DETAILED ACTION
1. The present application is being examined under the pre-AIA first to invent provisions.
2. Applicant’s species election of (i) SEQ ID NO:22, (ii) CD19, (iii) 4-1BB and (iv) SEQ ID NO: 1 in the reply filed on 6/19/2026 is acknowledged. Because applicant did not distinctly and specifically point out the supposed errors in the restriction requirement, the election has been treated as an election without traverse (MPEP § 818.01(a)).
3. Claims 1, 2, 48-56 and 58-67 are pending. Claims 3-47 and 57 are cancelled.
4. Claims 1, 2, 48-56 and 58-67 are under examination. It is noted that SEQ ID NOs: 2-6 and 20-21 are examined together with the elected species.
Information Disclosure Statement
5. The two information disclosure statements (IDS) submitted on 2/25/2025 have been considered by the examiner.
Claim Objections
6. Claim 52 is objected to because of the following informalities: claim 52 recites “the antigen binding fragment”. There is insufficient antecedent basis for this limitation in the claim. Claim 52 depends from claim 48. Claim 48 recites “one or more antigen binding domains”. Appropriate correction is required.
Improper Markush Grouping Rejection
7. Claim 1 is rejected on the basis that it contains an improper Markush grouping of alternatives. See In re Harnisch, 631 F.2d 716, 721-22 (CCPA 1980) and Ex parte Hozumi, 3 USPQ2d 1059, 1060 (Bd. Pat. App. & Int. 1984).
MPEP 2117 states “Claims that set forth a list of alternatives from which a selection is to be made are typically referred to as Markush claims, after the appellant in Ex parte Markush, 1925 Dec. Comm’r Pat. 126, 127 (1924). Although the term “Markush claim” is used throughout the MPEP, any claim that recites alternatively usable members, regardless of format, should be treated as a Markush claim.”.
A Markush grouping is proper if the alternatives defined by the Markush group (i.e., alternatives from which a selection is to be made in the context of a combination or process, or alternative chemical compounds as a whole) share a “single structural similarity” and a common use. A Markush grouping meets these requirements in two situations. First, a Markush grouping is proper if the alternatives are all members of the same recognized physical or chemical class or the same art-recognized class, and are disclosed in the specification or known in the art to be functionally equivalent and have a common use. Second, where a Markush grouping describes alternative chemical compounds, whether by words or chemical formulas, and the alternatives do not belong to a recognized class as set forth above, the members of the Markush grouping may be considered to share a “single structural similarity” and common use where the alternatives share both a substantial structural feature and a common use that flows from the substantial structural feature. See MPEP § 706.03(y).
The Markush grouping of claim 1 is improper because the alternatives defined by the Markush grouping (i.e. different SEQ ID NOs) are not disclosed in the specification or known in the art to be functionally equivalent and have a common use. The recited SEQ ID NOs are not functional equivalent because they encode different polypeptides. Furthermore, they do not share both a substantial structural feature and a common use that flows from the substantial structural feature.
To overcome this rejection, Applicant may set forth each alternative (or grouping of patentably indistinct alternatives) within an improper Markush grouping in a series of independent or dependent claims and/or present convincing arguments that the group members recited in the alternative within a single claim in fact share a single structural similarity as well as a common use.
Claim Rejections - 35 USC § 112
8. The following is a quotation of the first paragraph of 35 U.S.C. 112(a):
(a) IN GENERAL.—The specification shall contain a written description of the invention, and of the manner and process of making and using it, in such full, clear, concise, and exact terms as to enable any person skilled in the art to which it pertains, or with which it is most nearly connected, to make and use the same, and shall set forth the best mode contemplated by the inventor or joint inventor of carrying out the invention.
The following is a quotation of the first paragraph of pre-AIA 35 U.S.C. 112:
The specification shall contain a written description of the invention, and of the manner and process of making and using it, in such full, clear, concise, and exact terms as to enable any person skilled in the art to which it pertains, or with which it is most nearly connected, to make and use the same, and shall set forth the best mode contemplated by the inventor of carrying out his invention.
9. Claims 48-49, 51-56 and 58-67 are rejected under 35 U.S.C. 112, first paragraph, as failing to comply with the written description requirement. The claim(s) contains subject matter which was not described in the specification in such a way as to reasonably convey to one skilled in the relevant art that the inventor(s), at the time the application was filed, had possession of the claimed invention. This is a new matter rejection.
The disclosure of a continuation application must be the same as the disclosure of the prior-filed application; i.e., the continuation must not include anything which would constitute new matter if inserted in the original application. See MPEP § 201.07. The disclosure of a divisional application must be the same as the disclosure of the prior-filed application, or include at least that portion of the disclosure of the prior-filed application that is germane to the invention claimed in the divisional application. See MPEP § 201.06. The disclosure of a continuation or divisional application cannot include anything which would constitute new matter if inserted in the prior-filed application
The limitation “wherein the CAR comprises one or more antigen binding domains” recited in the claims (see line 3 of independent claim 48, emphasis added) introduces new matter since the specification, drawings and claims as filed disclose only “a CAR comprising an antigen binding domain” (emphasis added, see page 2, line 16, page 3, line 19 for example). There is no clear support for a CAR comprising more than one antigen binding domain.
If applicant believes that support for the above-mentioned phrases or terms is present in the specification, claims or drawing as originally filed, applicant must, in responding to this action, point out with particularity, where such support may be found.
Applicant is required to cancel the new matter in the reply to this Office Action.
Double Patenting
10. 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.
11. Claims 1, 2, 48-56 and 58-67 are rejected on the ground of nonstatutory double patenting as being unpatentable over claims 1-16 of U.S. Patent No. 11,795,240, in view of Sahm et al. (Cancer Immunol Immunother, Fab 5, 2012, 61:1451-1461).
The claims of the patent disclose an ex vivo or in vitro method of generating a modified T cell, comprising introducing into a T cell a composition comprising (a) a first RNA molecule encoding a chimeric antigen receptor (CAR), wherein the CAR comprises an antigen binding domain, a transmembrane domain, and a CD3 zeta signaling domain; and (b) a second RNA molecule encoding a bispecific antibody, wherein the bispecific antibody comprises a first antigen recognition domain that recognizes the same antigen as the antigen binding domain of the CAR, and a second antigen recognition domain that recognizes CD3,
wherein the bispecific antibody encoded by the second RNA molecule is secreted by the cell (indicating that the bispecific antibody does not comprise a transmembrane domain),
wherein the CAR further comprises a costimulatory signaling region,
wherein the antigen binding domain of the CAR binds CD19, CD20, CD22, ROR1, mesothelin, CD33/IL3Ra, c-Met, PSMA, Glycolipid F77, EGFRvIII, or GD-2,
wherein the bispecific antibody is encoded by a nucleic acid comprising a sequence selected from the group consisting of SEQ ID NO: 1, SEQ ID NO: 2, SEQ ID NO: 3, SEQ ID NO: 4, SEQ ID NO: 5, SEQ ID NO: 6, SEQ ID NO: 7, SEQ ID NO: 8, SEQ ID NO: 9, SEQ ID NO: 10, SEQ ID NO: 11, SEQ ID NO: 12, SEQ ID NO: 13, SEQ ID NO: 14, SEQ ID NO: 15, SEQ ID NO: 16, SEQ ID NO: 17, SEQ ID NO: 18, and SEQ ID NO: 19,
wherein the CAR comprises a polypeptide encoded by the nucleic acid sequence selected from the group consisting of SEQ ID NO: 20, SEQ ID NO: 21, and SEQ ID NO: 22,
wherein the bispecific antibody comprises: (a) a human antibody, or an antigen-binding fragment thereof, or (b) a humanized antibody, or an antigen-binding fragment thereof,
wherein the CAR further comprises a costimulatory signaling region.
The claims of the patent further disclose an ex vivo or in vitro method of enhancing an anti-tumor activity of a T cell, comprising introducing into a T cell a composition comprising (a) a first lentiviral vector encoding a chimeric antigen receptor (CAR), wherein the CAR comprises an antigen binding domain, a transmembrane domain, and a CD3 zeta signaling domain; and (b) a second lentiviral vector encoding a bispecific antibody, wherein the bispecific antibody comprises a first antigen recognition domain that recognizes the same antigen as the antigen binding domain of the CAR, and a second antigen recognition domain that recognizes CD3, wherein the bispecific antibody encoded by the second lentiviral vector is secreted by the cell, and wherein the secreted bispecific antibody further stimulates the modified T cell and non-modified bystander T cells to specifically recognize tumor cells.
The amino acid sequences of SEQ ID NOs: 1-21 are 100% identical to those of instant SEQ ID NOs: 1-21, respectively.
The claims of the patent do not teach that the two nucleic acids encoding the CAR and the bispecific antibody are on a single polynucleotide (same vector).
Sahm et al. teaches a method of co-expressing IL-15 and CAR on NK cells using a bicistronic lentiviral vector: CAR-IRES-IL-15 cassette (page 1456, column 2 and Fig. 4a).
It would have been prima facie obvious to one of ordinary skill in the art at the time the invention was made and one of ordinary skill in the art would have been motivated to have made a bicistronic lentiviral vector in view of Sahm for purpose of co-expression of the CAR and the bispecific antibody of the patent on T cells. One of ordinary skill in the art would have a reasonable expectation of success because Sahm et al. teaches a method of co-expressing IL-15 and CAR on NK cells using a bicistronic lentiviral vector: CAR-IRES-IL-15 cassette (page 1456, column 2 and Fig. 4a).
12. Claims 1, 2, 48-56 and 58-67 are rejected on the ground of nonstatutory double patenting as being unpatentable over claims 1-19 of U.S. Patent No. 10,696,749, in view of Sahm et al. (Cancer Immunol Immunother, Fab 5, 2012, 61:1451-1461).
Claims 1-19 of U.S. Patent No. 10,696,749 disclose an isolated cell comprising: a first nucleic acid sequence encoding a chimeric antigen receptor (CAR), wherein the CAR comprises one or more antigen binding domains of a first bispecific antibody, a transmembrane domain, and a CD3 zeta signaling domain, further wherein each antigen binding domain is selected from the group consisting of a human antibody, a humanized antibody, and an antigen binding fragment thereof; and a second nucleic acid sequence encoding a second bispecific antibody, wherein the second bispecific antibody does not comprise and is not linked to a transmembrane domain, wherein the first nucleic acid sequence comprises a nucleic acid sequence selected from the group consisting of SEQ ID NO: 20, SEQ ID NO: 21, and SEQ ID NO: 22, at least one antigen binding domain of the CAR binds to a tumor antigen, wherein the CAR further comprises a costimulatory signaling region comprising the intracellular domain of a costimulatory molecule selected from the group consisting of CD27, CD28, 4-1BB, OX40, CD30, CD40, PD-1, lymphocyte function-associated antigen-1 (LFA-1), CD2, CD7, LIGHT, NKG2C, B7-H3, CD83, and any combination thereof, the cell is a T cell, wherein the second bispecific antibody encoded by the second nucleic acid sequence comprises a human antibody, or an antigen binding fragment thereof, the second bispecific antibody encoded by the second nucleic acid sequence comprises an antigen binding domain that binds a T cell antigen,
wherein the antigen binding fragment is a Fab or a scFv,
wherein the tumor antigen is selected from the group consisting of CD19, CD20, CD22, ROR1, mesothelin, CD33, IL3Ra, c-Met, PSMA, Glycolipid F77, EGFRvIII, GD-2, NY-ESO-1, and MAGE A3, wherein the nucleic acid sequence encoding the antigen binding domains of the first bispecific antibody comprises a nucleic acid sequence selected from the group consisting of SEQ ID NO: 1, SEQ ID NO: 2, SEQ ID NO: 3, SEQ ID NO: 4, SEQ ID NO: 5, SEQ ID NO: 6, SEQ ID NO: 7, SEQ ID NO: 8, SEQ ID NO: 9, SEQ ID NO: 10, SEQ ID NO: 11, SEQ ID NO: 12, SEQ ID NO: 13, SEQ ID NO: 14, SEQ ID NO: 15, SEQ ID NO: 16, SEQ ID NO: 17, SEQ ID NO: 18, and SEQ ID NO: 19,
wherein the second nucleic acid sequence encoding the second bispecific antibody comprises the nucleic acid sequence selected from the group consisting of SEQ ID NO: 1, SEQ ID NO: 2, SEQ ID NO: 3, SEQ ID NO: 4, SEQ ID NO: 5, SEQ ID NO: 6, SEQ ID NO: 7, SEQ ID NO: 8, SEQ ID NO: 9, SEQ ID NO: 10, SEQ ID NO: 11, SEQ ID NO: 12, SEQ ID NO: 13, SEQ ID NO: 14, SEQ ID NO: 15, SEQ ID NO: 16, SEQ ID NO: 17, SEQ ID NO: 18, and SEQ ID NO: 19,
wherein the second bispecific antibody encoded by the second nucleic acid sequence comprises an antigen binding domain that binds a T cell antigen.
The amino acid sequences of SEQ ID NOs: 1-21 are 100% identical to those of instant SEQ ID NOs: 1-21, respectively.
The claims of the patent do not teach that the two nucleic acids encoding the CAR and the bispecific antibody are on a single polynucleotide (same vector).
Sahm et al. teaches a method of co-expressing IL-15 and CAR on NK cells using a bicistronic lentiviral vector: CAR-IRES-IL-15 cassette (page 1456, column 2 and Fig. 4a).
It would have been prima facie obvious to one of ordinary skill in the art at the time the invention was made and one of ordinary skill in the art would have been motivated to have made a bicistronic lentiviral vector in view of Sahm for purpose of co-expression of the CAR and the bispecific antibody of the patent on T cells. One of ordinary skill in the art would have a reasonable expectation of success because Sahm et al. teaches a method of co-expressing IL-15 and CAR on NK cells using a bicistronic lentiviral vector: CAR-IRES-IL-15 cassette (page 1456, column 2 and Fig. 4a).
13. Claims 1, 2, 48-56 and 58-67 are rejected on the ground of nonstatutory double patenting as being unpatentable over claims 1-12 of U.S. Patent No. 9,765,156, in view of Sahm et al. (Cancer Immunol Immunother, Fab 5, 2012, 61:1451-1461).
Claims 1-12 of U.S. Patent No. 9,765,156 disclose a method for stimulating a T cell-mediated immune response to a tumor cell population or tumor tissue in a mammal, the method comprising administering to the mammal an effective amount of a T cell, wherein the T cell is genetically modified to coexpress a CAR and a bispecific antibody, wherein the CAR comprises a tumor antigen binding domain, a transmembrane domain, and a CD3 zeta signaling domain, further wherein the tumor antigen binding domain is selected from the group consisting of a human antibody, a humanized antibody, and an antigen binding fragment thereof, thereby stimulating a T cell-mediated immune response to the tumor cell population or tumor tissue in the mammal, and wherein the bispecific antibody comprises a domain that binds a T cell antigen and does not comprise a transmembrane domain, wherein the CAR comprises a polypeptide encoded by the nucleic acid sequence selected from the group consisting of SEQ ID NOs: 20, SEQ ID NO: 21, and SEQ ID NO: 22, the bispecific antibody comprises a domain that binds a T cell antigen and does not comprise a transmembrane domain, the bispecific antibody comprises a polypeptide encoded by the nucleic acid sequence selected from the group consisting of SEQ ID NO: 1, SEQ ID NO: 2, SEQ ID NO: 3, SEQ ID NO: 4, SEQ ID NO: 5, SEQ ID NO: 6, SEQ ID NO: 7, SEQ ID NO: 8, SEQ ID NO: 9, SEQ ID NO: 10, SEQ ID NO: 11, SEQ ID NO: 12, SEQ ID NO: 13, SEQ ID NO: 14, SEQ ID NO: 15, SEQ ID NO: 16, SEQ ID NO: 17, SEQ ID NO: 18, and SEQ ID NO: 19. SEQ ID NO:1 is Blinatumomab which binds both CD19 and CD3
The amino acid sequences of SEQ ID NOs: 1-21 are 100% identical to those of instant SEQ ID NOs: 1-21, respectively.
The claims of the patent do not teach that the two nucleic acids encoding the CAR and the bispecific antibody are on a single polynucleotide (same vector).
Sahm et al. teaches a method of co-expressing IL-15 and CAR on NK cells using a bicistronic lentiviral vector: CAR-IRES-IL-15 cassette (page 1456, column 2 and Fig. 4a).
It would have been prima facie obvious to one of ordinary skill in the art at the time the invention was made and one of ordinary skill in the art would have been motivated to have made a bicistronic lentiviral vector in view of Sahm for purpose of co-expression of the CAR and the bispecific antibody of the patent on T cells. One of ordinary skill in the art would have a reasonable expectation of success because Sahm et al. teaches a method of co-expressing IL-15 and CAR on NK cells using a bicistronic lentiviral vector: CAR-IRES-IL-15 cassette (page 1456, column 2 and Fig. 4a).
14. Claims 48-49, 51-56 and 67 are rejected on the ground of nonstatutory double patenting as being unpatentable over claims 1-8 of U.S. Patent No. 11,890,301, in view of Sahm et al. (Cancer Immunol Immunother, Fab 5, 2012, 61:1451-1461).
The claims of the patent disclose a method of metabolically enhancing a tumor specific T cell, comprising: introducing a first nucleic acid encoding a chimeric antigen receptor (CAR) into a T cell in vitro to obtain a CAR T cell, wherein the CAR comprises an antigen binding domain that binds to CD19, a transmembrane domain, and intracellular signaling domains of a 4-1BB molecule and a CD3zeta molecule; arming the CAR T cell in vitro with a bispecific antibody, wherein arming the CAR T cell comprises introducing a second nucleic acid encoding the bispecific antibody into the CAR T cell, wherein the bispecific antibody binds CD3 on the CAR T cell, and wherein the bispecific antibody is capable of binding to an antigen on a tumor cell in vivo; and administering the armed CAR T cell to a CD19+ subject wherein the intracellular signaling domain is activated, thereby metabolically enhancing the tumor specific T cell,
wherein introducing the first nucleic acid comprises electroporating the first nucleic acid into the cell, wherein the first nucleic acid comprises an mRNA, wherein the antigen is HER2, epidermal growth factor receptor (EGFR), or CD20,
wherein the bispecific antibody comprises an anti-CD3 antibody,
wherein introducing the second nucleic acid comprises electroporating the second nucleic acid into the cell, wherein the second nucleic acid comprises an mRNA.
The method of claim 1, wherein the CAR comprises the sequence of SEQ ID NO: 1.
The claims of the patent do not teach that the two nucleic acids encoding the CAR and the bispecific antibody are on a single polynucleotide (same vector).
Sahm et al. teaches a method of co-expressing IL-15 and CAR on NK cells using a bicistronic lentiviral vector: CAR-IRES-IL-15 cassette (page 1456, column 2 and Fig. 4a).
It would have been prima facie obvious to one of ordinary skill in the art at the time the invention was made and one of ordinary skill in the art would have been motivated to have made a bicistronic lentiviral vector in view of Sahm for purpose of co-expression of the CAR and the bispecific antibody of the patent on T cells. One of ordinary skill in the art would have a reasonable expectation of success because Sahm et al. teaches a method of co-expressing IL-15 and CAR on NK cells using a bicistronic lentiviral vector: CAR-IRES-IL-15 cassette (page 1456, column 2 and Fig. 4a).
15. Claims 48-49, 51-56 and 67 are provisionally rejected on the ground of nonstatutory double patenting as being unpatentable over claims 14-18 of copending Application No. 18,416,459, in view of Sahm et al. (Cancer Immunol Immunother, Fab 5, 2012, 61:1451-1461).
This is a provisional nonstatutory double patenting rejection.
The claims of copending application disclose a metabolically enhanced, tumor specific T cell comprising a chimeric antigen receptor (CAR) and a bispecific antibody, wherein the CAR comprises an antigen binding domain, a transmembrane domain and an intracellular domain of a co-stimulatory molecule, and the bispecific antibody binds to a target on a tumor cell and the T cell, and wherein the T cell has improved cytotoxicity and resistance to immunosuppression at a solid tumor site,
wherein the T cell comprises a nucleic acid sequence encoding the CAR,
and wherein the T cell comprises a nucleic acid sequence encoding the bispecific antibody.
The claims of the copending application do not teach that the two nucleic acids encoding the CAR and the bispecific antibody are on a single polynucleotide (same vector).
Sahm et al. teaches a method of co-expressing IL-15 and CAR on NK cells using a bicistronic lentiviral vector: CAR-IRES-IL-15 cassette (page 1456, column 2 and Fig. 4a).
It would have been prima facie obvious to one of ordinary skill in the art at the time the invention was made and one of ordinary skill in the art would have been motivated to have made a bicistronic lentiviral vector in view of Sahm for purpose of co-expression of the CAR and the bispecific antibody of the patent on T cells. One of ordinary skill in the art would have a reasonable expectation of success because Sahm et al. teaches a method of co-expressing IL-15 and CAR on NK cells using a bicistronic lentiviral vector: CAR-IRES-IL-15 cassette (page 1456, column 2 and Fig. 4a).
Conclusion
16. No claims are allowed. SEQ ID NOs: 2-6 and 20-22 are free of prior art.
17. Any inquiry concerning this communication or earlier communications from the examiner should be directed to HONG SANG whose telephone number is (571)272-8145. The examiner can normally be reached Monday-Friday 8am-5pm.
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/HONG SANG/Primary Examiner, Art Unit 1646
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