DETAILED ACTION
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 .
Response to Amendment
Applicant’s amendments to the specifications have been acknowledged and objections to the specifications have been withdrawn. Specifically, the Nucleotide and/or Amino Acid Sequence disclosures of the CD8alpha signal peptide in the extracellular domain of the CAR in paragraph 0072 and 0163 as well as Myc-tag in paragraph 0072 and 0163 of the specification have been amended to include SEQ ID NOs. Applicant amended the specification to remove all hyperlinks (paragraph 0051, 0163, 0180) and trademarks (paragraph 0177) and therefore, objections to the specifications have been withdrawn.
Applicant’s amendment to the claims according to the claim objections have been acknowledged and claim objections have been withdrawn. Applicant amended the claims to define the CAR in claim 1 and define PEG in claim 4. Claim 15 has been cancelled and the objection to claim 15 is moot.
Rejections under 35 U.S.C. 112(d) for claim 14 is moot because claim 14 has been cancelled.
Applicant’s amendments to the claims filed on April 13th, 2026 have been acknowledged. Claims 5,6 and 12-17 have been cancelled. Claims 1, 2, 3, 4, 7, 8, 9, 10, and 11, filed on April 13th, 2026, are pending and have been re-examined under the merits herein.
Claim Rejections - 35 USC § 102
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 the appropriate paragraphs of 35 U.S.C. 102 that form the basis for the rejections under this section made in this Office action:
A person shall be entitled to a patent unless –
(a)(1) the claimed invention was patented, described in a printed publication, or in public use, on sale, or otherwise available to the public before the effective filing date of the claimed invention.
(a)(2) the claimed invention was described in a patent issued under section 151, or in an application for patent published or deemed published under section 122(b), in which the patent or application, as the case may be, names another inventor and was effectively filed before the effective filing date of the claimed invention.
Claim 1-4, and 7-11 are rejected under 35 U.S.C. 102(a)(1) and 102(a)(2) as being anticipated by US 2020/0230221 A1, published July 23, 2020, herein referred to as “Irvine.”
The applied reference has a common Applicant (Massachusetts Institute of Technology) and Inventor (Irvine, Darrell J) with the instant application. Based upon the earlier effectively filed date of the reference (September 19th, 2018), it constitutes as prior art under 35 U.S.C. 102(a)(2). See MPEP 2154. 01.
Regarding instant claim 1, Irvine teaches a method of treating cancer using an amphiphilic ligand conjugate (page 30, paragraph 0338, “the amphiphilic ligand conjugate described herein is useful for treating a disorder associated with abnormal apoptosis or a differentiative process (e.g., cellular proliferative disorders (e.g., hyperproliferative disorders) or cellular differentiative disorders, such as cancer). Irvine further teaches a method of administering an amphiphilic ligand conjugate, the composition or the immunogenic composition to the subject prior to receiving CAR-T cells (page 4, paragraph 0035). Irvine teaches a membrane-inserting amphiphilic ligand is administered intratumorally (page 4, paragraph 0040) and that the CAR-T cell are administered intravenously (page 23, paragraph 0266) and that the car T cell expression a binds specifically to the amphiphilic ligand (page 4, paragraph 0034, “n some aspects, the antigen is a viral antigen or caner antigen. In some aspects, the CAR comprises a tag binding domain and the CAR ligand of the amphiphilic ligand conjugate is a tag. In some aspects, the CAR comprises a tumor-associated antigen binding domain and the CAR ligand of the amphiphilic ligand conjugate is a tumor-associated antigen or fragment thereof. In some aspects, the CAR comprises a tag binding domain and a tumor-associated antigen binding domain, and the CAR ligand of the amphiphilic ligand conjugate is a tag.”).
Regarding instant claims 2 and 4, Irvine teaches that the membrane-inserting amphiphilic ligand is a fluorescein isothiocyanate lipid amphiphile ligand (page 2, paragraph 0017, “the disclosure provides an amphiphilic ligand conjugate comprising, 1,2-distearoyl-sn-glycero-3-phosphoethanolamine (DSPE) operably linked to fluorescein isothiocyanate (FITC) via PEG-2000.”).
Regarding instant claim 3, Irvine teaches an engineered cell expressing a CAR that specifically binds to the amphiphilic ligand is a fluorescein isothiocyanate (FITC) lipid amphiphile-specific engineered immune cell (page 13, paragraph 0170, “For example, human T cells have been engineered to express an anti-fluorescein isothiocyanate (FITC) CAR (referred to anti-FITC-CAR)” and page 24, paragraph 0269, “n some embodiments, the CAR ligand of the amphiphilic ligand conjugate is a tag, which binds to a CAR comprising a tag binding domain, as described supra. In some embodiments, the tag is fluorescein isothiocyanate (FITC)”).
Regarding instant claim 7, Irvine teaches introducing the membrane-inserting amphiphilic ligand into dendritic cells in lymph nodes of the subject by subcutaneous injection (page 4, paragraph 0036, “In some aspects, the amphiphilic ligand conjugate is inserted into the membrane of antigen presenting cells upon trafficking to the lymph nodes. In some aspects, the antigen presenting cells are medullary macrophages, CD8+ dendritic cells, and/or CD11b+ dendritic cells” and page 5, paragraph 0059, “FIG. 3C provides a graph of flow cytometric data depicting the uptake of DSP-PEG-FITC at various doses by three different APCs following subcutaneous injection”).
Regarding instant claim 8, Irvine teaches the tumor of the subject in need of treatment is a solid tumor (page 1, paragraph 0006, “As demonstrated herein, administration of CAR-T cells expressing a tumor-associated antigen were capable of delaying tumor growth of solid tumors and increasing the survival of tumor-bearing mice when administered in combination with an amphiphilic ligand conjugate, compared to control and CAR-T cells alone”).
Regarding instant claim 9, Irvine teaches the membrane-inserting amphiphilic ligand comprises a therapeutic compound conjugated to an amphiphilic poly(ethylene glycol)-lipid (page 3, paragraph 0026, “the immunogenic composition comprises an adjuvant, wherein the adjuvant is an amphiphilic oligonucleotide conjugate comprising an immunostimulatory oligonucleotide conjugated to a lipid, with or without a linker, and optionally a polar compound. In some aspects, the immunostimulatory oligonucleotide binds a pattern recognition receptor. In some aspects, the immunostimulatory oligonucleotide comprises CpG. In some aspects, the immunostimulatory oligonucleotide is a ligand for a toll-like receptor.”)
Regarding instant claim 10, Irvine teaches the Intratumoral injection is equal or less than about once every 6 days (page 38, column 2, paragraph 0387, “Notably, similar to DSPE-PEG-FITC vaccinated mice, no antibody response was elicited against EGFRvIII after four rounds of weekly vaccination, and only slight weight loss was observed following each vaccination, which indicated toxicity is at a manageable level (data not shown)”).
Regarding instant claim 11, Irvine teaches the immune cell expressing a CAR comprises a CD28 costimulatory domain (page 11, paragraph 0153, “In some embodiments, the CAR comprises one or more co-stimulatory domains derived from a protein such as CD28, CD137 (also known as 4-1BB), CD134 (also known as OX40) and CD278 (also known as ICOS)”).
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.
Claim 1-4, and 7-11 are rejected on the ground of nonstatutory double patenting as being unpatentable over claim 1, 2, 3, and 21, of U.S. Patent No. 12,433,954 B2, issued October 7th, 2025, herein “Pat’954” in view of Irvine (cited previously).
Regarding instant claim 1 and 3, Pat’954 claim 1 recites a method of activating anti-CD19 CAR T cells or increasing proliferation of anti-CD19 CAR T cells in a subject, comprising administering an amphiphilic ligand conjugate, wherein the amphiphilic ligand conjugate comprises: an anti-CD19 CAR ligand or a multimer thereof; and a lipid operably linked to the ligand or the multimer, wherein the anti-CD19 CAR ligand comprises a peptide comprising a sequence motif, wherein the sequence motif binds an anti-CD19 CAR antigen recognition domain, wherein the anti-CD19 CAR antigen recognition domain comprises an antigen recognition domain derived from FMC63, and wherein binding of the sequence motif to the anti-CD19 CAR antigen recognition domain activates a T cell expressing a CAR comprising the anti-CD19 CAR antigen recognition domain. Pat’954 claim 3 recites a method of inducing an anti-tumor response in a subject with cancer comprising administering to the subject an amphiphilic ligand conjugate, wherein the subject is receiving or has received anti-CD19 CAR T cells, and wherein the amphiphilic ligand conjugate comprises: an anti-CD19 CAR ligand or a multimer thereof; and a lipid operably linked to the ligand or the multimer, wherein the anti-CD19 CAR ligand comprises a peptide comprising a sequence motif, wherein the sequence motif binds an anti-CD19 CAR antigen recognition domain, wherein the anti-CD19 CAR antigen recognition domain comprises an antigen recognition domain derived from FMC63, and wherein binding of the sequence motif to the anti-CD19 CAR antigen recognition domain activates a T cell expressing a CAR comprising the anti-CD19 CAR antigen recognition domain.
Regarding instant claim 7, Pat’954 claim 2 recites a method of stimulating an immune response to a target cell population or a target tissue expressing CD19 in a subject, the method comprising administering to the subject anti-CD19 CAR T cells and an amphiphilic ligand conjugate, wherein the amphiphilic ligand conjugate comprises: an anti-CD19 CAR ligand or a multimer thereof; and a lipid operably linked to the ligand or the multimer, wherein the anti-CD19 CAR ligand comprises a peptide comprising a sequence motif, wherein the sequence motif binds an anti-CD19 CAR antigen recognition domain, wherein the anti-CD19 CAR antigen recognition domain comprises an antigen recognition domain derived from FMC63, and wherein binding of the sequence motif to the anti-CD19 CAR antigen recognition domain activates a T cell expressing a CAR comprising the anti-CD19 CAR antigen recognition domain.
Regarding instant claim 4, Pat’954 claim 21 recites the method of claim 19, wherein the lipid is 1,2-distearoyl-sn-glycero-3-phosphoethanolamine (DSPE).
Pat’954 claims do not recite intratumorally administering the membrane-inserting amphiphilic ligand into a tumor of a subject and intravenously administering the amphiphilic ligand as recited in instant claim 1 , Irvine teaches a method of treating cancer using an amphiphilic ligand conjugate (page 30, paragraph 0338, “the amphiphilic ligand conjugate described herein is useful for treating a disorder associated with abnormal apoptosis or a differentiative process (e.g., cellular proliferative disorders (e.g., hyperproliferative disorders) or cellular differentiative disorders, such as cancer). Irvine further teaches a method of administering an amphiphilic ligand conjugate, the composition or the immunogenic composition to the subject prior to receiving CAR-T cells (page 4, paragraph 0035). Irvine teaches a membrane-inserting amphiphilic ligand is administered intratumorally (page 4, paragraph 0040) and that the CAR-T cell are administered intravenously (page 23, paragraph 0266) and that the car T cell expression a binds specifically to the amphiphilic ligand (page 4, paragraph 0034, “n some aspects, the antigen is a viral antigen or caner antigen. In some aspects, the CAR comprises a tag binding domain and the CAR ligand of the amphiphilic ligand conjugate is a tag. In some aspects, the CAR comprises a tumor-associated antigen binding domain and the CAR ligand of the amphiphilic ligand conjugate is a tumor-associated antigen or fragment thereof. In some aspects, the CAR comprises a tag binding domain and a tumor-associated antigen binding domain, and the CAR ligand of the amphiphilic ligand conjugate is a tag.”). Further, Irvine teaches that the amphiphilic ligand conjugates overcome poor responses of CAR-T cells shown in solid tumors (page 1, paragraph 0006).
Therefore, it would have been obvious to the person of ordinary skill in the art to use the amphiphilic ligand conjugate in the method of treating a tumor comprising administering intratumorally the amphiphilic ligand conjugate following by intravenously administering the CAR-T cell to overcome poor responses to CAR-T cell therapy in solid tumors.
Pat’954 claims do not recite the that the amphiphilic ligand is a fluorescein isothiocyanate lipid amphiphile ligand as recited in instant claim 2, 3 and 4. Irvine teaches that the membrane-inserting amphiphilic ligand is a fluorescein isothiocyanate lipid amphiphile ligand (page 2, paragraph 0017, “the disclosure provides an amphiphilic ligand conjugate comprising, 1,2-distearoyl-sn-glycero-3-phosphoethanolamine (DSPE) operably linked to fluorescein isothiocyanate (FITC) via PEG-2000.”).
Pat’954 claims do not recite introducing the membrane-inserting amphiphilic ligand into dendritic cells in lymph nodes of the subject by subcutaneous injection as recited in instant claim 7. Irvine teaches introducing the membrane-inserting amphiphilic ligand into dendritic cells in lymph nodes of the subject by subcutaneous injection (page 4, paragraph 0036, “In some aspects, the amphiphilic ligand conjugate is inserted into the membrane of antigen presenting cells upon trafficking to the lymph nodes. In some aspects, the antigen presenting cells are medullary macrophages, CD8+ dendritic cells, and/or CD11b+ dendritic cells” and page 5, paragraph 0059, “FIG. 3C provides a graph of flow cytometric data depicting the uptake of DSP-PEG-FITC at various doses by three different APCs following subcutaneous injection”).
Pat’954 claims do not recite that the tumor is a solid tumor as recited in instant claim 8. Irvine teaches the tumor of the subject in need of treatment is a solid tumor (page 1, paragraph 0006, “As demonstrated herein, administration of CAR-T cells expressing a tumor-associated antigen were capable of delaying tumor growth of solid tumors and increasing the survival of tumor-bearing mice when administered in combination with an amphiphilic ligand conjugate, compared to control and CAR-T cells alone”).
Pat’954 claims do not recite that the membrane-inserting amphiphilic ligand comprises a therapeutic compound conjugated to an amphiphilic poly(ethylene glycol)-lipid as recited in instant claim 9. Irvine teaches the membrane-inserting amphiphilic ligand comprises a therapeutic compound conjugated to an amphiphilic poly(ethylene glycol)-lipid (page 3, paragraph 0026, “the immunogenic composition comprises an adjuvant, wherein the adjuvant is an amphiphilic oligonucleotide conjugate comprising an immunostimulatory oligonucleotide conjugated to a lipid, with or without a linker, and optionally a polar compound. In some aspects, the immunostimulatory oligonucleotide binds a pattern recognition receptor. In some aspects, the immunostimulatory oligonucleotide comprises CpG. In some aspects, the immunostimulatory oligonucleotide is a ligand for a toll-like receptor.”)
Pat’954 claims do not recite the frequency of intratumoral administration is equal to or less than about once every 6 days as recited in instant claim 10. Irvine further teaches that “In some embodiments, the frequency of dosing will take into account the pharmacokinetic parameters of the amphiphilic conjugate, in the formulation used. In some embodiments, a clinician will administer the composition until a dosage is reached that achieves the desired effect. In some embodiments, the composition can therefore be administered as a single dose, or as two or more doses (which may or may not contain the same amount of the desired molecule) over time, or as a continuous infusion via an implantation device or catheter. Further refinement of the appropriate dosage is routinely made by those of ordinary skill in the art and is within the ambit of tasks routinely performed by them. In some embodiments, appropriate dosages can be ascertained through use of appropriate dose-response data” (page 29, paragraph 0326). Even though Irvine does not explicitly teach the Intratumoral administration is equal or less than about every 6 days, the principle of law states from MPEP §§ 2144.05: "The normal desire of scientists or artisans to improve upon what is already generally known provides the motivation to determine where in a disclosed set of percentage ranges is the optimum combination of percentages," (see In re Peterson, 315 F.3d at 1330, 65 USPQ2d at 1382). Generally, differences in concentration or temperature will not support the patentability of subject matter encompassed by the prior art unless there is evidence indicating such concentration or temperature is critical. "[W]here the general conditions of a claim are disclosed in the prior art, it is not inventive to discover the optimum or workable ranges by routine experimentation," (See In re Aller, 220 F.2d 454, 456, 105 USPQ 233, 235 (CCPA 1955)). Irvine teaches FITC signal was almost lost at lowest dose of the DSPE-PEG-FITC amphiphilic ligand after 4 days (FIG. 3A and page 37, paragraph 0376, “While FITC signal was almost lost at the lowest dose (2 nmol) after 4 days, the signal was retained for more than 21 days at high dose (10 nmol) of DSPE-PEG-FITC (FIG. 3A)”). Irvine further teaches that the CAR ligand is retained in lymph nodes for at least 4 through 25 days (page 4, paragraph 0037). Therefore, Irvine recognized that dose optimization is within the skill of a person of ordinary skill in the art, wherein Irvine taught that a clinician can determine the dosage and timing (page 29, paragraph [0326])."
Pat’954 claims do not recite the engineered immune cell expressing a CAR comprises a CD28 costimulatory domain as recited in instant claim 11. Irvine teaches the immune cell expressing a CAR comprises a CD28 costimulatory domain (page 11, paragraph 0153, “In some embodiments, the CAR comprises one or more co-stimulatory domains derived from a protein such as CD28, CD137 (also known as 4-1BB), CD134 (also known as OX40) and CD278 (also known as ICOS)”).
Claim 1-4, and 7-11 are rejected on the ground of nonstatutory double patenting as being unpatentable over claim 1, 3, and 4 of U.S. Patent No. 12,453,777 B2 issued October 28th, 2025, herein “Pat’777” in view of Irvine (cited previously).
Regarding instant claim 1, 2, 3, 4, and 7, Pat’777 claim 1 recites a method of stimulating an immune response to a target cell population or a target tissue in a subject, the method comprising administering a composition to the subject, wherein the composition comprises an amphiphilic ligand conjugate comprising a lipid, a chimeric antigen receptor (CAR) ligand, and a polar block linker that couples the lipid to the CAR ligand, wherein the lipid is 1,2-distearoyl-sn-glycero-3-phosphoethanolamine (DSPE), the linker is a polyethylene glycol (PEG) linker, the CAR ligand is fluorescein isothiocyanate (FITC), wherein the subject comprises an immune cell comprising a CAR, wherein the CAR comprises an extracellular domain comprising a target-binding domain that binds to FITC.
However, Pat’777 claims do not recite the method of introducing the membrane-inserting amphiphilic ligand into dendritic cells in lymph nodes by subcutaneous injection as recited in instant claim 7. Irvine teaches introducing the membrane-inserting amphiphilic ligand into dendritic cells in lymph nodes of the subject by subcutaneous injection (page 4, paragraph 0036, “In some aspects, the amphiphilic ligand conjugate is inserted into the membrane of antigen presenting cells upon trafficking to the lymph nodes. In some aspects, the antigen presenting cells are medullary macrophages, CD8+ dendritic cells, and/or CD11b+ dendritic cells” and page 5, paragraph 0059, “FIG. 3C provides a graph of flow cytometric data depicting the uptake of DSP-PEG-FITC at various doses by three different APCs following subcutaneous injection”). Further, Irvine teaches that the amphiphilic ligand conjugates overcome poor responses of CAR-T cells shown in solid tumors (page 1, paragraph 0006).
Therefore, it would have been obvious to the person of ordinary skill in the art to use the amphiphilic ligand conjugate in the method of treating a tumor comprising administering intratumorally the amphiphilic ligand conjugate following by intravenously administering the CAR-T cell to overcome poor responses to CAR-T cell therapy in solid tumors.
Regarding instant claim 9, Pat’777 claim 4 recites the composition further comprises an adjuvant, wherein the adjuvant is an amphiphilic oligonucleotide conjugate comprising an immunostimulatory oligonucleotide conjugated to a lipid, with or without a linker, and optionally a polar compound.
However, Pat’777 claims do not recite the method of treating a tumor, comprising intratumorally administering the membrane-inserting amphiphilic ligand into a tumor of a subject and intravenously administering an engineered immune cell expressing the CAR that specifically binds to the amphiphilic ligand as recited in instant claim 1, Irvine teaches a method of treating cancer using an amphiphilic ligand conjugate (page 30, paragraph 0338, “the amphiphilic ligand conjugate described herein is useful for treating a disorder associated with abnormal apoptosis or a differentiative process (e.g., cellular proliferative disorders (e.g., hyperproliferative disorders) or cellular differentiative disorders, such as cancer). Irvine further teaches a method of administering an amphiphilic ligand conjugate, the composition or the immunogenic composition to the subject prior to receiving CAR-T cells (page 4, paragraph 0035). Irvine teaches a membrane-inserting amphiphilic ligand is administered intratumorally (page 4, paragraph 0040) and that the CAR-T cell are administered intravenously (page 23, paragraph 0266) and that the car T cell expression a binds specifically to the amphiphilic ligand (page 4, paragraph 0034, “n some aspects, the antigen is a viral antigen or caner antigen. In some aspects, the CAR comprises a tag binding domain and the CAR ligand of the amphiphilic ligand conjugate is a tag. In some aspects, the CAR comprises a tumor-associated antigen binding domain and the CAR ligand of the amphiphilic ligand conjugate is a tumor-associated antigen or fragment thereof. In some aspects, the CAR comprises a tag binding domain and a tumor-associated antigen binding domain, and the CAR ligand of the amphiphilic ligand conjugate is a tag.”).
Pat’777 claims do not recite the tumor of a subject in need of treatment is a solid tumor as recited in instant claim 8. Irvine teaches the tumor of the subject in need of treatment is a solid tumor (page 1, paragraph 0006, “As demonstrated herein, administration of CAR-T cells expressing a tumor-associated antigen were capable of delaying tumor growth of solid tumors and increasing the survival of tumor-bearing mice when administered in combination with an amphiphilic ligand conjugate, compared to control and CAR-T cells alone”).
Pat’777 claims do not recite the frequency of Intratumoral administration is equal to or less than about once every 6 days as recited in instant claim 10. Irvine further teaches that “In some embodiments, the frequency of dosing will take into account the pharmacokinetic parameters of the amphiphilic conjugate, in the formulation used. In some embodiments, a clinician will administer the composition until a dosage is reached that achieves the desired effect. In some embodiments, the composition can therefore be administered as a single dose, or as two or more doses (which may or may not contain the same amount of the desired molecule) over time, or as a continuous infusion via an implantation device or catheter. Further refinement of the appropriate dosage is routinely made by those of ordinary skill in the art and is within the ambit of tasks routinely performed by them. In some embodiments, appropriate dosages can be ascertained through use of appropriate dose-response data” (page 29, paragraph 0326). Even though Irvine does not explicitly teach the Intratumoral administration is equal or less than about every 6 days, the principle of law states from MPEP §§ 2144.05: "The normal desire of scientists or artisans to improve upon what is already generally known provides the motivation to determine where in a disclosed set of percentage ranges is the optimum combination of percentages," (see In re Peterson, 315 F.3d at 1330, 65 USPQ2d at 1382). Generally, differences in concentration or temperature will not support the patentability of subject matter encompassed by the prior art unless there is evidence indicating such concentration or temperature is critical. "[W]here the general conditions of a claim are disclosed in the prior art, it is not inventive to discover the optimum or workable ranges by routine experimentation," (See In re Aller, 220 F.2d 454, 456, 105 USPQ 233, 235 (CCPA 1955)). Irvine teaches FITC signal was almost lost at lowest dose of the DSPE-PEG-FITC amphiphilic ligand after 4 days (FIG. 3A and page 37, paragraph 0376, “While FITC signal was almost lost at the lowest dose (2 nmol) after 4 days, the signal was retained for more than 21 days at high dose (10 nmol) of DSPE-PEG-FITC (FIG. 3A)”). Irvine further teaches that the CAR ligand is retained in lymph nodes for at least 4 through 25 days (page 4, paragraph 0037). Therefore, Irvine recognized that dose optimization is within the skill of a person of ordinary skill in the art, wherein Irvine taught that a clinician can determine the dosage and timing (page 29, paragraph [0326])."
Regarding instant claim 11, Pat’777 claim 3 recites the method of claim 2, wherein the CAR further comprises one or more co-stimulatory domains but Pat’777 claims do not recite the engineered immune cell expressing a CAR comprises a CD28 costimulatory domain. Irvine teaches the immune cell expressing a CAR comprises a CD28 costimulatory domain (page 11, paragraph 0153, “In some embodiments, the CAR comprises one or more co-stimulatory domains derived from a protein such as CD28, CD137 (also known as 4-1BB), CD134 (also known as OX40) and CD278 (also known as ICOS)”).
Claim 1-4, and 7-11 are provisionally rejected on the ground of nonstatutory double patenting as being unpatentable over claim 77, 85, 86, 88, 89, 90, 91, 92, 96, 97, 99, 100, and 101 of copending Application No. 18/339,230, claims were amended on April 1st, 2026, in view of Irvine (cited previously).
Regarding instant claim 1, 7, App’230 claim 77 recite a method of activating, expanding or increasing proliferation of chimeric antigen receptor-T (CAR-T) cells in a subject, wherein the subject is receiving or has received CAR-T cell therapy comprising the CAR-T cells, the method comprising administering to the subject an amphiphilic ligand conjugate, wherein the amphiphilic ligand conjugate comprises:(i) a chimeric antigen receptor (CAR) ligand, and(ii) a lipid operably linked to the CAR ligand, wherein the lipid binds albumin under physiological conditions and can insert itself into a cell membrane under physiological conditions, wherein the CAR ligand binds to the CAR of the CAR-T cells and is capable of activating, expanding or increasing activates, expands or increases proliferation of the CAR-T cells. Withdrawn App’230 claim 99 recites a method of stimulating an immune response to a target cell population or target tissue expressing an antigen in a subject, wherein the subject is receiving or has received CAR-T cell therapy comprising CAR-T cells targeted to the antigen, the method comprising administering to the subject an amphiphilic ligand conjugate comprising: a chimeric antigen receptor (CAR) ligand; and a lipid operably linked to the CAR ligand, and wherein the CAR ligand binds to the CAR of the CAR-T cells. App’230 claim 96 recites the method further comprising administering to the subject the CAR-T cells. App’230 claim 97 recites the subject has cancer. App’230 claim 100 recites the immune response is a T-cell mediated immune response or an anti-tumor immune response. App’230 claim 101 (Withdrawn) recites the target cell population or target tissue is tumor cells or tumor tissue.
Regarding instant claims 2, 3, and 4, App’230 claims 85 and 86 recite that the lipid is 1,2-distearoyl-sn-glycero-3-phosphoethanolamine (DSPE) and wherein the linker is PEG-2000 and the CAR ligand is a tag selected from the group consisting of fluorescein isothiocyanate (FITC).
Regarding instant claim 9, App’230 claim 88 and 90 recites the CAR ligand is a viral antigen, a tumor-associated antigen, or a fragment thereof.
Regarding instant claim 11, App’230 claim 89 recites the CAR comprises a co- stimulation domain, but App’230 claims do not recite the engineered immune cell expressing a CAR comprises a CD28 costimulatory domain. Irvine teaches the immune cell expressing a CAR comprises a CD28 costimulatory domain (page 11, paragraph 0153, “In some embodiments, the CAR comprises one or more co-stimulatory domains derived from a protein such as CD28, CD137 (also known as 4-1BB), CD134 (also known as OX40) and CD278 (also known as ICOS)”).
Regarding instant claim 7, App’230 claim 91 recites the amphiphilic ligand conjugate is trafficked to lymph nodes. App’230 claim 92 recites the amphiphilic ligand conjugate is inserted into the membrane of antigen presenting cells upon trafficking to the lymph nodes.
App’230 claims do not recite intratumorally administering the membrane-inserting amphiphilic ligand into a tumor of a subject and intravenously administering the amphiphilic ligand as recited in instant claim 1 , Irvine teaches a method of treating cancer using an amphiphilic ligand conjugate (page 30, paragraph 0338, “the amphiphilic ligand conjugate described herein is useful for treating a disorder associated with abnormal apoptosis or a differentiative process (e.g., cellular proliferative disorders (e.g., hyperproliferative disorders) or cellular differentiative disorders, such as cancer). Irvine further teaches a method of administering an amphiphilic ligand conjugate, the composition or the immunogenic composition to the subject prior to receiving CAR-T cells (page 4, paragraph 0035). Irvine teaches a membrane-inserting amphiphilic ligand is administered intratumorally (page 4, paragraph 0040) and that the CAR-T cell are administered intravenously (page 23, paragraph 0266) and that the car T cell expression a binds specifically to the amphiphilic ligand (page 4, paragraph 0034, “n some aspects, the antigen is a viral antigen or caner antigen. In some aspects, the CAR comprises a tag binding domain and the CAR ligand of the amphiphilic ligand conjugate is a tag. In some aspects, the CAR comprises a tumor-associated antigen binding domain and the CAR ligand of the amphiphilic ligand conjugate is a tumor-associated antigen or fragment thereof. In some aspects, the CAR comprises a tag binding domain and a tumor-associated antigen binding domain, and the CAR ligand of the amphiphilic ligand conjugate is a tag.”). Further, Irvine teaches that the amphiphilic ligand conjugates overcome poor responses of CAR-T cells shown in solid tumors (page 1, paragraph 0006).
Therefore, it would have been obvious to the person of ordinary skill in the art to use the amphiphilic ligand conjugate in the method of treating a tumor comprising administering intratumorally the amphiphilic ligand conjugate following by intravenously administering the CAR-T cell to overcome poor responses to CAR-T cell therapy in solid tumors.
App’230 claims do not recite introducing the membrane-inserting amphiphilic ligand into dendritic cells in lymph nodes of the subject by subcutaneous injection as recited in instant claim 7. Irvine teaches introducing the membrane-inserting amphiphilic ligand into dendritic cells in lymph nodes of the subject by subcutaneous injection (page 4, paragraph 0036, “In some aspects, the amphiphilic ligand conjugate is inserted into the membrane of antigen presenting cells upon trafficking to the lymph nodes. In some aspects, the antigen presenting cells are medullary macrophages, CD8+ dendritic cells, and/or CD11b+ dendritic cells” and page 5, paragraph 0059, “FIG. 3C provides a graph of flow cytometric data depicting the uptake of DSP-PEG-FITC at various doses by three different APCs following subcutaneous injection”).
App’230 claims do not recite that the tumor is a solid tumor as recited in instant claim 8. Irvine teaches the tumor of the subject in need of treatment is a solid tumor (page 1, paragraph 0006, “As demonstrated herein, administration of CAR-T cells expressing a tumor-associated antigen were capable of delaying tumor growth of solid tumors and increasing the survival of tumor-bearing mice when administered in combination with an amphiphilic ligand conjugate, compared to control and CAR-T cells alone”).
App’230 claims do not recite the frequency of Intratumoral administration is equal to or less than about once every 6 days as recited in instant claim 10. Irvine further teaches that “In some embodiments, the frequency of dosing will take into account the pharmacokinetic parameters of the amphiphilic conjugate, in the formulation used. In some embodiments, a clinician will administer the composition until a dosage is reached that achieves the desired effect. In some embodiments, the composition can therefore be administered as a single dose, or as two or more doses (which may or may not contain the same amount of the desired molecule) over time, or as a continuous infusion via an implantation device or catheter. Further refinement of the appropriate dosage is routinely made by those of ordinary skill in the art and is within the ambit of tasks routinely performed by them. In some embodiments, appropriate dosages can be ascertained through use of appropriate dose-response data” (page 29, paragraph 0326). Even though Irvine does not explicitly teach the Intratumoral administration is equal or less than about every 6 days, the principle of law states from MPEP §§ 2144.05: "The normal desire of scientists or artisans to improve upon what is already generally known provides the motivation to determine where in a disclosed set of percentage ranges is the optimum combination of percentages," (see In re Peterson, 315 F.3d at 1330, 65 USPQ2d at 1382). Generally, differences in concentration or temperature will not support the patentability of subject matter encompassed by the prior art unless there is evidence indicating such concentration or temperature is critical. "[W]here the general conditions of a claim are disclosed in the prior art, it is not inventive to discover the optimum or workable ranges by routine experimentation," (See In re Aller, 220 F.2d 454, 456, 105 USPQ 233, 235 (CCPA 1955)). Irvine teaches FITC signal was almost lost at lowest dose of the DSPE-PEG-FITC amphiphilic ligand after 4 days (FIG. 3A and page 37, paragraph 0376, “While FITC signal was almost lost at the lowest dose (2 nmol) after 4 days, the signal was retained for more than 21 days at high dose (10 nmol) of DSPE-PEG-FITC (FIG. 3A)”). Irvine further teaches that the CAR ligand is retained in lymph nodes for at least 4 through 25 days (page 4, paragraph 0037). Therefore, Irvine recognized that dose optimization is within the skill of a person of ordinary skill in the art, wherein Irvine taught that a clinician can determine the dosage and timing (page 29, paragraph [0326])."
This is a provisional nonstatutory double patenting rejection.
Response to Arguments
Applicant's arguments filed April 13th, 2026 have been fully considered and they are persuasive in light of the claim amendments of 04/13/2026.
In response to Applicant’s argument that Jensen does not anticipate intratumorally administering a membrane-inserting ligand is not the same as locoregional administration taught in Jensen is persuasive and 102 rejections of the claims in view of Jensen in the office action of 11/13/2025 have been withdrawn.
In response to Applicant’s argument that Jensen does not anticipate the subject matter of claim 1 and Kolb, Ma and van der Burg fail to render obvious the claimed methods as a whole is persuasive in light of the claim amendments. Therefore the 103 rejections made in the office action of 11/13/2025 are withdrawn. Specifically, the amendment of 04/13/2026 included specific routes of administration of intratumorally administering the membrane-inserting amphiphilic ligand into a tumor of a subject followed by intravenously administering an engineered immune cell expressing a CAR which Jensen, Kolb, Ma and van der Burg fail to teach. Since claim 17 is cancelled after Applicant's amendment of April 13th, 2026, claim 17 rejection is moot.
Upon further consideration of the claim amendments of April 13th, 2026, however, new grounds of rejections of claims 1-4, 7-11 are being set forth as anticipated by Irvine as described above in the USC §102 rejection of this office action.
In response to Applicant’s request to reconsider U.S. Patent No. 12,453,777 has been reconsidered and in light of Applicant’s amendments, claims are rejected on the grounds of non-statutory double patenting in view of Irvine (cited in this office action).
Based on Applicant’s amendments filed April 13th, 2026, Application 18/339,230 and U.S. Patent 12,433,954 are newly rejected under non-statutory double patenting in view of Irvine (cited in this office action).
Conclusion
No Claims are allowed.
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.
Any inquiry concerning this communication or earlier communications from the examiner should be directed to Lam Thuy Vi Tran Ho whose telephone number is (571)272-9135. The examiner can normally be reached Monday-Friday 7:30-3.
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/LAM THUY VI TRAN HO/Examiner, Art Unit 1647 /L.T./Examiner, Art Unit 1647 /JOANNE HAMA/Supervisory Patent Examiner, Art Unit 1647
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