Notice of Pre-AIA or AIA Status
The present application, filed on or after March 16, 2013, is being examined under the first inventor to file provisions of the AIA .
Detailed Action
This action is in response to the papers filed December 15, 2025.
Claim Amendments
Applicant’s amendment to the claims filed 12/15/2025 is acknowledged.
Claims 86-90, 94-112 are pending.
Claims 87-90, 94-108 are withdrawn from further consideration pursuant to 37 CFR 1.142(b) as being drawn to a nonelected invention/species.
Claim 86, 109-112 are under examination.
Election/Restrictions
The following is a summary of the restriction/election requirements in the present application. See the Requirement for Restriction/Election mailed 01/02/025.
In the reply filed 04/29/2025, applicant elected without traverse Invention II, drawn to a cell comprising a first and second CAR polypeptide, and a nucleic acid encoding thereof;
Applicant further elected the following species:
the combination of:
a first anti-CD19 CAR polypeptide having the amino acid sequence according to SEQ ID NO: 270, wherein the antigen binding domain has the amino acid sequence according to SEQ ID NO: 84, and the intracellular domain has a CD3 zeta primary signaling domain and a 4-1BB costimulatory domain; and
a second anti-EGFRvIII CAR polypeptide having the amino acid sequence according to SEQ ID NO: 1073, wherein the antigen binding domain has the amino acid sequence according to SEQ ID NO: 76, and the intracellular domain has a CD3 zeta primary signaling domain and a 4-1BB costimulatory domain; and
the cancer for treatment of: glioblastoma.
Please note that the first, anti-CD19 CAR comprising the antigen binding domain of SEQ ID NO: 84, as elected by applicant, further comprises the HC CDR1 of SEQ ID NO: 255 (amino acids 148-157 of SEQ ID NO: 84), the HC CDR2 of SEQ ID NO: 258 (amino acids 172-187 of SEQ ID NO: 84), the HC CDR3 of SEQ ID NO: 260 (amino acids 220-231 of SEQ ID NO: 84), the LC CDR1 of SEQ ID NO: 261 (amino acids 24-34 of SEQ ID NO: 84), the LC CDR2 of SEQ ID NO: 262 (amino acids 50-56 of SEQ ID NO: 84), and the LC CDR3 of SEQ ID NO: 263 (amino acids 89-97 of SEQ ID NO: 84).
Claims 87-90, 94-108 are withdrawn from further consideration pursuant to 37 CFR 1.142(b) as being drawn to a nonelected invention/species, there being no allowable generic or linking claim. In this case, claim 87, upon which claims 88-90, 94-108 depend upon, does not read on the elected first CAR polypeptide because the elected first CAR polypeptide has a CD3 zeta primary signaling domain. Election was made without traverse in the reply filed on 04/29/2025.
Applicant’s remarks filed 12/15/2025 regarding withdrawal of claims 87-90, 94-108 have been carefully considered but are not persuasive. In this case, applicant elected without traverse a combination comprising a first, anti-CD19 CAR comprising a CD3 zeta primary signaling domain, and claims 87-90, 94-108 require a first, anti-CD19 CAR which does not comprise a primary signaling domain. See claim 87, upon which claims 88-90, 94-108 depend: “the intracellular signaling domain of said first CAR comprises a costimulatory signaling domain, but not a primary signaling domain.” Accordingly, applicant’s elected species is mutually exclusive with, and excluded from, the invention as claimed in claims 87-90, 94-108. For these reasons, claims 87-90, 94-108 are withdrawn from further consideration pursuant to 37 CFR 1.142(b) as being drawn to a nonelected invention/species. Election was made without traverse in the reply filed on 04/29/2025.
Priority
The instant application 18/309,370 was filed on 04/28/2023. This application is a continuation (CON) of U.S. Application No. 16/082,035 filed 09/04/2018, which is a national stage of international application PCT/IB2017/051267 filed 03/03/2017, which claims priority based on U.S. Provisional Application No. 62/303,466 filed 03/04/2016.
Applicant’s remarks filed 12/15/2025 regarding the priority claims in the present application have been carefully considered. In view of applicant’s remarks, and the amendment to the claims, claims 86, 109-112, presently under examination, are found to have an effective filing date of 03/04/2016, based on U.S. Provisional Application No. 62/303,466.
Information Disclosure Statement
The information disclosure statement (IDS) submitted on 12/15/2025 has been considered.
Terminal Disclaimer
The terminal disclaimer filed on 12/15/2025 disclaiming the terminal portion of any patent granted on this application which would extend beyond the expiration date of U.S. Patent No. 11,667,691 has been reviewed and is accepted. The terminal disclaimer has been recorded.
Withdrawal of Prior Rejections/Objections
Rejections and/or objections not reiterated from the previous Office action mailed 07/16/2025 are hereby withdrawn. The following rejections and/or objections are either newly applied or are reiterated and are the only rejections and/or objections presently applied to the instant application.
Claim Objections
Claim 86 is objected to because of the following informalities:
In claim 86, paragraph (a)(iii), the phrase “any light chain variable region of SEQ ID NO: 97” should be “the light chain variable region of SEQ ID NO: 97” because only a single light chain variable region is listed.
In claim 86, paragraph (a)(iv), the phrase “any heavy chain variable region of SEQ ID NO: 96” should be “the heavy chain variable region of SEQ ID NO: 96” because only a single heavy chain variable region is listed.
Appropriate action is required.
Claim Rejections - 35 USC § 112
The following is a quotation of 35 U.S.C. 112(b):
(b) CONCLUSION.—The specification shall conclude with one or more claims particularly pointing out and distinctly claiming the subject matter which the inventor or a joint inventor regards as the invention.
The following is a quotation of 35 U.S.C. 112 (pre-AIA ), second paragraph:
The specification shall conclude with one or more claims particularly pointing out and distinctly claiming the subject matter which the applicant regards as his invention.
Claim 110 is rejected under 35 U.S.C. 112(b) or 35 U.S.C. 112 (pre-AIA ), second paragraph, as being indefinite for failing to particularly point out and distinctly claim the subject matter which the inventor or a joint inventor (or for applications subject to pre-AIA 35 U.S.C. 112, the applicant), regards as the invention.
This rejection is newly applied.
Claim 110 recites the limitations “the primary signaling domain” and “the costimulatory signaling domain.” There is insufficient antecedent basis for these limitations in the claim. For these reasons, one of ordinary skill in the art would not be reasonably apprised of the scope of the invention.
Claim 111 is rejected under 35 U.S.C. 112(b) or 35 U.S.C. 112 (pre-AIA ), second paragraph, as being indefinite for failing to particularly point out and distinctly claim the subject matter which the inventor or a joint inventor (or for applications subject to pre-AIA 35 U.S.C. 112, the applicant), regards as the invention.
This rejection is newly applied.
Claim 111 recites the limitation “the costimulatory signaling domain.” There is insufficient antecedent basis for this limitation in the claim. For these reasons, one of ordinary skill in the art would not be reasonably apprised of the scope of the invention.
The following is a quotation of 35 U.S.C. 112(d):
(d) REFERENCE IN DEPENDENT FORMS.—Subject to subsection (e), a claim in dependent form shall contain a reference to a claim previously set forth and then specify a further limitation of the subject matter claimed. A claim in dependent form shall be construed to incorporate by reference all the limitations of the claim to which it refers.
The following is a quotation of pre-AIA 35 U.S.C. 112, fourth paragraph:
Subject to the following paragraph [i.e., the fifth paragraph of pre-AIA 35 U.S.C. 112], a claim in dependent form shall contain a reference to a claim previously set forth and then specify a further limitation of the subject matter claimed. A claim in dependent form shall be construed to incorporate by reference all the limitations of the claim to which it refers.
Claims 109 and 112 are rejected under 35 U.S.C. 112(d) or pre-AIA 35 U.S.C. 112, 4th paragraph, as being of improper dependent form for failing to further limit the subject matter of the claim upon which it depends, or for failing to include all the limitations of the claim upon which it depends.
Dependent claim 109 recites a nucleic acid encoding the first CAR and the second CAR of claim 86. However, claim 86 is directed to a cell comprising the first CAR and the second CAR. Accordingly, claim 109 is improper dependent form for failing to include all the limitations of the claim upon which it depends.
Dependent claim 112 is included in the basis of the rejection because it does not correct the deficiencies of the claim upon which it depends. Applicant may cancel the claim(s), amend the claim(s) to place the claim(s) in proper dependent form, rewrite the claim(s) in independent form, or present a sufficient showing that the dependent claim(s) complies with the statutory requirements.
Claim Rejections - 35 USC § 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.
Claims 86, 109-112 are rejected under 35 U.S.C. 103 as being unpatentable over WO 2015/075468 A1 to Pulé et al.; in view of US 2014/0322275 A1 to Brogdon et al.
This rejection is newly applied.
Pulé discloses a T cell comprising a first CAR and a second CAR for the treatment of cancer. See, e.g., pg. 16, ll. 10-24. The first CAR and second CAR each comprise an antigen-binding domain, a transmembrane domain, and an intracellular T cell signaling domain (endodomain), wherein the antigen binding domains of the first and second CARs bind to different antigens. See, e.g., pg. 12-13, joining paragraph; pg. 18, ll. 13-23. In one example, Pulé discloses a T cell expressing a first CAR that binds to CD19 and a second CAR that binds to EGFRvIII. See Figure 20; pg. 7-8, joining paragraph; Example 5 on pg. 66; pg. 30-31, joining paragraph.
Pulé discloses an exemplary amino acid sequence according to SEQ ID NO: 45, wherein an anti-CD19 CAR and an anti-EGFRvIII CAR are linked via a 2A self-cleaving peptide. See pages 66, 74-75. An alignment between SEQ ID NO: 84 and Pulé’s SEQ ID NO: 45 is provided below in this action. As shown in the alignment, Pulé’s SEQ ID NO: 45 comprises the LC CDR1 of SEQ ID NO: 261 (amino acids 24-34 of SEQ ID NO: 84), the LC CDR2 of SEQ ID NO: 262 (amino acids 50-56 of SEQ ID NO: 84), and the LC CDR3 of SEQ ID NO: 263 (amino acids 89-97 of SEQ ID NO: 84). Therefore, Pulé is found to teach or fairly suggest the limitations of paragraph (a)(ii) of claim 86 for the first, anti-CD19 CAR. However, Pulé does not teach or fairly suggest that the second, anti-EGFRvIII CAR comprises the amino acid sequence according to SEQ ID NO: 1073, as claimed in paragraph (b)(ii) of claim 86, or the antigen binding domain according to SEQ ID NO: 76, as claimed in paragraph (b)(i) of claim 86.
Prior to the effective filing date of the instantly claimed invention, US 2014/0322275 A1 discloses a T cell comprising a first CAR that binds to EGFRvIII for the treatment of cancer. See, e.g., par. 299-300. US 2014/0322275 A1 further discloses that the CAR-expressing cell further comprises a second CAR that binds to a target other than EGFRvIII. See, e.g., par. 210-0211. SEQ ID NO: 73 of US 2014/0322275 A1 is identical to SEQ ID NO: 1073 of the instant application, which comprises the antigen binding domain of SEQ ID NO: 76 of the instant application, i.e., amino acids 22-267 of SEQ ID NO: 1073. See, e.g., par. 140; see alignment below.
Therefore, it would have been prima facie obvious to one of ordinary skill in the art to substitute the antigen binding domain for the second CAR, as found in Pulé, with the antigen binding domain according to SEQ ID NO: 76 of the instant application, as found in US 2014/0322275 A1, with a reasonable expectation of success because both antigen binding domains are functionally capable of targeting and binding to the EGFRvIII antigen when expressed as part of a CAR on the surface of a cell, and the simple substitution of one known element for another would have yielded predictable results to one of ordinary skill in the art at the time of the invention.
For these reasons, claim 86 would have been prima facie obvious over the prior art.
Regarding dependent claim 109, Pulé teaches or fairly suggests a nucleic acid encoding the first CAR and the second CAR. See, e.g., pg. 14, ll. 5-7; pg. 15, ll. 27-28; pg. 75-76; Figure 8.
Regarding dependent claim 110, Pulé teaches or fairly suggests the first and/or second CAR comprises a CD3-zeta stimulatory domain. See, e.g., pg. 38, ll. 5-12; pg. 39, ll. 17-20; Figure 8. US 2014/0322275 A1 also teaches the CAR comprises a CD3-zeta stimulatory domain. See, e.g., par. 13-14.
Regarding dependent claim 111, Pulé teaches or fairly suggests the first and/or second CAR comprises a costimulatory domain comprising an intracellular domain of 4-1BB. See, e.g., pg. 23, ll. 9-21; pg. 38, ll. 5-26. US 2014/0322275 A1 also teaches the CAR comprises a 4-1BB costimulatory domain. See, e.g., par. 12-14.
Regarding claim 112, Pulé teaches or fairly suggests the first CAR coding sequence and the second CAR coding sequence are separated by an internal ribosome entry sequence (IRES) or a 2A self-cleaving peptide, such as Foot-and-Mouth disease virus (FMDV) 2a peptide, i.e., F2A. See, e.g., pg. 17, ll. 24-31; pg. 47, ll. 16-32 Figure 8.
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.
Compliance with 37 CFR 1.321:
The following nonstatutory double patenting (NSDP) rejections will not be held in abeyance. A complete response to a NSDP rejection is either a reply by applicant showing that the claims subject to the rejection are patentably distinct from the reference claims or the filing of a terminal disclaimer in accordance with 37 CFR 1.321 in the pending application(s) with a reply to the Office action (see MPEP § 1490 for a discussion of terminal disclaimers). Such a response is required even when the nonstatutory double patenting rejection is provisional. See MPEP 804(I)(B)(1).
Claims 86, 109-112 are rejected on the ground of nonstatutory double patenting as being unpatentable over the claims of U.S. Patent No. 10,829,735 B2; in view of US 2014/0322275 A1 to Brogdon et al.; and WO 2015/075468 A1 to Pulé et al.
This rejection is newly applied.
The reference claims recite a method (claim 1) and an immune cell preparation (claim 17) comprising a cell comprising a first, anti-CD19 CAR molecule (claim 1) and a second, anti-EGFRvIII CAR (claim 11).
The reference claims recite that the anti-CD19 CAR comprises an antigen binding domain comprising the LC CDR1 of SEQ ID NO: 128, the LC CDR2 of SEQ ID NO: 129, and the LC CDR3 of SEQ ID NO: 130 (claim 25). Reference SEQ ID NOs: 128, 129 and 130 are identical to instant SEQ ID NOs: 261, 262 and 263, respectively, as instantly claimed in paragraph (a)(ii) of claim 86.
The reference claims do not recite an amino acid sequence of the anti-EGFRvIII CAR, as claimed in part (b) of claim 86.
Prior to the effective filing date of the instantly claimed invention, US 2014/0322275 A1 discloses a T cell comprising a first CAR that binds to EGFRvIII for the treatment of cancer. See, e.g., par. 299-300. US 2014/0322275 A1 further discloses that the CAR-expressing cell further comprises a second CAR that binds to a target other than EGFRvIII. See, e.g., par. 210-0211. SEQ ID NO: 73 of US 2014/0322275 A1 is identical to SEQ ID NO: 1073 of the instant application, which comprises the antigen binding domain of SEQ ID NO: 76 of the instant application. See, e.g., par. 140; see alignments, below.
Therefore, it would have been prima facie obvious to one of ordinary skill in the art to modify the invention of the reference claims by using the anti-EGFRvIII CAR according to SEQ ID NO: 1073, or a CAR comprising the antigen binding domain of SEQ ID NO: 76, as found in US 2014/0322275 A1, with a reasonable expectation of success because the reference claims are silent with regards to the amino acid sequence of the anti-EGFRvIII CAR, and therefore one of ordinary skill in the art would have sought known sequences available in the prior art suitable for the claimed invention, such as found in US 2014/0322275 A1.
US 2014/0322275 A1 further discloses that a CAR comprises at least an extracellular antigen binding domain, a transmembrane domain and an intracellular signaling domain. See, e.g. par. 65. SEQ ID NO: 1073, as instantly claimed and found in US 2014/0322275 A1, comprises an intracellular domain having a CD3 zeta primary signaling domain and a 4-1BB costimulatory domain.
The reference claims do not recite a nucleic acid encoding the first CAR and the second CAR, and wherein the first CAR coding sequence and the second CAR coding sequence are separated by a IRES or F2A element. However, WO 2015/075468 A1 discloses bicistronic nucleic acid constructs comprising a first CAR coding sequence and the second CAR coding sequence separated by a IRES or F2A element. See, e.g., pg. 17, ll. 24-31; pg. 47, ll. 16-32 Figure 8. Therefore, prior to the effective filing date of the instantly claimed invention, it would have been prima facie obvious to one of ordinary skill in the art to modify the invention of the reference claims by constructing a bicistronic nucleic acid construct comprising a first CAR coding sequence and the second CAR coding sequence separated by a IRES or F2A element, as taught by WO 2015/075468 A1, with a reasonable expectation of success because the bicistronic construct would produce a cell engineered to co-express the two CARs using a single transfection or transduction step.
For these reasons, the instant claims would have been prima facie obvious over the reference claims and secondary references.
Response to arguments: Applicant’s remarks filed 12/15/2025 have been carefully considered, but are not found persuasive.
Applicant argues that the reference claims recite that the first CAR is “transiently expressed” and the second CAR is “stably expressed,” but the instant claims do not recite that the CAR molecules are transiently or stably expressed. See pages 17-18 of applicant’s reply. The argument is not persuasive because the instant claims broadly encompass transient or stable expression of the CAR molecules.
The remainder of the arguments are sufficiently addressed by the new grounds of rejection.
Claims 86, 109-112 are rejected on the ground of nonstatutory double patenting as being unpatentable over the claims of U.S. Patent No. 12,240,884 B2; in view of US 2014/0322275 A1 to Brogdon et al.; and WO 2015/075468 A1 to Pulé et al.
This rejection is newly applied.
The reference claims recite a method comprising a cell comprising a first, anti-CD19 CAR molecule and a second, anti-EGFRvIII CAR (claims 1 and 13).
The reference claims recite that the anti-CD19 CAR comprises an antigen binding domain comprising the LC CDR1 of SEQ ID NO: 128, the LC CDR2 of SEQ ID NO: 129, and the LC CDR3 of SEQ ID NO: 130 (claim 23). Reference SEQ ID NOs: 128, 129 and 130 are identical to instant SEQ ID NOs: 261, 262 and 263, respectively, as instantly claimed in paragraph (a)(ii) of claim 86.
The reference claims do not recite an amino acid sequence of the anti-EGFRvIII CAR, as claimed in part (b) of claim 86.
Prior to the effective filing date of the instantly claimed invention, US 2014/0322275 A1 discloses a T cell comprising a first CAR that binds to EGFRvIII for the treatment of cancer. See, e.g., par. 299-300. US 2014/0322275 A1 further discloses that the CAR-expressing cell further comprises a second CAR that binds to a target other than EGFRvIII. See, e.g., par. 210-0211. SEQ ID NO: 73 of US 2014/0322275 A1 is identical to SEQ ID NO: 1073 of the instant application, which comprises the antigen binding domain of SEQ ID NO: 76 of the instant application. See, e.g., par. 140; see alignments, below.
Therefore, it would have been prima facie obvious to one of ordinary skill in the art to modify the invention of the reference claims by using the anti-EGFRvIII CAR according to SEQ ID NO: 1073, or a CAR comprising the antigen binding domain of SEQ ID NO: 76, as found in US 2014/0322275 A1, with a reasonable expectation of success because the reference claims are silent with regards to the amino acid sequence of the anti-EGFRvIII CAR, and therefore one of ordinary skill in the art would have sought known sequences available in the prior art suitable for the claimed invention, such as found in US 2014/0322275 A1.
US 2014/0322275 A1 further discloses that a CAR comprises at least an extracellular antigen binding domain, a transmembrane domain and an intracellular signaling domain. See, e.g. par. 65. SEQ ID NO: 1073, as instantly claimed and found in US 2014/0322275 A1, comprises an intracellular domain having a CD3 zeta primary signaling domain and a 4-1BB costimulatory domain.
The reference claims do not recite a nucleic acid encoding the first CAR and the second CAR, and wherein the first CAR coding sequence and the second CAR coding sequence are separated by a IRES or F2A element. However, WO 2015/075468 A1 discloses bicistronic nucleic acid constructs comprising a first CAR coding sequence and the second CAR coding sequence separated by a IRES or F2A element. See, e.g., pg. 17, ll. 24-31; pg. 47, ll. 16-32 Figure 8. Therefore, prior to the effective filing date of the instantly claimed invention, it would have been prima facie obvious to one of ordinary skill in the art to modify the invention of the reference claims by constructing a bicistronic nucleic acid construct comprising a first CAR coding sequence and the second CAR coding sequence separated by a IRES or F2A element, as taught by WO 2015/075468 A1, with a reasonable expectation of success because the bicistronic construct would produce a cell engineered to co-express the two CARs using a single transfection or transduction step.
For these reasons, the instant claims would have been prima facie obvious over the reference claims and secondary references.
Response to arguments: Applicant’s remarks filed 12/15/2025 have been carefully considered, but are not found persuasive.
Applicant argues that the reference claims recite that the first CAR is “transiently expressed” and the second CAR is “stably expressed,” but the instant claims do not recite that the CAR molecules are transiently or stably expressed. See page 18 of applicant’s reply. The argument is not persuasive because the instant claims broadly encompass transient or stable expression of the CAR molecules.
The remainder of the arguments are sufficiently addressed by the new grounds of rejection.
Claims 86, 109-112 are provisionally rejected on the ground of nonstatutory double patenting as being unpatentable over the claims of U.S. Application No. 19/050,596 (reference claim listing filed 02/11/2025); in view of US 2014/0322275 A1 to Brogdon et al.; and US 2014/0271635 A1 to Brogdon et al.; and WO 2015/075468 A1 to Pulé et al.
This rejection is newly applied.
The reference claims recite a method comprising a cell comprising a first, anti-CD19 CAR molecule and a second, anti-EGFRvIII CAR (claims 36, 46 and 74).
The reference claims do not recite an amino acid sequence of the anti-EGFRvIII CAR, as claimed in part (b) of claim 86.
Prior to the effective filing date of the instantly claimed invention, US 2014/0322275 A1 discloses a T cell comprising a first CAR that binds to EGFRvIII for the treatment of cancer. See, e.g., par. 299-300. US 2014/0322275 A1 further discloses that the CAR-expressing cell further comprises a second CAR that binds to a target other than EGFRvIII. See, e.g., par. 210-0211. SEQ ID NO: 73 of US 2014/0322275 A1 is identical to SEQ ID NO: 1073 of the instant application, which comprises the antigen binding domain of SEQ ID NO: 76 of the instant application. See, e.g., par. 140; see alignments, below.
Therefore, it would have been prima facie obvious to one of ordinary skill in the art to modify the invention of the reference claims by using the anti-EGFRvIII CAR according to SEQ ID NO: 1073, or a CAR comprising the antigen binding domain of SEQ ID NO: 76, as found in US 2014/0322275 A1, with a reasonable expectation of success because the reference claims are silent with regards to the amino acid sequence of the anti-EGFRvIII CAR, and therefore one of ordinary skill in the art would have sought known sequences available in the prior art suitable for the claimed invention, such as found in US 2014/0322275 A1.
US 2014/0322275 A1 further discloses that a CAR comprises at least an extracellular antigen binding domain, a transmembrane domain and an intracellular signaling domain. See, e.g. par. 65. SEQ ID NO: 1073, as instantly claimed and found in US 2014/0322275 A1, comprises an intracellular domain having a CD3 zeta primary signaling domain and a 4-1BB costimulatory domain.
The reference claims do not recite an amino acid sequence of the anti-CD19 CAR, as claimed in part (a) of claim 86.
Prior to the effective filing date of the instantly claimed invention, US 2014/0271635 A1 discloses a T cell comprising a first CAR that binds to CD19 for the treatment of cancer. See, e.g., par. 34-39, 139-141. US 2014/0271635 A1 further discloses that the CAR-expressing cell further comprises a second CAR that binds to a target other than CD19. See, e.g., par. 0215. SEQ ID NO: 32 of US 2014/0271635 A1 is identical to SEQ ID NO: 270 of the instant application, which comprises the antigen binding domain of SEQ ID NO: 84 of the instant application. See, e.g., par. 13; see alignments, below.
Therefore, it would have been prima facie obvious to one of ordinary skill in the art to modify the invention of the reference claims by using the anti-CD19 CAR according to SEQ ID NO: 270, or a CAR comprising the antigen binding domain of SEQ ID NO: 84, as found in US 2014/0271635 A1, with a reasonable expectation of success because the reference claims are silent with regards to the amino acid sequence of the anti-CD19 CAR, and therefore one of ordinary skill in the art would have sought known sequences available in the prior art suitable for the claimed invention, such as found in US 2014/0271635 A1.
US 2014/0271635 A1 further discloses that a CAR comprises at least an extracellular antigen binding domain, a transmembrane domain and an intracellular signaling domain. See, e.g. par. 65. SEQ ID NO: 270, as instantly claimed and found in US 2014/0271635 A1, comprises an intracellular domain having a CD3 zeta primary signaling domain and a 4-1BB costimulatory domain.
The reference claims do not recite a nucleic acid encoding the first CAR and the second CAR, and wherein the first CAR coding sequence and the second CAR coding sequence are separated by a IRES or F2A element. However, WO 2015/075468 A1 discloses bicistronic nucleic acid constructs comprising a first CAR coding sequence and the second CAR coding sequence separated by a IRES or F2A element. See, e.g., pg. 17, ll. 24-31; pg. 47, ll. 16-32 Figure 8. Therefore, prior to the effective filing date of the instantly claimed invention, it would have been prima facie obvious to one of ordinary skill in the art to modify the invention of the reference claims by constructing a bicistronic nucleic acid construct comprising a first CAR coding sequence and the second CAR coding sequence separated by a IRES or F2A element, as taught by WO 2015/075468 A1, with a reasonable expectation of success because the bicistronic construct would produce a cell engineered to co-express the two CARs using a single transfection or transduction step.
For these reasons, the instant claims would have been prima facie obvious over the reference claims and secondary references.
Response to arguments: Applicant’s remarks filed 12/15/2025 have been carefully considered, but are not found persuasive.
Applicant argues that the reference claims recite that the first CAR is “transiently expressed” and the second CAR is “stably expressed,” but the instant claims do not recite that the CAR molecules are transiently or stably expressed. See pages 18-19 of applicant’s reply. The argument is not persuasive because the instant claims broadly encompass transient or stable expression of the CAR molecules.
The remainder of the arguments are sufficiently addressed by the new grounds of rejection.
Claims 86, 110-111 are provisionally rejected on the ground of nonstatutory double patenting as being unpatentable over the claims of U.S. Application No. 15/327,794 (reference claim listing filed 11/26/2025).
This rejection is newly applied.
The reference claims recite a composition comprising a cell comprising a first, anti-CD19 CAR molecule and a second, anti-EGFRvIII CAR (claims 14 and 33).
The reference claims further recite that the CAR polypeptides have an antigen binding domain according to SEQ ID NO: 49 and 76 (claim 35). SEQ ID NO: 76 of the reference application is identical to SEQ ID NO: 76 of the instant application, and SEQ ID NO: 49 of the reference application is identical to SEQ ID NO: 84 of the instant application. Accordingly, the reference claims anticipate the anti-CD19 CAR, as claimed in part (a) of claim 86, and the anti-EGFRvIII CAR, as claimed in part (b) of claim 86.
The reference claims further recite that a CAR comprises at least an extracellular antigen binding domain, a transmembrane domain and an intracellular signaling domain. See, e.g. claim 14. The first and/or second CAR further comprises a CD3 zeta primary signalling domain and 4-1BB costimulatory domain (claims 14, 24-27).
For these reasons, the instant claims are anticipated by reference claims.
Response to arguments: Applicant’s remarks filed 12/15/2025 have been carefully considered, but are not found persuasive.
Applicant argues that the reference claims recite a method of treating a cancer, or providing an anti-tumor immunity, in a subject, comprising administering to the subject an expanded and/or activated immune cell population, and the instant claims are directed to a cell comprising a first CAR and a second CAR. See page 20 of applicant’s reply. The argument is not persuasive because the argument relies on incorrect statements. Reference claim 14 recites a “composition” and not a “method.”
The remainder of the arguments are sufficiently addressed by the new grounds of rejection.
Claims 109 and 112 are provisionally rejected on the ground of nonstatutory double patenting as being unpatentable over the claims of U.S. Application No. 15/327,794, as applied to claims 86, 110-111 above; in view of WO 2015/075468 A1 to Pulé et al.
This rejection is newly applied.
The reference claims do not recite a nucleic acid encoding the first CAR and the second CAR, and wherein the first CAR coding sequence and the second CAR coding sequence are separated by a IRES or F2A element. However, WO 2015/075468 A1 discloses bicistronic nucleic acid constructs comprising a first CAR coding sequence and the second CAR coding sequence separated by a IRES or F2A element. See, e.g., pg. 17, ll. 24-31; pg. 47, ll. 16-32 Figure 8. Therefore, prior to the effective filing date of the instantly claimed invention, it would have been prima facie obvious to one of ordinary skill in the art to modify the invention of the reference claims by constructing a bicistronic nucleic acid construct comprising a first CAR coding sequence and the second CAR coding sequence separated by a IRES or F2A element, as taught by WO 2015/075468 A1, with a reasonable expectation of success because the bicistronic construct would produce a cell engineered to co-express the two CARs using a single transfection or transduction step.
For these reasons, the instant claims would have been prima facie obvious over the reference claims and secondary references.
Claims 86, 109-112 are rejected on the ground of nonstatutory double patenting as being unpatentable over the claims of U.S. Patent No. 11,161,907 B2; in view of US 2014/0322275 A1 to Brogdon et al.; and US 2014/0271635 A1 to Brogdon et al.
This rejection is newly applied.
The reference claims recite an isolated nucleic acid encoding (claim 1), and a cell comprising (claim 22), a first, anti-CD19 CAR molecule and a second, anti-EGFRvIII CAR (claim 3).
The reference claims do not recite an amino acid sequence of the anti-EGFRvIII CAR, as claimed in part (b) of claim 86.
Prior to the effective filing date of the instantly claimed invention, US 2014/0322275 A1 discloses a T cell comprising a first CAR that binds to EGFRvIII for the treatment of cancer. See, e.g., par. 299-300. US 2014/0322275 A1 further discloses that the CAR-expressing cell further comprises a second CAR that binds to a target other than EGFRvIII. See, e.g., par. 210-0211. SEQ ID NO: 73 of US 2014/0322275 A1 is identical to SEQ ID NO: 1073 of the instant application, which comprises the antigen binding domain of SEQ ID NO: 76 of the instant application. See, e.g., par. 140; see alignments, below.
Therefore, it would have been prima facie obvious to one of ordinary skill in the art to modify the invention of the reference claims by using the anti-EGFRvIII CAR according to SEQ ID NO: 1073, or a CAR comprising the antigen binding domain of SEQ ID NO: 76, as found in US 2014/0322275 A1, with a reasonable expectation of success because the reference claims are silent with regards to the amino acid sequence of the anti-EGFRvIII CAR, and therefore one of ordinary skill in the art would have sought known sequences available in the prior art suitable for the claimed invention, such as found in US 2014/0322275 A1.
US 2014/0322275 A1 further discloses that a CAR comprises at least an extracellular antigen binding domain, a transmembrane domain and an intracellular signaling domain. See, e.g. par. 65. SEQ ID NO: 1073, as instantly claimed and found in US 2014/0322275 A1, comprises an intracellular domain having a CD3 zeta primary signaling domain and a 4-1BB costimulatory domain.
The reference claims do not recite an amino acid sequence of the anti-CD19 CAR, as claimed in part (a) of claim 86.
Prior to the effective filing date of the instantly claimed invention, US 2014/0271635 A1 discloses a T cell comprising a first CAR that binds to CD19 for the treatment of cancer. See, e.g., par. 34-39, 139-141. US 2014/0271635 A1 further discloses that the CAR-expressing cell further comprises a second CAR that binds to a target other than CD19. See, e.g., par. 0215. SEQ ID NO: 32 of US 2014/0271635 A1 is identical to SEQ ID NO: 270 of the instant application, which comprises the antigen binding domain of SEQ ID NO: 84 of the instant application. See, e.g., par. 13; see alignments, below.
Therefore, it would have been prima facie obvious to one of ordinary skill in the art to modify the invention of the reference claims by using the anti-CD19 CAR according to SEQ ID NO: 270, or a CAR comprising the antigen binding domain of SEQ ID NO: 84, as found in US 2014/0271635 A1, with a reasonable expectation of success because the reference claims are silent with regards to the amino acid sequence of the anti-CD19 CAR, and therefore one of ordinary skill in the art would have sought known sequences available in the prior art suitable for the claimed invention, such as found in US 2014/0271635 A1.
US 2014/0271635 A1 further discloses that a CAR comprises at least an extracellular antigen binding domain, a transmembrane domain and an intracellular signaling domain. See, e.g. par. 65. SEQ ID NO: 270, as instantly claimed and found in US 2014/0271635 A1, comprises an intracellular domain having a CD3 zeta primary signaling domain and a 4-1BB costimulatory domain.
The reference claims further recite a nucleic acid encoding the first CAR and the second CAR, and wherein the first CAR sequence and the second CAR sequence are controlled by separate promoter elements (claims 1-2).
For these reasons, the instant claims would have been prima facie obvious over the reference claims and secondary references.
Response to arguments: Applicant’s remarks filed 12/15/2025 have been carefully considered, but are not found persuasive.
Applicant argues that the instant claims do not recite an activation-conditional control region operatively linked to the first CAR or a second control region operatively linked to the second CAR, as claimed by the reference claims. See pages 20-21 of applicant’s reply. The argument is not persuasive because these features are not mutually exclusive, nor excluded, from the broader recitation of the instant claims.
The remainder of the arguments are sufficiently addressed by the new grounds of rejection.
Claims 86, 109-112 are provisionally rejected on the ground of nonstatutory double patenting as being unpatentable over the claims of U.S. Application No. 18/923,085 (reference to claim listing filed 04/21/2025); in view of US 2014/0322275 A1 to Brogdon et al.; and US 2014/0271635 A1 to Brogdon et al.
This rejection is newly applied.
The reference claims recite an isolated nucleic acid encoding (claim 3), and a cell comprising (claim 64), a first, anti-CD19 CAR molecule and a second, anti-EGFRvIII CAR (claim 5).
The reference claims do not recite an amino acid sequence of the anti-EGFRvIII CAR, as claimed in part (b) of claim 86.
Prior to the effective filing date of the instantly claimed invention, US 2014/0322275 A1 discloses a T cell comprising a first CAR that binds to EGFRvIII for the treatment of cancer. See, e.g., par. 299-300. US 2014/0322275 A1 further discloses that the CAR-expressing cell further comprises a second CAR that binds to a target other than EGFRvIII. See, e.g., par. 210-0211. SEQ ID NO: 73 of US 2014/0322275 A1 is identical to SEQ ID NO: 1073 of the instant application, which comprises the antigen binding domain of SEQ ID NO: 76 of the instant application. See, e.g., par. 140; see alignments, below.
Therefore, it would have been prima facie obvious to one of ordinary skill in the art to modify the invention of the reference claims by using the anti-EGFRvIII CAR according to SEQ ID NO: 1073, or a CAR comprising the antigen binding domain of SEQ ID NO: 76, as found in US 2014/0322275 A1, with a reasonable expectation of success because the reference claims are silent with regards to the amino acid sequence of the anti-EGFRvIII CAR, and therefore one of ordinary skill in the art would have sought known sequences available in the prior art suitable for the claimed invention, such as found in US 2014/0322275 A1.
US 2014/0322275 A1 further discloses that a CAR comprises at least an extracellular antigen binding domain, a transmembrane domain and an intracellular signaling domain. See, e.g. par. 65. SEQ ID NO: 1073, as instantly claimed and found in US 2014/0322275 A1, comprises an intracellular domain having a CD3 zeta primary signaling domain and a 4-1BB costimulatory domain.
The reference claims do not recite an amino acid sequence of the anti-CD19 CAR, as claimed in part (a) of claim 86.
Prior to the effective filing date of the instantly claimed invention, US 2014/0271635 A1 discloses a T cell comprising a first CAR that binds to CD19 for the treatment of cancer. See, e.g., par. 34-39, 139-141. US 2014/0271635 A1 further discloses that the CAR-expressing cell further comprises a second CAR that binds to a target other than CD19. See, e.g., par. 0215. SEQ ID NO: 32 of US 2014/0271635 A1 is identical to SEQ ID NO: 270 of the instant application, which comprises the antigen binding domain of SEQ ID NO: 84 of the instant application. See, e.g., par. 13; see alignments, below.
Therefore, it would have been prima facie obvious to one of ordinary skill in the art to modify the invention of the reference claims by using the anti-CD19 CAR according to SEQ ID NO: 270, or a CAR comprising the antigen binding domain of SEQ ID NO: 84, as found in US 2014/0271635 A1, with a reasonable expectation of success because the reference claims are silent with regards to the amino acid sequence of the anti-CD19 CAR, and therefore one of ordinary skill in the art would have sought known sequences available in the prior art suitable for the claimed invention, such as found in US 2014/0271635 A1.
US 2014/0271635 A1 further discloses that a CAR comprises at least an extracellular antigen binding domain, a transmembrane domain and an intracellular signaling domain. See, e.g. par. 65. SEQ ID NO: 270, as instantly claimed and found in US 2014/0271635 A1, comprises an intracellular domain having a CD3 zeta primary signaling domain and a 4-1BB costimulatory domain.
The reference claims further recite a nucleic acid encoding the first CAR and the second CAR, and wherein the first CAR sequence and the second CAR sequence are controlled by separate promoter elements (claim 3).
For these reasons, the instant claims would have been prima facie obvious over the reference claims and secondary references.
Response to arguments: Applicant’s remarks filed 12/15/2025 have been carefully considered, but are not found persuasive.
Applicant argues that the instant claims do not recite an activation-conditional control region operatively linked to the first CAR or a second control region operatively linked to the second CAR, nor that the cell comprises an inhibitor of a checkpoint inhibitor or a cytokine, as claimed by the reference claims. See pages 21-22 of applicant’s reply. The argument is not persuasive because these features are not mutually exclusive, nor excluded, from the broader recitation of the instant claims.
The remainder of the arguments are sufficiently addressed by the new grounds of rejection.
Alignments
SEQ ID NO: 84 of the instant application and SEQ ID NO: 45 of WO 2015/075468 A1
PNG
media_image1.png
342
578
media_image1.png
Greyscale
SEQ ID NO: 76 of the instant application and SEQ ID NO: 45 of WO 2015/075468 A1
PNG
media_image2.png
352
585
media_image2.png
Greyscale
SEQ ID NO: 1073 of the instant application and SEQ ID NO: 73 of US 2014/0322275 A1
PNG
media_image3.png
915
884
media_image3.png
Greyscale
SEQ ID NO: 270 of the instant application and SEQ ID NO: 32 of US 2014/0271635 A1
PNG
media_image4.png
906
872
media_image4.png
Greyscale
Conclusion
Applicant's amendment necessitated the new ground(s) of rejection presented in this Office action. Accordingly, THIS ACTION IS MADE FINAL. See MPEP § 706.07(a). Applicant is reminded of the extension of time policy as set forth in 37 CFR 1.136(a).
A shortened statutory period for reply to this final action is set to expire THREE MONTHS from the mailing date of this action. In the event a first reply is filed within TWO MONTHS of the mailing date of this final action and the advisory action is not mailed until after the end of the THREE-MONTH shortened statutory period, then the shortened statutory period will expire on the date the advisory action is mailed, and any nonprovisional extension fee (37 CFR 1.17(a)) pursuant to 37 CFR 1.136(a) will be calculated from the mailing date of the advisory action. In no event, however, will the statutory period for reply expire later than SIX MONTHS from the mailing date of this final action.
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/JAMES JOSEPH GRABER/Examiner, Art Unit 1631