SEQ ID NO: 114 comprises the variable heavy chain according to SEQ ID NO: 116 and the variable light chain according to SEQ ID NO: 119, and the CAR polypeptide according to SEQ ID NO: 19 comprises the elected antigen-binding domain according to SEQ ID NO: 114. The nonelected antigen-binding domains according to SEQ ID NOs: 126 and 128 each comprise the variable heavy chain according to SEQ ID NO: 125 and the variable light chain according to SEQ ID NO: 127.
Claims 91-93, and 121 are withdrawn from further consideration pursuant to 37 CFR 1.142(b) as being drawn to a nonelected invention, there being no allowable generic or linking claim. Election was made without traverse in the reply filed on 10/29/2025.
Claim Amendments
Applicant’s amendment to the claims filed 10/29/2025 is acknowledged.
Claims 6-21, 23-28, 31-53, 55-65, 67-72, 78-79, 82-87, 94-104, 107-119 have been cancelled.
Claims 1-5, 22, 29-30, 54, 66, 73-77, 80-81, 88-93, 105-106, 120-121 are pending.
Claims 91-93, and 121 are withdrawn from further consideration pursuant to 37 CFR 1.142(b) as being drawn to a nonelected invention.
Claims 1-5, 22, 29-30, 54, 66, 73-77, 80-81, 88-90, 105-106, and 120 are under examination.
Priority
The instant application 17/799,239 was filed on 08/11/2022. This application is a national stage of international application PCT/US2021/017737 filed 02/11/2021, claiming priority based on U.S. Provisional Application 62/975,731 filed 02/12/2020.
Information Disclosure Statement
Applicant’s submission of an information disclosure statement (IDS) on 03/06/2023, 07/10/2024, 03/26/2025 and 10/29/2025, citing 703 references, is acknowledged.
The listing of references in the specification is not a proper information disclosure statement. 37 CFR 1.98(b) requires a list of all patents, publications, or other information submitted for consideration by the Office, and MPEP § 609.04(a) states, "the list may not be incorporated into the specification but must be submitted in a separate paper." Therefore, unless the references have been cited by the examiner on form PTO-892, or by applicant in an information disclosure statement (IDS), they have not been considered.
Specification
The disclosure is objected to because of the following informalities:
The disclosure is objected to because it contains an embedded hyperlink and/or other form of browser-executable code. See paragraph #99. Applicant is required to delete the embedded hyperlink and/or other form of browser-executable code; references to websites should be limited to the top-level domain name without any prefix such as http:// or other browser-executable code. See MPEP § 608.01.
Appropriate action is required.
Claim Rejections - 35 USC § 112
The following is a quotation of 35 U.S.C. 112(b):
(b) CONCLUSION.—The specification shall conclude with one or more claims particularly pointing out and distinctly claiming the subject matter which the inventor or a joint inventor regards as the invention.
The following is a quotation of 35 U.S.C. 112 (pre-AIA ), second paragraph:
The specification shall conclude with one or more claims particularly pointing out and distinctly claiming the subject matter which the applicant regards as his invention.
Claims 1-5, 22, 29-30, 54, 66, 73-77, 80-81, 88-90, 105-106, and 120 are rejected under 35 U.S.C. 112(b) or 35 U.S.C. 112 (pre-AIA ), second paragraph, as being indefinite for failing to particularly point out and distinctly claim the subject matter which the inventor or a joint inventor (or for applications subject to pre-AIA 35 U.S.C. 112, the applicant), regards as the invention.
Claims 1 and 2 each recite a “method of treating multiple myeloma (MM), the method comprising administering to a subject having or suspected having MM a composition.” The recitation is found to be indefinite for the following reasons:
Reciting that the subject is “suspected” of having MM suggests that the subject may not, in fact, have MM. Therefore, one cannot “treat” MM, as stated in the preamble, when the subject does not have MM. Furthermore, the term “suspected” is not clearly defined by the claims, and one of ordinary skill in the art would not be reasonably apprised of the scope of the term “suspected.” For example, “suspecting” that a subject has a disease or disorder is not the same as “diagnosing” a subject with a disease or disorder. Rather, merely “suspecting” the presence of a disease or disorder would be considered, at least, significantly broader in scope than a diagnosis of a disease or disorder in a subject. Therefore, the recitation is indefinite because one of ordinary skill in the art would not have known what standard or criteria must be applied to determine whether or not any subject should be considered as “suspected” of having MM.
For these reasons, one of ordinary skill in the art would not be reasonably apprised of the scope of the invention. Dependent claims 3-5, 22, 29-30, 54, 66, 73-77, 80-81, 88-90, 105-106, and 120 are included in the basis of the rejection because they do not correct the deficiencies of the claim upon which they depend. Changing the term “suspected” to “diagnosed” would be remedial.
Claims 73-77, 80-81 are rejected under 35 U.S.C. 112(b) or 35 U.S.C. 112 (pre-AIA ), second paragraph, as being indefinite for failing to particularly point out and distinctly claim the subject matter which the inventor or a joint inventor (or for applications subject to pre-AIA 35 U.S.C. 112, the applicant), regards as the invention.
Claim 73 recites a that the extracellular antigen-binding domain comprises a CDR-H1, -H2 and -H3 “contained within the sequence set forth in SEQ ID NO: 116,” and the CDR-L1, -L2 and -L3 “contained within the sequence set forth in SEQ ID NO: 119.” The recitation is found to be indefinite for the following reasons:
In this case, according to the specification (Table 9 on pg. 90), SEQ ID NO: 116 and 119 provide the sequences for the variable heavy chain (VH) and variable light chain (VL), respectively. SEQ ID NOs: 116 and 119 do not correspond to the sequences for the complementarity determining regions (CDRs), as claimed. Therefore, the claim fails to define the subsequences of SEQ ID NOs: 116 and 119 which provide the sequences for each CDR. For example, it would have been unclear to one of ordinary skill in the art which amino acid residues of SEQ ID NO: 116 define the CDR-H1.
For these reasons, one of ordinary skill in the art would not be reasonably apprised of the scope of the invention. Dependent claims 74-77, 80-81 are included in the basis of the rejection because they do not correct the deficiencies of the claim upon which they depend. Amending claim 73 to recite the SEQ ID NO for each CDR, as described in Table 9 on page 90 of the specification, would be remedial.
Claims 73-77, 80-81 are rejected under 35 U.S.C. 112(b) or 35 U.S.C. 112 (pre-AIA ), second paragraph, as being indefinite for failing to particularly point out and distinctly claim the subject matter which the inventor or a joint inventor (or for applications subject to pre-AIA 35 U.S.C. 112, the applicant), regards as the invention.
Claim 73 recites a CAR comprising “a spacer comprising an IgG4/2 chimeric hinge or a modified IgG4 hinge; an IgG2/4 chimeric CH2 region; and an IgG4 CH3 region.” The recitation is found to be indefinite for the following reasons:
The terms “IgG4/2” and “IgG2/4” are neither defined by the claims nor specification, and one of ordinary skill in the art would not be reasonably apprised of the scope of the claimed invention. For example, it is unclear if “IgG4/2” means “IgG4 or IgG2” or “IgG4 and 2,” or any hybrid structure of IgG4 and IgG2, or if the term has some other meaning. Furthermore, it is unclear if the terms “IgG4/2” and “IgG2/4” are equivalent to one another, or, otherwise, it is unclear how “IgG4/2” is structurally different from “IgG2/4.”
For these reasons, one of ordinary skill in the art would not be reasonably apprised of the scope of the invention. Dependent claims 74-77, 80-81 are included in the basis of the rejection because they do not correct the deficiencies of the claim upon which they depend.
Claim Rejections - 35 USC § 102
The following is a quotation of the appropriate paragraphs of 35 U.S.C. 102 that form the basis for the rejections under this section made in this Office action:
A person shall be entitled to a patent unless –
(a)(1) the claimed invention was patented, described in a printed publication, or in public use, on sale, or otherwise available to the public before the effective filing date of the claimed invention.
(a)(2) the claimed invention was described in a patent issued under section 151, or in an application for patent published or deemed published under section 122(b), in which the patent or application, as the case may be, names another inventor and was effectively filed before the effective filing date of the claimed invention.
Claims 1-5, 22, 29-30, 66, 73-77, 80-81, 88, 105-106, and 120 are rejected under 35 U.S.C. 102(a)(1) and 35 U.S.C. 102(a)(2) as being anticipated by WO 2019/113557 A1 to Mujacic et al.
Mujacic teaches a method of treating multiple myeloma in a subject in need thereof, comprising administering to the subject a composition comprising engineered T cells expressing a BCMA-targeting CAR. See, e.g., Abstract; paragraphs 785, 788, 906, 921-923, etc.
Mujacic is further found to teach or fairly suggest a composition comprising CD8+ T cells expressing the CAR and CD4+ T cells expressing the CAR; at least or at least about 80% of the cells in the composition are CD3+ cells; and at least or at least about 80% of the CAR+ T cells in the composition are of a naïve-like or central memory phenotype; and at least or at least about 50% of the CD4+CAR+ T cells in the composition are CD27+CCR7+ and/or at least or at least about 50% of the CD8+CAR+ T cells in the composition are CD27+CCR7+. See, e.g., Abstract; paragraphs 7, 11-12, 67-69, 84, 127, 130, 163, etc. CD3 is a defining marker of the T-cell lineage.
For these reasons, claims 1 and 2 are anticipated by Mujacic.
Regarding dependent claim 3, Mujacic teaches the composition comprises CD4+ T cells expressing the CAR and CD8+ T cells expressing the CAR at a ratio between about 1:2.5 and about 5:1. See, e.g., Abstract; paragraphs 5, 8-13, etc.
Regarding dependent claims 4-5, Mujacic teaches the composition comprises between at or about 5 x 106 CAR-expressing T cells and at or about 80 x 106 or 100 x 106 CAR-expressing T cells, inclusive. See, e.g., paragraphs 173-174, 211, etc.
Regarding dependent claim 22, Mujacic teaches at least or at least about 80% of the CAR+ T cells in the composition are of a naïve-like or central memory phenotype. See, e.g., Abstract; paragraphs 7, 11-12, 67-69, 84, 127, 130, 163, etc.
Regarding dependent claim 29, Mujacic teaches the marker expressed on naïve-like or central memory T cell is selected from the group consisting of CD45RA, CD27, CD28, and CCR7. See, e.g., Abstract; paragraphs 7, 11-12, 67-69, 84, 127, 130, 163, etc.
Regarding dependent claim 30, Mujacic teaches the at least or at least about 80% of the CAR+ T cells in the composition that are of a naïve-like or central memory phenotype have a phenotype selected from CCR7+CD45RA+, CD27+CCR7+, or CD62L-CCR7+. See, e.g., Abstract; paragraphs 7, 11-12, 67-69, 84, 127, 130, 163, etc.
Regarding dependent claim 66 and 120, Mujacic teaches the cancer is a relapsed/refractory multiple myeloma. See paragraph 788.
Regarding dependent claims 73-77, 80-81, and 88, Mujacic teaches that the CAR comprises a scFv antigen-binding domain (par. 653); a variable heavy chain according to SEQ ID NO: 27 (par. 653), which is identical to SEQ ID NO: 116 of the instant application; a variable light chain according to SEQ ID NO: 28 (par. 653), which is identical to SEQ ID NO: 119 of the instant application; a spacer comprising an IgG4/2 chimeric hinge or a modified IgG4 hinge, an IgG2/4 chimeric CH2 region and an IgG4 CH3 region, and having a sequence according to SEQ ID NO: 29 (par. 685, 687), which is identical to SEQ ID NO: 174 of the instant application; a transmembrane domain according to SEQ ID NO: 8 (par. 689, 705), which has at least 90% sequence identity to SEQ ID NO: 138 of the instant application; a scFv linker according to SEQ ID NO: 38 (par. 662), which is identical to SEQ ID NO: 1 of the instant application; an intracellular signaling region comprising a CD3-zeta chain according to SEQ ID NO: 13 (par. 708), which is identical to SEQ ID NO: 143 of the instant application; and a 4-1BB costimulatory domain according to SEQ ID NO: 12 (par. 707), which is identical to SEQ ID NO: 4 of the instant application.
Regarding dependent claim 105, Mujacic teaches the subject is human. See, e.g., paragraph 807.
Regarding dependent claim 106, Mujacic teaches the composition comprising engineered T cells is produced by a manufacturing process comprising: (i) exposing an input composition comprising primary T cells with a stimulatory reagent comprising an oligomeric particle reagent comprising a plurality of streptavidin mutein molecules under conditions to stimulate T cells, thereby generating a stimulated population, wherein the oligomeric particle reagent comprises a first agent comprising an anti-CD3 antibody or antigen binding fragment thereof and a second agent comprising an anti-CD28 antibody or antigen binding fragment thereof; (ii) introducing into T cells of the stimulated population, a heterologous polynucleotide encoding the CAR that targets BCMA, thereby generating a population of transformed cells; (iii) incubating the population of transformed cells, wherein the incubating is completed at, at about, or within 120 hours; and (iv) harvesting T cells of the population of transformed cells, thereby producing a composition of engineered cells. See, e.g., paragraphs 14, 34, 99, 264, 268, 291, 312 etc.
For these reasons, dependent claims 3-5, 22, 29-30, 66, 73-77, 80-81, 88, 105-106, and 120 are also anticipated by Mujacic.
Claims 1-5, 22, 29-30, 105-106 are rejected under 35 U.S.C. 102(a)(1) and 35 U.S.C. 102(a)(2) as being anticipated by WO 2019/032927 A1 to Mujacic et al.
Mujacic teaches a method of treating multiple myeloma in a subject in need thereof, comprising administering to the subject a composition comprising engineered T cells expressing a BCMA-targeting CAR. See, e.g., Abstract; paragraphs 249, 366-367, 375, 450, etc.
Mujacic is further found to teach or fairly suggest a composition comprising CD8+ T cells expressing the CAR and CD4+ T cells expressing the CAR; at least or at least about 80% of the cells in the composition are CD3+ cells; and at least or at least about 80% of the CAR+ T cells in the composition are of a naïve-like or central memory phenotype; and at least or at least about 50% of the CD4+CAR+ T cells in the composition are CD27+CCR7+ and/or at least or at least about 50% of the CD8+CAR+ T cells in the composition are CD27+CCR7+. See, e.g., Abstract; paragraphs 12, 35-36, 44-51, 121, 124-125, 154-155, 169, 446-451, etc. CD3 is a defining marker of the T-cell lineage.
For these reasons, claims 1 and 2 are anticipated by Mujacic.
Regarding dependent claim 3, Mujacic teaches the composition comprises CD4+ T cells expressing the CAR and CD8+ T cells expressing the CAR at a ratio between about 1:2.5 and about 5:1. See, e.g., Abstract; paragraphs 5, 15, 36, 46, etc.
Regarding dependent claims 4-5, Mujacic teaches the composition comprises between at or about 5 x 106 CAR-expressing T cells and at or about 80 x 106 or 100 x 106 CAR-expressing T cells, inclusive. See, e.g., paragraphs 119-120, 167, 387-388, etc.
Regarding dependent claim 22, Mujacic teaches at least or at least about 80% of the CAR+ T cells in the composition are of a naïve-like or central memory phenotype. See, e.g., Abstract; paragraphs 12, 35-36, 44-51, 121, 124-125, 154-155, 169, 446-451, etc.
Regarding dependent claim 29, Mujacic teaches the marker expressed on naïve-like or central memory T cell is selected from the group consisting of CD45RA, CD27, CD28, and CCR7. See, e.g., Abstract; paragraphs 12, 35-36, 44-51, 121, 124-125, 154-155, 169, 446-451, etc.
Regarding dependent claim 30, Mujacic teaches the at least or at least about 80% of the CAR+ T cells in the composition that are of a naïve-like or central memory phenotype have a phenotype selected from CCR7+CD45RA+, CD27+CCR7+, or CD62L-CCR7+. See, e.g., Abstract; paragraphs 12, 35-36, 44-51, 121, 124-125, 154-155, 169, 446-451, etc.
Regarding dependent claim 105, Mujacic teaches the subject is human. See, e.g., paragraph 86.
Regarding dependent claim 106, Mujacic does not teach the composition comprising engineered T cells is produced by a manufacturing process comprising: (i) exposing an input composition comprising primary T cells with a stimulatory reagent comprising an oligomeric particle reagent comprising a plurality of streptavidin mutein molecules under conditions to stimulate T cells, thereby generating a stimulated population, wherein the oligomeric particle reagent comprises a first agent comprising an anti-CD3 antibody or antigen binding fragment thereof and a second agent comprising an anti-CD28 antibody or antigen binding fragment thereof; (ii) introducing into T cells of the stimulated population, a heterologous polynucleotide encoding the CAR that targets BCMA, thereby generating a population of transformed cells; (iii) incubating the population of transformed cells, wherein the incubating is completed at, at about, or within 120 hours; and (iv) harvesting T cells of the population of transformed cells, thereby producing a composition of engineered cells.
However, dependent claim 106 describes the engineered T cells by a product-by-process limitation. Even though product-by-process claims are limited by and defined by the process, determination of patentability is based on the product itself. The patentability of a product does not depend on its method of production. If the product in the product-by-process claim is the same as or obvious from a product of the prior art, the claim is unpatentable even though the prior product was made by a different process. In re Thorpe, 777 F.2d 695, 698, 227 USPQ 964, 966 (Fed. Cir. 1985). In this case, the cited prior art teaches or fairly suggests a composition of engineered T cells as claimed in claim 1. Therefore, absent evidence to the contrary, both the claimed composition and that of the cited prior art are considered structurally similar, even if the claimed composition was produced by a different process. The product-by-process limitations recited by the instant claims are not found to necessarily imply a structural characteristic that patentably distinguishes the instantly claimed composition from that found in the cited prior art, absent evidence to the contrary. For these reasons, the product of claim 106 is also found to be anticipated by the cited prior art.
The Patent Office bears a lesser burden of proof in making out a case of prima facie obviousness for product-by-process claims because of their peculiar nature than when a product is claimed in the conventional fashion. In re Fessmann, 489 F.2d 742, 744, 180 USPQ 324, 326 (CCPA 1974). Once the examiner provides a rationale tending to show that the claimed product appears to be the same or similar to that of the prior art, although produced by a different process, the burden shifts to applicant to come forward with evidence establishing a nonobvious difference between the claimed product and the prior art product. In re Marosi, 710 F.2d 799, 803, 218 USPQ 289, 292-33 (Fed. Cir. 1983). See MPEP 2113.
For these reasons, dependent claims 3-5, 22, 29-30, 105-106 are also anticipated by Mujacic.
Claims 1-5, 22, 29-30, 105-106 are rejected under 35 U.S.C. 102(a)(1) and 35 U.S.C. 102(a)(2) as being anticipated by WO 2019/032929 A1 to Bonyhadi, Mark L.
Bonyhadi teaches a method of treating multiple myeloma in a subject in need thereof, comprising administering to the subject a composition comprising engineered T cells expressing a BCMA-targeting CAR. See, e.g., Abstract; paragraphs 280, 288, 352-353, 361, 427, etc.
Bonyhadi is further found to teach or fairly suggest a composition comprising CD8+ T cells expressing the CAR and CD4+ T cells expressing the CAR; at least or at least about 80% of the cells in the composition are CD3+ cells; and at least or at least about 80% of the CAR+ T cells in the composition are of a naïve-like or central memory phenotype; and at least or at least about 50% of the CD4+CAR+ T cells in the composition are CD27+CCR7+ and/or at least or at least about 50% of the CD8+CAR+ T cells in the composition are CD27+CCR7+. See, e.g., Abstract; fig. 1A; paragraphs 11-12, 35, 45, 53, 125, 201, 209, 335, etc. CD3 is a defining marker of the T-cell lineage.
For these reasons, claims 1 and 2 are anticipated by Bonyhadi.
Regarding dependent claim 3, Bonyhadi teaches the composition comprises CD4+ T cells expressing the CAR and CD8+ T cells expressing the CAR at a ratio between about 1:2.5 and about 5:1. See, e.g., Abstract; paragraphs 29, 67, 379, 437, etc.
Regarding dependent claims 4-5, Bonyhadi teaches the composition comprises between at or about 5 x 106 CAR-expressing T cells and at or about 80 x 106 or 100 x 106 CAR-expressing T cells, inclusive. See, e.g., paragraphs 368-373, etc.
Regarding dependent claim 22, Bonyhadi teaches at least or at least about 80% of the CAR+ T cells in the composition are of a naïve-like or central memory phenotype. See, e.g., Abstract; fig. 1A; paragraphs 11-12, 35, 45, 53, 125, 201, 209, 335, etc.
Regarding dependent claim 29, Bonyhadi teaches the marker expressed on naïve-like or central memory T cell is selected from the group consisting of CD45RA, CD27, CD28, and CCR7. See, e.g., Abstract; fig. 1A; paragraphs 11-12, 35, 45, 53, 125, 201, 209, 335, etc.
Regarding dependent claim 30, Bonyhadi teaches the at least or at least about 80% of the CAR+ T cells in the composition that are of a naïve-like or central memory phenotype have a phenotype selected from CCR7+CD45RA+, CD27+CCR7+, or CD62L-CCR7+. See, e.g., Abstract; fig. 1A; paragraphs 11-12, 35, 45, 53, 125, 201, 209, 335, etc.
Regarding dependent claim 105, Bonyhadi teaches the subject is human. See, e.g., paragraph 70.
Regarding dependent claim 106, Bonyhadi does not teach the composition comprising engineered T cells is produced by a manufacturing process comprising: (i) exposing an input composition comprising primary T cells with a stimulatory reagent comprising an oligomeric particle reagent comprising a plurality of streptavidin mutein molecules under conditions to stimulate T cells, thereby generating a stimulated population, wherein the oligomeric particle reagent comprises a first agent comprising an anti-CD3 antibody or antigen binding fragment thereof and a second agent comprising an anti-CD28 antibody or antigen binding fragment thereof; (ii) introducing into T cells of the stimulated population, a heterologous polynucleotide encoding the CAR that targets BCMA, thereby generating a population of transformed cells; (iii) incubating the population of transformed cells, wherein the incubating is completed at, at about, or within 120 hours; and (iv) harvesting T cells of the population of transformed cells, thereby producing a composition of engineered cells.
However, dependent claim 106 describes the engineered T cells by a product-by-process limitation. Even though product-by-process claims are limited by and defined by the process, determination of patentability is based on the product itself. The patentability of a product does not depend on its method of production. If the product in the product-by-process claim is the same as or obvious from a product of the prior art, the claim is unpatentable even though the prior product was made by a different process. In re Thorpe, 777 F.2d 695, 698, 227 USPQ 964, 966 (Fed. Cir. 1985). In this case, the cited prior art teaches or fairly suggests a composition of engineered T cells as claimed in claim 1. Therefore, absent evidence to the contrary, both the claimed composition and that of the cited prior art are considered structurally similar, even if the claimed composition was produced by a different process. The product-by-process limitations recited by the instant claims are not found to necessarily imply a structural characteristic that patentably distinguishes the instantly claimed composition from that found in the cited prior art, absent evidence to the contrary. For these reasons, the product of claim 106 is also found to be anticipated by the cited prior art.
The Patent Office bears a lesser burden of proof in making out a case of prima facie obviousness for product-by-process claims because of their peculiar nature than when a product is claimed in the conventional fashion. In re Fessmann, 489 F.2d 742, 744, 180 USPQ 324, 326 (CCPA 1974). Once the examiner provides a rationale tending to show that the claimed product appears to be the same or similar to that of the prior art, although produced by a different process, the burden shifts to applicant to come forward with evidence establishing a nonobvious difference between the claimed product and the prior art product. In re Marosi, 710 F.2d 799, 803, 218 USPQ 289, 292-33 (Fed. Cir. 1983). See MPEP 2113.
For these reasons, dependent claims 3-5, 22, 29-30, 105-106 are also anticipated by Bonyhadi.
Claims 1-5, 22, 29-30, 66, 105-106, and 120 are rejected under 35 U.S.C. 102(a)(1) and 35 U.S.C. 102(a)(2) as being anticipated by WO 2019/113559 A2 to Larson, Ryan P.
Larson teaches a method of treating multiple myeloma in a subject in need thereof, comprising administering to the subject a composition comprising engineered T cells expressing a BCMA-targeting CAR. See, e.g., Abstract; paragraphs 37, 346, 725, etc.
Larson is further found to teach or fairly suggest a composition comprising CD8+ T cells expressing the CAR and CD4+ T cells expressing the CAR; at least or at least about 80% of the cells in the composition are CD3+ cells; and at least or at least about 80% of the CAR+ T cells in the composition are of a naïve-like or central memory phenotype; and at least or at least about 50% of the CD4+CAR+ T cells in the composition are CD27+CCR7+ and/or at least or at least about 50% of the CD8+CAR+ T cells in the composition are CD27+CCR7+. See, e.g., Abstract; fig. 1A; paragraphs 5, 11, 13, 37, 137, 237-239, 540-543, etc. CD3 is a defining marker of the T-cell lineage.
For these reasons, claims 1 and 2 are anticipated by Larson.
Regarding dependent claim 3, Larson teaches the composition comprises CD4+ T cells expressing the CAR and CD8+ T cells expressing the CAR at a ratio between about 1:2.5 and about 5:1. See, e.g., Abstract; paragraphs 16-17, 22, 49, etc.
Regarding dependent claims 4-5, Larson teaches the composition comprises between at or about 5 x 106 CAR-expressing T cells and at or about 80 x 106 or 100 x 106 CAR-expressing T cells, inclusive. See, e.g., paragraphs 312-317, etc.
Regarding dependent claim 22, Larson teaches at least or at least about 80% of the CAR+ T cells in the composition are of a naïve-like or central memory phenotype. See, e.g., Abstract; fig. 1A; paragraphs 5, 11, 13, 37, 137, 237-239, 540-543, etc.
Regarding dependent claim 29, Larson teaches the marker expressed on naïve-like or central memory T cell is selected from the group consisting of CD45RA, CD27, CD28, and CCR7. See, e.g., Abstract; fig. 1A; paragraphs 5, 11, 13, 37, 137, 237-239, 540-543, etc.
Regarding dependent claim 30, Larson teaches the at least or at least about 80% of the CAR+ T cells in the composition that are of a naïve-like or central memory phenotype have a phenotype selected from CCR7+CD45RA+, CD27+CCR7+, or CD62L-CCR7+. See, e.g., Abstract; fig. 1A; paragraphs 5, 11, 13, 37, 137, 237-239, 540-543, etc.
Regarding dependent claim 66 and 120, Larson teaches the cancer is a relapsed/refractory multiple myeloma. See paragraph 349.
Regarding dependent claim 105, Larson teaches the subject is human. See, e.g., paragraph 317.
Regarding dependent claim 106, Larson teaches the composition comprising engineered T cells is produced by a manufacturing process comprising: (i) exposing an input composition comprising primary T cells with a stimulatory reagent comprising an oligomeric particle reagent comprising a plurality of streptavidin mutein molecules under conditions to stimulate T cells, thereby generating a stimulated population, wherein the oligomeric particle reagent comprises a first agent comprising an anti-CD3 antibody or antigen binding fragment thereof and a second agent comprising an anti-CD28 antibody or antigen binding fragment thereof; (ii) introducing into T cells of the stimulated population, a heterologous polynucleotide encoding the CAR that targets BCMA, thereby generating a population of transformed cells; (iii) incubating the population of transformed cells, wherein the incubating is completed at, at about, or within 120 hours; and (iv) harvesting T cells of the population of transformed cells, thereby producing a composition of engineered cells. See, e.g., paragraphs 161-162, 254, 453-454, 477, 571, etc.
For these reasons, dependent claims 3-5, 22, 29-30, 66, 105-106, and 120 are also anticipated by Larson.
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.
Claim 54 is rejected under 35 U.S.C. 103 as being unpatentable over WO 2019/113557 A1 to Mujacic et al., as applied 1-5, 22, 29-30, 66, 73-77, 80-81, 88, 105-106, and 120 above; in view of Okamoto et al. (2009) “Improved expression and reactivity of transduced tumor-specific TCRs in human lymphocytes by specific silencing of endogenous TCR” Cancer research, 69(23), 9003-9011.
Regarding dependent claim 54, the cited prior art does not teach the fraction of integrated vector copy number (iVCN) to total VCN in the CAR+ T cells in the composition, on average, is less than or less than about 0.9; and/or the integrated vector copy number (iVCN) of the CAR+ T cells in the composition, on average, is between or between about 0.4 copies per diploid genome and 2.0 copies per diploid genome, inclusive.
"[W]here the general conditions of a claim are disclosed in the prior art, it is not inventive to discover the optimum or workable ranges by routine experimentation." In re Aller, 220 F.2d 454, 456, 105 USPQ 233, 235 (CCPA 1955). See MPEP 2144.05.
In this case, both the claimed invention and that of the cited prior art are directed to genetically-modifying T cells to express a CAR polypeptide for cancer therapy. Although the cited prior art does not teach the limitations of dependent claim 54, one of ordinary skill in the art would have recognized that the integrated vector copy number was a result-effective variable. For example, prior to the effective filing date of the instantly claimed invention, Okamoto teaches that the expression level of a transgene can be enhanced by increasing the vector copy number in the transduced cells, but a low copy number is ideal for reducing the risk of insertional mutagenesis even when using mature T cells. See page 9003, right column. Therefore, one of ordinary skill in the art would have been motivated to optimize the integrated vector copy number through routine optimization in order to improve the efficacy and safety of the CAR-T therapy.
For these reasons, dependent claim 54 would have been prima facie obvious over the prior art.
Claim 54 is rejected under 35 U.S.C. 103 as being unpatentable over WO 2019/032927 A1 to Mujacic et al., as applied 1-5, 22, 29-30, 105-106 above; in view of Okamoto et al. (2009) “Improved expression and reactivity of transduced tumor-specific TCRs in human lymphocytes by specific silencing of endogenous TCR” Cancer research, 69(23), 9003-9011.
Regarding dependent claim 54, the cited prior art does not teach the fraction of integrated vector copy number (iVCN) to total VCN in the CAR+ T cells in the composition, on average, is less than or less than about 0.9; and/or the integrated vector copy number (iVCN) of the CAR+ T cells in the composition, on average, is between or between about 0.4 copies per diploid genome and 2.0 copies per diploid genome, inclusive.
"[W]here the general conditions of a claim are disclosed in the prior art, it is not inventive to discover the optimum or workable ranges by routine experimentation." In re Aller, 220 F.2d 454, 456, 105 USPQ 233, 235 (CCPA 1955). See MPEP 2144.05.
In this case, both the claimed invention and that of the cited prior art are directed to genetically-modifying T cells to express a CAR polypeptide for cancer therapy. Although the cited prior art does not teach the limitations of dependent claim 54, one of ordinary skill in the art would have recognized that the integrated vector copy number was a result-effective variable. For example, prior to the effective filing date of the instantly claimed invention, Okamoto teaches that the expression level of a transgene can be enhanced by increasing the vector copy number in the transduced cells, but a low copy number is ideal for reducing the risk of insertional mutagenesis even when using mature T cells. See page 9003, right column. Therefore, one of ordinary skill in the art would have been motivated to optimize the integrated vector copy number through routine optimization in order to improve the efficacy and safety of the CAR-T therapy.
For these reasons, dependent claim 54 would have been prima facie obvious over the prior art.
Claim 54 is rejected under 35 U.S.C. 103 as being unpatentable over WO 2019/032929 A1 to Bonyhadi, Mark L., as applied 1-5, 22, 29-30, 105-106 above; in view of Okamoto et al. (2009) “Improved expression and reactivity of transduced tumor-specific TCRs in human lymphocytes by specific silencing of endogenous TCR” Cancer research, 69(23), 9003-9011.
Regarding dependent claim 54, the cited prior art does not teach the fraction of integrated vector copy number (iVCN) to total VCN in the CAR+ T cells in the composition, on average, is less than or less than about 0.9; and/or the integrated vector copy number (iVCN) of the CAR+ T cells in the composition, on average, is between or between about 0.4 copies per diploid genome and 2.0 copies per diploid genome, inclusive.
"[W]here the general conditions of a claim are disclosed in the prior art, it is not inventive to discover the optimum or workable ranges by routine experimentation." In re Aller, 220 F.2d 454, 456, 105 USPQ 233, 235 (CCPA 1955). See MPEP 2144.05.
In this case, both the claimed invention and that of the cited prior art are directed to genetically-modifying T cells to express a CAR polypeptide for cancer therapy. Although the cited prior art does not teach the limitations of dependent claim 54, one of ordinary skill in the art would have recognized that the integrated vector copy number was a result-effective variable. For example, prior to the effective filing date of the instantly claimed invention, Okamoto teaches that the expression level of a transgene can be enhanced by increasing the vector copy number in the transduced cells, but a low copy number is ideal for reducing the risk of insertional mutagenesis even when using mature T cells. See page 9003, right column. Therefore, one of ordinary skill in the art would have been motivated to optimize the integrated vector copy number through routine optimization in order to improve the efficacy and safety of the CAR-T therapy.
For these reasons, dependent claim 54 would have been prima facie obvious over the prior art.
Claim 54 is rejected under 35 U.S.C. 103 as being unpatentable over WO 2019/113559 A2 to Larson, Ryan P., as applied 1-5, 22, 29-30, 66, 105-106, and 120 above; in view of Okamoto et al. (2009) “Improved expression and reactivity of transduced tumor-specific TCRs in human lymphocytes by specific silencing of endogenous TCR” Cancer research, 69(23), 9003-9011.
Regarding dependent claim 54, the cited prior art does not teach the fraction of integrated vector copy number (iVCN) to total VCN in the CAR+ T cells in the composition, on average, is less than or less than about 0.9; and/or the integrated vector copy number (iVCN) of the CAR+ T cells in the composition, on average, is between or between about 0.4 copies per diploid genome and 2.0 copies per diploid genome, inclusive.
"[W]here the general conditions of a claim are disclosed in the prior art, it is not inventive to discover the optimum or workable ranges by routine experimentation." In re Aller, 220 F.2d 454, 456, 105 USPQ 233, 235 (CCPA 1955). See MPEP 2144.05.
In this case, both the claimed invention and that of the cited prior art are directed to genetically-modifying T cells to express a CAR polypeptide for cancer therapy. Although the cited prior art does not teach the limitations of dependent claim 54, one of ordinary skill in the art would have recognized that the integrated vector copy number was a result-effective variable. For example, prior to the effective filing date of the instantly claimed invention, Okamoto teaches that the expression level of a transgene can be enhanced by increasing the vector copy number in the transduced cells, but a low copy number is ideal for reducing the risk of insertional mutagenesis even when using mature T cells. See page 9003, right column. Therefore, one of ordinary skill in the art would have been motivated to optimize the integrated vector copy number through routine optimization in order to improve the efficacy and safety of the CAR-T therapy.
For these reasons, dependent claim 54 would have been prima facie obvious over the prior art.
Claims 89-90 are rejected under 35 U.S.C. 103 as being unpatentable over WO 2019/113557 A1 to Mujacic et al., as applied 1-5, 22, 29-30, 66, 73-77, 80-81, 88, 105-106, and 120 above; in view of US 2019/0161553 A1 to Sather et al.
Mujacic does not teach the CAR polypeptide according to SEQ ID NO: 19, as claimed.
Sather is relevant prior art for teaching CAR polypeptides targeting BCMA for use in adoptive cell therapy. See, e.g., Abstract. In particular, Sather teaches an anti-BCMA CAR polypeptide according to SEQ ID NO: 761, which is identical to SEQ ID NO: 19 of the instant application.
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Therefore, prior to the effective filing date of the instantly claimed invention, it would have been prima facie obvious to one of ordinary skill in the art to modify the invention of Mujacic by using the CAR polypeptide according to SEQ ID NO: 19, as found in Sather, with a reasonable expectation of success because the CAR polypeptide targets BCMA and would be useful in treating multiple myeloma by adoptive cell therapy.
The CAR polypeptide according to SEQ ID NO: 19 the scFv antigen-binding domain according to SEQ ID NO: 114 (amino acids 1-244); the variable heavy chain according to SEQ ID NO: 116; the variable light chain according to SEQ ID NO: 119; the spacer comprising an IgG4/2 chimeric hinge or a modified IgG4 hinge, an IgG2/4 chimeric CH2 region and an IgG4 CH3 region, and having the sequence according to SEQ ID NO: 174 (amino acids 245-472); the transmembrane domain according to SEQ ID NO: 138 (amino acids 473-500); the scFv linker according to SEQ ID NO: 1 (amino acids 108-122); the 4-1BB costimulatory domain according to SEQ ID NO: 4 (amino acids 501-542); and the intracellular signaling region comprising a CD3-zeta chain according to SEQ ID NO: 143 (amino acids 543-654).
For these reasons, dependent claims 89-90 would have been prima facie obvious over the prior art.
Claims 73-77, 80-81, 88-90 are rejected under 35 U.S.C. 103 as being unpatentable over WO 2019/032927 A1 to Mujacic et al., as applied 1-5, 22, 29-30, 105-106 above; in view of US 2019/0161553 A1 to Sather et al.
Mujacic does not teach the CAR polypeptide according to SEQ ID NO: 19, as claimed.
Sather is relevant prior art for teaching CAR polypeptides targeting BCMA for use in adoptive cell therapy. See, e.g., Abstract. In particular, Sather teaches an anti-BCMA CAR polypeptide according to SEQ ID NO: 761, which is identical to SEQ ID NO: 19 of the instant application.
Therefore, prior to the effective filing date of the instantly claimed invention, it would have been prima facie obvious to one of ordinary skill in the art to modify the invention of Mujacic by using the CAR polypeptide according to SEQ ID NO: 19, as found in Sather, with a reasonable expectation of success because the CAR polypeptide targets BCMA and would be useful in treating multiple myeloma by adoptive cell therapy.
The CAR polypeptide according to SEQ ID NO: 19 the scFv antigen-binding domain according to SEQ ID NO: 114 (amino acids 1-244); the variable heavy chain according to SEQ ID NO: 116; the variable light chain according to SEQ ID NO: 119; the spacer comprising an IgG4/2 chimeric hinge or a modified IgG4 hinge, an IgG2/4 chimeric CH2 region and an IgG4 CH3 region, and having the sequence according to SEQ ID NO: 174 (amino acids 245-472); the transmembrane domain according to SEQ ID NO: 138 (amino acids 473-500); the scFv linker according to SEQ ID NO: 1 (amino acids 108-122); the 4-1BB costimulatory domain according to SEQ ID NO: 4 (amino acids 501-542); and the intracellular signaling region comprising a CD3-zeta chain according to SEQ ID NO: 143 (amino acids 543-654).
For these reasons, dependent claims 73-77, 80-81, 88-90 would have been prima facie obvious over the prior art.
Claims 73-77, 80-81, 88-90 are rejected under 35 U.S.C. 103 as being unpatentable over WO 2019/032929 A1 to Bonyhadi, Mark L., as applied 1-5, 22, 29-30, 105-106 above; in view of US 2019/0161553 A1 to Sather et al.
Bonyhadi does not teach the CAR polypeptide according to SEQ ID NO: 19, as claimed.
Sather is relevant prior art for teaching CAR polypeptides targeting BCMA for use in adoptive cell therapy. See, e.g., Abstract. In particular, Sather teaches an anti-BCMA CAR polypeptide according to SEQ ID NO: 761, which is identical to SEQ ID NO: 19 of the instant application.
Therefore, prior to the effective filing date of the instantly claimed invention, it would have been prima facie obvious to one of ordinary skill in the art to modify the invention of Bonyhadi by using the CAR polypeptide according to SEQ ID NO: 19, as found in Sather, with a reasonable expectation of success because the CAR polypeptide targets BCMA and would be useful in treating multiple myeloma by adoptive cell therapy.
The CAR polypeptide according to SEQ ID NO: 19 the scFv antigen-binding domain according to SEQ ID NO: 114 (amino acids 1-244); the variable heavy chain according to SEQ ID NO: 116; the variable light chain according to SEQ ID NO: 119; the spacer comprising an IgG4/2 chimeric hinge or a modified IgG4 hinge, an IgG2/4 chimeric CH2 region and an IgG4 CH3 region, and having the sequence according to SEQ ID NO: 174 (amino acids 245-472); the transmembrane domain according to SEQ ID NO: 138 (amino acids 473-500); the scFv linker according to SEQ ID NO: 1 (amino acids 108-122); the 4-1BB costimulatory domain according to SEQ ID NO: 4 (amino acids 501-542); and the intracellular signaling region comprising a CD3-zeta chain according to SEQ ID NO: 143 (amino acids 543-654).
For these reasons, dependent claims 73-77, 80-81, 88-90 would have been prima facie obvious over the prior art.
Claims 73-77, 80-81, 88-90 are rejected under 35 U.S.C. 103 as being unpatentable over WO 2019/113559 A2 to Larson, Ryan P., as applied 1-5, 22, 29-30, 66, 105-106, and 120 above; in view of US 2019/0161553 A1 to Sather et al.
Larson does not teach the CAR polypeptide according to SEQ ID NO: 19, as claimed.
Sather is relevant prior art for teaching CAR polypeptides targeting BCMA for use in adoptive cell therapy. See, e.g., Abstract. In particular, Sather teaches an anti-BCMA CAR polypeptide according to SEQ ID NO: 761, which is identical to SEQ ID NO: 19 of the instant application.
Therefore, prior to the effective filing date of the instantly claimed invention, it would have been prima facie obvious to one of ordinary skill in the art to modify the invention of Larson by using the CAR polypeptide according to SEQ ID NO: 19, as found in Sather, with a reasonable expectation of success because the CAR polypeptide targets BCMA and would be useful in treating multiple myeloma by adoptive cell therapy.
The CAR polypeptide according to SEQ ID NO: 19 the scFv antigen-binding domain according to SEQ ID NO: 114 (amino acids 1-244); the variable heavy chain according to SEQ ID NO: 116; the variable light chain according to SEQ ID NO: 119; the spacer comprising an IgG4/2 chimeric hinge or a modified IgG4 hinge, an IgG2/4 chimeric CH2 region and an IgG4 CH3 region, and having the sequence according to SEQ ID NO: 174 (amino acids 245-472); the transmembrane domain according to SEQ ID NO: 138 (amino acids 473-500); the scFv linker according to SEQ ID NO: 1 (amino acids 108-122); the 4-1BB costimulatory domain according to SEQ ID NO: 4 (amino acids 501-542); and the intracellular signaling region comprising a CD3-zeta chain according to SEQ ID NO: 143 (amino acids 543-654).
For these reasons, dependent claims 73-77, 80-81, 88-90 would have been prima facie obvious over the prior art.
Double Patenting
The nonstatutory double patenting rejection is based on a judicially created doctrine grounded in public policy (a policy reflected in the statute) so as to prevent the unjustified or improper timewise extension of the “right to exclude” granted by a patent and to prevent possible harassment by multiple assignees. A nonstatutory double patenting rejection is appropriate where the conflicting claims are not identical, but at least one examined application claim is not patentably distinct from the reference claim(s) because the examined application claim is either anticipated by, or would have been obvious over, the reference claim(s). See, e.g., In re Berg, 140 F.3d 1428, 46 USPQ2d 1226 (Fed. Cir. 1998); In re Goodman, 11 F.3d 1046, 29 USPQ2d 2010 (Fed. Cir. 1993); In re Longi, 759 F.2d 887, 225 USPQ 645 (Fed. Cir. 1985); In re Van Ornum, 686 F.2d 937, 214 USPQ 761 (CCPA 1982); In re Vogel, 422 F.2d 438, 164 USPQ 619 (CCPA 1970); In re Thorington, 418 F.2d 528, 163 USPQ 644 (CCPA 1969).
A timely filed terminal disclaimer in compliance with 37 CFR 1.321(c) or 1.321(d) may be used to overcome an actual or provisional rejection based on nonstatutory double patenting provided the reference application or patent either is shown to be commonly owned with the examined application, or claims an invention made as a result of activities undertaken within the scope of a joint research agreement. See MPEP § 717.02 for applications subject to examination under the first inventor to file provisions of the AIA as explained in MPEP § 2159. See MPEP § 2146 et seq. for applications not subject to examination under the first inventor to file provisions of the AIA . A terminal disclaimer must be signed in compliance with 37 CFR 1.321(b).
The filing of a terminal disclaimer by itself is not a complete reply to a nonstatutory double patenting (NSDP) rejection. A complete reply requires that the terminal disclaimer be accompanied by a reply requesting reconsideration of the prior Office action. Even where the NSDP rejection is provisional the reply must be complete. See MPEP § 804, subsection I.B.1. For a reply to a non-final Office action, see 37 CFR 1.111(a). For a reply to final Office action, see 37 CFR 1.113(c). A request for reconsideration while not provided for in 37 CFR 1.113(c) may be filed after final for consideration. See MPEP §§ 706.07(e) and 714.13.
The USPTO Internet website contains terminal disclaimer forms which may be used. Please visit www.uspto.gov/patent/patents-forms. The actual filing date of the application in which the form is filed determines what form (e.g., PTO/SB/25, PTO/SB/26, PTO/AIA /25, or PTO/AIA /26) should be used. A web-based eTerminal Disclaimer may be filled out completely online using web-screens. An eTerminal Disclaimer that meets all requirements is auto-processed and approved immediately upon submission. For more information about eTerminal Disclaimers, refer to www.uspto.gov/patents/apply/applying-online/eterminal-disclaimer.
Claims 1-5, 22, 29-30, 54, 66, 73-77, 80-81, 88-90, 105-106, and 120 are provisionally rejected on the ground of nonstatutory double patenting as being unpatentable over the claims of copending U.S. Application No. 19/399,291 (reference to claim listing filed 11/24/2025); in view of US 2019/0161553 A1 to Sather et al. Although the claims at issue are not identical, they are not patentably distinct from each other because the instant claims would have been prima facie obvious over the cited references. This is a provisional nonstatutory double patenting rejection because the patentably indistinct claims have not in fact been patented.
The reference claims recite a method for producing a composition of engineered T cells expressing a recombinant protein (claim 1); wherein the recombinant protein is a CAR (claim 191); wherein the CAR targets BCMA (claim 189).
The T cells are CD27+CCR7+ (claim 2); wherein the T cells are naïve-like and/or central memory T cells (claim 12); wherein the percentage of naïve-like and/or central memory T cells is greater than about 80% of total recombinant protein-expressing CD3+ T cells, greater than about 80% of total recombinant protein-expressing CD4+ cells, or greater than about 80% of total recombinant protein-expressing CD8+ cells (claims 13-14); wherein the naïve-like T cells are CD27+CCR7+ (claims 27-28).
The reference claims do not recite a step of administering the engineered T cells to a subject having multiple myeloma, as instantly claimed.
Sather is relevant prior art for teaching CAR polypeptides targeting BCMA for use in adoptive cell therapy. In particular, anti-BCMA CAR-expressing T cells are administered to a subject in need of treatment for multiple myeloma. See, e.g., Abstract, par. 114-116, 455, 491, 1395-1387.
Therefore, prior to the effective filing date of the instantly claimed invention, it would have been prima facie obvious to one of ordinary skill in the art to modify the invention of the reference claims by further including a step of administering the engineered T cells to a subject in need of treatment for multiple myeloma, as found in Sather, with a reasonable expectation of success because anti-BCMA CAR-T cells target the cancer cells in patients with multiple myeloma, thereby treating multiple myeloma.
For these reasons, claims 1-2 would have been prima facie obvious over the cited references.
Regarding claim 3, the ratio of between CD4+ and CD8+ cells is about 1:1, between 1:2 and 2:1, between 1:3 and 3:1 (claims 210-212).
Regarding claims 4-5, the number of viable T cells is at about 25 x 106 cells (claim 215).
Regarding claims 22, 29-30, the T cells are CD27+CCR7+ (claim 2); wherein the T cells are naïve-like and/or central memory T cells (claim 12); wherein the percentage of naïve-like and/or central memory T cells is greater than about 80% of total recombinant protein-expressing CD3+ T cells, greater than about 80% of total recombinant protein-expressing CD4+ cells, or greater than about 80% of total recombinant protein-expressing CD8+ cells (claims 13-14); wherein the naïve-like T cells are CD27+CCR7+ (claims 27-28).
Regarding claim 54, the fraction of iVCN to total vector copy number (VCN) in the diploid genome of the population of transformed cells, on average, is or is about 1.0 or is within a tolerated error thereof (claim 8), and the integrated vector copy number (iVCN) to total VCN in the population of transformed cells, on average, is less than 0.8 (claim 9).
Regarding claims 66 and 120, Sather teaches the subject has relapsed and/or refractory multiple myeloma. See, e.g., par. 1395.
Regarding claims 73-77, 80-81, 88-90, Sather teaches an anti-BCMA CAR polypeptide according to SEQ ID NO: 761, which is identical to SEQ ID NO: 19 of the instant application. The CAR polypeptide according to SEQ ID NO: 19 the scFv antigen-binding domain according to SEQ ID NO: 114 (amino acids 1-244); the variable heavy chain according to SEQ ID NO: 116; the variable light chain according to SEQ ID NO: 119; the spacer comprising an IgG4/2 chimeric hinge or a modified IgG4 hinge, an IgG2/4 chimeric CH2 region and an IgG4 CH3 region, and having the sequence according to SEQ ID NO: 174 (amino acids 245-472); the transmembrane domain according to SEQ ID NO: 138 (amino acids 473-500); the scFv linker according to SEQ ID NO: 1 (amino acids 108-122); the 4-1BB costimulatory domain according to SEQ ID NO: 4 (amino acids 501-542); and the intracellular signaling region comprising a CD3-zeta chain according to SEQ ID NO: 143 (amino acids 543-654).
Regarding claims 105, Sather teaches the subject is human. See, e.g., par. 1395.
Regarding claim 106, the reference claims recite the engineered T cells is produced by a manufacturing process comprising: (i) exposing an input composition comprising primary T cells with a stimulatory reagent comprising an oligomeric particle reagent comprising a plurality of streptavidin mutein molecules under conditions to stimulate T cells, thereby generating a stimulated population, wherein the oligomeric particle reagent comprises a first agent comprising an anti-CD3 antibody or antigen binding fragment thereof and a second agent comprising an anti-CD28 antibody or antigen binding fragment thereof; (ii) introducing into T cells of the stimulated population, a heterologous polynucleotide encoding the CAR that targets BCMA, thereby generating a population of transformed cells; (iii) incubating the population of transformed cells, wherein the incubating is completed at, at about, or within 120 hours; and (iv) harvesting T cells of the population of transformed cells, thereby producing a composition of engineered cells. See, e.g., claims 1-2, 39.
Claims 1-5, 22, 29-30, 66, 73-77, 80-81, 88-90, 105-106, and 120 are rejected on the ground of nonstatutory double patenting as being unpatentable over the claims of U.S. Patent No. 11,851,678 B2; in view of US 2019/0161553 A1 to Sather et al. Although the claims at issue are not identical, they are not patentably distinct from each other because the instant claims would have been prima facie obvious over the cited references.
The reference claims recite a method for producing a composition of engineered T cells expressing a recombinant receptor (claim 1); wherein the recombinant receptor is a CAR (claim 33). The reference claims further recite a method of treatment, comprising administering to a subject the engineered T cells (claim 34).
The composition comprises a mixture of naïve-like CD4+ T cells and naïve-like CD8+ T cells, wherein the naïve-like CD4+ T cells and naïve-like CD8+ T cells are CD27+CCR7+ (claim 1).
The reference claims do not recite the at least or at least about 80% of the cells in the composition are CD3+ cells; at least or at least about 80% of the CAR+ T cells in the composition are of a naïve-like or central memory phenotype; at least or at least about 50% of the CD4+CAR+ T cells in the composition are CD27+CCR7+ and/or at least or at least about 50% of the CD8+CAR+ T cells in the composition are CD27+CCR7+, as instantly claimed.
Generally, differences in concentration or amount will not support the patentability of subject matter encompassed by the prior art unless there is evidence indicating such concentration or amount is critical."[W]here the general conditions of a claim are disclosed in the prior art, it is not inventive to discover the optimum or workable ranges by routine experimentation." In re Aller, 220 F.2d 454, 456, 105 USPQ 233, 235 (CCPA 1955). See MPEP 2144.05. In this case, both the instantly claimed invention and that of the reference claims are directed to a therapeutic CAR-T cell composition comprising a mixture of naïve-like CD4+ T cells and naïve-like CD8+ T cells, wherein the naïve-like CD4+ T cells and naïve-like CD8+ T cells are CD27+CCR7+. Therefore, absent a secondary consideration, the claimed amounts would have been prima facie obvious over the cited references.
The reference claims do not recite that the CAR targets BCMA and the subject has multiple myeloma, as instantly claimed.
Sather is relevant prior art for teaching CAR polypeptides targeting BCMA for use in adoptive cell therapy. In particular, anti-BCMA CAR-expressing T cells are administered to a subject in need of treatment for multiple myeloma. See, e.g., Abstract, par. 114-116, 455, 491, 1395-1387.
Therefore, prior to the effective filing date of the instantly claimed invention, it would have been prima facie obvious to one of ordinary skill in the art to modify the invention of the reference claims by using an anti-BCMA CAR and treating a subject having multiple myeloma, as found in Sather, with a reasonable expectation of success because anti-BCMA CAR-T cells target the cancer cells in patients with multiple myeloma, thereby treating multiple myeloma.
For these reasons, claims 1-2 would have been prima facie obvious over the cited references.
Regarding claim 3, the ratio of the naive-like CD4+ T cells to the naive-like CD8+ T cells in the input composition is between or about between 0.8:1 and 2.2:1, inclusive (claim 1).
Regarding claims 4-5, the input cell composition comprises from or from about 1 x 107 to 5 x 109 total cells or total T cells (claim 29). As discussed above, differences in concentration or amount will not support the patentability of subject matter encompassed by the prior art unless there is evidence indicating such concentration or amount is critical."[W]here the general conditions of a claim are disclosed in the prior art, it is not inventive to discover the optimum or workable ranges by routine experimentation." In re Aller, 220 F.2d 454, 456, 105 USPQ 233, 235 (CCPA 1955). See MPEP 2144.05.
Regarding claims 22, 29-30, composition comprises a mixture of naïve-like CD4+ T cells and naïve-like CD8+ T cells, wherein the naïve-like CD4+ T cells and naïve-like CD8+ T cells are CD27+CCR7+ (claim 1). As indicated above, differences in concentration or amount will not support the patentability of subject matter encompassed by the prior art unless there is evidence indicating such concentration or amount is critical."[W]here the general conditions of a claim are disclosed in the prior art, it is not inventive to discover the optimum or workable ranges by routine experimentation." In re Aller, 220 F.2d 454, 456, 105 USPQ 233, 235 (CCPA 1955). See MPEP 2144.05.
Regarding claims 66 and 120, Sather teaches the subject has relapsed and/or refractory multiple myeloma. See, e.g., par. 1395.
Regarding claims 73-77, 80-81, 88-90, Sather teaches an anti-BCMA CAR polypeptide according to SEQ ID NO: 761, which is identical to SEQ ID NO: 19 of the instant application. The CAR polypeptide according to SEQ ID NO: 19 the scFv antigen-binding domain according to SEQ ID NO: 114 (amino acids 1-244); the variable heavy chain according to SEQ ID NO: 116; the variable light chain according to SEQ ID NO: 119; the spacer comprising an IgG4/2 chimeric hinge or a modified IgG4 hinge, an IgG2/4 chimeric CH2 region and an IgG4 CH3 region, and having the sequence according to SEQ ID NO: 174 (amino acids 245-472); the transmembrane domain according to SEQ ID NO: 138 (amino acids 473-500); the scFv linker according to SEQ ID NO: 1 (amino acids 108-122); the 4-1BB costimulatory domain according to SEQ ID NO: 4 (amino acids 501-542); and the intracellular signaling region comprising a CD3-zeta chain according to SEQ ID NO: 143 (amino acids 543-654).
Regarding claims 105, the reference claims recite the subject is human (claim 36). Sather teaches the subject is human. See, e.g., par. 1395.
Regarding dependent claim 106, the reference claims do not recite the composition comprising engineered T cells is produced by a manufacturing process comprising: (i) exposing an input composition comprising primary T cells with a stimulatory reagent comprising an oligomeric particle reagent comprising a plurality of streptavidin mutein molecules under conditions to stimulate T cells, thereby generating a stimulated population, wherein the oligomeric particle reagent comprises a first agent comprising an anti-CD3 antibody or antigen binding fragment thereof and a second agent comprising an anti-CD28 antibody or antigen binding fragment thereof; (ii) introducing into T cells of the stimulated population, a heterologous polynucleotide encoding the CAR that targets BCMA, thereby generating a population of transformed cells; (iii) incubating the population of transformed cells, wherein the incubating is completed at, at about, or within 120 hours; and (iv) harvesting T cells of the population of transformed cells, thereby producing a composition of engineered cells.
However, dependent claim 106 describes the engineered T cells by a product-by-process limitation. Even though product-by-process claims are limited by and defined by the process, determination of patentability is based on the product itself. The patentability of a product does not depend on its method of production. If the product in the product-by-process claim is the same as or obvious from a product of the prior art, the claim is unpatentable even though the prior product was made by a different process. In re Thorpe, 777 F.2d 695, 698, 227 USPQ 964, 966 (Fed. Cir. 1985). In this case, the cited prior art teaches or fairly suggests a composition of engineered T cells as claimed in claim 1. Therefore, absent evidence to the contrary, both the claimed composition and that of the cited references are considered structurally similar, even if the claimed composition was produced by a different process. The product-by-process limitations recited by the instant claims are not found to necessarily imply a structural characteristic that patentably distinguishes the instantly claimed composition from that found in the cited references, absent evidence to the contrary. For these reasons, the product of claim 106 is also found to be anticipated by the cited references. See MPEP 2113.
Claim 54 is rejected on the ground of nonstatutory double patenting as being unpatentable over the claims of U.S. Patent No. 11,851,678 B2; and US 2019/0161553 A1 to Sather et al., as applied to claims 1-5, 22, 29-30, 66, 73-77, 80-81, 88-90, 105-106, and 120 above; in further view of Okamoto et al. (2009) “Improved expression and reactivity of transduced tumor-specific TCRs in human lymphocytes by specific silencing of endogenous TCR” Cancer research, 69(23), 9003-9011.
Regarding dependent claim 54, the reference claims do not recite the fraction of integrated vector copy number (iVCN) to total VCN in the CAR+ T cells in the composition, on average, is less than or less than about 0.9; and/or the integrated vector copy number (iVCN) of the CAR+ T cells in the composition, on average, is between or between about 0.4 copies per diploid genome and 2.0 copies per diploid genome, inclusive.
"[W]here the general conditions of a claim are disclosed in the prior art, it is not inventive to discover the optimum or workable ranges by routine experimentation." In re Aller, 220 F.2d 454, 456, 105 USPQ 233, 235 (CCPA 1955). See MPEP 2144.05.
In this case, both the claimed invention and that of the reference claims are directed to genetically-modifying T cells to express a CAR polypeptide for cancer therapy. Although the reference claims do not recite the limitations of dependent claim 54, one of ordinary skill in the art would have recognized that the integrated vector copy number was a result-effective variable. For example, prior to the effective filing date of the instantly claimed invention, Okamoto teaches that the expression level of a transgene can be enhanced by increasing the vector copy number in the transduced cells, but a low copy number is ideal for reducing the risk of insertional mutagenesis even when using mature T cells. See page 9003, right column. Therefore, one of ordinary skill in the art would have been motivated to optimize the integrated vector copy number through routine optimization in order to improve the efficacy and safety of the CAR-T therapy. For these reasons, dependent claim 54 would have been prima facie obvious over the references.
Claims 1-5, 22, 29-30, 66, 73-77, 80-81, 88-90, 105-106, and 120 are rejected on the ground of nonstatutory double patenting as being unpatentable over the claims of U.S. Patent No. 12,215,348 B2; in view of US 2019/0161553 A1 to Sather et al. Although the claims at issue are not identical, they are not patentably distinct from each other because the instant claims would have been prima facie obvious over the cited references.
The reference claims recite a method for producing a composition of engineered T cells expressing a recombinant receptor (claim 1); wherein the recombinant receptor is a CAR (claim 21).
The composition comprises a mixture of naïve-like CD4+ T cells and naïve-like CD8+ T cells, wherein the naïve-like CD4+ T cells and naïve-like CD8+ T cells are CD27+CCR7+ (claim 1).
The reference claims do not recite the at least or at least about 80% of the cells in the composition are CD3+ cells; at least or at least about 80% of the CAR+ T cells in the composition are of a naïve-like or central memory phenotype; at least or at least about 50% of the CD4+CAR+ T cells in the composition are CD27+CCR7+ and/or at least or at least about 50% of the CD8+CAR+ T cells in the composition are CD27+CCR7+, as instantly claimed.
Generally, differences in concentration or amount will not support the patentability of subject matter encompassed by the prior art unless there is evidence indicating such concentration or amount is critical."[W]here the general conditions of a claim are disclosed in the prior art, it is not inventive to discover the optimum or workable ranges by routine experimentation." In re Aller, 220 F.2d 454, 456, 105 USPQ 233, 235 (CCPA 1955). See MPEP 2144.05. In this case, both the instantly claimed invention and that of the reference claims are directed to a therapeutic CAR-T cell composition comprising a mixture of naïve-like CD4+ T cells and naïve-like CD8+ T cells, wherein the naïve-like CD4+ T cells and naïve-like CD8+ T cells are CD27+CCR7+. Therefore, absent a secondary consideration, the claimed amounts would have been prima facie obvious over the cited references.
The reference claims do not recite that the CAR targets BCMA and the engineered T cells are administered to a subject in need of treatment for multiple myeloma, as instantly claimed.
Sather is relevant prior art for teaching CAR polypeptides targeting BCMA for use in adoptive cell therapy. In particular, anti-BCMA CAR-expressing T cells are administered to a subject in need of treatment for multiple myeloma. See, e.g., Abstract, par. 114-116, 455, 491, 1395-1387.
Therefore, prior to the effective filing date of the instantly claimed invention, it would have been prima facie obvious to one of ordinary skill in the art to modify the invention of the reference claims by using a CAR targeting BCMA and administering the engineered T cells to a subject in need of treatment for multiple myeloma, as found in Sather, with a reasonable expectation of success because anti-BCMA CAR-T cells target the cancer cells in patients with multiple myeloma, thereby treating multiple myeloma.
For these reasons, claims 1-2 would have been prima facie obvious over the cited references.
Regarding claim 3, the ratio of the naive-like CD4+ T cells to the naive-like CD8+ T cells in is between 10:1 and 0.05:1 (claim 1) or 1.2:1 and 2.4:1 (claim 10).
Regarding claims 4-5, the input cell composition comprises from or from about 1 x 107 to 5 x 109 total cells or total T cells (claim 24). As discussed above, differences in concentration or amount will not support the patentability of subject matter encompassed by the prior art unless there is evidence indicating such concentration or amount is critical."[W]here the general conditions of a claim are disclosed in the prior art, it is not inventive to discover the optimum or workable ranges by routine experimentation." In re Aller, 220 F.2d 454, 456, 105 USPQ 233, 235 (CCPA 1955). See MPEP 2144.05.
Regarding claims 22, 29-30, composition comprises a mixture of naïve-like CD4+ T cells and naïve-like CD8+ T cells, wherein the naïve-like CD4+ T cells and naïve-like CD8+ T cells are CD27+CCR7+ (claim 1). As indicated above, differences in concentration or amount will not support the patentability of subject matter encompassed by the prior art unless there is evidence indicating such concentration or amount is critical."[W]here the general conditions of a claim are disclosed in the prior art, it is not inventive to discover the optimum or workable ranges by routine experimentation." In re Aller, 220 F.2d 454, 456, 105 USPQ 233, 235 (CCPA 1955). See MPEP 2144.05.
Regarding claims 66 and 120, Sather teaches the subject has relapsed and/or refractory multiple myeloma. See, e.g., par. 1395.
Regarding claims 73-77, 80-81, 88-90, Sather teaches an anti-BCMA CAR polypeptide according to SEQ ID NO: 761, which is identical to SEQ ID NO: 19 of the instant application. The CAR polypeptide according to SEQ ID NO: 19 the scFv antigen-binding domain according to SEQ ID NO: 114 (amino acids 1-244); the variable heavy chain according to SEQ ID NO: 116; the variable light chain according to SEQ ID NO: 119; the spacer comprising an IgG4/2 chimeric hinge or a modified IgG4 hinge, an IgG2/4 chimeric CH2 region and an IgG4 CH3 region, and having the sequence according to SEQ ID NO: 174 (amino acids 245-472); the transmembrane domain according to SEQ ID NO: 138 (amino acids 473-500); the scFv linker according to SEQ ID NO: 1 (amino acids 108-122); the 4-1BB costimulatory domain according to SEQ ID NO: 4 (amino acids 501-542); and the intracellular signaling region comprising a CD3-zeta chain according to SEQ ID NO: 143 (amino acids 543-654).
Regarding claims 105, the reference claims recite the subject is human (claim 23). Sather teaches the subject is human. See, e.g., par. 1395.
Regarding dependent claim 106, the reference claims do not recite the composition comprising engineered T cells is produced by a manufacturing process comprising: (i) exposing an input composition comprising primary T cells with a stimulatory reagent comprising an oligomeric particle reagent comprising a plurality of streptavidin mutein molecules under conditions to stimulate T cells, thereby generating a stimulated population, wherein the oligomeric particle reagent comprises a first agent comprising an anti-CD3 antibody or antigen binding fragment thereof and a second agent comprising an anti-CD28 antibody or antigen binding fragment thereof; (ii) introducing into T cells of the stimulated population, a heterologous polynucleotide encoding the CAR that targets BCMA, thereby generating a population of transformed cells; (iii) incubating the population of transformed cells, wherein the incubating is completed at, at about, or within 120 hours; and (iv) harvesting T cells of the population of transformed cells, thereby producing a composition of engineered cells.
However, dependent claim 106 describes the engineered T cells by a product-by-process limitation. Even though product-by-process claims are limited by and defined by the process, determination of patentability is based on the product itself. The patentability of a product does not depend on its method of production. If the product in the product-by-process claim is the same as or obvious from a product of the prior art, the claim is unpatentable even though the prior product was made by a different process. In re Thorpe, 777 F.2d 695, 698, 227 USPQ 964, 966 (Fed. Cir. 1985). In this case, the cited prior art teaches or fairly suggests a composition of engineered T cells as claimed in claim 1. Therefore, absent evidence to the contrary, both the claimed composition and that of the cited references are considered structurally similar, even if the claimed composition was produced by a different process. The product-by-process limitations recited by the instant claims are not found to necessarily imply a structural characteristic that patentably distinguishes the instantly claimed composition from that found in the cited references, absent evidence to the contrary. For these reasons, the product of claim 106 is also found to be anticipated by the cited references. See MPEP 2113.
Claim 54 is rejected on the ground of nonstatutory double patenting as being unpatentable over the claims of U.S. Patent No. 12,215,348 B2; and US 2019/0161553 A1 to Sather et al., as applied to claims 1-5, 22, 29-30, 66, 73-77, 80-81, 88-90, 105-106, and 120 above; in further view of Okamoto et al. (2009) “Improved expression and reactivity of transduced tumor-specific TCRs in human lymphocytes by specific silencing of endogenous TCR” Cancer research, 69(23), 9003-9011.
Regarding dependent claim 54, the reference claims do not recite the fraction of integrated vector copy number (iVCN) to total VCN in the CAR+ T cells in the composition, on average, is less than or less than about 0.9; and/or the integrated vector copy number (iVCN) of the CAR+ T cells in the composition, on average, is between or between about 0.4 copies per diploid genome and 2.0 copies per diploid genome, inclusive.
"[W]here the general conditions of a claim are disclosed in the prior art, it is not inventive to discover the optimum or workable ranges by routine experimentation." In re Aller, 220 F.2d 454, 456, 105 USPQ 233, 235 (CCPA 1955). See MPEP 2144.05.
In this case, both the claimed invention and that of the reference claims are directed to genetically-modifying T cells to express a CAR polypeptide for cancer therapy. Although the reference claims do not recite the limitations of dependent claim 54, one of ordinary skill in the art would have recognized that the integrated vector copy number was a result-effective variable. For example, prior to the effective filing date of the instantly claimed invention, Okamoto teaches that the expression level of a transgene can be enhanced by increasing the vector copy number in the transduced cells, but a low copy number is ideal for reducing the risk of insertional mutagenesis even when using mature T cells. See page 9003, right column. Therefore, one of ordinary skill in the art would have been motivated to optimize the integrated vector copy number through routine optimization in order to improve the efficacy and safety of the CAR-T therapy. For these reasons, dependent claim 54 would have been prima facie obvious over the references.
Claims 1-5, 22, 29-30, 66, 73-77, 80-81, 88-90, 105-106, and 120 are provisionally rejected on the ground of nonstatutory double patenting as being unpatentable over the claims of copending U.S. Application No. 19/011,463 (reference to claim listing filed 04/28/2025); in view of US 2019/0161553 A1 to Sather et al. Although the claims at issue are not identical, they are not patentably distinct from each other because the instant claims would have been prima facie obvious over the cited references. This is a provisional nonstatutory double patenting rejection because the patentably indistinct claims have not in fact been patented.
The reference claims recite a method for producing a composition of engineered T cells expressing a recombinant receptor (claim 1); wherein the recombinant receptor is a CAR (claim 21).
The composition comprises a mixture of naïve-like CD4+ T cells and naïve-like CD8+ T cells, wherein the naïve-like CD4+ T cells and naïve-like CD8+ T cells are CD27+CCR7+ (claim 1).
The reference claims do not recite the at least or at least about 80% of the cells in the composition are CD3+ cells; at least or at least about 80% of the CAR+ T cells in the composition are of a naïve-like or central memory phenotype; at least or at least about 50% of the CD4+CAR+ T cells in the composition are CD27+CCR7+ and/or at least or at least about 50% of the CD8+CAR+ T cells in the composition are CD27+CCR7+, as instantly claimed.
Generally, differences in concentration or amount will not support the patentability of subject matter encompassed by the prior art unless there is evidence indicating such concentration or amount is critical."[W]here the general conditions of a claim are disclosed in the prior art, it is not inventive to discover the optimum or workable ranges by routine experimentation." In re Aller, 220 F.2d 454, 456, 105 USPQ 233, 235 (CCPA 1955). See MPEP 2144.05. In this case, both the instantly claimed invention and that of the reference claims are directed to a therapeutic CAR-T cell composition comprising a mixture of naïve-like CD4+ T cells and naïve-like CD8+ T cells, wherein the naïve-like CD4+ T cells and naïve-like CD8+ T cells are CD27+CCR7+. Therefore, absent a secondary consideration, the claimed amounts would have been prima facie obvious over the cited references.
The reference claims do not recite that the CAR targets BCMA and the engineered T cells are administered to a subject in need of treatment for multiple myeloma, as instantly claimed.
Sather is relevant prior art for teaching CAR polypeptides targeting BCMA for use in adoptive cell therapy. In particular, anti-BCMA CAR-expressing T cells are administered to a subject in need of treatment for multiple myeloma. See, e.g., Abstract, par. 114-116, 455, 491, 1395-1387.
Therefore, prior to the effective filing date of the instantly claimed invention, it would have been prima facie obvious to one of ordinary skill in the art to modify the invention of the reference claims by using a CAR targeting BCMA and administering the engineered T cells to a subject in need of treatment for multiple myeloma, as found in Sather, with a reasonable expectation of success because anti-BCMA CAR-T cells target the cancer cells in patients with multiple myeloma, thereby treating multiple myeloma.
For these reasons, claims 1-2 would have been prima facie obvious over the cited references.
Regarding claim 3, the ratio of the naive-like CD4+ T cells to the naive-like CD8+ T cells in is between 10:1 and 0.05:1 (claim 1) or 1.2:1 and 2.4:1 (claim 36).
Regarding claims 4-5, the input cell composition comprises from or from about 1 x 107 to 5 x 109 total cells or total T cells (claim 24). As discussed above, differences in concentration or amount will not support the patentability of subject matter encompassed by the prior art unless there is evidence indicating such concentration or amount is critical."[W]here the general conditions of a claim are disclosed in the prior art, it is not inventive to discover the optimum or workable ranges by routine experimentation." In re Aller, 220 F.2d 454, 456, 105 USPQ 233, 235 (CCPA 1955). See MPEP 2144.05.
Regarding claims 22, 29-30, composition comprises a mixture of naïve-like CD4+ T cells and naïve-like CD8+ T cells, wherein the naïve-like CD4+ T cells and naïve-like CD8+ T cells are CD27+CCR7+ (claim 1). As indicated above, differences in concentration or amount will not support the patentability of subject matter encompassed by the prior art unless there is evidence indicating such concentration or amount is critical."[W]here the general conditions of a claim are disclosed in the prior art, it is not inventive to discover the optimum or workable ranges by routine experimentation." In re Aller, 220 F.2d 454, 456, 105 USPQ 233, 235 (CCPA 1955). See MPEP 2144.05.
Regarding claims 66 and 120, Sather teaches the subject has relapsed and/or refractory multiple myeloma. See, e.g., par. 1395.
Regarding claims 73-77, 80-81, 88-90, Sather teaches an anti-BCMA CAR polypeptide according to SEQ ID NO: 761, which is identical to SEQ ID NO: 19 of the instant application. The CAR polypeptide according to SEQ ID NO: 19 the scFv antigen-binding domain according to SEQ ID NO: 114 (amino acids 1-244); the variable heavy chain according to SEQ ID NO: 116; the variable light chain according to SEQ ID NO: 119; the spacer comprising an IgG4/2 chimeric hinge or a modified IgG4 hinge, an IgG2/4 chimeric CH2 region and an IgG4 CH3 region, and having the sequence according to SEQ ID NO: 174 (amino acids 245-472); the transmembrane domain according to SEQ ID NO: 138 (amino acids 473-500); the scFv linker according to SEQ ID NO: 1 (amino acids 108-122); the 4-1BB costimulatory domain according to SEQ ID NO: 4 (amino acids 501-542); and the intracellular signaling region comprising a CD3-zeta chain according to SEQ ID NO: 143 (amino acids 543-654).
Regarding claims 105, the reference claims recite the subject is human (claim 1). Sather teaches the subject is human. See, e.g., par. 1395.
Regarding dependent claim 106, the reference claims do not recite the composition comprising engineered T cells is produced by a manufacturing process comprising: (i) exposing an input composition comprising primary T cells with a stimulatory reagent comprising an oligomeric particle reagent comprising a plurality of streptavidin mutein molecules under conditions to stimulate T cells, thereby generating a stimulated population, wherein the oligomeric particle reagent comprises a first agent comprising an anti-CD3 antibody or antigen binding fragment thereof and a second agent comprising an anti-CD28 antibody or antigen binding fragment thereof; (ii) introducing into T cells of the stimulated population, a heterologous polynucleotide encoding the CAR that targets BCMA, thereby generating a population of transformed cells; (iii) incubating the population of transformed cells, wherein the incubating is completed at, at about, or within 120 hours; and (iv) harvesting T cells of the population of transformed cells, thereby producing a composition of engineered cells.
However, dependent claim 106 describes the engineered T cells by a product-by-process limitation. Even though product-by-process claims are limited by and defined by the process, determination of patentability is based on the product itself. The patentability of a product does not depend on its method of production. If the product in the product-by-process claim is the same as or obvious from a product of the prior art, the claim is unpatentable even though the prior product was made by a different process. In re Thorpe, 777 F.2d 695, 698, 227 USPQ 964, 966 (Fed. Cir. 1985). In this case, the cited prior art teaches or fairly suggests a composition of engineered T cells as claimed in claim 1. Therefore, absent evidence to the contrary, both the claimed composition and that of the cited references are considered structurally similar, even if the claimed composition was produced by a different process. The product-by-process limitations recited by the instant claims are not found to necessarily imply a structural characteristic that patentably distinguishes the instantly claimed composition from that found in the cited references, absent evidence to the contrary. For these reasons, the product of claim 106 is also found to be anticipated by the cited references. See MPEP 2113.
Claim 54 is provisionally rejected on the ground of nonstatutory double patenting as being unpatentable over the claims of copending U.S. Application No. 19/011,463; and US 2019/0161553 A1 to Sather et al., as applied to claims 1-5, 22, 29-30, 66, 73-77, 80-81, 88-90, 105-106, and 120 above; in further view of Okamoto et al. (2009) “Improved expression and reactivity of transduced tumor-specific TCRs in human lymphocytes by specific silencing of endogenous TCR” Cancer research, 69(23), 9003-9011.
Regarding dependent claim 54, the reference claims do not recite the fraction of integrated vector copy number (iVCN) to total VCN in the CAR+ T cells in the composition, on average, is less than or less than about 0.9; and/or the integrated vector copy number (iVCN) of the CAR+ T cells in the composition, on average, is between or between about 0.4 copies per diploid genome and 2.0 copies per diploid genome, inclusive.
"[W]here the general conditions of a claim are disclosed in the prior art, it is not inventive to discover the optimum or workable ranges by routine experimentation." In re Aller, 220 F.2d 454, 456, 105 USPQ 233, 235 (CCPA 1955). See MPEP 2144.05.
In this case, both the claimed invention and that of the reference claims are directed to genetically-modifying T cells to express a CAR polypeptide for cancer therapy. Although the reference claims do not recite the limitations of dependent claim 54, one of ordinary skill in the art would have recognized that the integrated vector copy number was a result-effective variable. For example, prior to the effective filing date of the instantly claimed invention, Okamoto teaches that the expression level of a transgene can be enhanced by increasing the vector copy number in the transduced cells, but a low copy number is ideal for reducing the risk of insertional mutagenesis even when using mature T cells. See page 9003, right column. Therefore, one of ordinary skill in the art would have been motivated to optimize the integrated vector copy number through routine optimization in order to improve the efficacy and safety of the CAR-T therapy. For these reasons, dependent claim 54 would have been prima facie obvious over the references.
Claims 1-5, 22, 29-30, 66, 73-77, 80-81, 88-90, 105-106, and 120 are rejected on the ground of nonstatutory double patenting as being unpatentable over the claims of U.S. Patent No. 12,161,670 B2; in view of US 2019/0161553 A1 to Sather et al. Although the claims at issue are not identical, they are not patentably distinct from each other because the instant claims would have been prima facie obvious over the cited references.
The reference claims recite a method of treatment comprising the administration of a composition of engineered T cells expressing a CAR to a subject in need thereof (claim 1).
The composition comprises a mixture of naïve-like CD4+ T cells and naïve-like CD8+ T cells, wherein the naïve-like CD4+ T cells and naïve-like CD8+ T cells are CD27+CCR7+ (claim 1). Between 15% and 90% of the total receptor+ T cells in the unit dose are receptor+/CD8+/ CCR7+CD27+ or receptor+/CD4+/CCR7+/CD27+, each inclusive (claim 6).
The reference claims do not recite the at least or at least about 80% of the cells in the composition are CD3+ cells; at least or at least about 80% of the CAR+ T cells in the composition are of a naïve-like or central memory phenotype; at least or at least about 50% of the CD4+CAR+ T cells in the composition are CD27+CCR7+ and/or at least or at least about 50% of the CD8+CAR+ T cells in the composition are CD27+CCR7+, as instantly claimed.
Generally, differences in concentration or amount will not support the patentability of subject matter encompassed by the prior art unless there is evidence indicating such concentration or amount is critical."[W]here the general conditions of a claim are disclosed in the prior art, it is not inventive to discover the optimum or workable ranges by routine experimentation." In re Aller, 220 F.2d 454, 456, 105 USPQ 233, 235 (CCPA 1955). See MPEP 2144.05. In this case, both the instantly claimed invention and that of the reference claims are directed to a therapeutic CAR-T cell composition comprising a mixture of naïve-like CD4+ T cells and naïve-like CD8+ T cells, wherein the naïve-like CD4+ T cells and naïve-like CD8+ T cells are CD27+CCR7+. Therefore, absent a secondary consideration, the claimed amounts would have been prima facie obvious over the cited references.
The reference claims do not recite that the CAR targets BCMA and the engineered T cells are administered to a subject in need of treatment for multiple myeloma, as instantly claimed.
Sather is relevant prior art for teaching CAR polypeptides targeting BCMA for use in adoptive cell therapy. In particular, anti-BCMA CAR-expressing T cells are administered to a subject in need of treatment for multiple myeloma. See, e.g., Abstract, par. 114-116, 455, 491, 1395-1387.
Therefore, prior to the effective filing date of the instantly claimed invention, it would have been prima facie obvious to one of ordinary skill in the art to modify the invention of the reference claims by using a CAR targeting BCMA and administering the engineered T cells to a subject in need of treatment for multiple myeloma, as found in Sather, with a reasonable expectation of success because anti-BCMA CAR-T cells target the cancer cells in patients with multiple myeloma, thereby treating multiple myeloma.
For these reasons, claims 1-2 would have been prima facie obvious over the cited references.
Regarding claim 3, the ratio of the naive-like CD4+ T cells to the naive-like CD8+ T cells in is between 3:1 and 1:3 (claim 7).
Regarding claims 4-5, the unit dose of cells comprises between 1 x 105 and 1 x 108 (claim 1) or between 3 x 106 and 2.5 x 107 (claim 6). As discussed above, differences in concentration or amount will not support the patentability of subject matter encompassed by the prior art unless there is evidence indicating such concentration or amount is critical."[W]here the general conditions of a claim are disclosed in the prior art, it is not inventive to discover the optimum or workable ranges by routine experimentation." In re Aller, 220 F.2d 454, 456, 105 USPQ 233, 235 (CCPA 1955). See MPEP 2144.05.
Regarding claims 22, 29-30, composition comprises a mixture of naïve-like CD4+ T cells and naïve-like CD8+ T cells, wherein the naïve-like CD4+ T cells and naïve-like CD8+ T cells are CD27+CCR7+ (claim 1). As indicated above, differences in concentration or amount will not support the patentability of subject matter encompassed by the prior art unless there is evidence indicating such concentration or amount is critical."[W]here the general conditions of a claim are disclosed in the prior art, it is not inventive to discover the optimum or workable ranges by routine experimentation." In re Aller, 220 F.2d 454, 456, 105 USPQ 233, 235 (CCPA 1955). See MPEP 2144.05.
Regarding claims 66 and 120, Sather teaches the subject has relapsed and/or refractory multiple myeloma. See, e.g., par. 1395.
Regarding claims 73-77, 80-81, 88-90, Sather teaches an anti-BCMA CAR polypeptide according to SEQ ID NO: 761, which is identical to SEQ ID NO: 19 of the instant application. The CAR polypeptide according to SEQ ID NO: 19 the scFv antigen-binding domain according to SEQ ID NO: 114 (amino acids 1-244); the variable heavy chain according to SEQ ID NO: 116; the variable light chain according to SEQ ID NO: 119; the spacer comprising an IgG4/2 chimeric hinge or a modified IgG4 hinge, an IgG2/4 chimeric CH2 region and an IgG4 CH3 region, and having the sequence according to SEQ ID NO: 174 (amino acids 245-472); the transmembrane domain according to SEQ ID NO: 138 (amino acids 473-500); the scFv linker according to SEQ ID NO: 1 (amino acids 108-122); the 4-1BB costimulatory domain according to SEQ ID NO: 4 (amino acids 501-542); and the intracellular signaling region comprising a CD3-zeta chain according to SEQ ID NO: 143 (amino acids 543-654).
Regarding claims 105, Sather teaches the subject is human. See, e.g., par. 1395.
Regarding dependent claim 106, the reference claims do not recite the composition comprising engineered T cells is produced by a manufacturing process comprising: (i) exposing an input composition comprising primary T cells with a stimulatory reagent comprising an oligomeric particle reagent comprising a plurality of streptavidin mutein molecules under conditions to stimulate T cells, thereby generating a stimulated population, wherein the oligomeric particle reagent comprises a first agent comprising an anti-CD3 antibody or antigen binding fragment thereof and a second agent comprising an anti-CD28 antibody or antigen binding fragment thereof; (ii) introducing into T cells of the stimulated population, a heterologous polynucleotide encoding the CAR that targets BCMA, thereby generating a population of transformed cells; (iii) incubating the population of transformed cells, wherein the incubating is completed at, at about, or within 120 hours; and (iv) harvesting T cells of the population of transformed cells, thereby producing a composition of engineered cells.
However, dependent claim 106 describes the engineered T cells by a product-by-process limitation. Even though product-by-process claims are limited by and defined by the process, determination of patentability is based on the product itself. The patentability of a product does not depend on its method of production. If the product in the product-by-process claim is the same as or obvious from a product of the prior art, the claim is unpatentable even though the prior product was made by a different process. In re Thorpe, 777 F.2d 695, 698, 227 USPQ 964, 966 (Fed. Cir. 1985). In this case, the cited prior art teaches or fairly suggests a composition of engineered T cells as claimed in claim 1. Therefore, absent evidence to the contrary, both the claimed composition and that of the cited references are considered structurally similar, even if the claimed composition was produced by a different process. The product-by-process limitations recited by the instant claims are not found to necessarily imply a structural characteristic that patentably distinguishes the instantly claimed composition from that found in the cited references, absent evidence to the contrary. For these reasons, the product of claim 106 is also found to be anticipated by the cited references. See MPEP 2113.
Claim 54 is rejected on the ground of nonstatutory double patenting as being unpatentable over the claims of U.S. Patent No. 12,161,670 B2; and US 2019/0161553 A1 to Sather et al., as applied to claims 1-5, 22, 29-30, 66, 73-77, 80-81, 88-90, 105-106, and 120 above; in further view of Okamoto et al. (2009) “Improved expression and reactivity of transduced tumor-specific TCRs in human lymphocytes by specific silencing of endogenous TCR” Cancer research, 69(23), 9003-9011.
Regarding dependent claim 54, the reference claims do not recite the fraction of integrated vector copy number (iVCN) to total VCN in the CAR+ T cells in the composition, on average, is less than or less than about 0.9; and/or the integrated vector copy number (iVCN) of the CAR+ T cells in the composition, on average, is between or between about 0.4 copies per diploid genome and 2.0 copies per diploid genome, inclusive.
"[W]here the general conditions of a claim are disclosed in the prior art, it is not inventive to discover the optimum or workable ranges by routine experimentation." In re Aller, 220 F.2d 454, 456, 105 USPQ 233, 235 (CCPA 1955). See MPEP 2144.05.
In this case, both the claimed invention and that of the reference claims are directed to genetically-modifying T cells to express a CAR polypeptide for cancer therapy. Although the reference claims do not recite the limitations of dependent claim 54, one of ordinary skill in the art would have recognized that the integrated vector copy number was a result-effective variable. For example, prior to the effective filing date of the instantly claimed invention, Okamoto teaches that the expression level of a transgene can be enhanced by increasing the vector copy number in the transduced cells, but a low copy number is ideal for reducing the risk of insertional mutagenesis even when using mature T cells. See page 9003, right column. Therefore, one of ordinary skill in the art would have been motivated to optimize the integrated vector copy number through routine optimization in order to improve the efficacy and safety of the CAR-T therapy. For these reasons, dependent claim 54 would have been prima facie obvious over the references.
Claims 1-5, 22, 29-30, 66, 73-77, 80-81, 88-90, 105-106, and 120 are provisionally rejected on the ground of nonstatutory double patenting as being unpatentable over the claims of copending U.S. Application No. 18/935,276 (reference to claim listing filed 11/01/2024); in view of US 2019/0161553 A1 to Sather et al. Although the claims at issue are not identical, they are not patentably distinct from each other because the instant claims would have been prima facie obvious over the cited references. This is a provisional nonstatutory double patenting rejection because the patentably indistinct claims have not in fact been patented.
The reference claims recite a therapeutic composition comprising engineered T cells expressing a recombinant receptor (claim 1); wherein the recombinant receptor targets BCMA (claim 14) and is a CAR (claim 15); wherein the engineered T cells are obtained from a subject having cancer (claim 18).
The T cells are CD27+CCR7+ (claim 1); the composition comprises a mixture of CD4+ T cells and CD8+ T cells (claim 5); wherein the naïve-like CD4+ T cells and naïve-like CD8+ T cells are CD27+CCR7+ (claim 1); wherein at least 15% of the total receptor+ cells in the composition are receptor+/CD8+/CCR7+/CD27+, receptor+/CD8+/CCR 7+/CD45RA-, receptor+/CD4+ /CCR 7+/CD27+, or receptor+/CD4+/CCR7+/CD45RA- (claim 7). Since the CD3+ T cells are surface positive for CD27 and CCR7, the T cells are found to read on naïve-like T cells, as claimed.
The reference claims do not recite the at least or at least about 80% of the cells in the composition are CD3+ cells; at least or at least about 80% of the CAR+ T cells in the composition are of a naïve-like or central memory phenotype; at least or at least about 50% of the CD4+CAR+ T cells in the composition are CD27+CCR7+ and/or at least or at least about 50% of the CD8+CAR+ T cells in the composition are CD27+CCR7+, as instantly claimed.
Generally, differences in concentration or amount will not support the patentability of subject matter encompassed by the prior art unless there is evidence indicating such concentration or amount is critical."[W]here the general conditions of a claim are disclosed in the prior art, it is not inventive to discover the optimum or workable ranges by routine experimentation." In re Aller, 220 F.2d 454, 456, 105 USPQ 233, 235 (CCPA 1955). See MPEP 2144.05. In this case, both the instantly claimed invention and that of the reference claims are directed to a therapeutic CAR-T cell composition comprising a mixture of naïve-like CD4+ T cells and naïve-like CD8+ T cells, wherein the naïve-like CD4+ T cells and naïve-like CD8+ T cells are CD27+CCR7+. Therefore, absent a secondary consideration, the claimed amounts would have been prima facie obvious over the cited references.
The reference claims do not recite a step of administering the engineered T cells to a subject in need of treatment for multiple myeloma, as instantly claimed.
Sather is relevant prior art for teaching CAR polypeptides targeting BCMA for use in adoptive cell therapy. In particular, anti-BCMA CAR-expressing T cells are administered to a subject in need of treatment for multiple myeloma. See, e.g., Abstract, par. 114-116, 455, 491, 1395-1387.
Therefore, prior to the effective filing date of the instantly claimed invention, it would have been prima facie obvious to one of ordinary skill in the art to modify the invention of the reference claims by further including a step of administering the engineered T cells to a subject in need of treatment for multiple myeloma, as found in Sather, with a reasonable expectation of success because anti-BCMA CAR-T cells target the cancer cells in patients with multiple myeloma, thereby treating multiple myeloma.
For these reasons, claims 1-2 would have been prima facie obvious over the cited references.
Regarding claim 3, the reference claims do not recite a ratio of CD4+ cells to CD8+ cells. As indicated above, differences in concentration or amount will not support the patentability of subject matter encompassed by the prior art unless there is evidence indicating such concentration or amount is critical."[W]here the general conditions of a claim are disclosed in the prior art, it is not inventive to discover the optimum or workable ranges by routine experimentation." In re Aller, 220 F.2d 454, 456, 105 USPQ 233, 235 (CCPA 1955). See MPEP 2144.05. In this case, both the instantly claimed invention and that of the reference claims are directed to a therapeutic CAR-T cell composition comprising a mixture of naïve-like CD4+ T cells and naïve-like CD8+ T cells, wherein the naïve-like CD4+ T cells and naïve-like CD8+ T cells are CD27+CCR7+. Therefore, absent a secondary consideration, the claimed amounts would have been prima facie obvious over the cited references.
Regarding claims 4-5, the composition comprises about 1 x 105 to 1 x 108 total cells or total T cells (claims 6, 8). As discussed above, differences in concentration or amount will not support the patentability of subject matter encompassed by the prior art unless there is evidence indicating such concentration or amount is critical."[W]here the general conditions of a claim are disclosed in the prior art, it is not inventive to discover the optimum or workable ranges by routine experimentation." In re Aller, 220 F.2d 454, 456, 105 USPQ 233, 235 (CCPA 1955). See MPEP 2144.05.
Regarding claims 22, 29-30, composition comprises a mixture of CD4+ T cells and CD8+ T cells, wherein the CD4+ T cells and CD8+ T cells are CD27+CCR7+ (claims 1, 5). As indicated above, differences in concentration or amount will not support the patentability of subject matter encompassed by the prior art unless there is evidence indicating such concentration or amount is critical."[W]here the general conditions of a claim are disclosed in the prior art, it is not inventive to discover the optimum or workable ranges by routine experimentation." In re Aller, 220 F.2d 454, 456, 105 USPQ 233, 235 (CCPA 1955). See MPEP 2144.05.
Regarding claims 66 and 120, Sather teaches the subject has relapsed and/or refractory multiple myeloma. See, e.g., par. 1395.
Regarding claims 73-77, 80-81, 88-90, Sather teaches an anti-BCMA CAR polypeptide according to SEQ ID NO: 761, which is identical to SEQ ID NO: 19 of the instant application. The CAR polypeptide according to SEQ ID NO: 19 the scFv antigen-binding domain according to SEQ ID NO: 114 (amino acids 1-244); the variable heavy chain according to SEQ ID NO: 116; the variable light chain according to SEQ ID NO: 119; the spacer comprising an IgG4/2 chimeric hinge or a modified IgG4 hinge, an IgG2/4 chimeric CH2 region and an IgG4 CH3 region, and having the sequence according to SEQ ID NO: 174 (amino acids 245-472); the transmembrane domain according to SEQ ID NO: 138 (amino acids 473-500); the scFv linker according to SEQ ID NO: 1 (amino acids 108-122); the 4-1BB costimulatory domain according to SEQ ID NO: 4 (amino acids 501-542); and the intracellular signaling region comprising a CD3-zeta chain according to SEQ ID NO: 143 (amino acids 543-654).
Regarding claims 105, Sather teaches the subject is human. See, e.g., par. 1395.
Regarding dependent claim 106, the reference claims do not recite the composition comprising engineered T cells is produced by a manufacturing process comprising: (i) exposing an input composition comprising primary T cells with a stimulatory reagent comprising an oligomeric particle reagent comprising a plurality of streptavidin mutein molecules under conditions to stimulate T cells, thereby generating a stimulated population, wherein the oligomeric particle reagent comprises a first agent comprising an anti-CD3 antibody or antigen binding fragment thereof and a second agent comprising an anti-CD28 antibody or antigen binding fragment thereof; (ii) introducing into T cells of the stimulated population, a heterologous polynucleotide encoding the CAR that targets BCMA, thereby generating a population of transformed cells; (iii) incubating the population of transformed cells, wherein the incubating is completed at, at about, or within 120 hours; and (iv) harvesting T cells of the population of transformed cells, thereby producing a composition of engineered cells.
However, dependent claim 106 describes the engineered T cells by a product-by-process limitation. Even though product-by-process claims are limited by and defined by the process, determination of patentability is based on the product itself. The patentability of a product does not depend on its method of production. If the product in the product-by-process claim is the same as or obvious from a product of the prior art, the claim is unpatentable even though the prior product was made by a different process. In re Thorpe, 777 F.2d 695, 698, 227 USPQ 964, 966 (Fed. Cir. 1985). In this case, the cited prior art teaches or fairly suggests a composition of engineered T cells as claimed in claim 1. Therefore, absent evidence to the contrary, both the claimed composition and that of the cited references are considered structurally similar, even if the claimed composition was produced by a different process. The product-by-process limitations recited by the instant claims are not found to necessarily imply a structural characteristic that patentably distinguishes the instantly claimed composition from that found in the cited references, absent evidence to the contrary. For these reasons, the product of claim 106 is also found to be anticipated by the cited references. See MPEP 2113.
Claim 54 is provisionally rejected on the ground of nonstatutory double patenting as being unpatentable over the claims of copending U.S. Application No. 18/935,276; and US 2019/0161553 A1 to Sather et al., as applied to claims 1-5, 22, 29-30, 66, 73-77, 80-81, 88-90, 105-106, and 120 above; in further view of Okamoto et al. (2009) “Improved expression and reactivity of transduced tumor-specific TCRs in human lymphocytes by specific silencing of endogenous TCR” Cancer research, 69(23), 9003-9011.
Regarding dependent claim 54, the reference claims do not recite the fraction of integrated vector copy number (iVCN) to total VCN in the CAR+ T cells in the composition, on average, is less than or less than about 0.9; and/or the integrated vector copy number (iVCN) of the CAR+ T cells in the composition, on average, is between or between about 0.4 copies per diploid genome and 2.0 copies per diploid genome, inclusive.
"[W]here the general conditions of a claim are disclosed in the prior art, it is not inventive to discover the optimum or workable ranges by routine experimentation." In re Aller, 220 F.2d 454, 456, 105 USPQ 233, 235 (CCPA 1955). See MPEP 2144.05.
In this case, both the claimed invention and that of the reference claims are directed to genetically-modifying T cells to express a CAR polypeptide for cancer therapy. Although the reference claims do not recite the limitations of dependent claim 54, one of ordinary skill in the art would have recognized that the integrated vector copy number was a result-effective variable. For example, prior to the effective filing date of the instantly claimed invention, Okamoto teaches that the expression level of a transgene can be enhanced by increasing the vector copy number in the transduced cells, but a low copy number is ideal for reducing the risk of insertional mutagenesis even when using mature T cells. See page 9003, right column. Therefore, one of ordinary skill in the art would have been motivated to optimize the integrated vector copy number through routine optimization in order to improve the efficacy and safety of the CAR-T therapy. For these reasons, dependent claim 54 would have been prima facie obvious over the references.
Claims 1-5, 22, 29-30, 66, 73-77, 80-81, 88-90, 105-106, and 120 are provisionally rejected on the ground of nonstatutory double patenting as being unpatentable over the claims of copending U.S. Application No. 18/617,271 (reference to claim listing filed 07/30/2024); in view of US 2019/0161553 A1 to Sather et al. Although the claims at issue are not identical, they are not patentably distinct from each other because the instant claims would have been prima facie obvious over the cited references. This is a provisional nonstatutory double patenting rejection because the patentably indistinct claims have not in fact been patented.
The reference claims recite a method of producing a composition comprising engineered T cells expressing a recombinant receptor (claim 1); wherein the recombinant receptor is a CAR (claim 16).
The reference claims further recite a method of treatment, comprising administering to a mammalian subject the engineered T cells (claim 44).
The T cells are naïve-like T cells (claim 1); the naïve-like T cells are CD27+CCR7+ (claims 7-8); the composition comprises a mixture of CD4+ T cells and CD8+ T cells (claim 1); the stimulated composition comprises greater than 75% of cells that are derived from naïve-like T cells of the input composition (claim 37).
The reference claims do not recite the at least or at least about 80% of the cells in the composition are CD3+ cells; at least or at least about 80% of the CAR+ T cells in the composition are of a naïve-like or central memory phenotype; at least or at least about 50% of the CD4+CAR+ T cells in the composition are CD27+CCR7+ and/or at least or at least about 50% of the CD8+CAR+ T cells in the composition are CD27+CCR7+, as instantly claimed.
Generally, differences in concentration or amount will not support the patentability of subject matter encompassed by the prior art unless there is evidence indicating such concentration or amount is critical."[W]here the general conditions of a claim are disclosed in the prior art, it is not inventive to discover the optimum or workable ranges by routine experimentation." In re Aller, 220 F.2d 454, 456, 105 USPQ 233, 235 (CCPA 1955). See MPEP 2144.05. In this case, both the instantly claimed invention and that of the reference claims are directed to a therapeutic CAR-T cell composition comprising a mixture of naïve-like CD4+ T cells and naïve-like CD8+ T cells, wherein the naïve-like CD4+ T cells and naïve-like CD8+ T cells are CD27+CCR7+. Therefore, absent a secondary consideration, the claimed amounts would have been prima facie obvious over the cited references.
The reference claims do not recite that the CAR targets BCMA and the engineered T cells are administered to a subject in need of treatment for multiple myeloma, as instantly claimed.
Sather is relevant prior art for teaching CAR polypeptides targeting BCMA for use in adoptive cell therapy. In particular, anti-BCMA CAR-expressing T cells are administered to a subject in need of treatment for multiple myeloma. See, e.g., Abstract, par. 114-116, 455, 491, 1395-1387.
Therefore, prior to the effective filing date of the instantly claimed invention, it would have been prima facie obvious to one of ordinary skill in the art to modify the invention of the reference claims by using a CAR targeting BCMA and further including a step of administering the engineered T cells to a subject in need of treatment for multiple myeloma, as found in Sather, with a reasonable expectation of success because anti-BCMA CAR-T cells target the cancer cells in patients with multiple myeloma, thereby treating multiple myeloma.
For these reasons, claims 1-2 would have been prima facie obvious over the cited references.
Regarding claim 3, the reference claims recite a ratio of CD4+ to CD8+ cells between 2:1 and 1:5, about 1:1, about 1:2, about 2:1, about 1:3, and about 3:1 (claims 32-33).
Regarding claims 4-5, the culture-initiating amount is at least 2.0 x 108 of the naïve-like T cells that are CD4+ or CD8+ (claim 1). As discussed above, differences in concentration or amount will not support the patentability of subject matter encompassed by the prior art unless there is evidence indicating such concentration or amount is critical."[W]here the general conditions of a claim are disclosed in the prior art, it is not inventive to discover the optimum or workable ranges by routine experimentation." In re Aller, 220 F.2d 454, 456, 105 USPQ 233, 235 (CCPA 1955). See MPEP 2144.05.
Regarding claims 22, 29-30, composition comprises a mixture of CD4+ T cells and CD8+ T cells, wherein the CD4+ T cells and CD8+ T cells are CD27+CCR7+ (claims 1, 7-8). As indicated above, differences in concentration or amount will not support the patentability of subject matter encompassed by the prior art unless there is evidence indicating such concentration or amount is critical."[W]here the general conditions of a claim are disclosed in the prior art, it is not inventive to discover the optimum or workable ranges by routine experimentation." In re Aller, 220 F.2d 454, 456, 105 USPQ 233, 235 (CCPA 1955). See MPEP 2144.05.
Regarding claims 66 and 120, Sather teaches the subject has relapsed and/or refractory multiple myeloma. See, e.g., par. 1395.
Regarding claims 73-77, 80-81, 88-90, Sather teaches an anti-BCMA CAR polypeptide according to SEQ ID NO: 761, which is identical to SEQ ID NO: 19 of the instant application. The CAR polypeptide according to SEQ ID NO: 19 the scFv antigen-binding domain according to SEQ ID NO: 114 (amino acids 1-244); the variable heavy chain according to SEQ ID NO: 116; the variable light chain according to SEQ ID NO: 119; the spacer comprising an IgG4/2 chimeric hinge or a modified IgG4 hinge, an IgG2/4 chimeric CH2 region and an IgG4 CH3 region, and having the sequence according to SEQ ID NO: 174 (amino acids 245-472); the transmembrane domain according to SEQ ID NO: 138 (amino acids 473-500); the scFv linker according to SEQ ID NO: 1 (amino acids 108-122); the 4-1BB costimulatory domain according to SEQ ID NO: 4 (amino acids 501-542); and the intracellular signaling region comprising a CD3-zeta chain according to SEQ ID NO: 143 (amino acids 543-654).
Regarding claims 105, Sather teaches the subject is human. See, e.g., par. 1395.
Regarding dependent claim 106, the reference claims do not recite the composition comprising engineered T cells is produced by a manufacturing process comprising: (i) exposing an input composition comprising primary T cells with a stimulatory reagent comprising an oligomeric particle reagent comprising a plurality of streptavidin mutein molecules under conditions to stimulate T cells, thereby generating a stimulated population, wherein the oligomeric particle reagent comprises a first agent comprising an anti-CD3 antibody or antigen binding fragment thereof and a second agent comprising an anti-CD28 antibody or antigen binding fragment thereof; (ii) introducing into T cells of the stimulated population, a heterologous polynucleotide encoding the CAR that targets BCMA, thereby generating a population of transformed cells; (iii) incubating the population of transformed cells, wherein the incubating is completed at, at about, or within 120 hours; and (iv) harvesting T cells of the population of transformed cells, thereby producing a composition of engineered cells.
However, dependent claim 106 describes the engineered T cells by a product-by-process limitation. Even though product-by-process claims are limited by and defined by the process, determination of patentability is based on the product itself. The patentability of a product does not depend on its method of production. If the product in the product-by-process claim is the same as or obvious from a product of the prior art, the claim is unpatentable even though the prior product was made by a different process. In re Thorpe, 777 F.2d 695, 698, 227 USPQ 964, 966 (Fed. Cir. 1985). In this case, the cited prior art teaches or fairly suggests a composition of engineered T cells as claimed in claim 1. Therefore, absent evidence to the contrary, both the claimed composition and that of the cited references are considered structurally similar, even if the claimed composition was produced by a different process. The product-by-process limitations recited by the instant claims are not found to necessarily imply a structural characteristic that patentably distinguishes the instantly claimed composition from that found in the cited references, absent evidence to the contrary. For these reasons, the product of claim 106 is also found to be anticipated by the cited references. See MPEP 2113.
Claim 54 is provisionally rejected on the ground of nonstatutory double patenting as being unpatentable over the claims of copending U.S. Application No. 18/617,271; and US 2019/0161553 A1 to Sather et al., as applied to claims 1-5, 22, 29-30, 66, 73-77, 80-81, 88-90, 105-106, and 120 above; in further view of Okamoto et al. (2009) “Improved expression and reactivity of transduced tumor-specific TCRs in human lymphocytes by specific silencing of endogenous TCR” Cancer research, 69(23), 9003-9011.
Regarding dependent claim 54, the reference claims do not recite the fraction of integrated vector copy number (iVCN) to total VCN in the CAR+ T cells in the composition, on average, is less than or less than about 0.9; and/or the integrated vector copy number (iVCN) of the CAR+ T cells in the composition, on average, is between or between about 0.4 copies per diploid genome and 2.0 copies per diploid genome, inclusive.
"[W]here the general conditions of a claim are disclosed in the prior art, it is not inventive to discover the optimum or workable ranges by routine experimentation." In re Aller, 220 F.2d 454, 456, 105 USPQ 233, 235 (CCPA 1955). See MPEP 2144.05.
In this case, both the claimed invention and that of the reference claims are directed to genetically-modifying T cells to express a CAR polypeptide for cancer therapy. Although the reference claims do not recite the limitations of dependent claim 54, one of ordinary skill in the art would have recognized that the integrated vector copy number was a result-effective variable. For example, prior to the effective filing date of the instantly claimed invention, Okamoto teaches that the expression level of a transgene can be enhanced by increasing the vector copy number in the transduced cells, but a low copy number is ideal for reducing the risk of insertional mutagenesis even when using mature T cells. See page 9003, right column. Therefore, one of ordinary skill in the art would have been motivated to optimize the integrated vector copy number through routine optimization in order to improve the efficacy and safety of the CAR-T therapy. For these reasons, dependent claim 54 would have been prima facie obvious over the references.
Conclusion
The above rejections will not be held in abeyance. A complete response to a nonstatutory double patenting (NSDP) rejection is either a reply by applicant showing that the claims subject to the rejection are patentably distinct from the reference claims or the filing of a terminal disclaimer in accordance with 37 CFR 1.321 in the pending application(s) with a reply to the Office action (see MPEP § 1490 for a discussion of terminal disclaimers). Such a response is required even when the nonstatutory double patenting rejection is provisional. See MPEP 804(I)(B)(1).
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/JAMES JOSEPH GRABER/Examiner, Art Unit 1631