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 .
Response to Amendment
Applicant’s remarks and amendments to the claims received 01/29/2026 have been acknowledged. Claims 14, 97, and 99 have been amended. Claim 93 has been canceled.
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.
This application currently names joint inventors. In considering patentability of the claims the examiner presumes that the subject matter of the various claims was commonly owned as of the effective filing date of the claimed invention(s) absent any evidence to the contrary. Applicant is advised of the obligation under 37 CFR 1.56 to point out the inventor and effective filing dates of each claim that was not commonly owned as of the effective filing date of the later invention in order for the examiner to consider the applicability of 35 U.S.C. 102(b)(2)(C) for any potential 35 U.S.C. 102(a)(2) prior art against the later invention.
Claims 14-16, 20, 38, 40, 48, 51, 52, 55-57, 62, 64-67, 82, 85, 87, 89-92, 97, and 99 are rejected under 35 U.S.C. 103 as being unpatentable over Mueller et al (WO2017210617A2), hereinafter Mueller, in view of Centers for Disease Control and Prevention (CDC Growth Charts: United States. “Weight for Age Percentiles, Girls and Boys 2-20 Years of Age”. U.S. Department of Health and Human Services, 2000), hereinafter the CDC, and Food and Drug administration (“E11: Clinical Investigation of Medicinal Products in the Pediatric Population”. International Conference on Harmonisation, Dec. 2000, U.S. Food and Drug Administration), hereinafter the FDA.
Mueller teaches methods of treating a B cell malignancy such as B-cell acute lymphoblastic leukemia (B-ALL) in a subject comprising administering a therapeutically effective amount of a composition comprising CD19-CAR expressing cells such as T cells, wherein the subject is a pediatric or young adult (i.e. about 3 to 23 years of age, or about 1 to 24 years of age, or about 3 to 25 years of age, Page 8, Ln. 26-30) and the CAR-T cells are administered at a dose of about 0.2 x 106 to 5.0 x 106 cells/kg when the subject weighs <50 kg; or at a dose of about 0.1 x 108 to 2.5 x 108 cells when the subject weighs >50 kg (Page 4, Ln. 27-34; Page 5; Ln. 5-11; Page 13, Ln. 23-35 to Page 14: Ln. 5-15; Page 45 to Page 52; Page 91 to Page 133). In other embodiments, the CAR T cells can be administered, for example, at a dose of about 0.2 x 106 to 2.0 x 106 cells/kg when the subject weighs <50 kg; or at a dose of about 0.1 x 108 to 1.0 x 108 cells when the subject weighs >50 kg (Page 3 to 4), and thus does not exceed at or about 1.5 x 108 CAR T cells. The T cells can be a mixture of CD4+ T cells and CD8+ T cells (Page 37, Ln. 16); and at least two doses of CAR-expressing cells are administered separately with a time interval of about one day (Page 7, Ln. 23-24). The B-cell ALL can be relapsed/refractory (Page 10, Ln. 26-27). Prior to administration of the CD19 CAR T cells, the subject is preconditioned with a lymphodepleting therapy comprising cyclophosphamide and/or fludarabine 1 to 4 days prior to CAR T cell infusion, wherein cyclophosphamide is administered at a dosage of about 200 mg/m2 -300 mg/m2) and fludarabine at a dosage of about 10-50 mg/m2 (e.g. 200 mg/m2 cyclophosphamide and 20 mg/m2 fludarabine, daily x 3) (Page 11, Ln. 19-20; Page 305, Ln. 25-35 to Page 306, Ln. 5-9; and Page 330). The CAR comprises an scFv specific for human CD19, a transmembrane domain, human a 4-1BB costimulatory molecule, and a primary signaling domain derived from a human CD3zeta comprising SEQ ID NO: 43 (corresponding to SEQ ID NO: 13 of the instant claims) (see “CAR molecules” section, in particular, Page 44, Ln. 15-24, Page 46, Ln. 19-22). The CAR can further comprise a hinge, or spacer, between the scFv binding domain and the transmembrane domain, wherein the hinge or spacer comprises an IgG4 hinge of SEQ ID NO: 45 (Page 222, Ln. 24-35 to Page 223, Ln. 5-9), which fully comprises the amino acid sequence of SEQ ID NO: 1 of the instant claims. The antigen binding domain of the CAR includes the FMC63 scFv (Page 100, Ln. 7-11), corresponding to SEQ ID NO: 43 of the instant claims. The FMC63 clone fully comprises the VH and VL chains of SEQ ID NOs: 41 and 42, respectively, of the instant claims and the CDRs of SEQ ID NOs: 35-40 of the instant claims. The exact dosage regimen recited in the instant claims are not specifically taught; however, Mueller does state that the precise amount of the compositions of to be administered can be determined by a physician with consideration of individual differences in age, weight, tumor size, extent of infection or metastasis, and condition of the patient (subject) (Page 369).
Mueller does not specifically teach age-based stratification of CAR T cell doses wherein subjects < 18 years of age receive a weight-based dose and subjects 18-25 years of age receive a flat dose.
However, the CDC growth charts teach that age and weight are strongly correlated in pediatric and young adult populations. By age 18, the 50th percentile (median) weight for males is ~ 66 kg and for females ~57 kg –both above 50 kg. For most younger children (<18 years of age), the median weight is less than 50 kg.
The FDA’s Center for Biologics/Drug Evaluation and Research further teaches that dosing recommendations for most medicinal products used in the pediatric population are based on milligram (mg)/kilogram (kg) body weight up to a maximum adult dose (see last paragraph of Section 2.4.1: Pharmacokinetics on Page 7).
It would have been obvious to one of ordinary skill in the art that modify the method of Mueller such that doses of CD19 CAR T cells are administered based on age stratification rather than directly on weight wherein pediatric subjects (<18 years) receive a weight-based dose and adult patients (>18 years) receive a flat or fixed dose of CD19 CAR T cells. One of ordinary skill in the art would have been motivated to do so since Mueller teaches that patients <50 kg receive a weight-based dose and patients >50 kg receive a flat dose; the FDA guidance recommends weight-based dosing for pediatric subjects; and CDC growth charts show that age and weight are closely correlated in the intended patient populations with most pediatric subjects (<18 years) weighing <50 kg and most adult subjects ( ≥ 18 years) weighing > 50 kg. As such, artisans would reasonably expect that applying an age cutoff instead of a weight cutoff would yield similar dosing groups. Further, the courts have stated "[W]here the general conditions of a claim are disclosed in the prior art, it is not inventive to discover optimum or workable ranges by routine experimentation." In re Aller, 220 F.2d 454, 456, 105 USPQ 233, 235 (CCPA 1955); thus, it would have been prima facie obvious to one of ordinary skill in the art to determine by routine experimentation the optimum dose of CD19 CAR expressing T cells administered based on age and/or body weight in kg, volume of CD19 CAR expressing T cells, amount of lymphodepleting agents, and optimal ratio or CD4:CD8 CAR expressing T cells to effectively treat a B-cell malignancy such as B-cell ALL in a subject 25 years of age or younger according to the different embodiments of the instantly claimed invention.
Therefore, it would have been obvious to one of ordinary skill in the art to administer anti-CD19 CAR T cell therapy based on age-stratification wherein pediatric patients (generally weight <50 kg) receive a weight-based dose and adults (generally weight >50 kg) receive a flat-dose.
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 14-16, 20, 38, 40, 48, 51, 52, 55-57, 62, 64-67, 82, 85, 87, 89-92, 97, and 99 are rejected on the ground of nonstatutory double patenting as being unpatentable over claims 1-55 of U.S. Patent No. 11413310B2 in view of Mueller et al (WO2017210617A2), hereinafter Mueller, the Centers for Disease Control and Prevention (CDC Growth Charts: United States. “Weight for Age Percentiles, Girls and Boys 2-20 Years of Age”. U.S. Department of Health and Human Services, 2000), hereinafter the CDC, and the Food and Drug administration (“E11: Clinical Investigation of Medicinal Products in the Pediatric Population”. International Conference on Harmonisation, Dec. 2000, U.S. Food and Drug Administration), hereinafter the FDA.
The issued claims recite a method of treating a subject having or suspected of having a cancer comprising administering to the subject a dose of CD4+ and CD8+ T cells each individually expressing a chimeric antigen receptor that specifically binds to an antigen expressed by the cancer, wherein dose of CD4+ and CD8+ T cells comprises a defined ratio of approximately 1:1 and the cancer is a B cell malignancy (issued claims 1, 2, 8, 9, 11, 12, 13, 14, 16, and 50). The administration comprises a plurality of separate compositions having a first composition comprising one of the CD4+ and CD8+ T cells and a second composition comprising the other of the CD4+ and CD8+ T cells (issued claim 1). The dose of CD4+ and CD8+ T cells is between at or about 1x10^7 to at or about 2x10^8 total CAR-expressing cells (issued claim 10, 16, and 39). The CAR comprises an scFv specific for CD19, a transmembrane domain, a cytoplasmic signaling domain derived from costimulatory domain, a cytoplasmic domain that comprises a CD3 zeta signaling domain, and a spacer between the transmembrane domain and the scFv (issued claim 25). The costimulatory molecule is or comprises a 4-1BB (issued claim 32) and the spacer consists of the sequence of SEQ ID NO: 1 (corresponding to SEQ ID NO: 1 of the instant claims (issued claim 35). The scFv comprises (i) CDRs of SEQ ID NOs: 35-40 (corresponding to SEQ ID NOs: 35-40 of the instant claims) (issued claim 36), (ii) the VH/VL pair of SEQ ID NOs: 41 and 42 (corresponding to SEQ ID NOs: 41 and 42 of the instant claims) (issued claim 37); or (iii) the amino acid sequence of SEQ ID NO: 43 (corresponding to SEQ ID NO: 43 of the instant claims) (issued claim 38). Prior to administration of the CAR-expressing T cells, the subject is preconditioned with a lymphodepleting therapy comprising administration of fludarabine and/or cyclophosphamide (issued claim 26).
The issued claims do not recite that the subject is 25 years of age or younger, the B cell malignancy is relapsed/refractory B-cell ALL, the specific dosage regimen, or particular CAR components of the instant claims.
However, Mueller teaches methods of treating a B cell malignancy such as B-cell acute lymphoblastic leukemia (B-ALL) in a subject comprising administering a therapeutically effective amount of a composition comprising CD19-CAR expressing cells such as T cells, wherein the subject is a pediatric or young adult (i.e. about 3 to 23 years of age, or about 1 to 24 years of age, or about 3 to 25 years of age) and the CAR-T cells are administered at a dose of about 0.2 x 106 to 5.0 x 106 cells/kg when the subject weighs <50 kg; or at a dose of about 0.1 x 108 to 2.5 x 108 cells when the subject weighs >50 kg (Page 4, Ln. 27-34; Page 5; Ln. 5-11; Page 8, Ln. 26-30; Page 13, Ln. 23-35 to Page 14: Ln. 5-15; Page 45 to Page 52; Page 91 to Page 133). The B-cell ALL can be relapsed/refractory (Page 10, Ln. 26-27). In other embodiments, the CAR T cells can be administered, for example, at a dose of about 0.2 x 106 to 2.0 x 106 cells/kg when the subject weighs <50 kg; or at a dose of about 0.1 x 108 to 1.0 x 108 cells when the subject weighs >50 kg (Page 3 to 4), and thus does not exceed at or about 1.5 x 108 CAR T cells. Prior to administration of the CD19 CAR T cells, the subject is preconditioned with a lymphodepleting therapy comprising cyclophosphamide and/or fludarabine 1 to 4 days prior to CAR T cell infusion, wherein cyclophosphamide is administered at a dosage of about 200 mg/m2 -300 mg/m2) and fludarabine at a dosage of about 10-50 mg/m2 (e.g. 200 mg/m2 cyclophosphamide and 20 mg/m2 fludarabine, daily x 3) (Page 11, Ln. 19-20; Page 305, Ln. 25-35 to Page 306, Ln. 5-9; and Page 330). The CAR comprises an scFv specific for human CD19, a transmembrane domain, human a 4-1BB costimulatory molecule, and a primary signaling domain derived from a human CD3zeta comprising SEQ ID NO: 43 (corresponding to SEQ ID NO: 13 of the instant claims) (see “CAR molecules” section, in particular, Page 44, Ln. 15-24, Page 46, Ln. 19-22). The CAR can further comprise a hinge, or spacer, between the scFv binding domain and the transmembrane domain, wherein the hinge or spacer comprises an IgG4 hinge of SEQ ID NO: 45 (Page 222, Ln. 24-35 to Page 223, Ln. 5-9), which fully comprises the amino acid sequence of SEQ ID NO: 1 of the instant claims. The antigen binding domain of the CAR includes the FMC63 scFv (Page 100, Ln. 7-11), corresponding to SEQ ID NO: 43 of the instant claims. The FMC63 clone fully comprises the VH and VL chains of SEQ ID NOs: 41 and 42, respectively, of the instant claims and the CDRs of SEQ ID NOs: 35-40 of the instant claims. The exact dosage regimen recited in the instant claims are not specifically taught; however, Mueller does state that the precise amount of the compositions of to be administered can be determined by a physician with consideration of individual differences in age, weight, tumor size, extent of infection or metastasis, and condition of the patient (subject) (Page 369).
The CDC growth charts further teach that age and weight are strongly correlated in pediatric and young adult populations. By age 18, the 50th percentile (median) weight for males is ~ 66 kg and for females ~57 kg –clearly above 50 kg. For younger children (<18 years of age), the median weight is less than 50 kg.
The FDA’s Centers for Biologics/Drug Evaluation and Research further teach that dosing recommendations for most medicinal products used in the pediatric population are based on milligram (mg)/kilogram (kg) body weight up to a maximum adult dose (see last paragraph of Section 2.4.1: Pharmacokinetics on Page 7).
It would have been obvious to one of ordinary skill in the art that modify the method of the issued claims such that the anti-CD19 CAR T cell 1) comprises a spacer, co-stimulatory domain, and signaling domain recited in the instant claims and as disclosed by Mueller and 2) is administered to treat B-ALL in pediatric and young adult subjects using a dosing regimen based on age stratification rather than directly on weight, wherein pediatric subjects (<18 years) receive a weight-based dose and adult patients (>18 years) receive a flat or fixed dose of CD19 CAR T cells. One of ordinary skill in the art would have been motivated to do so since Mueller teaches that patients <50 kg receive a weight-based dose and patients >50 kg receive a flat dose; the FDA guidance recommends weight-based dosing for pediatric subjects; and CDC growth charts show that age and weight are closely correlated in the intended patient populations with most pediatric subjects (<18 years) weighing <50 kg and most adult subjects ( ≥ 18 years) weighing > 50 kg. As such, artisans would reasonably expect that applying an age cutoff instead of a weight cutoff would yield similar dosing groups for the majority of the intended patients, particularly in view of FDA recommendations for pediatric dosing. Further, the courts have stated "[W]here the general conditions of a claim are disclosed in the prior art, it is not inventive to discover optimum or workable ranges by routine experimentation." In re Aller, 220 F.2d 454, 456, 105 USPQ 233, 235 (CCPA 1955); thus, it would have been prima facie obvious to one of ordinary skill in the art to determine by routine experimentation the optimum dose of CD19 CAR expressing T cells administered based on age and/or body weight in kg, volume of CD19 CAR expressing T cells, amount of lymphodepleting agents, and optimal ratio or CD4:CD8 CAR expressing T cells to effectively treat a B-cell malignancy such as B-cell ALL in a subject 25 years of age or younger according to the different embodiments of the instantly claimed invention. Additionally, it would have been obvious to artisans to substitute the CD19 CAR T cell components recited in the issued claims with that disclosed by Mueller since they have the same function and can be used for the same purpose. An express suggestion to substitute one equivalent component or process for another is not necessary to render such substitution obvious. In re Fout, 675 F.2d 297, 213USPQ 532 (CCPA 1982). Therefore, it would have been obvious to one of ordinary skill in the art to administer anti-CD19 CAR T cell therapy based on age-stratification wherein pediatric patients (generally weight <50 kg) receive a weight-based dose and adults (generally weight >50 kg) receive a flat-dose.
Claims 14-16, 20, 38, 40, 48, 51, 52, 55-57, 62, 64-67, 82, 85, 87, 89-92, 97, and 99 are rejected on the ground of nonstatutory double patenting as being unpatentable over claims 1-20 of U.S. Patent No. 11944647B2 in view of Mueller et al (WO2017210617A2), hereinafter Mueller, the Centers for Disease Control and Prevention (CDC Growth Charts: United States. “Weight for Age Percentiles, Girls and Boys 2-20 Years of Age”. U.S. Department of Health and Human Services, 2000), hereinafter the CDC, and the Food and Drug administration (“E11: Clinical Investigation of Medicinal Products in the Pediatric Population”. International Conference on Harmonisation, Dec. 2000, U.S. Food and Drug Administration), hereinafter the FDA.
The issued claims recite a method of treating a subject having relapsed/refractory small lymphocytic lymphoma (SLL), chronic lymphocytic leukemia (CLL), or mantle cell lymphoma comprising administering to the subject a dose of T cells expressing a chimeric antigen receptor (CAR) that specifically binds to CD19, wherein the dose of T cells comprising a ratio of CD4+ and CD8+ cells expressing CAR in a ratio between 5:1 and 1:5; administering the dose of T cells comprises administering a plurality of separate compositions, the plurality of separate compositions comprising a first composition comprising one of the CD4+ T cells and the CD8+ T cells and a second composition comprising the other of the CD4+ T cells and the CD8+ T cells; and the CAR comprises an scFv specific for CD19, a transmembrane domain, a cytoplasmic signaling domain derived from a costimulatory molecule, a cytoplasmic signaling domain that comprises a CD3zeta signaling domain, and a spacer between the transmembrane domain and the scFv (issued claims 1-3, 8-10, and 14-16). The dose of T cells comprises between at or about 5×107 CAR-expressing viable T cells and about 1.5×108 CAR-expressing viable T cells; and the ratio of CD4+ cells expressing the CAR to CD8+ cells expressing the CAR is about 1:1 (issued claims 4-6, 10-13, and 17-19). The costimulatory domain is 4-1BB (issued claims 7, 14, and 20).
The issued claims do not recite that the subject is 25 years of age or younger, the specific dosage regimen of the instant claims, a spacer of SEQ ID NO: 1, a costimulatory domain of SEQ ID NO: 12, a signaling domain of SEQ ID NO: 13, or the CD19-specific scFv amino acid sequences of the instant claims.
However, Mueller teaches methods of treating a B cell malignancy in a subject comprising administering a therapeutically effective amount of a composition comprising CD19-CAR expressing cells such as T cells, wherein the subject is a pediatric or young adult (i.e. about 3 to 23 years of age, or about 1 to 24 years of age, or about 3 to 25 years of age) and the CAR-T cells are administered at a dose of about 0.2 x 106 to 5.0 x 106 cells/kg when the subject weighs <50 kg; or at a dose of about 0.1 x 108 to 2.5 x 108 cells when the subject weighs >50 kg (Page 4, Ln. 27-34; Page 5; Ln. 5-11; Page 8, Ln. 26-30; Page 13, Ln. 23-35 to Page 14: Ln. 5-15; Page 45 to Page 52; Page 91 to Page 133). In other embodiments, the CAR T cells can be administered, for example, at a dose of about 0.2 x 106 to 2.0 x 106 cells/kg when the subject weighs <50 kg; or at a dose of about 0.1 x 108 to 1.0 x 108 cells when the subject weighs >50 kg (Page 3 to 4), and thus does not exceed at or about 1.5 x 108 CAR T cells. Prior to administration of the CD19 CAR T cells, the subject is preconditioned with a lymphodepleting therapy comprising cyclophosphamide and/or fludarabine 1 to 4 days prior to CAR T cell infusion, wherein cyclophosphamide is administered at a dosage of about 200 mg/m2 -300 mg/m2) and fludarabine at a dosage of about 10-50 mg/m2 (e.g. 200 mg/m2 cyclophosphamide and 20 mg/m2 fludarabine, daily x 3) (Page 11, Ln. 19-20; Page 305, Ln. 25-35 to Page 306, Ln. 5-9; and Page 330). The CAR comprises an scFv specific for human CD19, a transmembrane domain, human a 4-1BB costimulatory molecule, and a primary signaling domain derived from a human CD3zeta comprising SEQ ID NO: 43 (corresponding to SEQ ID NO: 13 of the instant claims) (see “CAR molecules” section, in particular, Page 44, Ln. 15-24, Page 46, Ln. 19-22). The CAR can further comprise a hinge, or spacer, between the scFv binding domain and the transmembrane domain, wherein the hinge or spacer comprises an IgG4 hinge of SEQ ID NO: 45 (Page 222, Ln. 24-35 to Page 223, Ln. 5-9), which fully comprises the amino acid sequence of SEQ ID NO: 1 of the instant claims. The antigen binding domain of the CAR includes the FMC63 scFv (Page 100, Ln. 7-11), corresponding to SEQ ID NO: 43 of the instant claims. The FMC63 clone fully comprises the VH and VL chains of SEQ ID NOs: 41 and 42, respectively, of the instant claims and the CDRs of SEQ ID NOs: 35-40 of the instant claims. While the exact dosage regimen recited in the instant claims are not specifically taught, Mueller does state that the precise amount of the compositions of to be administered can be determined by a physician with consideration of individual differences in age, weight, tumor size, extent of infection or metastasis, and condition of the patient (subject) (Page 369).
The CDC growth charts further teach that age and weight are strongly correlated in pediatric and young adult populations. By age 18, the 50th percentile (median) weight for males is ~ 66 kg and for females ~57 kg –clearly above 50 kg. For younger children (<18 years of age), the median weight is less than 50 kg.
The FDA’s Centers for Biologics/Drug Evaluation and Research further teach that dosing recommendations for most medicinal products used in the pediatric population are based on milligram (mg)/kilogram (kg) body weight up to a maximum adult dose (see last paragraph of Section 2.4.1: Pharmacokinetics on Page 7).
It would have been obvious to one of ordinary skill in the art that modify the method of the issued claims such that the anti-CD19 CAR T cell 1) comprises a scFv domain, spacer, co-stimulatory domain, and signaling domain recited in the instant claims and as disclosed by Mueller and 2) is administered to treat B-ALL in pediatric and young adult subjects using a dosing regimen based on age stratification rather than directly on weight, wherein pediatric subjects (<18 years) receive a weight-based dose and adult patients (>18 years) receive a flat or fixed dose of CD19 CAR T cells. One of ordinary skill in the art would have been motivated to do so since Mueller teaches that patients <50 kg receive a weight-based dose and patients >50 kg receive a flat dose; the FDA guidance recommends weight-based dosing for pediatric subjects; and CDC growth charts show that age and weight are closely correlated in the intended patient populations with most pediatric subjects (<18 years) weighing <50 kg and most adult subjects ( ≥ 18 years) weighing > 50 kg. As such, artisans would reasonably expect that applying an age cutoff instead of a weight cutoff would yield similar dosing groups for the majority of the intended patients, particularly in view of FDA recommendations for pediatric dosing. Further, the courts have stated "[W]here the general conditions of a claim are disclosed in the prior art, it is not inventive to discover optimum or workable ranges by routine experimentation." In re Aller, 220 F.2d 454, 456, 105 USPQ 233, 235 (CCPA 1955); thus, it would have been prima facie obvious to one of ordinary skill in the art to determine by routine experimentation the optimum dose of CD19 CAR expressing T cells administered based on age and/or body weight in kg, volume of CD19 CAR expressing T cells, amount of lymphodepleting agents, and optimal ratio or CD4:CD8 CAR expressing T cells to effectively treat a B-cell malignancy such as B-cell ALL in a subject 25 years of age or younger according to the different embodiments of the instantly claimed invention. Additionally, it would have been obvious to artisans to substitute the CD19 CAR T cell components recited in the issued claims with that disclosed by Mueller since they have the same function and can be used for the same purpose. An express suggestion to substitute one equivalent component or process for another is not necessary to render such substitution obvious. In re Fout, 675 F.2d 297, 213USPQ 532 (CCPA 1982). Therefore, it would have been obvious to one of ordinary skill in the art to administer anti-CD19 CAR T cell therapy based on age-stratification wherein pediatric patients (generally weigh <50 kg) receive a weight-based dose and adults (generally weigh >50 kg) receive a flat-dose.
Claims 14-16, 20, 38, 40, 48, 51, 52, 55-57, 62, 64-67, 82, 85, 87, 89-92, 97, and 99 are provisionally rejected on the ground of nonstatutory double patenting as being unpatentable over claims 1-3, 5-10, 12-16, and 18-20 of copending Application No. 18510460 in view of Mueller et al (WO2017210617A2), hereinafter Mueller, the Centers for Disease Control and Prevention (CDC Growth Charts: United States. “Weight for Age Percentiles, Girls and Boys 2-20 Years of Age”. U.S. Department of Health and Human Services, 2000), hereinafter the CDC, and the Food and Drug administration (“E11: Clinical Investigation of Medicinal Products in the Pediatric Population”. International Conference on Harmonisation, Dec. 2000, U.S. Food and Drug Administration), hereinafter the FDA.
This is a provisional nonstatutory double patenting rejection.
The co-pending claims recite a method of treating a subject having relapsed/refractory small lymphocytic lymphoma (SLL), chronic lymphocytic leukemia (CLL), or mantle cell lymphoma comprising administering to the subject a dose of CD19 CAR-expressing T cells, the dose of T cells comprising a ratio of CD4+ cells expressing the CAR to CD8+ cells expressing the CAR in a ratio of about 1:5 and 5:1, wherein the CAR comprises an scFv specific for CD19, a transmembrane domain, a cytoplasmic signaling domain derived from a costimulatory molecule, a cytoplasmic signaling domain that comprises a CD3zeta signaling domain, and a spacer between the transmembrane domain and the scFv; wherein the dose of T cells comprises between at or about 2.5 x 107 viable CAR- expressing T cells and 2 x 108 viable CAR-expressing T cells; and wherein the method comprises administering a lymphodepleting therapy to the subject prior to administering the dose of T cells to the subject, wherein the lymphodepleting therapy comprises cyclophosphamide and fludarabine, wherein the cyclophosphamide comprises between about 100 mg/m2/day and 500 mg/m2/day (co-pending claims 1-3, 5-6, 8-10, 12-13, 14-16, and 18-19). The costimulatory domain is 4-1BB (co-pending claims 7 and 20).
The co-pending claims do not recite that the subject is 25 years of age or younger, the specific dosage regimen of the instant claims, a spacer of SEQ ID NO: 1, a costimulatory domain of SEQ ID NO: 12, a signaling domain of SEQ ID NO: 13, or the CD19-specific scFv amino acid sequences of the instant claims.
However, Mueller teaches methods of treating a B cell malignancy in a subject comprising administering a therapeutically effective amount of a composition comprising CD19-CAR expressing cells such as T cells, wherein the subject is a pediatric or young adult (i.e. about 3 to 23 years of age, or about 1 to 24 years of age, or about 3 to 25 years of age) and the CAR-T cells are administered at a dose of about 0.2 x 106 to 5.0 x 106 cells/kg when the subject weighs <50 kg; or at a dose of about 0.1 x 108 to 2.5 x 108 cells when the subject weighs >50 kg (Page 4, Ln. 27-34; Page 5; Ln. 5-11; Page 8, Ln. 26-30; Page 13, Ln. 23-35 to Page 14: Ln. 5-15; Page 45 to Page 52; Page 91 to Page 133). In other embodiments, the CAR T cells can be administered, for example, at a dose of about 0.2 x 106 to 2.0 x 106 cells/kg when the subject weighs <50 kg; or at a dose of about 0.1 x 108 to 1.0 x 108 cells when the subject weighs >50 kg (Page 3 to 4), and thus does not exceed at or about 1.5 x 108 CAR T cells. The T cells can be a mixture of CD4+ T cells and CD8+ T cells (Page 37, Ln. 16); and at least two doses of CAR-expressing cells are administered separately with a time interval of about one day (Page 7, Ln. 23-24). The B-cell ALL can be relapsed/refractory (Page 10, Ln. 26-27). Prior to administration of the CD19 CAR T cells, the subject is preconditioned with a lymphodepleting therapy comprising cyclophosphamide and/or fludarabine 1 to 4 days prior to CAR T cell infusion, wherein cyclophosphamide is administered at a dosage of about 200 mg/m2 -300 mg/m2) and fludarabine at a dosage of about 10-50 mg/m2 (e.g. 200 mg/m2 cyclophosphamide and 20 mg/m2 fludarabine, daily x 3) (Page 11, Ln. 19-20; Page 305, Ln. 25-35 to Page 306, Ln. 5-9; and Page 330). The CAR comprises an scFv specific for human CD19, a transmembrane domain, human a 4-1BB costimulatory molecule, and a primary signaling domain derived from a human CD3zeta comprising SEQ ID NO: 43 (corresponding to SEQ ID NO: 13 of the instant claims) (see “CAR molecules” section, in particular, Page 44, Ln. 15-24, Page 46, Ln. 19-22). The CAR can further comprise a hinge, or spacer, between the scFv binding domain and the transmembrane domain, wherein the hinge or spacer comprises an IgG4 hinge of SEQ ID NO: 45 (Page 222, Ln. 24-35 to Page 223, Ln. 5-9), which fully comprises the amino acid sequence of SEQ ID NO: 1 of the instant claims. The antigen binding domain of the CAR includes the FMC63 scFv (Page 100, Ln. 7-11), corresponding to SEQ ID NO: 43 of the instant claims. The FMC63 clone fully comprises the VH and VL chains of SEQ ID NOs: 41 and 42, respectively, of the instant claims and the CDRs of SEQ ID NOs: 35-40 of the instant claims. While the exact dosage regimen recited in the instant claims are not specifically taught, Mueller does state that the precise amount of the compositions of to be administered can be determined by a physician with consideration of individual differences in age, weight, tumor size, extent of infection or metastasis, and condition of the patient (subject) (Page 369).
The CDC growth charts further teach that age and weight are strongly correlated in pediatric and young adult populations. By age 18, the 50th percentile (median) weight for males is ~ 66 kg and for females ~57 kg –clearly above 50 kg. For younger children (<18 years of age), the median weight is less than 50 kg.
The FDA’s Centers for Biologics/Drug Evaluation and Research further teach that dosing recommendations for most medicinal products used in the pediatric population are based on milligram (mg)/kilogram (kg) body weight up to a maximum adult dose (see last paragraph of Section 2.4.1: Pharmacokinetics on Page 7).
It would have been obvious to one of ordinary skill in the art that modify the method of the co-pending claims such that the anti-CD19 CAR T cell 1) comprises a scFv domain, spacer, co-stimulatory domain, and signaling domain recited in the instant claims and as disclosed by Mueller and 2) is administered to treat a B cell malignancy in pediatric and young adult subjects using a dosing regimen based on age stratification rather than directly on weight, wherein pediatric subjects (<18 years) receive a weight-based dose and adult patients (>18 years) receive a flat or fixed dose of CD19 CAR T cells. One of ordinary skill in the art would have been motivated to do so since Mueller teaches that patients <50 kg receive a weight-based dose and patients >50 kg receive a flat dose; the FDA guidance recommends weight-based dosing for pediatric subjects; and CDC growth charts show that age and weight are closely correlated in the intended patient populations with most pediatric subjects (<18 years) weighing <50 kg and most adult subjects ( ≥ 18 years) weighing > 50 kg. As such, artisans would reasonably expect that applying an age cutoff instead of a weight cutoff would yield similar dosing groups for the majority of the intended patients, particularly in view of FDA recommendations for pediatric dosing. Further, the courts have stated "[W]here the general conditions of a claim are disclosed in the prior art, it is not inventive to discover optimum or workable ranges by routine experimentation." In re Aller, 220 F.2d 454, 456, 105 USPQ 233, 235 (CCPA 1955); thus, it would have been prima facie obvious to one of ordinary skill in the art to determine by routine experimentation the optimum dose of CD19 CAR expressing T cells administered based on age and/or body weight in kg, volume of CD19 CAR expressing T cells, amount of lymphodepleting agents, and optimal ratio or CD4:CD8 CAR expressing T cells to effectively treat a B-cell malignancy in a subject 25 years of age or younger according to the different embodiments of the instantly claimed invention. Additionally, it would have been obvious to artisans to substitute the CD19 CAR T cell components recited in the co-pending claims with that disclosed by Mueller since they have the same function and can be used for the same purpose. An express suggestion to substitute one equivalent component or process for another is not necessary to render such substitution obvious. In re Fout, 675 F.2d 297, 213USPQ 532 (CCPA 1982). Therefore, it would have been obvious to one of ordinary skill in the art to administer anti-CD19 CAR T cell therapy of the co-pending claims based on age-stratification wherein pediatric patients (generally weigh <50 kg) receive a weight-based dose and adults (generally weigh >50 kg) receive a flat-dose.
Response to Arguments
Applicant's arguments filed 01/29/26 have been fully considered but they are not persuasive.
With respect to the rejection made under 35 U.S.C. 103, Applicant argues that the claimed method recites that the dose of T cells to be administered is determined based on the age of the subject, with the patient being assigned to one of two types of doses based on their age. The method in particular includes a first step of determining the dose of CAR T cells based on the age of the subject followed by a second step of administering the dose to the subject. Thus, claim 1 presents one age-based dosing regimen, in which a subject is assigned to a treatment group based on their age and the treatment that is given is either a weight-based dose or a flat dose, depending on which group the subject is allocated to.
Mueller is cited for allegedly teaching methods of treatment that involve administering CAR-T cells to subjects ranging from 3 to 23 years of age, 1 to 24 years of age, or about 3 to 25 years of age, with the dosage specifically based on whether the subject's body weight is less than or greater than 50 kg. In other words, there is no consideration of age whatsoever with regards to what dosing a particular subject of 25 years of age or younger would receive - nor is there any description related to a method in which patients are assigned a treatment group based on age as recited in the present claims. Rather, Mueller is solely focused on whether the subject weighs more or less than 50 kg for determining whether to administer a weight-based dosing or a fixed dosing.
Applicant states that the Office has alleged since the median weight for males and females at age 18 is above 50 kg, then all males and females age 18 or older - regardless of actual weight - should be dosed with a flat rate, and since the median weight for males and females younger than 18 is below 50 kg, then all males and females younger than 18 years of age - regardless of actual weight - should be dosed with a weight-based dose. However, such a modification is incompatible with the dosing regimen of Mueller, which is based on age stratification independent of age. As shown in the Table (Remarks -01/29/26) and the CDC Growth Chart provided by the Office, Applicant argues that the majority of both males and females age 15 to 17 (along with the majority of 14-year-old males) weigh more than 50 kg and, thus, would be administered a fixed dose per Mueller's dosing regimen.
Applicant contends that The Office has not articulated why, absent impermissible hindsight bias, a POSITA would completely replace its dosing regimen with one that conflicts with its dosing regimen for a majority of its pediatric subjects who are at least 14 or 15 years of age. Applicant’s position is that Mueller teaches a very specific dosing regimen intended to distinguish between subjects who receive a particular fixed dose vs a particular weight-based dose solely based on the subject's weight being above or below 50 kg. Thus, Applicant asserts that there is no teaching or suggestion anywhere in Mueller of specifically replacing a weight-based threshold for stratifying subject into an age-based threshold, let alone specifically where if the subject is younger than 18 years of age, the dose being administered is weight-based (as recited in part (i) of claim 14), and if the subject is between 18 and 25 years of age, the dose being administered is a flat dose that is independent of the weight of the subject (as recited in part (ii) of claim 1).
Further Applicant states that examples provided in MPEP 2143(I)(A) further demonstrate that the Office’s rational is insufficient for modification of the prior art. In particular, Applicant notes the “Like in to In re Omeprazole 3, where it was not recognized by the prior art that "the prior art coating was actually interacting with omeprazole, thereby contributing to undesirable degradation of the active ingredient," it was not recognized by Mueller that cells from pediatric subjects less than 18 years of age was found to exhibit phenotypic markers associated with less differentiated or more naive-like cells and with a low percentage of apoptotic markers, which supports the administration of a lower dose of cells for pediatric patients based on body weight for pediatric subjects less than 18 years of age. See, e.g., Example 2 and described at paragraph [0716] of the present application as originally filed. Not only did Mueller not recognize this, but it specifically chose a dosing regimen based on 50 kg as a threshold for determining whether to administer a weight-based dose vs a fixed dose, without any regard or consideration of the subject being younger than 18 years or age or from 18 to 25 years of age.
In response to applicant's arguments against the references individually, one cannot show nonobviousness by attacking references individually where the rejections are based on combinations of references. See In re Keller, 642 F.2d 413, 208 USPQ 871 (CCPA 1981); In re Merck & Co., 800 F.2d 1091, 231 USPQ 375 (Fed. Cir. 1986). In this case, Mueller teaches a method of treating a B cell malignancy comprising administering CD19 CAR T cells, wherein the subject is younger than 25 years of age (e.g. 1 to 24 years of age) and in certain embodiments the CAR-T cells are administered at a dose of about 0.2 x 106 to 5.0 x 106 cells/kg when the subject weighs <50 kg; or at a dose of about 0.1 x 108 to 2.5 x 108 cells when the subject weighs >50 kg. Of note, the dosing regimen for CD19 CAR T cells taught by Mueller is not limited to weight-based dosing regimens as Applicant appears to suggest. The selection from Mueller, for example, specifically reads as follows:
“In one embodiment, the plurality of cells is administered at:
at a dose of about 0.2 x 106 to 5.0 x 106 (e.g., 0.2 x 106 to 5.0 x 106) viable CAR- expressing cells/kg, e.g., when the subject weighs <50 kg; or at a dose of about 0.1 x 10 to 2.5 x 108 (e.g., 0.1 x 108 to 2.5 x 108 ) viable CAR-expressing cells, e.g. when the subject weighs >50 kg.” (emphasis added).
Accordingly, the skilled artisan reading the prior art would interpret the weight-based dosing regimen taught by Mueller as a non-limiting embodiment rather than the only conceivable way to practice the invention. As further evidenced by the CDC growth charts, age and weight are strongly correlated in pediatric and young adult populations. By age 18, the 50th percentile (median) weight for males is ~ 66 kg and for females ~57 kg –clearly above 50 kg. For younger children (<18 years of age), the median weight is less than 50 kg. Thus, artisans could appreciate that pediatric and adult stratification could be performed either by age or weight, since both variables generally capture the same underlying distinction between smaller pediatric patients and larger adult patients. Further, the FDA guidance cited, which Applicant fails to acknowledge, explicitly recommends weight-based dosing for pediatric patients. Taken together, a skilled artisan would have motivation to modify the dosing scheme suggested by Mueller so that pediatric subjects receive weight-based dosing; and selecting dosing by age rather than weight would have been an obvious alternative.
In addition, as summarized in Polsinelli’s analysis of the decision, the Federal Circuit’s recent ruling in Immunogen, Inc. v. Stewart illustrates that a dosing patent may be obvious even if the prior art does not expressly teach the specific nuances of how to arrive at the claimed dose or dosing methodology (e.g., where the total body weight – TBW – dose necessarily meant the same thing as the adjusted ideal body weight –AIBW – dose in at least some patients) (Polsinelli, Conclusion and Takeaways section). In particular, the court held that modifying the dosing regimen of the antibody drug conjugate IMGN853 from total body weight (TBW) to 6 mg/kg adjusted ideal body weight (AIBW) to reduce ocular toxicity was obvious and a matter of routine optimization of the prior art (ImmunoGen, Inc. v. Stewart , last paragraph on Pages 8 to first paragraph on Page 10; first paragraph on Page 11). The Federal Circuit acknowledged that TBW and AIBW are different types of weight-based dosing methodologies, but explained that the prior art reference’s 6 mg/kg TBW dose of IMGN853 would have also led to a 6 mg/kg AIBW dose of IMGN853 in certain situations. And the Federal Circuit explained that “[a] doctor dosing a patient at his or her IBW with IMGN853 at a dose of 6 mg/kg TBW would necessarily be dosing that patient at 6 mg/kg AIBW, as claimed. This would be true regardless of whether a doctor knew of AIBW dosing” (Polsinelli, Section 2: The Federal Circuit’s Decision, particularly last three paragraphs; ImmunoGen, Inc. v. Stewart, Pages 10-12).
Lastly, in response to applicant's argument that the references fail to show certain features of the invention, it is noted that the features upon which applicant relies (i.e., cells from pediatric subjects less than 18 years of age were found to exhibit phenotypic markers associated with less differentiated or more naive-like cells and with a low percentage of apoptotic markers,) are not recited in the rejected claim(s). Although the claims are interpreted in light of the specification, limitations from the specification are not read into the claims. See In re Van Geuns, 988 F.2d 1181, 26 USPQ2d 1057 (Fed. Cir. 1993). Nevertheless, as discussed above, the combined teachings of the prior art do provide motivation to an artisan to administer a weight-based dose to pediatric subjects (<18 years of age) and a flat dose to adults (>18 years of age) contrary to Applicant’s assertion.
Therefore, the rejection under 35 USC 103 is maintained.
With respect to the double patenting rejections, Applicant sets forth arguments similar to those against the rejections made under 103. Thus, the double patenting rejections—with the exception of the rejection over copending Application No. 18510460 (now abandoned) –are maintained for the reasons set forth above.
Applicant’s arguments with respect to rejection of claims under 35 USC 112(a) written description have been fully considered. Upon further review of the record, the rejection has been withdrawn.
Conclusion
No claims are allowable.
THIS ACTION IS MADE FINAL. Applicant is reminded of the extension of time policy as set forth in 37 CFR 1.136(a).
A shortened statutory period for reply to this final action is set to expire THREE MONTHS from the mailing date of this action. In the event a first reply is filed within TWO MONTHS of the mailing date of this final action and the advisory action is not mailed until after the end of the THREE-MONTH shortened statutory period, then the shortened statutory period will expire on the date the advisory action is mailed, and any nonprovisional extension fee (37 CFR 1.17(a)) pursuant to 37 CFR 1.136(a) will be calculated from the mailing date of the advisory action. In no event, however, will the statutory period for reply expire later than SIX MONTHS from the mailing date of this final action.
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/LIA E TAYLOR/Examiner, Art Unit 1641
/MISOOK YU/Supervisory Patent Examiner, Art Unit 1641
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