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 .
Continued Examination Under 37 CFR 1.114
A request for continued examination under 37 CFR 1.114, including the fee set forth in 37 CFR 1.17(e), was filed in this application after final rejection. Since this application is eligible for continued examination under 37 CFR 1.114, and the fee set forth in 37 CFR 1.17(e) has been timely paid, the finality of the previous Office action has been withdrawn pursuant to 37 CFR 1.114. Applicant's submission filed on January 23, 2026 has been entered.
DETAILED ACTION
The amendment filed January 23, 2026 in response to the Office Action of October 23, 2025 is acknowledged and has been entered.
Claims 1, 77 and 199 have been amended.
Claims 1-3, 16, 22, 23, 27, 31, 34, 39, 42, 49, 50, 60, 77, 79, 97, 188, 190, 192, 193, and 195-200 are pending.
Claims 16, 22, 23 and 31 are withdrawn from further consideration pursuant to 37 CFR 1.142(b) as being drawn to a nonelected inventions or species, there being no allowable generic or linking claim.
Claims 1-3, 27, 34, 39, 42, 49, 50, 60, 77, 79, 97, 188, 190, 192, 193, and 195-200 are currently under consideration as drawn to the elected invention.
The 112(b) rejection set forth in the previous Office Action of October 23, 2025 is hereby withdrawn in view of the claim amendments.
The 103 rejections set forth in the previous Office Action of October 23, 2025 is hereby withdrawn in view of the claim amendments and Applicant’s arguments.
Information Disclosure Statement
The information disclosure statement (IDS) filed on January 23, 2026 has been considered by the examiner.
NEW REJECTION
Claim Rejections - 35 USC § 103
In the event the determination of the status of the application as subject to AIA 35 U.S.C. 102 and 103 (or as subject to pre-AIA 35 U.S.C. 102 and 103) is incorrect, any correction of the statutory basis (i.e., changing from AIA to pre-AIA ) for the rejection will not be considered a new ground of rejection if the prior art relied upon, and the rationale supporting the rejection, would be the same under either status.
The following is a quotation of 35 U.S.C. 103 which forms the basis for all obviousness rejections set forth in this Office action:
A patent for a claimed invention may not be obtained, notwithstanding that the claimed invention is not identically disclosed as set forth in section 102, if the differences between the claimed invention and the prior art are such that the claimed invention as a whole would have been obvious before the effective filing date of the claimed invention to a person having ordinary skill in the art to which the claimed invention pertains. Patentability shall not be negated by the manner in which the invention was made.
The factual inquiries for establishing a background for determining obviousness under 35 U.S.C. 103 are summarized as follows:
1. Determining the scope and contents of the prior art.
2. Ascertaining the differences between the prior art and the claims at issue.
3. Resolving the level of ordinary skill in the pertinent art.
4. Considering objective evidence present in the application indicating obviousness or nonobviousness.
This application currently names joint inventors. In considering patentability of the claims the examiner presumes that the subject matter of the various claims was commonly owned as of the effective filing date of the claimed invention(s) absent any evidence to the contrary. Applicant is advised of the obligation under 37 CFR 1.56 to point out the inventor and effective filing dates of each claim that was not commonly owned as of the effective filing date of the later invention in order for the examiner to consider the applicability of 35 U.S.C. 102(b)(2)(C) for any potential 35 U.S.C. 102(a)(2) prior art against the later invention.
Claims 1-3, 27, 34, 39, 49, 50, 60, 77, 79, 97, 190, and 195-200 are rejected under 35 U.S.C. 103 as being unpatentable over NCT02631044 (Version 2: 2015-12-14, downloaded from: https://www.clinicaltrials.gov/study/NCT02631044?tab=history&a=2#version-content-panel, Publication Date: December 2015, of record) and further in view of Abramson2017 (Abramson et al., Blood (2017) 130 (Supplement 1): 581, Publication Date: 12/07/2017, cited as #244 ref in IDS of 03/17/2022, a copy of this reference is also attached with this office action), as evidenced by JCAR017_drugbank (downloaded from: https://go.drugbank.com/drugs/DB16582, on 10/07/2025, of record) and Zeng (Zeng et al., Cancer Investigation, Vol. 40, No.3, 282-292, Publication Year: 2022) .
Regrading claims 1-3, 50, 196, and 199 clinical trial NCT02631044 teaches JCAR017, a CD-19 targeted CAR T cells for r/r B-cell NHL (Official Title on page 6). NCT02631044 teaches administering modified T cells (JCAR017) to adult patients with relapsed or refractory NHL (e.g. inclusive of DLBCL) (§ Detailed Description on pages 8-9, § Condition on page 9, § Arms and Interventions on pages 10-11). NCT02631044 teaches patients must have received treatment with anthracycline and rituximab (or other CD20-targeted agent) and have at least one of the followings, such as: i) biopsy-proven refractory disease after frontline chemo-immunotherapy; ii) relapse within 1 year of frontline chemo-immunotherapy and not eligible for autologous hematopoietic stem cell transplant (auto-HSCT) (§ Inclusion Criteria on page 12-13). This reads on claim 1 (ii): “the subject is ineligible for HSTC and the first line of immunochemotherapy for aggressive B-cell non-Hodgkin lymphoma (NHL)”, claim 196, and claim 199 (ii) “the subject is ineligible for HSTC and the first line of immunochemotherapy for aggressive B-cell non-Hodgkin lymphoma (NHL)”.
As evidenced by JCAR017_drugbank, JCAR017 is the same as Breyanzi (Brand Name), or Lisocabtagene maraleucel (Generic Name). See pages 1-2. JCAR017 is composed of an FMC63 monoclonal antibody single chain variable fragment, IgG4 hinge region, CD28 transmembrane domain, 4-1BB costimulatory domain, and CD3z activation domain. FMC63 is an IgG2a mouse monoclonal antibody that target CD19. It appears that the same CAR was used in the Examples of the instant specification, see page 15, para. 4 of the Remarks of 08/11/2025. JCAR017 reads on the CAR of claims 1, 195 and 199. Thus, JACR017 reads on the CAR of instant claims 1, 195 and 199.
As evidenced by Zeng (page 283, col. 2), the variable region of the VL of FMC63 has the recited CDR-L1, CDR-L2 and CDR-L3 as cited (shown below): DIQMTQTTSSLSASLGDRVTISCRASQDISKYLNWYQQKPDGTVKLLIYHTSRLHSGVPSRFSGSGSGTDYSLTISNLEQEDIATYFCQQGNTLPYTFGGGTKLEIT
The variable region of the VH of FMC63 has the recited CDR-H1, CDR-H2 and CDR-H3 as cited (shown below):
EVKLQESGPGLVAPSQSLSVTCTVSGVSLPDYGVSWIRQPPRKGLEWLGVIWGSETTYYNSALKSRLTIIKDNSKSQVFLKMNSLQTDDTAIYYCAKHYYYGGSYAMDYWGQGTSVTVSS
Thus, JACR017 reads on the CAR of instant claims 1, 195 and 199.
It is noted that because the patients have received a first line therapy (treatment with chemo-immunotherapy, e.g. anthracycline and rituximab), the administration of JCAR017 is used as a second line therapy.
NCT02631044 teaches as set forth above, but does not explicitly teach the dose of T cells comprises between at or about 7.5 x 107 CAR-expressing T cells and at or about 5 x 108 CAR-expressing T cells, inclusive.
Abramson2017 teaches treating r/r DLBCL with JCAR017 (§ Background) and a starting dose of 5 x 107 CAR+ T cells (DL1) and 108 CAR+ T cells (DL2) (§ Methods).
Abramson2017 teaches that a trend toward improved response rate at 3 months was observed in patients treated at DL2 compared to DL1: 63% (12/19; 95% CI 38, 84) vs 40% (12/30; 95% CI 23, 59) for ORR with p=0.148, and 58% (11/19; 95% CI 34, 80) vs 27% (8/30; 95% CI: 12, 46) for CR with p=0.0385 (§ Results, paragraph 3).
Abramson2017 teaches that a similar trend in improved durable ORR and CR at 3 months at higher doses was again observed: 80% (12/15; 95% CI 52, 96) and 73% (11/15; 95% CI 45, 92) at DL2 compared to 52% (11/21; 95% CI 30, 74) and 33% (7/21; 95% CI 15, 57) in DL1 with p=0.159 and p=0.0409 respectively (§ Results, paragraph 4).
Abramson2017 teaches that toxicities are manageable and compare favorably to other reported CAR T-cell products (§ Conclusions).
It would have prima facie been obvious to one of ordinarily skilled in the art at the time the invention was filed to use JACR017 as a second line therapy to treat an adult subject with r/r DLBCL who has relapsed from, or is refractory to, a single line of immunochemotherapy for aggressive B-cell non-Hodgkin lymphoma (NHL) (e.g. r/r DLBCL) and is ineligible for HSCT, as taught by NCT02631044, and to use a dosage of 108 CAR+ T cells as taught by Abramson2017, because this dosage is more effective for DLBCL with manageable toxicities. One of ordinary skilled in the art would have had a reasonable expectation that the dosage would be effective for r/r DLBCL patients. The motivation would have been to improve success rate with a well-tested dosage in well-tested patient population.
Furthermore, one of ordinary skill in the art would have known to adjust dosage accordingly to patients conditions, administration regimen by routine experimentation. It is noted that optimum suitable ranges may be obtained by routine experimentation, absent a showing of criticality or unexpected results. “[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(II)(A).
Regarding claims 27, 198 and 200, NCT02631044 teaches patients have received treatment with anthracycline and rituximab (or other CD20-targeted agent) (§ Inclusion Criteria on page 12-13).
Regarding claim 34, given Broadest Reasonable Interpretation (BRI), all r/r/DLBCL can be considered as poor prognosis because it is resistant to the previous treatment. Consequently, the teachings of NCT02631044 and Abramson2017 that subjects with r/r DLBCL were treated support the notion of treating a subject has been identified as having poor prognosis.
Regarding claim 39, Abramson2017 further teaches that the median age was 61 years (range 26-82) (§ Results). Thus, Abramson2017 teaches JCAR017 can be used for treating patients 65 years or older. One of ordinary skill in the art would have been motivated to include patients 65 years or older for the treatment to expand the application.
Regarding claim 49, 60 and 190, it is noted based on paragraph [1605] and Table E34A of the instant publication US 2022/0088070 A1, subjects were deemed ineligible for high-dose chemotherapy followed by HSTC if they met at least one of the following criteria: age ≥ 70 years, Eastern Cooperative Oncology Group (ECOG) performance status of 2, impaired pulmonary (DLCOs 60%, but SaO2≥92% on room air and CTCAE≤1 dyspnea), cardiac (LVEF≥40% and <50%), renal (creatinine clearance>30 and <60 mL/min), or hepatic function (AST/ALT>2 and ≤5xULN). NCT02631044 teaches that subjects with ECOG performance status of 2 were included in treatment. Abramson2017 teaches that the subjects can be older than 70 (e.g. range 26 to 82) (§ Results). Thus, these subjects told by NCT02631044 and Abramson reads on the subject is or has been identified as being ineligible for high-dose chemotherapy.
Regarding claim 77, Abramson2017 teaches that treatment with JCAR017 following lymphodepletion with fludarabine and cyclophosphamide (§ Methods). It would have prima facie been obvious to one of ordinarily skilled in the art at the time the invention was filed to use the lymphodepletion step to obtain good therapeutic efficacy as shown by Abramson2017.
Regarding claim 79, it is a routine practice for one of ordinary skilled in the art to develop suitable administration method. Given that the toxicity of JCAR017 is low as taught by Abramson2017, one of ordinary skilled would have had a reasonable expectation that outpatient delivery would be suitable for administration of JCAR017. The motivation would have been to improve flexibility in treating DLBCL and to reduce cost for the claimed methods.
Regard claim 97, Abramson2017 teaches that most treated patients do not exhibit CRS or neurotoxicity (§ Results, paragraph 2).
Regarding claim 197, as evidenced by paragraph [0209] of the instant publication US 2022/0088070, not eligible for HSCT is considered as not eligible for TNE. Thus, NCT02631044 teaches treating subjects are deemed ineligible for both high-dose chemotherapy and HSCT, and is transplant ineligible (TNE), while remaining eligible for CAR T cell therapy.
Claim 42 is rejected under 35 U.S.C. 103 as being unpatentable over NCT02631044 (Version 2: 2015-12-14, downloaded from: https://www.clinicaltrials.gov/study/NCT02631044?tab=history&a=2#version-content-panel, Publication Date: December 2015, of record) in view of Abramson2017 (Abramson et al., Blood (2017) 130 (Supplement 1): 581, Publication Date: 12/07/2017, cited as #244 ref in IDS of 03/17/2022, a copy of this reference is also attached with this office action), as evidenced by JCAR017_drugbank (downloaded from: https://go.drugbank.com/drugs/DB16582, on 10/07/2025, of record) and Zeng (Zeng et al., Cancer Investigation, Vol. 40, No.3, 282-292, Publication Year: 2022), as applied to claims 1-3, 27, 34, 39, 49, 50, 60, 77, 79, 97, 190, and 194-200 above, and further in view of Lichtman (Lichtman et al., Journal of Clinical Oncology, vol. 35, number 33, 3753-3759, Publication Date: 11/20/2017, of record).
NCT02631044 and Abramson2017 teach method of claim 1 as set forth above. However, NCT0231044 and Abramson2017 do not teach “wherein, at or prior to the administration of the dose of cells, the subject is or has been identified as having: (a) an impaired cardiac function; (b) an impaired renal function; (c) an impaired pulmonary function; and/or (d) an impaired hepatic function”.
NCT02631044 teaches that patients with adequate renal, hepatic, pulmonary, and cardiac function can be treated by JCAR017 (§ Inclusion Criteria, point 5).
Lichtman teaches that adequate renal function characterized as calculated creatinine clearance (CrCl; commonly set at >60 mL/min) (i.e. a reflection of stage 2 of renal impairment in the art); adequate hepatic function characterized as total bilirubin (commonly set at <1.5mg/dL) and/or ALT and AST (commonly set at <2 to 3 x upper limit of normal [ULN]); and parameters for left ventricular ejection fraction (commonly set at >50%). (see page 3754, col. 1, para. 3). Thus, for example, an ALT and AST of 2-3 x upper limit of normal (ULN) would be considered as adequate hepatic function. As evidenced by [0074] of instant publication (“more than at or about twice the upper limit of normal”), an ALT and AST of 2-3 x upper limit of normal (ULN) would be classified as impaired hepatic function.
Therefore, it would have been prima facie obvious to one of the ordinary skills in the art before the effective filing date of the claimed invention to use CD8+ and CD4+ T cell comprising a CAR targeting CD19 (such as JCAR017) to treat r/r DLBCL as taught by NCT02631044 and Abramson2017, and to apply the treatment to patients with adequate hepatic function, e.g. patients with an ALT and AST of 2.5 x upper limit of normal (ULN) since Litchman classified such patients as having impaired hepatic function, as taught by NCT02631044 and Lichtman. One would have been motivated to have done so in order to expand the treatment to the r/r LBCL population with adequate but impaired hepatic function. Given the low toxicity of JCAR017 in clinical trial as taught by Abramson2017, one of ordinary skill in the art would have a reasonable expectation that the treatment would be effective and safe for the patient population.
Claims 188, 192 and 193 are rejected under 35 U.S.C. 103 as being unpatentable over NCT02631044 (Version 2: 2015-12-14, downloaded from: https://www.clinicaltrials.gov/study/NCT02631044?tab=history&a=2#version-content-panel, Publication Date: December 2015) in view of Abramson2017 (Abramson et al., Blood (2017) 130 (Supplement 1): 581, Publication Date: 12/07/2017, cited as #244 ref in IDS of 03/17/2022, a copy of this reference is also attached with this office action), as evidenced by JCAR017_drugbank (downloaded from: https://go.drugbank.com/drugs/DB16582, on 10/07/2025, of record) and Zeng (Zeng et al., Cancer Investigation, Vol. 40, No.3, 282-292, Publication Year: 2022), as applied to claims 1-3, 27, 34, 39, 49, 50, 60, 77, 79, 97, 190, and 194-200 above, and further in view of Jensen (Jensen, WO 2015/157384 A1, Publication Date: 10/15/2015, cited as #217 ref in IDS of 03/17/202, also attached with this Office Action, of record) and Abramson (Abramson et al., Blood (2016) 128 (22): 4192, Publication Date: 12/02/2016, cited as #251 ref in IDS of 03/17/202, of record).
NCT02631044 and Abramson2017 teach method of claim 1 as set forth above. However, NCT02631044 and Abramson2017 do not teach that CD8+ T cells and CD4+ T cells are CD8+ T cells and CD4+ T cells are administered as separated compositions, e.g. administration of CD8+ T cells is carried out prior to the initiation of the administration of the second composition.
Jensen teaches a first composition comprising enriched anti-CD19 CAR-expressing viable CD8+ T-cells that can kill cancer cells, virally infected cells, or damaged cells and a second composition comprising enriched anti-CD19 CAR-expressing viable CD4+ T-cells that play an important role in the immune system, and in the adaptive immune system and help the activity of other immune cells by releasing T-cell cytokines ([0120], [0121] and [0140], claims 1 and 31), which is mixed or co-administered or administered in advance, in a ratio of 1:1, wherein the CD8+ expressing T-cells are administered in advance of the CD4+ expressing T-cells, such as 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 20, 30, 40, 50, or 60 minutes (claims 48, 54, 60, 68-69, and [0141], [0146]). The composition can be used to treat CD19 bearing cancer or cells ([0189]).
Abramson teaches that JCAR017 is a second-generation, CD19-directed CAR-T cell product of defined cellular composition consisting of a 1:1 ratio of CD8+:CD4+ CAR+ T cells (§ Background).
Therefore, it would have been prima facie obvious to one of the ordinary skills in
the art before the effective filing date of the claimed invention to use CD8+ and CD4+ T cell comprising a CAR targeting CD19 to treat r/r DLBCL as taught by NCT02631044, Abramson2017 and Abramson, and to administer the engineered T cells comprising CD4+ and CD8+ T cells in two separate compositions, such that the first composition comprises the CD8+ T cells and the second composition comprises the CD4+ T cells and the first composition comprising the CD8+ T cells is administered before the second composition comprising the CD4+ T cells by less than two hours apart with a reasonable expectation of success. One would have been motivated to have done so in order to take advantage of the benefits of combining CD8+ and CD4+ expressing T-cell in CART cell therapy in the treatment of r/r LBCL (e.g. r/r DLBCL), including killing cancer cells, virally infected cells, or damaged cells in addition to helping the adaptive immune system and the activity of other immune cells by releasing T-cell cytokines as taught by Jensen et al. The motivation would be to expand the options of using the engineered T cells and to enhanced the flexibility of the treatment.
Regarding claim 192, it would have prima facie been obvious to one of ordinarily skilled in the art at the time the invention was filed to use the ratio of JCAR017 taught by Abramson for the claimed method, because this ratio have been clinically tested and proven to be effective and safe.
Response to Arguments
For the rejection under 35 U.S.C. 103, Applicant first argues that Abramson does not teach the dosage ranges recited by the amended claims. In view of the amendment, new reference Abramson2017 and Zeng have been added. As set forth above, the combined references teach the dosage range and sequence of scFV as claimed.
Applicant further argues that Breyanzi shows superior results:
Approval of Breyanzi® was based on data from a Phase II study (PILOT), the first and
only study of a CAR T cell therapy in patients with primary r/r LBCL who were ineligible for
transplant, in which Breyanzi® delivered deep and durable responses. In a Phase III trial
(TRANSFORM), Breyanzi® significantly outperformed the nearly 30-year SOC resulting in
patients achieving median event-free survival (EFS) of 10.1 months, which is 4 times longer than the EFS of 2.3 months in patients that received SOC therapy. The patients also exhibited a well-established safety profile. In view of the clinical trial data and resulting approval, Breyanzi® now has the broadest patient eligibility of any CART cell therapy in r/r LBCL and has been approved for use in the United States, Europe and Japan for the treatment of r/r DLBCL (e.g.NHL, a large B cell lymphoma).
Claims 1 and 199 are amended to recite, inter alia, the specific CDR sequences of the
CD19 CAR. Accordingly, claims 1 and 199 do not encompass a broad genus of CARs that have
different scFv regions and CDR sequences. Instead, claims 1 and 199 encompass a specific
CD19 CAR comprising an anti-CD19 scFv having the recited CDR sequences, a transmembrane domain, a cytoplasmic signaling domain derived from a costimulatory molecule, a cytoplasmic signaling domain that comprises a CD3zeta signaling domain and an IgG4 spacer between the transmembrane domain and the scFv. As amended, the claims relate to, inter alia, features of Breyanzi®.
Applicant’s arguments have been fully considered but they are not persuasive. “Whether the unexpected results are the result of unexpectedly improved results or a property not taught by the prior art, the "objective evidence of nonobviousness must be commensurate in scope with the claims which the evidence is offered to support." In other words, the showing of unexpected results must be reviewed to see if the results occur over the entire claimed range. In re Clemens, 622 F.2d 1029, 1036, 206 USPQ 289, 296 (CCPA 1980) (Claims were directed to a process for removing corrosion at "elevated temperatures" using a certain ion exchange resin (with the exception of claim 8 which recited a temperature in excess of 100C). Appellant demonstrated unexpected results via comparative tests with the prior art ion exchange resin at 110C and 130C. The court affirmed the rejection of claims 1-7 and 9-10 because the term "elevated temperatures" encompassed temperatures as low as 60C where the prior art ion exchange resin was known to perform well. The rejection of claim 8, directed to a temperature in excess of 100C, was reversed.). See also In re Peterson, 315 F.3d 1325, 1329-31, 65 USPQ2d 1379, 1382-85 (Fed. Cir. 2003) (data showing improved alloy strength with the addition of 2% rhenium did not evidence unexpected results for the entire claimed range of about 1-3% rhenium); In re Grasselli, 713 F.2d 731, 741, 218 USPQ 769, 777 (Fed. Cir. 1983) (Claims were directed to certain catalysts containing an alkali metal. Evidence presented to rebut an obviousness rejection compared catalysts containing sodium with the prior art. The court held this evidence insufficient to rebut the prima facie case because experiments limited to sodium were not commensurate in scope with the claims.)”. MPEP 716.02
As acknowledged by Applicant, Breyanzi comprises an anti-CD19 scFv, an IgG hinge-only region, CD28 transmembrane domain, 4-1BB costimulatory domain and CD3zeta activation domain (see page 13, para 1 of the Remarks on 01/23/2026). However, the amended claims encompasses a broad genus of CARs which could have a different transmembrane domain, different spacer and a different costimulatory domain. In addition, the amended claims encompass different ratios between CD4+ and CD8+ T cell CAR-expressing cells. Accordingly, the data is not commensurate in scope with the claimed invention and does not demonstrate the non-obviousness of the claimed invention.
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.
U.S. Patent No. 11,413,310
Claims 1-3, 27, 34, 39, 49, 50, 60, 77, 79, 97, 188, 190, 192, 193, and 195-200 are rejected on the ground of nonstatutory double patenting as being unpatentable over claims 1-55 of U.S. Patent No. 11,413,310 (hereinafter Pat. 310, corresponding Appl. No.: 16/616,938), in view of NCT02631044 (Version 2: 2015-12-14, downloaded from: https://www.clinicaltrials.gov/study/NCT02631044?tab=history&a=2#version-content-panel, Publication Date: December 2015, of record) and Abramson2017 (Abramson et al., Blood (2017) 130 (Supplement 1): 581, Publication Date: 12/07/2017, cited as #244 ref in IDS of 03/17/2022, a copy of this reference is also attached with this office action), as evidenced by JCAR017_drugbank (downloaded from: https://go.drugbank.com/drugs/DB16582, on 10/07/2025, of record) and Zeng (Zeng et al., Cancer Investigation, Vol. 40, No.3, 282-292, Publication Year: 2022).
Regarding claims 1-3, 199, the claims of Pat. 310 teach a method of treating a subject having or suspected of having a cancer, the method comprising administering to the subject a dose of CD4+ and CD8+ T cells, each of the CD4+ and the CD8+ T cells, individually, comprising a recombinant receptor that specifically binds to a target antigen expressed by the cancer or a cell or tissue thereof and/or that is associated with the cancer, wherein the administration 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 (claim 1), wherein the dose of CD4+ and CD8+ T cells comprises between at or about 1×107 and at or about 2×108 total recombinant receptor-expressing T cells, inclusive (claims 10, 16, 39), wherein the disease is a B cell malignancy, e.g. aggressive NHL (claims 11, 19, 22) or DLBCL (claims 43, 44), wherein the recombinant receptor is a CAR targeting CD19 (claims 12, 25), immediately prior to the time of the administration of the dose of cells the subject has relapsed following remission after treatment with, or become refractory to, one or more prior therapies for the NHL (claim 23), 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 (claim 25), wherein the spacer consists of all or a portion of an immunoglobulin hinge and is 15 amino acid or fewer in length, e.g. SEQ ID NO:1 (claim 33 and claim 35), as evidenced by the specification of Pat. 310, SEQ ID NO: 1 represents an IgG4 hinge (see the table of col. 56, description for SEQ ID NO: 1).
The claims of Pat. 310 teach that the CAR comprises an scFv specific for CD19 comprising a CDR-L1 having an amino acid sequence of RASQDISKYLN (SEQ ID NO: 35), a CDR-L2 having an amino acid sequence of SRLHSGV (SEQ ID NO: 36), a CDR-L3 having an amino acid sequence of GNTLPYTFG (SEQ ID NO: 37), a CDR-H1 having an amino acid sequence of DYGVS (SEQ ID NO: 38), a CDR- H2 having an amino acid sequence of VIWGSETTYYNSALKS (SEQ ID NO: 39), and a CDR- H3 having an amino acid sequence of YAMDYWG (SEQ ID NO: 40) (claims 25 and 36). These CDRs are identical to the CDRs of instant claim 1.
Thus, the claims of Pat. 310 teach the CAR of instant claim 1 and 199. It is also noted that “prior to administration of the dose of cells the subject has relapsed following remission after treatment with, or become refractory to, one prior therapy” would read on administration of the cells as a second line therapy.
Thus, the claims of Pat. 310 teaches a method of treating a subject having or suspected of having a r/r NHL (e.g. DLBCL or NHL), the method comprising administering the subject a CD4+ and CD8+ comprising a CD19 targeting CAR with a dosage between at or about 1×107 and at or about 2×108 T cells.
However, the claims of Pat. 310 do not explicitly teach the subject have characteristic as recited in claim 1 (i) to (iv).
NCT02631044 and Abramson2017 teach as set forth above. In particular, NCT02631044 teaches JCAR017, a CD-19 targeted CAR T cells (comprising CD4+ and CD8+ T cells) for r/r B-cell NHL and patients must have received treatment with anthracycline and rituximab (or other CD20-targeted agent) and have at least one of the followings, such as: i) biopsy-proven refractory disease after frontline chemo-immunotherapy; ii) relapse within 1 year of frontline chemo-immunotherapy and not eligible for autologous hematopoietic stem cell transplant (auto-HSCT) (§ Inclusion Criteria on page 12-13). Abramson2017 teaches treating r/r DLBCL with JCAR017 and a starting dose of 108 CAR+ T cells (DL2) is more effective with manageable toxicity (§ Results).
As evidenced by JCAR017_drugbank, JCAR017 is the same as Breyanzi (Brand Name), or Lisocabtagene maraleucel (Generic Name). See pages 1-2. JCAR017 is composed of an FMC63 monoclonal antibody single chain variable fragment, IgG4 hinge region, CD28 transmembrane domain, 4-1BB costimulatory domain, and CD3z activation domain. FMC63 is an IgG2a mouse monoclonal antibody that target CD19. As evidenced by Zeng, the variable region of the VL and VH of FMC63 comprise the recited CDRs, as set forth above. It appears that the same CAR was used in the Examples of the instant specification, see page 15, para. 4 of the Remarks of 08/11/2025.
It would have prima facie been obvious to one of ordinarily skilled in the art at the time the invention was filed to treat a subject having or suspected of having a r/r NHL (e.g. DLBCL or NHL), the method comprising administering the subject a CD4+ and CD8+ comprising a CD19 targeting CAR with a dosage between at or about 1×107 and at or about 2×108 T cells as a second line therapy, as taught by the claims Pat. 310, and to use JCAR017 at a dosage of 108 T cells as a second line therapy and to treat an adult subject who has relapsed from, or is refractory to, a single line of immunochemotherapy for aggressive B-cell non-Hodgkin lymphoma (NHL) and is ineligible for HSCT, as taught by NCT02631044 and Abramson2017, because JCAR017 have been clinically tested as a second line therapy and show good therapeutic activity for the r/r/ DLBCL patients. Based on the teachings from NCT02631044 and Abramson2017, one of ordinary skill in the art would have had a reasonable expectation the JACR017 as a second therapy would be effective for this population of patients. The motivation would be to use a well-tested product to treat a suitable patient population, which would improve success rate for the treatment.
Regarding claims 27, 198 and 200, NCT02631044 teaches patients must have received treatment with anthracycline and rituximab (or other CD20-targeted agent) (§ Inclusion Criteria on page 12-13).
Regarding claim 34, given Broadest Reasonable Interpretation (BRI), all r/r/DLBCL can be considered as poor prognosis. Consequently, the teachings of NCT02631044 and Abramson that subjects with r/r DLBCL were treated support the notion of treating a subject has been identified as having poor prognosis because it is resistant to the previous treatment.
Regarding claim 39, Abramson2017 further teaches that the median age was 61 years (range 26-82) (§ Results). Thus, Abramson2017 teaches JCAR017 can be used for treating patients 65 years or older. One of ordinary skill in the art would have been motivated to include patients 65 years or older for the treatment to expand the application.
Regarding claim 49, 60 and 190, it is noted based on paragraph [1605] and Table E34A of the instant publication US 2022/0088070 A1, subjects were deemed ineligible for high-dose chemotherapy followed by HSTC if they met at least one of the following criteria: age ≥ 70 years, Eastern Cooperative Oncology Group (ECOG) performance status of 2, impaired pulmonary (DLCOs60%, but SaO2≥92% on room air and CTCAE≤1 dyspnea), cardiac (LVEF≥40% and <50%), renal (creatinine clearance>30 and <60 mL/min), or hepatic function (AST/ALT>2 and ≤5xULN). NCT02631044 teaches that subjects with ECOG performance status of 2 were included in treatment. Abramson2017 teaches that the subjects can be older than 70 (e.g. range 26-82) (§ Results). Thus, these subjects told by NCT02631044 and Abramson2017 reads on the subject is or has been identified as being ineligible for high-dose chemotherapy.
Regarding claim 77, Abramson2017 teaches that treatment with JCAR017 following lymphodepletion with fludarabine and cyclophosphamide (§ Method). It would have prima facie been obvious to one of ordinarily skilled in the art at the time the invention was filed to use the lymphodepletion step to obtain good therapeutic efficacy as shown by Abramson2017.
Regarding claim 79, the claims of Pat. 310 teach the administration and any follow up is carried out on an outpatient basis or without requiring admission to or an overnight stay at a hospital (claim 21).
Regard claim 97, Abramson2017 teaches that most treated patients do not exhibit CRS or neurotoxicity (§ Results, paragraph 2).
Regarding claims 188, 193, the claims of Pat. 310 teach the method of claim 1, wherein the first composition comprises the CD8+ T cells (claim 6) and wherein the initiation of the administration of the first composition is carried out prior to the initiation of the administration of the second composition (claims 7, 31).
Regarding claim 192, the claims of Pat. 310 teach the dose of CD4+ and CD8+ T cells comprises a defined ratio of CD4+ cells expressing the recombinant receptor to CD8+ cells expressing the recombinant receptor (claim 8), wherein the ratio is about 1:1 (claim 9).
Regarding claim 197, as evidenced by paragraph [0209] of the instant publication US 2022/0088070, not eligible for HSCT is considered as not eligible for TNE. Thus, NCT02631044 teaches treating subjects are deemed ineligible for both high-dose chemotherapy and HSCT, and is transplant ineligible (TNE), while remaining eligible for CAR T cell therapy.
Claim 42 is rejected on the ground of nonstatutory double patenting as being unpatentable over claims 1-55 of U.S. Patent No. 11,413,310 (hereinafter Pat. 310, corresponding Appl. No.: 16/616,938), in view of NCT02631044 (Version 2: 2015-12-14, downloaded from: https://www.clinicaltrials.gov/study/NCT02631044?tab=history&a=2#version-content-panel, Publication Date: December 2015, of record) and Abramson2017 (Abramson et al., Blood (2017) 130 (Supplement 1): 581, Publication Date: 12/07/2017, cited as #244 ref in IDS of 03/17/2022, a copy of this reference is also attached with this office action), as evidenced by JCAR017_drugbank (downloaded from: https://go.drugbank.com/drugs/DB16582, on 10/07/2025, of record) and Zeng (Zeng et al., Cancer Investigation, Vol. 40, No.3, 282-292, Publication Year: 2022), as applied to claims 1-3, 27, 34, 39, 49, 50, 60, 77, 79, 97, 188, 190, 192, 193, and 195-200 above, and further in view of Lichtman (Lichtman et al., Journal of Clinical Oncology, vol. 35, number 33, 3753-3759, Publication Date: 11/20/2017, of record).
As set forth above, the claims of Pat. 310, NCT02631044 and Abramson2017 teach method of claim 1 as set forth above. However, the claims of Pat. 310, NCT0231944 and Abramson2017 do not teach “wherein, at or prior to the administration of the dose of cells, the subject is or has been identified as having: (a) an impaired cardiac function; (b) an impaired renal function; (c) an impaired pulmonary function; and/or (d) an impaired hepatic function”.
NCT02631044 also teaches that patients with adequate renal, hepatic, pulmonary, and cardiac function can be treated by JCAR017 (§ Inclusion Criteria, point 5).
Lichtman teaches that adequate renal function characterized as calculated creatinine clearance (CrCl; commonly set at >60 mL/min) (i.e. a reflection of stage 2 of renal impairment in the art); adequate hepatic function characterized as total bilirubin (commonly set at <1.5mg/dL) and/or ALT and AST (commonly set at <2 to 3 x upper limit of normal [ULN]); and parameters for left ventricular ejection fraction (commonly set at >50%). (see page 3754, col. 1, para. 3). Thus, for example, an ALT and AST of 2-3 x upper limit of normal (ULN) would be considered as adequate hepatic function. As evidenced by [0074] of instant publication (“more than at or about twice the upper limit of normal”), an ALT and AST of 2-3 x upper limit of normal (ULN) would be classified as impaired hepatic function.
It would have prima facie been obvious to one of ordinarily skilled in the art at the time the invention was filed to treat a subject having or suspected of having a r/r NHL (e.g. DLBCL or NHL), with a method of instantly claimed as taught by the combination of the claims of Pat. 310, NCT02631044 and Abramson2017, as set forth above, and to apply the treatment to patients with adequate hepatic function, e.g. patients with an ALT and AST of 2-3 x upper limit of normal (ULN) since Litchman classified such patients as having impaired hepatic function, as taught by NCT02631044 and Lichtman. One would have been motivated to have done so in order to expand the treatment to the r/r LBCL population with adequate but impaired hepatic function. Given the low toxicity of JCAR017 in clinical trial as taught by Abramson2017 (§ Results), one of ordinary skill in the art would have a reasonable expectation that the treatment would be effective and safe for the patient population.
U.S. Patent No. 11,944,647
Claims 1-3, 27, 34, 39, 49, 50, 60, 77, 79, 97, 190, and 195-200 are rejected on the ground of nonstatutory double patenting as being unpatentable over claims 1-20 of U.S. Patent No. 11,944,647 (hereinafter Pat. 647, corresponding Appl. No.: 17/846,868), in view of NCT02631044 (Version 2: 2015-12-14, downloaded from: https://www.clinicaltrials.gov/study/NCT02631044?tab=history&a=2#version-content-panel, Publication Date: December 2015, of record) and Abramson2017 (Abramson et al., Blood (2017) 130 (Supplement 1): 581, Publication Date: 12/07/2017, cited as #244 ref in IDS of 03/17/2022, a copy of this reference is also attached with this office action), as evidenced by JCAR017_drugbank (downloaded from: https://go.drugbank.com/drugs/DB16582, on 10/07/2025, of record) and Zeng (Zeng et al., Cancer Investigation, Vol. 40, No.3, 282-292, Publication Year: 2022).
The claims of Pat. 647 teach a method of treating a subject having Mantle cell lymphoma (MCL), the method comprising administering to the subject a dose of T cells comprising T cells expressing a chimeric antigen receptor (CAR) that specifically binds to CD19, the dose of T cells comprising a ratio of CD4+ cells expressing the CAR to CD8+ cells expressing the CAR of between at or about 5:1 and at or about 1:5, wherein: 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; the subject has relapsed following remission after treatment with, or become refractory to, one or more prior therapies; 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 (claim 14), wherein the costimulatory molecule is 4-1BB (claim 20). As evidenced by instant claim 2, MCL reads on large B cell lymphoma. It is also noted that “prior to administration of the dose of cells the subject has relapsed following remission after treatment with, or become refractory to, one prior therapies” would read on administration of the cells as a second line therapy. It is also noted that administration the T cells to a subject wherein the subject has relapsed following remission after treatment with, or become refractory to, one prior therapy would read on administration of the cells as a second line therapy.
The claims of Pat. 647 teach 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 (claim 17).
Thus, the claims of Pat. 647 teaches a method of treating a subject having or suspected of having a r/r MCL (i.e. a subset of NHL), the method comprising administering the subject a CD4+ and CD8+ comprising a CD19 targeting CAR with a dosage between at or about 5×107 and at or about 1.5×108 T cells as a second line therapy. However, the claims of Pat. 647 do not explicitly teach the subject have characteristic as recited in claim 1 (i) to (iv), or treating r/r DLBCL (the elected species); or the spacer is a IgG4 hinge for the CAR, or the specific CDRs of the scFv.
NCT02631044 and Abramson2017 teachings are set forth above. In particular, NCT02631044 teaches JCAR017, a CD-19 targeted CAR T cells (comprising CD4+ and CD8+ T cells) for r/r B-cell NHL and patients must have received treatment with anthracycline and rituximab (or other CD20-targeted agent) and have at least one of the followings, such as: i) biopsy-proven refractory disease after frontline chemo-immunotherapy; ii) relapse within 1 year of frontline chemo-immunotherapy and not eligible for autologous hematopoietic stem cell transplant (auto-HSCT) (§ Inclusion Criteria on page 12-13). Abramson2017 teaches treating r/r DLBCL with JCAR017 and a starting dose of 108 CAR+ T cells (DL2) (§ Methods). Abramson2017 teaches that the dosage is safe and effective (§ Results).
As evidenced by JCAR017_drugbank, JCAR017 is the same as Breyanzi (Brand Name), or Lisocabtagene maraleucel (Generic Name). See pages 1-2. JCAR017 is composed of an FMC63 monoclonal antibody single chain variable fragment, IgG4 hinge region, CD28 transmembrane domain, 4-1BB costimulatory domain, and CD3z activation domain. FMC63 is an IgG2a mouse monoclonal antibody that target CD19. It appears that the same CAR was used in the Examples of the instant specification, see page 15, para. 4 of the Remarks of 08/11/2025. As evidenced by Zeng, the variable region of the VL and VH of FMC63 comprise the recited CDRs, as set forth above.
Thus, JCAR017 is a species read on the claims of Pat. 647 and also reads on the CAR of instant claims 1, 195 and 199.
It would have prima facie been obvious to one of ordinarily skilled in the art at the time the invention was filed to treat a subject having or suspected of having a r/r MCL, the method comprising administering the subject a CD4+ and CD8+ comprising a CD19 targeting CAR with a dosage between at or about 5×107 CAR-expressing viable T cells and about 1.5×108 T cells as a second line th3rapy, as taught by the claims Pat. 647, and to use JCAR017 at a dose of 108 T cells as a second line therapy and to treat an adult subject who has relapsed from, or is refractory to, a single line of immunochemotherapy for r/r MCL and to apply the treatment to other LBCL (e.g. DLBCL), who is ineligible for HSCT, as taught by NCT02631044 and Abramson2017, because JCAR017 have been clinically tested as a second line therapy for r/r/ DLBCL and show good therapeutic activity low toxicity for the r/r/ DLBCL patients. Based on the teachings from NCT02631044 and Abramson2017, one of ordinary skill in the art would have had a reasonable expectation the JACR017 at a dose of 108 T cells would be effective for this population of patients. The motivation would be to use a well-tested product to treat a suitable patient population, which would improve success rate for the treatment.
Regarding claims 27, 198 and 200, NCT02631044 teaches patients must have received treatment with anthracycline and rituximab (or other CD20-targeted agent) (§ Inclusion Criteria on page 12-13).
Regarding claim 34, given Broadest Reasonable Interpretation (BRI), all r/r/DLBCL can be considered as poor prognosis because it is resistant to the previous treatment. Consequently, the teachings of NCT02631044 and Abramson that subjects with r/r DLBCL were treated support the notion of treating a subject has been identified as having poor prognosis.
Regarding claim 39, Abramson2017 further teaches that the median age was 61 years (range 26-82) (§ Results). Thus, Abramson2017 teaches JCAR017 can be used for treating patients 65 years or older. One of ordinary skill in the art would have been motivated to include patients 65 years or older for the treatment to expand the application.
Regarding claim 49, 60 and 190, it is noted based on paragraph [1605] and Table E34A of the instant publication US 2022/0088070 A1, subjects were deemed ineligible for high-dose chemotherapy followed by HSTC if they met at least one of the following criteria: age ≥ 70 years, Eastern Cooperative Oncology Group (ECOG) performance status of 2, impaired pulmonary (DLCOs60%, but SaO2≥92% on room air and CTCAE≤1 dyspnea), cardiac (LVEF≥40% and <50%), renal (creatinine clearance>30 and <60 mL/min), or hepatic function (AST/ALT>2 and ≤5xULN). NCT02631044 teaches that subjects with ECOG performance status of 2 were included in treatment. Abramson2017 teaches that the subjects can be older than 70 (e.g. range 26-82) (§ Results). Thus, these subjects told by NCT02631044 and Abramson2017 reads on the subject is or has been identified as being ineligible for high-dose chemotherapy.
Regarding claim 77, Abramson2017 teaches that treatment with JCAR017 following lymphodepletion with fludarabine and cyclophosphamide (§ Method). It would have prima facie been obvious to one of ordinarily skilled in the art at the time the invention was filed to use the lymphodepletion step to obtain good therapeutic efficacy as shown by Abramson2017.
Regarding claim 79, it is a routine practice for one of ordinary skilled in the art to develop suitable administration method. Given that the toxicity of JCAR017 is low as taught by Abramson2017, one of ordinary skilled would have had a reasonable expectation that outpatient delivery would be suitable for JCAR017. The motivation would have been to improve flexibility and to reduce cost for the claimed methos.
Regard claim 97, Abramson2017 teaches that most treated patients do not exhibit CRS or neurotoxicity (§ Results, paragraph 2).
Regarding claim 195, as set forth above, JCAR017 read the CAR of instant claim 195.
Regarding claim 197, as evidenced by paragraph [0209] of the instant publication US 2022/0088070, not eligible for HSCT is considered as not eligible for TNE. Thus, NCT02631044 teaches treating subjects are deemed ineligible for both high-dose chemotherapy and HSCT, and is transplant ineligible (TNE), while remaining eligible for CAR T cell therapy.
Claim 42 is rejected on the ground of nonstatutory double patenting as being unpatentable over claims 1-20 of U.S. Patent No. 11,944,647 (hereinafter Pat. 647, corresponding Appl. No.: 17/846,868), in view of NCT02631044 (Version 2: 2015-12-14, downloaded from: https://www.clinicaltrials.gov/study/NCT02631044?tab=history&a=2#version-content-panel, Publication Date: December 2015, of record) and Abramson2017 (Abramson et al., Blood (2017) 130 (Supplement 1): 581, Publication Date: 12/07/2017, cited as #244 ref in IDS of 03/17/2022, a copy of this reference is also attached with this office action), as evidenced by JCAR017_drugbank (downloaded from: https://go.drugbank.com/drugs/DB16582, on 10/07/2025, of record) and Zeng (Zeng et al., Cancer Investigation, Vol. 40, No.3, 282-292, Publication Year: 2022), as applied to claims 1-3, 27, 34, 39, 49, 50, 60, 77, 79, 97, 190, and 195-200 above, and further in view of Lichtman (Lichtman et al., Journal of Clinical Oncology, vol. 35, number 33, 3753-3759, Publication Date: 11/20/2017, of record).
As set forth above, the claims of Pat. 647, NCT02631044 and Abramson2017 teach method of claim 1 as set forth above. However, the claims of Pat. 647, NCT0231944 and Abramson2017 do not teach “wherein, at or prior to the administration of the dose of cells, the subject is or has been identified as having: (a) an impaired cardiac function; (b) an impaired renal function; (c) an impaired pulmonary function; and/or (d) an impaired hepatic function”.
NCT02631044 also teaches that patients with adequate renal, hepatic, pulmonary, and cardiac function can be treated by JCAR017 (§ Inclusion Criteria, point 5).
Lichtman teaches that adequate renal function characterized as calculated creatinine clearance (CrCl; commonly set at >60 mL/min) (i.e. a reflection of stage 2 of renal impairment in the art); adequate hepatic function characterized as total bilirubin (commonly set at <1.5mg/dL) and/or ALT and AST (commonly set at <2 to 3 x upper limit of normal [ULN]); and parameters for left ventricular ejection fraction (commonly set at >50%). (see page 3754, col. 1, para. 3). Thus, for example, an ALT and AST of 2-3 x upper limit of normal (ULN) would be considered as adequate hepatic function. As evidenced by [0074] of instant publication (“more than at or about twice the upper limit of normal”), an ALT and AST of 2-3 x upper limit of normal (ULN) would be classified as impaired hepatic function.
It would have prima facie been obvious to one of ordinarily skilled in the art at the time the invention was filed to treat a subject having or suspected of having a r/r NHL (e.g. DLBCL or NHL), with a method of instantly claimed as taught by the combination of the claims of Pat. 647, NCT02631044 and Abramson2017, as set forth above, and to apply the treatment to patients with adequate hepatic function, e.g. patients with an ALT and AST of 2-3 x upper limit of normal (ULN) since Litchman also classified such patients as having impaired hepatic function, as taught by NCT02631044 and Lichtman. One would have been motivated to have done so in order to expand the treatment to the r/r LBCL population with adequate but impaired hepatic function. Given the low toxicity of JCAR017 in clinical trial as taught by Abramson2017 (§ Results), one of ordinary skill in the art would have a reasonable expectation that the treatment would be effective and safe for the patient population.
Claims 188, 192 and 193 are rejected on the ground of nonstatutory double patenting as being unpatentable over claims 1-20 of U.S. Patent No. 11,944,647 (hereinafter Pat. 647, corresponding Appl. No.: 17/846,868), in view of NCT02631044 (Version 2: 2015-12-14, downloaded from: https://www.clinicaltrials.gov/study/NCT02631044?tab=history&a=2#version-content-panel, Publication Date: December 2015, of record) and Abramson2017 (Abramson et al., Blood (2017) 130 (Supplement 1): 581, Publication Date: 12/07/2017, cited as #244 ref in IDS of 03/17/2022, a copy of this reference is also attached with this office action), as evidenced by JCAR017_drugbank (downloaded from: https://go.drugbank.com/drugs/DB16582, on 10/07/2025, of record) and Zeng (Zeng et al., Cancer Investigation, Vol. 40, No.3, 282-292, Publication Year: 2022), as applied to claims 1-3, 27, 34, 39, 49, 50, 60, 77, 79, 97, 190, and 194-200 above, and further in view of Jensen (Jensen, WO 2015/157384 A1, Publication Date: 10/15/2015, cited as #217 ref in IDS of 03/17/202, also attached with this Office Action, of record) and Abramson (Abramson et al., Blood (2016) 128 (22): 4192, Publication Date: 12/02/2016, cited as #251 ref in IDS of 03/17/202, of record).
As set forth above, the claims of Pat. 647, NCT02631044 and Abramson2017 teach method of claim 1 as set forth above. However, the claims of Pat. 647, NCT0231944 and Abramson2017 do not teach that CD8+ T cells and CD4+ T cells are CD8+ T cells and CD4+ T cells are administered as separated compositions, e.g. administration of CD8+ T cells is carried out prior to the initiation of the administration of the second composition.
Jensen and Abramson’s teachings are set forth above.
Therefore, it would have been prima facie obvious to one of the ordinary skills in
the art before the effective filing date of the claimed invention to use CD8+ and CD4+ T cell comprising a CAR targeting CD19 to treat r/r MCL or DLBCL as taught by the claims of Pat. 647, NCT02631044 and Abramson2017, and to administer the engineered T cells comprising CD4+ and CD8+ T cells in 2 separate compositions, such that the first composition comprises the CD8+ T cells and the second composition comprises the CD4+ T cells and the first composition comprising the CD8+ T cells is administered before the second composition comprising the CD4+ T cells by less than two hours apart with a reasonable expectation of success. One would have been motivated to have done so in order to take advantage of the benefits of combining CD8+ and CD4+ expressing T-cell in CART cell therapy in the treatment of r/r LBCL (e.g. r/r DLBCL), including killing cancer cells, virally infected cells, or damaged cells in addition to helping the adaptive immune system and the activity of other immune cells by releasing T-cell cytokines as taught by Jensen et al. The motivation would also be to expand the options of using the engineered T cells and to enhanced the flexibility of the treatment.
Regarding claim 192, Abramson teaches that JCAR017 is a second-generation, CD19-directed CAR-T cell product of defined cellular composition consisting of a 1:1 ratio of CD8+:CD4+ CAR+ T cells (§ Background). It would have prima facie been obvious to one of ordinarily skilled in the art at the time the invention was filed to use the ratio of JCAR017 for the claimed method, because this ratio have been clinically tested and proven to be effective and safe.
Application No. 18/882,479
Claims 1-3, 27, 34, 39, 49, 50, 60, 77, 79, 97, 106, 190, and 195-200 are provisionally rejected on the ground of nonstatutory double patenting as being unpatentable over claims 1-4, 6-14 and 16-20 of copending Application No. 18/882,479 (hereinafter Appl. 479, of record) in view of NCT02631044 (Version 2: 2015-12-14, downloaded from: https://www.clinicaltrials.gov/study/NCT02631044?tab=history&a=2#version-content-panel, Publication Date: December 2015, of record) and Abramson2017 (Abramson et al., Blood (2017) 130 (Supplement 1): 581, Publication Date: 12/07/2017, cited as #244 ref in IDS of 03/17/2022, a copy of this reference is also attached with this office action), as evidenced by JCAR017_drugbank (downloaded from: https://go.drugbank.com/drugs/DB16582, on 10/07/2025, of record) and Zeng (Zeng et al., Cancer Investigation, Vol. 40, No.3, 282-292, Publication Year: 2022).
The claims of Appl. 479 teach a method of treating a subject having follicular lymphoma (FL), a subset of NHL, the method comprising administering to the subject a dose of T cells comprising T cells expressing a chimeric antigen receptor (CAR) that specifically binds to CD19, wherein: the dose of T cells comprises between at or about 5 x 107 viable CAR-expressing T cells and at or about 1 x 108 viable CAR-expressing T cells, inclusive; the dose of T cells comprising a ratio of CD4+ cells expressing the CAR to CD8+ cells expressing the CAR of between at or about 5:1 and at or about 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 subject has relapsed following remission after treatment with, or become refractory to, one or more prior therapies (claim 1). As evidenced by instant claim 2, follicular lymphoma is large B cell lymphoma. It is also noted that administration the T cells to a subject wherein the subject has relapsed following remission after treatment with, or become refractory to, one prior therapy would read on administration of the cells as a second line therapy.
The claims of Appl. 479 teach 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 CD3z signaling domain, and a spacer between the transmembrane domain and the scFv (claim 3 and claim 10), wherein the costimulatory molecule is 4-1BB (claim 4); wherein the ratio of CD4+ cells expressing the CAR to CD8+ cells expressing the CAR is about 1:1 (claim 7 and claim 10).
Thus, the claims of Appl. 479 teaches a method of treating a subject having or suspected of having a r/r FL, the method comprising administering the subject a CD4+ and CD8+ comprising a CD19 targeting CAR with a dosage between at or about 5×107 and at or about 1×108 T cells. However, the claims of Appl. 479 do not explicitly teach the subject have characteristic as recited in claim 1 (i) to (iv), or treating r/r DLBCL (the elected species); or the spacer is a IgG4 hinge for the CAR; or the specific CDRs for scFv.
NCT02631044 and Abramson2017 teachings are set forth above. In particular, NCT02631044 teaches JCAR017, a CD-19 targeted CAR T cells (comprising CD4+ and CD8+ T cells) for r/r B-cell NHL and patients must have received treatment with anthracycline and rituximab (or other CD20-targeted agent) and have at least one of the followings, such as: i) biopsy-proven refractory disease after frontline chemo-immunotherapy; ii) relapse within 1 year of frontline chemo-immunotherapy and not eligible for autologous hematopoietic stem cell transplant (auto-HSCT) (§ Inclusion Criteria on page 12-13). Abramson2017 teaches treating r/r DLBCL with JCAR017 and a starting dose of 108 CAR+ T cells (DL2) (§ Methods). Abramson2017 teaches that the dosage is more effective and safe ( Results)
As evidenced by JCAR017_drugbank, JCAR017 is the same as Breyanzi (Brand Name), or Lisocabtagene maraleucel (Generic Name). See pages 1-2. JCAR017 is composed of an FMC63 monoclonal antibody single chain variable fragment, IgG4 hinge region, CD28 transmembrane domain, 4-1BB costimulatory domain, and CD3z activation domain. FMC63 is an IgG2a mouse monoclonal antibody that target CD19. It appears that the same CAR was used in the Examples of the instant specification, see page 15, para. 4 of the Remarks of 08/11/2025. Thus, JCAR017 is a species read on the claims of Pat. 647 and also reads on the CAR of instant claims 1, 195 and 199.
As evidenced by Zeng, the variable region of the VL and VH of FMC63 comprise the recited CDRs, as set forth above.
It would have prima facie been obvious to one of ordinarily skilled in the art at the time the invention was filed to treat a subject having or suspected of having a r/r FL, the method comprising administering the subject a CD4+ and CD8+ comprising a CD19 targeting CAR with a dosage between at or about 5×107 CAR-expressing viable T cells and about 1×108 T cells as taught by the claims Appl. 479, and to use JCAR017 at a dosage of 108 T cells as a second line therapy and to treat an adult subject who has relapsed from, or is refractory to, a single line of immunochemotherapy for r/r MCL and to apply the treatment to other LBCL (e.g. DLBCL), who is ineligible for HSCT, as taught by NCT02631044 and Abramson2017, because JCAR017 have been clinically tested and show good therapeutic activity low toxicity for the claimed subjects. Based on the teachings from NCT02631044 and Abramson2017, one of ordinary skill in the art would have had a reasonable expectation the JACR017 at a dosage of 108 T cells would be effective for this population of patients. The motivation would be to use a well-tested product to treat a suitable patient population, which would improve success rate for the treatment.
Regarding claims 27, 198 and 200, NCT02631044 teaches patients must have received treatment with anthracycline and rituximab (or other CD20-targeted agent) (§ Inclusion Criteria on page 12-13).
Regarding claim 34, given Broadest Reasonable Interpretation (BRI), all r/r/DLBCL can be considered as poor prognosis because it is resistant to the previous treatment. Consequently, the teachings of NCT02631044 and Abramson that subjects with r/r DLBCL were treated support the notion of treating a subject has been identified as having poor prognosis.
Regarding claim 39, Abramson2017 further teaches that the median age was 61 years (range 26-82) (§ Results). Thus, Abramson2017 teaches JCAR017 can be used for treating patients 65 years or older. One of ordinary skill in the art would have been motivated to include patients 65 years or older for the treatment to expand the application.
Regarding claim 49, 60 and 190, it is noted based on paragraph [1605] and Table E34A of the instant publication US 2022/0088070 A1, subjects were deemed ineligible for high-dose chemotherapy followed by HSTC if they met at least one of the following criteria: age ≥ 70 years, Eastern Cooperative Oncology Group (ECOG) performance status of 2, impaired pulmonary (DLCOs60%, but SaO2≥92% on room air and CTCAE≤1 dyspnea), cardiac (LVEF≥40% and <50%), renal (creatinine clearance>30 and <60 mL/min), or hepatic function (AST/ALT>2 and ≤5xULN). NCT02631044 teaches that subjects with ECOG performance status of 2 were included in treatment. Abramson2017 teaches that the subjects can be older than 70 (e.g. range 26-82) (§ Results). Thus, these subjects told by NCT02631044 and Abramson2017 reads on the subject is or has been identified as being ineligible for high-dose chemotherapy.
Regarding claim 77, Abramson2017 teaches that treatment with JCAR017 following lymphodepletion with fludarabine and cyclophosphamide (§ Method). It would have prima facie been obvious to one of ordinarily skilled in the art at the time the invention was filed to use the lymphodepletion step to obtain good therapeutic efficacy as shown by Abramson2017.
Regarding claim 79, it is a routine practice for one of ordinary skilled in the art to develop suitable administration method. Given that the toxicity of JCAR017 is low as taught by Abramson2017, one of ordinary skilled would have had a reasonable expectation that outpatient delivery would be suitable for JCAR017. The motivation would have been to improve flexibility and to reduce cost for the claimed methos.
Regard claim 97, Abramson2017 teaches that most treated patients do not exhibit CRS or neurotoxicity (§ Results, paragraph 2).
Regarding claim 195, as set forth above, JCAR017 read the CAR of instant claim 195.
Regarding claim 197, as evidenced by paragraph [0209] of the instant publication US 2022/0088070, not eligible for HSCT is considered as not eligible for TNE. Thus, NCT02631044 teaches treating subjects are deemed ineligible for both high-dose chemotherapy and HSCT, and is transplant ineligible (TNE), while remaining eligible for CAR T cell therapy.
This is a provisional nonstatutory double patenting rejection.
Claim 42 is provisionally rejected on the ground of nonstatutory double patenting as being unpatentable over claims 1-4, 6-14 and 16-20 of copending Application No. 18/882,479 (hereinafter Appl. 479, of record) in view of NCT02631044 (Version 2: 2015-12-14, downloaded from: https://www.clinicaltrials.gov/study/NCT02631044?tab=history&a=2#version-content-panel, Publication Date: December 2015, of record) and Abramson2017 (Abramson et al., Blood (2017) 130 (Supplement 1): 581, Publication Date: 12/07/2017, cited as #244 ref in IDS of 03/17/2022, a copy of this reference is also attached with this office action), as evidenced by JCAR017_drugbank (downloaded from: https://go.drugbank.com/drugs/DB16582, on 10/07/2025, of record) and Zeng (Zeng et al., Cancer Investigation, Vol. 40, No.3, 282-292, Publication Year: 2022), as applied to claims 1-3, 27, 34, 39, 49, 50, 60, 77, 79, 97, 106, 190, and 195-200 above; and further in view of Lichtman (Lichtman et al., Journal of Clinical Oncology, vol. 35, number 33, 3753-3759, Publication Date: 11/20/2017, of record).
As set forth above, the claims of Appl. 479, NCT02631044 and Abramson2017 teach method of claim 1 as set forth above. However, the claims of Appl. 479, NCT0231944 and Abramson2017 do not teach “wherein, at or prior to the administration of the dose of cells, the subject is or has been identified as having: (a) an impaired cardiac function; (b) an impaired renal function; (c) an impaired pulmonary function; and/or (d) an impaired hepatic function”.
NCT02631044 also teaches that patients with adequate renal, hepatic, pulmonary, and cardiac function can be treated by JCAR017 (§ Inclusion Criteria, point 5).
Lichtman teaches that adequate renal function characterized as calculated creatinine clearance (CrCl; commonly set at >60 mL/min) (i.e. a reflection of stage 2 of renal impairment in the art); adequate hepatic function characterized as total bilirubin (commonly set at <1.5mg/dL) and/or ALT and AST (commonly set at <2 to 3 x upper limit of normal [ULN]); and parameters for left ventricular ejection fraction (commonly set at >50%). (see page 3754, col. 1, para. 3). Thus, for example, an ALT and AST of 2-3 x upper limit of normal (ULN) would be considered as adequate hepatic function. As evidenced by [0074] of instant publication (“more than at or about twice the upper limit of normal”), an ALT and AST of 2-3 x upper limit of normal (ULN) would be classified as impaired hepatic function.
It would have prima facie been obvious to one of ordinarily skilled in the art at the time the invention was filed to use CD8+ and CD4+ T cell comprising a CAR targeting CD19 to treat r/r MCL or DLBCL as taught by the combination of the claims of Appl. 479, NCT02631044 and Abramson2017, as set forth above, and to apply the treatment to patients with adequate hepatic function, e.g. patients with an ALT and AST of 2-3 x upper limit of normal (ULN) since Litchman classified such patients as having impaired hepatic function, as taught by NCT02631044 and Lichtman. One would have been motivated to have done so in order to expand the treatment to the r/r LBCL population with adequate but impaired hepatic function. Given the low toxicity of JCAR017 in clinical trial as taught by Abramson (§ Conclusions), one of ordinary skill in the art would have a reasonable expectation that the treatment would be effective and safe for the patient population.
This is a provisional nonstatutory double patenting rejection.
Claims 188, 192 and 193 are provisionally rejected on the ground of nonstatutory double patenting as being unpatentable over claims 1-4, 6-14 and 16-20 of copending Application No. 18/882,479 (hereinafter Appl. 479, of record) in view of NCT02631044 (Version 2: 2015-12-14, downloaded from: https://www.clinicaltrials.gov/study/NCT02631044?tab=history&a=2#version-content-panel, Publication Date: December 2015, of record) and Abramson2017 (Abramson et al., Blood (2017) 130 (Supplement 1): 581, Publication Date: 12/07/2017, cited as #244 ref in IDS of 03/17/2022, a copy of this reference is also attached with this office action), as evidenced by JCAR017_drugbank (downloaded from: https://go.drugbank.com/drugs/DB16582, on 10/07/2025, of record) and Zeng (Zeng et al., Cancer Investigation, Vol. 40, No.3, 282-292, Publication Year: 2022), as applied to claims 1-3, 27, 34, 39, 49, 50, 60, 77, 79, 97, 106, 190, and 195-200 above; and further in view of Jensen (Jensen, WO 2015/157384 A1, Publication Date: 10/15/2015, cited as #217 ref in IDS of 03/17/202, of record) and Abramson (Abramson et al., Blood (2016) 128 (22): 4192, Publication Date: 12/02/2016, cited as #251 ref in IDS of 03/17/202, of record).
As set forth above, the claims of Appl. 479, NCT02631044 and Abramson2017 teach method of claim 1 as set forth above. However, the claims of Appl. 479, NCT0231944 and Abramson2017 do not teach that CD8+ T cells and CD4+ T cells are CD8+ T cells and CD4+ T cells are administered as separated compositions, e.g. administration of CD8+ T cells is carried out prior to the initiation of the administration of the second composition.
Jensen’s teachings are set forth above.
Therefore, it would have been prima facie obvious to one of the ordinary skills in
the art before the effective filing date of the claimed invention to use CD8+ and CD4+ T cell comprising a CAR targeting CD19 to treat r/r MCL or DLBCL as taught by the claims of Appl. 479, NCT02631044 and Abramson2017, and to administer the engineered T cells comprising CD4+ and CD8+ T cells in 2 separate compositions, such that the first composition comprises the CD8+ T cells and the second composition comprises the CD4+ T cells and the first composition comprising the CD8+ T cells is administered before the second composition comprising the CD4+ T cells by less than two hours apart with a reasonable expectation of success. One would have been motivated to have done so in order to take advantage of the benefits of combining CD8+ and CD4+ expressing T-cell in CART cell therapy in the treatment of r/r LBCL (e.g. r/r DLBCL), including killing cancer cells, virally infected cells, or damaged cells in addition to helping the adaptive immune system and the activity of other immune cells by releasing T-cell cytokines as taught by Jensen et al. The motivation would also be to expand the options of using the engineered T cells and to enhanced the flexibility of the treatment.
Regarding claim 192, Abramson teaches that JCAR017 is a second-generation, CD19-directed CAR-T cell product of defined cellular composition consisting of a 1:1 ratio of CD8+:CD4+ CAR+ T cells (§ Background). It would have prima facie been obvious to one of ordinarily skilled in the art at the time the invention was filed to use the ratio of JCAR017 for the claimed method, because this ratio have been clinically tested and proven to be effective and safe.
This is a provisional nonstatutory double patenting rejection.
Response to Arguments
For the Double Patenting rejections, Applicant argues:
For the same reasons discussed above for the 35 USC§ 103 rejection, the Examiner has
failed to set forth a prima facie case of obviousness at least because a skilled artisan would not
have a reasonable expectation of success that the higher, recited dose would be expected to
achieve the same effects of Abramson when administered as a second-line therapy. Moreover, secondary considerations, including advantageous results of the claimed subject matter, also
support a finding of non-obviousness.
Applicant’s arguments have been fully considered but they are not persuasive. Applicant use the same arguments discussed above for 103 rejection. Therefore, the rejections above are maintained for the reasons of set forth above.
Conclusion
No claims are allowed.
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/CHENG LU/ Examiner, Art Unit 1642