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
Amendments
In the reply filed 11/24/2025, Applicant has amended claims 2, 6, 8, 10-14 and 17, newly canceled claims 3 and 7.
Claim Status
Claims 2, 6, 8, 10-14, 17-18 and 23-30 are pending.
Claims 18 and 23-30 have been withdrawn from further consideration pursuant to 37 CFR 1.142(b) as being drawn to non-elected inventions, there being no allowable generic or linking claim. Election was made without traverse in the reply filed on 07/10/2025.
Claims 2, 6, 8, 10-14 and 17 are considered on the merits.
Withdrawn Claim Objections
The prior objection to claim 13 because of typographic error is withdrawn in light of Applicant’s amendment to the claim.
New Claim Objections
Claim 13 is objected to because of the following informalities:
Claim 13 recites “CIAX” in the last line. It seems to be referring to “CAIX”.
Appropriate correction is required.
Withdrawn Claim Rejections - 35 USC § 112(b)
The prior rejection of claims 8 and 14 under 35 U.S.C. 112(b) or 35 U.S.C. 112 (pre-AIA ), second paragraph, as being indefinite is withdrawn in light of Applicant’s amendment to the claims.
Withdrawn Claim Rejections - 35 USC § 112(d)
The prior rejection of claim 8 under 35 U.S.C. 112(d) or pre-AIA 35 U.S.C. 112, 4th paragraph, as being of improper dependent form is withdrawn in light of Applicant’s amendment to claim 8.
Withdrawn Claim Rejections - 35 USC § 102
The prior rejection of claims 2, 6, 8, 10-11, 13-14 and 17 under 35 U.S.C. 102 (a)(1) as being anticipated by De Palma et al., (WO 2017/134100, prior art of record) is withdrawn in light of Applicant’s amendment to claim 2 to recite new limitation “a conventional type 1 dendritic cell (cDC1)” that is not taught by De Palma.
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.
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 2, 6, 8, 10-11, 13-14 and 17 stand rejected under 35 U.S.C. 103 as being unpatentable over De Palma et al., (WO 2017/134100, prior art of record) in view of Böttcher et al., (Trends Cancer. 2018;4(11):784-792, prior art of record).
It is noted that the following rejection is maintained and updated to address amendments to claims 2 and 8.
With respect to claim 2, De Palma teaches an engineered extracellular vesicle internalizing receptor (EVIR, equivalent to a chimeric antigen receptor (CAR), e.g., reference claim 1) having the ability to enhance uptake, processing, and presentation to T-cells of tumor-associated antigens by antigen-presenting cells (e.g., abstract). De Palma teaches antigen presenting cells including dendritic cells (e.g., p. 12, ln. 28 and reference claim 20) are transduced with an EVIR-F lentivirus (see p. 39, Example 2 for isolating bone marrow derived dendritic cells (BMDCs) and lentiviral transduction). Thus, De Palma teaches a chimeric antigen receptor dendritic cell (CAR-DC) comprising a CAR construct.
De Palma teaches the EVIR comprises an extracellular antibody domain including an antigen binding fragment (e.g., p. 9, ln. 12 and 18, related to claim 2 (i)), a transmembrane domain (e.g., p. 9, ln. 4, related to claim 2 (ii)), and an intracellular signaling domain (e.g., p. 9, ln. 4 and 13) that comprises a Flt3 intracellular signaling domain (see e.g., p. 12, ln. 4 and p. 18, ln. 8, especially see p. 38, ln. 26-28 for “EVIR-F (FLT3-CHA21)” that comprises a CHA21 anti-HER2 antigen-binding domain and a FLT3 intracellular signaling domain, related to claim 2 (iii)).
However, De Palma is silent on the DC being a conventional type 1 dendritic cell (cDC1) in claim 2.
Böttcher summarizes the role of cDC1 in cancer immunity and teaches cDC1 is critical for the spontaneous rejection of immunogenic cancers and for the success of T cell-based immunotherapies, and the unique role of cDC1 reflects the ability to initiate de novo T cell responses as well as to attract T cells, secrete cytokines, and present tumor antigens within the tumor microenvironment, enhancing local cytotoxic T cell function (see e.g., abstract). Böttcher teaches “strategies aimed at increasing cDC1 abundance in tumors and enhancing their functionality provide attractive new avenues to boost anti-tumor immunity and overcome resistance to cancer immunotherapies” (see e.g., abstract).
Therefore, it would have been obvious for one of ordinary skill in the art before the effective filing date of the claimed invention to have modified the CAR-DC comprising the CAR with enhanced ability to present TAAs and to promote cancer-specific T cell proliferation disclosed by De Palma, by choosing a specific DC subset, cDC1, as suggested by Böttcher with a reasonable expectation of success. Since De Palma aims to enhance uptake, processing, and presentation to T-cells of TAAs by engineering dendritic cells with an anti-tumor CAR (e.g., abstract), and since Böttcher suggests to increase cDC1 abundance in tumors and to enhance functionality of cDC1 to provide attractive new avenues to boost anti-tumor immunity and overcome resistance to cancer immunotherapies (see e.g., abstract), one of ordinary skill in the art would have had a reason to choose to modify a cDC1 subset with the CAR in De Palma in order to increase cDC1 abundance in tumors and to enhance the functionality of cDC1 to provide a new avenue to boost anti-tumor immunity and to overcome resistance to cancer immunotherapies as suggested by Böttcher.
With respect to claim 6 directed to a signal peptide in the CAR construct, De Palma teaches an exemplary IgK signal domain incorporated in the EVIR to increase the export of a receptor to membrane (e.g., p. 37, ln. 1-2 and reference claim 9).
With respect to claim 8 directed to the CAR-DC being derived from a progenitor cell such as a stem cell, De Palma teaches the CAR-DC cell can be an isolated antigen presenting cell or a stem or progenitor cell thereof (see reference claim 20 and see e.g., p. 27, ln. 21-25 and p. 29, 1st two paragraphs).
With respect to claim 10 directed to the antigen binding domain comprising an antibody fragment, claim 11 directed to the antigen binding domain binding to a tumor cell antigen, and claim 13 directed to the antigen binding domain binding to a disease-associated antigen, as stated supra, De Palma teaches the EVIR-F comprises a CHA21 anti-HER2 scFv antigen-binding domain (p. 38, ln. 26-28 and also e.g., p. 9, ln. 12 and 18, and see reference claims 3-4 for Her2, CEA, mesothelin, GD2 or mucins).
With respect to claim 14 directed to the CAR-DC being capable of cross-presenting a tumor antigen or activating T-cell to respond to the tumor antigen, De Palma teaches the CAR-DC being contacted with cancer cells have an enhanced ability to present tumor-associated antigens (TAAs) from cancer subject as compared to a cell not expressing an EVIR (see reference claim 21, see Example 5 “Anti-HER2 EVIRs enhance TAA presentation by APCs” in p. 45 and Example 6 for EVIRs enhance EV uptake by APCs and promote cancer-specific T cell proliferation in p. 46).
With respect to claim 17 directed to a pharmaceutical composition, De Palma teaches a pharmaceutical composition comprising the engineered cells and a pharmaceutically acceptable carrier, diluent or excipient (see e.g., reference claim 22).
Hence, the claimed invention as a whole was prima facie obvious to a person of ordinary skill before the effective filing date of the claimed invention in the absence of evidence to the contrary.
Response to Traversal:
Applicant’s arguments filed on 11/24/2025 are acknowledged.
Applicant argues that the cited art does not teach or suggest the claimed subject matter involving cDC1 cells comprising a CAR construct comprising a Flt3 signaling domain. Specifically, De Palma merely describes various CAR constructs that can have nearly a dozen different intracellular domains. De Palma is silent on cDC1 cells, and provides no motivation, and a person of ordinary skill in the art could not have reasonably predicted that the instantly claimed CAR-DC would work. Bottcher merely describes cDC1 can enhance local cytotoxic T cell function in subjects with cancer. Applicant further argues that the Office has applied impermissible hindsight. (Remarks, p. 9, para 3-5).
Applicant’s arguments have been fully considered but they are not persuasive.
As a first matter, in regard to the argument of De Palma’s merely describing 11 different intracellular domains, De Palma does not simply describe the constructs, but indeed makes all 11 EVIR constructs comprising the intracellular domains (see p. 38, last para), and tests each and every one of them for the expression, proliferation, specific binding and internalization by macrophages or DCs (see Examples 2-4 and see Figures 3-5 and 7). For example, De Palma teaches EVIR-expressing bone marrow macrophages could efficiently bind to HER2-expressing MC38 cells, in particular when EVIR-N, EVIR-C2, EVIR-F are used (see p. 43, end of Example 3 and Fig 5A). It is noted that this “EVIR-F” is the receptor construct comprising a Flt3 signaling domain that is equivalent to the claimed CAR. Therefore, De Palma reduces to practice all 11 CAR constructs, and, in particular, suggests a more limited number of constructs including EVIR-F. Thus, one of ordinary skill in the art would have immediately envisaged the taught option of EVIR-F, a CAR construct comprising a Flt3 signaling domain, among the limited genus of options. See MPEP 2131.02 (III).
In regard to the argument of De Palma being silent on cDC1 cells and providing no motivation, Applicant is reminded, one cannot show nonobviousness by attacking references individually where the rejections are based on combinations of references. See In re Keller, 642 F.2d 413, 208 USPQ 871 (CCPA 1981); In re Merck & Co., 800 F.2d 1091, 231 USPQ 375 (Fed. Cir. 1986). In the instant case, De Palma teaches the CAR constructs are transduced into dendritic cells, e.g., bone marrow derived dendritic cells (BMDCs), to enhance the ability to present TAAs and to promote cancer-specific T cell proliferation and demonstrates that CAR-expressing cells (e.g., macrophages) could efficiently bind to HER2-expressing tumor cells. The only difference between De Palma and the instant invention is the cell being a specific subset of DC, a conventional type 1 dendritic cell (cDC1). Böttcher summarizes the role of cDC1 in cancer immunity and teaches the unique role of cDC1 reflects the ability to present tumor antigens within the tumor microenvironment, to attract T cells and to enhance cytotoxic T cell function (see e.g., abstract). Böttcher further suggests “strategies aimed at increasing cDC1 abundance in tumors and enhancing their functionality provide attractive new avenues to boost anti-tumor immunity and overcome resistance to cancer immunotherapies” (see e.g., abstract). Thus, one of ordinary skill in the art would have had a reason to choose to modify a subset of DC, i.e., cDC1 cells, with the tumor-specific CAR of De Palma in order to increase cDC1 abundance in tumors and to enhance the functionality of cDC1 to provide a new avenue to boost anti-tumor immunity and to overcome resistance to cancer immunotherapies as suggested by Böttcher.
In regard to the argument that a person of ordinary skill in the art could not have reasonably predicted that the instantly claimed CAR-DC would work, as stated supra, De Palma teaches EVIR-expressing cells (e.g., macrophages) could efficiently bind to HER2-expressing MC38 cells, in particular when EVIR-N, EVIR-C2, EVIR-F are used (see p. 43, end of Example 3 and Fig 5A), thus suggests the CAR-expressing cells would specifically and efficiently bind to tumor cells. Böttcher suggests to increase cDC1 abundance in tumors and enhance their functionality in presenting tumor antigens within the tumor microenvironment (e.g., abstract). Thus, one of ordinary skill in the art would have had a reasonable expectation of success in obtaining CAR-cDC1 that could specifically and efficiently bind to tumor cells so as to increase cDC1 abundance in tumors and enhance their functionality in presenting tumor antigens within the tumor microenvironment.
In regard to the argument of impermissible hindsight, it must be recognized that any judgment on obviousness is in a sense necessarily a reconstruction based upon hindsight reasoning. But so long as it takes into account only knowledge which was within the level of ordinary skill at the time the claimed invention was made, and does not include knowledge gleaned only from the applicant's disclosure, such a reconstruction is proper. See In re McLaughlin, 443 F.2d 1392, 170 USPQ 209 (CCPA 1971).
In the instant case, De Palma reduces to practice a dendritic cell transduced with an EVIR-F construct that is equivalent to the claimed CAR construct comprising a Flt3 signaling domain, and demonstrates the expression, proliferation, binding and internalization of the CAR. For example, De Palma teaches EVIR-expressing bone marrow macrophages could efficiently bind to HER2-expressing tumor cells, in particular when EVIR-N, EVIR-C2, EVIR-F are used (see p. 43, end of Example 3 and Fig 5A). De Palma teaches the DCs are modified with the CAR to enhance the ability to present TAAs and to promote cancer-specific T cell proliferation.
Böttcher summarizes the role of cDC1 in cancer immunity and teaches the unique role of cDC1 reflects the ability to present tumor antigens within the tumor microenvironment, to attract T cells and to enhance cytotoxic T cell function. Böttcher suggests to increase cDC1 abundance in tumors and enhance their functionality in presenting tumor antigens within the tumor microenvironment (e.g., abstract).
Thus, one of ordinary skill in the art would have had a reason to combine the cDC1 of Böttcher to be modified by the CAR of De Palma in order to obtain CAR-cDC1 that could specifically and efficiently bind to tumor cells so as to increase cDC1 abundance in tumors and enhance their functionality in presenting tumor antigens (TAAs) within the tumor microenvironment.
Claims 12-13 are rejected under 35 U.S.C. 103 as being unpatentable over De Palma et al., (WO 2017/134100, prior art of record) in view of Böttcher et al., (Trends Cancer. 2018;4(11):784-792, prior art of record), as applied to claims 11, 10 and 2 above, and further in view of Lobb et al., (US 2018/0311269 A1, published Nov. 1, 2018, prior art of record).
It is noted that this new ground of rejection is necessitated by Applicant’s amendment to claim 2 to recite new limitation of cDC1.
Claims 12 and 13 are directed to the tumor cell antigen being EphA2.
However, De Palma and Böttcher are silent on the CAR binding a tumor antigen EphA2.
Lobb teaches an immune cell expressing a receptor that binds to an antigen expressed on a tumor cell (see abstract). Lobb teaches an immune cell is a dendritic cell (e.g., [0014] and reference claim 35) and a receptor expressed by an immune cell is a chimeric antigen receptor (e.g., [0015] and reference claim 37). Lobb teaches the tumor antigen is a tumor-associated antigen EphA2 among a list of antigens including Her2, CEA and mesothelin (see e.g., [0006] and reference claims 8 and 45).
Therefore, it would have been obvious for one of ordinary skill in the art before the effective filing date of the claimed invention to have modified the CAR-DC comprising an antigen binding domain binding to tumor associated antigens such as Her2, CEA or mesothelin suggested by De Palma and Böttcher, by choosing a tumor associated antigen EphA2 suggested by Lobb with a reasonable expectation of success. Since De Palma teaches the CAR directed against a tumor associated antigen enhances the presentation of TAAs by the engineered dendritic cell and promotes the expansion of antigen-specific T cells thereby offering a promising tool for cancer treatment (see e.g. p. 3, “Summary of the invention”), and since Lobb teaches a dendritic cell expressing a CAR that binds to a tumor associated antigen EphA2 in cancer treatment, one of ordinary skill in the art would have had a reason to choose EphA2 as the tumor associated antigen suggested by Lobb in engineering the CAR of De Palma and Böttcher in order to direct the CAR against EphA2-expressing cancer cells to enhance TAA presentation for cancer treatment.
Hence, the claimed invention as a whole was prima facie obvious to a person of ordinary skill before the effective filing date of the claimed invention in the absence of evidence to the contrary.
Response to Traversal:
Applicant’s arguments filed on 11/24/2025 are acknowledged and have been discussed above.
Maintained Provisional Double Patenting Rejections
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 USPTO Internet website contains terminal disclaimer forms which may be used. Please visit www.uspto.gov/patent/patents-forms. The 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/process/file/efs/guidance/eTD-info-I.jsp.
Claims 2, 6, 8, 10-14 and 17 stand provisionally rejected on the ground of nonstatutory double patenting as being unpatentable over copending claims 1, 3, 7-8, 10, 12-13, 15-17, 22-24, 26-27, 30, 46, 59 of copending Application No. 18/706,321 (‘321). Although the claims at issue are not identical, they are not patentably distinct from each other.
The copending claims in the Application recite a chimeric antigen receptor (CAR) comprising an extracellular domain comprising a tumor antigen binding domain wherein the tumor antigen comprises EphA2, a transmembrane domain and an intracellular domain comprising a Flt3 signaling domain (see especially reference claim 59), the CAR further comprising a signal peptide (reference claim 46), a modified cell comprising the CAR (reference claim 22) being a dendritic cell (reference claim 23), being a conventional type 1 dendritic cell (cDC1) or a progenitor thereof (reference claim 24), the progenitor being selected from a list of cells including a stem cell (reference claim 26), the modified cell capable of cross presenting a tumor antigen (reference claim 27), a pharmaceutical composition (reference claim 30).
The difference between the cited application claims and the instant claims lies in the fact that the cited application claims are much more specific. Thus the invention of said claims of the cited application are in effect “species” of the “generic” invention of the instant claim. It has been held that the generic invention is “anticipated” by the “species”. See In re Goodman, 29 USPQ2d 2010 (Fed. Cir. 1993).
Since the instant application claims are anticipated by cited application claims, said claims are not patentably distinct.
This is a provisional nonstatutory double patenting rejection because the patentably indistinct claims in the copending application have not in fact been patented.
Response to Traversal:
Applicant’s arguments filed on 11/24/2025 are acknowledged. Applicant requests the double patenting rejection be held in abeyance until claims are found allowable. This is not found persuasive. Applicant is reminded that a complete response to a nonstatutory double patenting (NSDP) rejection is either a reply by applicant showing that the claims subject to the rejection are patentably distinct from the reference claims, or the filing of a terminal disclaimer. Such a response is required even when the nonstatutory double patenting rejection is provisional. See MPEP 804.I.B.1.
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 extension fee 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 date of this final action.
No claims are allowed.
Examiner Contact Information
Any inquiry concerning this communication or earlier communications from the examiner should be directed to Jianjian Zhu whose telephone number is (571)272-0956. The examiner can normally be reached M - F 8:30AM - 4PM (EST).
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If attempts to reach the examiner by telephone are unsuccessful, the examiner’s supervisor, James Douglas (Doug) Schultz can be reached on (571) 272-0763. The fax phone number for the organization where this application or proceeding is assigned is 571-273-8300.
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/JIANJIAN ZHU/Examiner, Art Unit 1631
/JAMES D SCHULTZ/Supervisory Patent Examiner, Art Unit 1631