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
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and the fee set forth in 37 CFR 1.17(e) has been timely paid, the finality of the previous Office action has been withdrawn pursuant to 37 CFR 1.114.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 April 7, 2026 has been entered.
Claim Status
Claims 21, 26, 28, and 40 have been amended.
Claims 1-20, 22-23, and 36-39 were previously canceled.
Claims 42-44 have been added.
Claims 21, 24-35, and 40-44 are pending and under consideration.
Claim Rejections
In view of the Applicant’s claim amendments, the previous ground of rejection under U.S.C. 112(a) - Written Description has been withdrawn. The following are new grounds of rejection necessitated by Applicant’s claim amendments. Applicant’s arguments relevant to the new grounds of rejection will be addressed below.
Claim Rejections - 35 USC § 112(b)
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.
Claims 21, 24-35, and 40-44 are rejected under 35 U.S.C. 112(b) as being indefinite for failing to particularly point out and distinctly claim the subject matter which the inventor regards as the invention.
Claim 21 is drawn to a chimeric antigen receptor (CAR) comprising an anti-fluorescein scFv, wherein the CAR comprises the amino acid sequence of residues 23-276 of SEQ ID NO: 3, 23-706 of SEQ ID NO: 3, or 23-709 of SEQ ID NO: 3.
It is unclear what domains of the CAR that residues 23-276, 23-706, and 23-709 of SEQ ID NO: 3 correspond to.
The specification recites that “SEQ ID NO: 3 means the sequence beginning at the underlined “D” and ending with the underlined “G”. This portion of the longer sequence is the amino acid sequence for the CAR that is inserted into the T cell membrane. The other portions of the longer sequence include amino acid sequences for signal peptides and the EGFRt domain, etc. which are not part of the CAR inserted into the membrane and which functions as the chimeric antigen receptor” [pg. 111, par. 1].
PNG
media_image1.png
466
662
media_image1.png
Greyscale
As such, one of ordinary skill in the art would not be able to map each domain of the instantly claimed CAR from the description recited in the specification. Although, dependent claim 28 recites that residues 1-22 correspond to the signal peptide, and residues 710-1068 correspond to the EGFRt selectable marker, one cannot discern what residues 23-276, 23-706, and 23-709 correspond to. Are they each different variants of an anti-fluorescein scFv? This is unclear, as Applicant has only disclosed 2 anti-fluorescein scFvs (E2 and 4M5.3), wherein SEQ ID NOs: 1 and 2 are E2-CARs and SEQ ID NOs: 3 and 4 are 4M5.3-CARs. However, the scFvs cannot clearly be ascertained by the description provided by the specification or by looking at the annotated sequence.
Claims 24-35 and 40-44 are included in the rejection as they depend from or otherwise require all the limitations of the rejected claim and fail to clarify the issue.
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 21, 27, 29-31, 33-35, and 42 are rejected under 35 U.S.C. 103 as being unpatentable over Novina et al. (WO 2018/200713) (“Novina”).
The instant claims are drawn to a nucleic acid comprising a polynucleotide encoding a chimeric antigen receptor (CAR) comprising an anti-fluorescein scFv, wherein the CAR comprises the amino acid sequence of residues 3-276 of SEQ ID NO: 3, 23-706 of SEQ ID NO: 3, or 23-709 of SEQ ID NO: 3. Wherein the nucleic acid further comprises a polynucleotide encoding a signal peptide, wherein the polypeptide comprises or consists of humanized, or human amino acid sequences. Also claimed is a vector comprising the nucleic acid, a T cell or cytotoxic T cell comprising the nucleic acid, and a pharmaceutical composition comprising the CAR expressing T cell and a pharmaceutically acceptable excipient.
Novina teaches a polynucleotide that encodes an anti-fluorescein CAR with binding specificity for a tag that is conjugated to a human or humanized antibody fragment that binds to a tumor associated antigen (TAA) [000103-000104, 000115]. The CAR comprises a single chain variable fragment (scFv) fluorescein tag-binding domain [000108] and a CD28 transmembrane domain (TM) attached to the extracellular antigen binding domain via an IgG4 hinge. The CAR further comprises a CD3z T cell activation domain, also known as the intracellular signaling domain, and a 4-1BB costimulatory domain [00110-00113] (instant claims 21, 24, 29-30).
Novina teaches that T cells may be generated to express CARs by constructing a polynucleotide that is inserted into a viral vector and transducing the vector into a population of T cells which are then grown under conditions to promote expression of the polynucleotide encoding the CAR [000116] (instant claims 31, 33-34).
Populations of CAR T cells may be formulated in a pharmaceutical composition that may include one or more pharmaceutically acceptable excipients for administration to a subject [000118] (instant claim 35).
Novina teaches Construct #1 encoding a polypeptide comprising an anti-fluorescein CAR T comprising the anti-Fluorescein-4M5.3 antibody (antigen binding domain) of SEQ ID NO: 2, a signal peptide, a hinge region, a TM, an intracellular domain and a costimulatory domain [000167] (instant claims 21, 27, 42).
SEQ ID NO: 2 (254 AA) taught by Novina is 100% identical to presently claimed residues 23-276 of SEQ ID NO: 3 (254 AA) which corresponds to the 4M5.3 anti-fluorescein scFv.
Therefore, Novina teaches each element as recited in the instant claims making the invention as a whole prima facie obvious to a person having ordinary skill in the art before the effective filing date of the claimed invention.
Claims 24-26, 28, and 32 are rejected under 35 U.S.C. 103 as being unpatentable over Novina et al. (WO 2018/200713) (“Novina”) as applied to claims 21, 27, 29-31, 33-35, and 42 above, and in further view of Jensen (WO 2013/123061) (“Jensen”).
The instant claims are drawn to a nucleic acid comprising a polynucleotide encoding a chimeric antigen receptor (CAR) comprising an anti-fluorescein scFv, wherein the CAR comprises the amino acid sequence of residues 23-276 of SEQ ID NO: 3, 23-706 of SEQ ID NO: 3, or 23-709 of SEQ ID NO: 3. Wherein the nucleic acid further comprises a polynucleotide encoding a truncated EGFR (EGFRt) polypeptide as a cell surface selectable marker having the amino acid sequence of residues 710-1068 of SEQ ID NO: 3, a polynucleotide encoding a signal peptide having the amino acid sequence of residues 1-22 of SEQ ID NO: 3, wherein the vector comprising the polynucleotide is a lentiviral vector.
The teachings of Novina are set forth above.
Novina does not teach an EGFRt selectable marker domain or the T cells are transduced with a lentiviral vector.
Jensen teaches CARs comprising antigen targeting regions, a transmembrane domain, at least one costimulatory domain, an intracellular signaling domain, and truncated epidermal growth factor receptor (EGFRt) [pg. 2, lines 1-8]. Jensen teaches that EGFRt acts as a therapeutic control (i.e. selectable marker) for ex vivo cell purification, in vivo cell tracking, and cell ablation as required [pg. 29] (instant claims 24-25).
Jensen teaches the CAR comprises a GMCSFR signal sequence [pg. 4] as shown in Figures 8-11 and the EGFRt amino acid sequence shown in Figure 13 (instant claims 26, 28).
DNA encoding the CAR is cloned in a suitable expression lentiviral vector in proper orientation for expression [pg. 12, lines 6-8] (instant claim 32).
The amino acid sequences of the CAR signal peptide and the EGFRt therapeutic control taught by Jensen are 100% identical to the instantly claimed signal peptide sequence corresponding to residues 1-22 of SEQ ID NO: 3 and the EGFRt selectable marker corresponding to residues 710-1068 of SEQ ID NO: 3, respectively.
The teachings of Novina differ from the instant claimed invention in that even though a polynucleotide encoding a chimeric antigen receptor (CAR) comprising an anti-fluorescein scFv identical to residues of 23-276 of SEQ ID NO: 3 is taught, the CAR is not taught as further comprising an EGFRt selectable marker. The skilled artisan would be motivated to combine the methods of Novina with those of Jensen to include an EGFRt domain in the CAR construct because Jensen teaches EGFRt can be used as a therapeutic control for ex vivo cell purification, in vivo cell tracking, and cell ablation. One would have more than a reasonable expectation of success in also incorporating the signal sequence taught by Jensen given that it successfully directed the CAR comprising EGFRt to the target cell. Therefore, the instant invention was prima facie obvious to a person having ordinary skill in the art before the effective filing date of the claimed invention in view of the combined references.
Claims 43-44 are rejected under 35 U.S.C. 103 as being unpatentable over Novina et al. (WO 2018/200713) (“Novina”) as applied to claims 21, 27, 29-31, 33-35, and 42 above, and in further view of Jonnalagadda et al. (Mol Ther, 2015; 23(4):757-768) (“Jonnalagadda”).
The instant claims are drawn to a nucleic acid comprising a polynucleotide encoding a chimeric antigen receptor (CAR) comprising an anti-fluorescein scFv, wherein the CAR comprises the amino acid sequence of residues 3-276 of SEQ ID NO: 3, 23-706 of SEQ ID NO: 3, or 23-709 of SEQ ID NO: 3, wherein the CAR comprises an IgG4-CH2(L235D, N297Q)-CH3 hinge spacer domain, a CD28 transmembrane domain, a CD3z activation domain, and a 4-1BB costimulation domain.
The teachings of Novina are set forth above. Specifically, Novina teaches a CAR comprising a single chain variable fragment (scFv) fluorescein tag-binding domain [000108],a CD28 transmembrane domain (TM) attached to the extracellular antigen binding domain via an IgG4 hinge. The CAR further comprises a CD3z T cell activation domain, also known as the intracellular signaling domain, and a 4-1BB costimulatory domain [00110-00113].
Novina does not specifically teach the IgG4 spacer hinge domain is an IgG4-CH2(L235D, N297Q)-CH3 spacer hinge.
Jonnalagadda teaches the success of adoptive therapy using chimeric antigen receptor (CAR) expressing T cells partly depends on optimal CAR design. CARs frequently incorporate a spacer/linker region based on the constant region of either IgG1 or IgG4 to connect extracellular ligand-binding with intracellular signaling domains. Jonnalagadda engineered CARs with IgG4-Fc spacers that were mutated at two sites, L235E and N297Q. The IgG4-CH2 (L235D, N297Q)-CH3 hinge spacer domain prevents Fc gamma receptor (FcgR) binding, thereby reducing unwanted off-target interactions, minimizing activation-induced cell death, and improving the in vivo persistence and antitumor efficacy of CAR T cells [Abstract].
The teachings of Novina differ from the instant claimed invention in that even though a polynucleotide encoding a chimeric antigen receptor (CAR) comprising an anti-fluorescein scFv identical to residues of 23-276 of SEQ ID NO: 3 and an IgG4 spacer hinge domain is taught, the spacer domain is not specifically taught as being an IgG4-CH2(L235D, N297Q)-CH3 hinge spacer hinge. The skilled artisan would be motivated to combine the methods of Novina with those of Jonnalagadda to include an IgG4-CH2(L235D, N297Q)-CH3 hinge spacer because Jonnalagadda teaches making these two mutation in the IgG4-Fc can reduce unwanted off-target interactions, minimize activation-induced cell death, and improve the in vivo engraftment and antitumor efficacy of CAR T cells. Therefore, the instant invention was prima facie obvious to a person having ordinary skill in the art before the effective filing date of the claimed invention in view of the combined references.
Double Patenting
Pursuant to 37 CFR 1.78(f), when two or more applications filed by the same applicant or assignee contain patentably indistinct claims, elimination of such claims from all but one application may be required in the absence of good and sufficient reason for their retention during pendency in more than one application. Applicant is required to either cancel the patentably indistinct claims from all but one application or maintain a clear line of demarcation between the applications. See MPEP § 822.
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.
Double Patenting - Withdrawn
The previous nonstatutory double patenting rejections over claims of U.S. Patent Nos. 11,779,602 and 12,269,862 have been withdrawn because the amended claims are now drawn to a different anti-fluorescein scFv amino acid sequence than disclosed in the issued claims. Although the issued claims allow for an anti-fluorescein CAR at least 80% identical to the disclosed sequences, the presently claimed CAR comprising the amino acid sequence of SEQ ID NO: 3 is only 79% identical to the CAR disclosed in the issued patent.
Claims 21, 24-35, and 42 are rejected on the ground of nonstatutory double patenting as being unpatentable over claims 1, 6-7, 13 and 16 of U.S. Patent No. 12,312,416 in view of Jensen (WO 2013/123061). Although the claims at issue are not identical, they are not patentably distinct from each other because the patented claims teach engineered T cells comprising a chimeric antigen receptor (CAR) that specifically binds fluorescein with a ligand binding domain comprising an amino acid sequence of SEQ ID NO: 2 which is 100% identical to residues 23-276 of SEQ ID NO: 3 as recited in the instant claims.
The patented claims differ from the instant claims in that they do not recite the polypeptide is encoded by a polynucleotide, that it further comprises an EGFRt selectable marker and a signal peptide, the CAR is delivered to a T cell using a lentiviral vector, and a pharmaceutical composition.
The teachings of Jensen are set forth above, which teaches CARs comprising a signal peptide and an EGFRt selectable marker with the same amino acid sequence recited in the instant claims, wherein the CAR T cells are generated using a lentiviral vector to transduce the polynucleotide sequence into T lymphocytes.
It would have been obvious to skilled artisans to modify the generic methods of the patented claims to include an EGFRt domain in the CAR construct because Jensen teaches EGFRt can be used as a therapeutic control for ex vivo cell purification, in vivo cell tracking, and cell ablation. One would have more than a reasonable expectation of success in also incorporating the signal sequence taught by Jensen given that the same signal peptide successfully directed the CAR comprising EGFRt to the target cell. Accordingly, the instant claimed invention is an obvious modification of the issued claims in view of Jensen.
Claims 43-44 are rejected on the ground of nonstatutory double patenting as being unpatentable over claims 1, 6-7, 13 and 16 of U.S. Patent No. 12,312,416 in view of Jensen (WO 2013/123061) and further in view of Jonnalagadda et al. (Mol Ther, 2015; 23(4):757-768) (“Jonnalagadda”). Although the claims at issue are not identical, they are not patentably distinct from each other because the patented claims teach engineered T cells comprising a chimeric antigen receptor (CAR) that specifically binds fluorescein with a ligand binding domain comprising an amino acid sequence of SEQ ID NO: 2 which is 100% identical to residues 23-276 of SEQ ID NO: 3 as recited in the instant claims.
The patented claims differ from the instant claims in that they do not recite the polypeptide is encoded by a polynucleotide that includes humanized or human sequences, that it further comprises an EGFRt selectable marker and a signal peptide, the CAR is delivered to a T cell using a lentiviral vector, and a pharmaceutical composition.
The teachings of Jensen is set forth above. Both Jensen teaches an IgG4 spacer hinge domain, however, does not teach an IgG4-CH2 (L235D, N297Q)-CH3 hinge spacer domain.
Jonnalagadda generated an IgG4-CH2 (L235D, N297Q)-CH3 hinge spacer domain that prevents Fc gamma receptor (FcgR) binding, thereby reducing unwanted off-target interactions, minimizing activation-induced cell death, and improving the in vivo persistence and antitumor efficacy of CAR T cells [Abstract].
The skilled artisan would be motivated to modify the patented claims to include an EGFRt selectable marker and signal peptide as taught by Jensen and a modified IgG4 spacer as taught by Jonnalagadda because EGFRt can be used as a selectable marker while the IgG4-CH2-(L235D, N297Q)-CH3 hinge spacer can reduce unwanted off-target interactions, minimize activation-induced cell death, and improve the in vivo engraftment and antitumor efficacy of CAR T cells. Accordingly, the instant claimed invention is an obvious modification of the issued claims in view of Jensen and Jonnalagadda.
Response to Arguments
Applicant’s arguments received April 7, 2026, with respect to the rejections set forth in the Office action mailed October 9, 2025 have been considered but are moot because the new grounds of rejections do not rely on any reference applied in the prior rejections of record for any teaching or matter specifically challenged in the argument as Applicant has amended the scope of claim 21 to be directed to SEQ ID NO: 3 only.
Conclusion
No claim is allowed.
Any inquiry concerning this communication or earlier communications from the examiner should be directed to MAUREEN DRISCOLL whose telephone number is (571) 270-0730. The examiner can normally be reached Monday through Friday.
Examiner interviews are available via telephone, in-person, and video conferencing using a USPTO supplied web-based collaboration tool. To schedule an interview, applicant is encouraged to use the USPTO Automated Interview Request (AIR) at http://www.uspto.gov/interviewpractice.
If attempts to reach the examiner by telephone are unsuccessful, the examiner’s supervisor, Samira Jean-Louis can be reached on (571) 270-3503. The fax phone number for the organization where this application or proceeding is assigned is (571) 273-8300.
Information regarding the status of published or unpublished applications may be obtained from Patent Center. Unpublished application information in Patent Center is available to registered users. To file and manage patent submissions in Patent Center, visit: https://patentcenter.uspto.gov. Visit https://www.uspto.gov/patents/apply/patent-center for more information about Patent Center and https://www.uspto.gov/patents/docx for information about filing in DOCX format. For additional questions, contact the Electronic Business Center (EBC) at (866) 217-9197 (toll-free). If you would like assistance from a USPTO Customer Service Representative, call (800) 786-9199 (IN USA OR CANADA) or (571) 272-1000.
/MAUREEN VARINA DRISCOLL/ Examiner, Art Unit 1642
/SAMIRA J JEAN-LOUIS/ Supervisory Patent Examiner, Art Unit 1642
Prosecution Insights