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 .
Priority
The instant application, filed on 03/17/2023, claims domestic benefit from a provisional application PRO 63/343,804 filed on 05/19/2022.
Acknowledgement is made of the applicant’s claim for domestic benefit on the instant application.
Status of Claims/Application
Claims 1-17 as filed on 03/17/2023 are currently pending and are examined on the merits herein.
Information Disclosure Statement
The information disclosure statement (IDS) was submitted on 08/15/2023. The submission is in compliance with the provisions of 37 CFR 1.97. Accordingly, the information disclosure statement is being considered by the examiner.
Nucleotide and/or Amino Acid Sequence Disclosures
Summary of Requirements for Patent Applications Filed On Or After July 1, 2022, That Have Sequence Disclosures
37 CFR 1.831(a) requires that patent applications which contain disclosures of nucleotide and/or amino acid sequences that fall within the definitions of 37 CFR 1.831(b) must contain a “Sequence Listing XML”, as a separate part of the disclosure, which presents the nucleotide and/or amino acid sequences and associated information using the symbols and format in accordance with the requirements of 37 CFR 1.831-1.835. This “Sequence Listing XML” part of the disclosure may be submitted:
1. In accordance with 37 CFR 1.831(a) using the symbols and format requirements of 37 CFR 1.832 through 1.834 via the USPTO patent electronic filing system (see Section I.1 of the Legal Framework for Patent Electronic System (https://www.uspto.gov/PatentLegalFramework), hereinafter “Legal Framework”) in XML format, together with an incorporation by reference statement of the material in the XML file in a separate paragraph of the specification (an incorporation by reference paragraph) as required by 37 CFR 1.835(a)(2) or 1.835(b)(2) identifying:
a. the name of the XML file
b. the date of creation; and
c. the size of the XML file in bytes; or
2. In accordance with 37 CFR 1.831(a) using the symbols and format requirements of 37 CFR 1.832 through 1.834 on read-only optical disc(s) as permitted by 37 CFR 1.52(e)(1)(ii), labeled according to 37 CFR 1.52(e)(5), with an incorporation by reference statement of the material in the XML format according to 37 CFR 1.52(e)(8) and 37 CFR 1.835(a)(2) or 1.835(b)(2) in a separate paragraph of the specification identifying:
a. the name of the XML file;
b. the date of creation; and
c. the size of the XML file in bytes.
SPECIFIC DEFICIENCIES AND THE REQUIRED RESPONSE TO THIS NOTICE ARE AS FOLLOWS:
Specific deficiency - This application fails to comply with the requirements of 37 CFR 1.831-1.834 because it does not contain a “Sequence Listing XML” as a separate part of the disclosure. A “Sequence Listing XML” is required because:
1. No SEQ ID NO and no corresponding CRF are available for the recited amino acid sequence for CD8alpha signal peptide in the extracellular domain of the CAR (paragraph 0072 and 0163).
2. No SEQ ID NO and no corresponding CRF are available the amino acid sequence for Myc-tag (paragraph 0072 and paragraph 0163).
Required response - Applicant must provide:
• A “Sequence Listing XML” part of the disclosure, as described above in item 1. or 2.; together with
o A statement that indicates the basis for the amendment, with specific references to particular parts of the application as originally filed, as required by 37 CFR 1.835(a)(3);
o A statement that the “Sequence Listing XML” includes no new matter as required by 37 CFR 1.835(a)(4)
AND
• A substitute specification in compliance with 37 CFR 1.52, 1.121(b)(3), and 1.125 inserting the required incorporation by reference paragraph as required by 37 CFR 1.835(a)(2), consisting of:
o A copy of the previously-submitted specification, with deletions shown with strikethrough or brackets and insertions shown with underlining (marked-up version);
o A copy of the amended specification without markings (clean version); and
o A statement that the substitute specification contains no new matter.
Specification
The disclosure is objected to because it contains an embedded hyperlink and/or other form of browser-executable code. Specifically in Paragraphs 0051, 0163 and 0180 contain embedded hyperlinks. Applicant is required to delete the embedded hyperlink and/or other form of browser-executable code; references to websites should be limited to the top-level domain name without any prefix such as http:// or other browser-executable code. See MPEP § 608.01.
The use of the term CellMark™ in Paragraph 0177, which is a trade name or a mark used in commerce, has been noted in this application. The term should be accompanied by the generic terminology; furthermore, the term should be capitalized wherever it appears or, where appropriate, include a proper symbol indicating use in commerce such as ™, SM , or ® following the term.
Although the use of trade names and marks used in commerce (i.e., trademarks, service marks, certification marks, and collective marks) are permissible in patent applications, the proprietary nature of the marks should be respected and every effort made to prevent their use in any manner which might adversely affect their validity as commercial marks.
Claim Objections
Claims 1, 4, 15 is objected to because of the following informality:
Regarding claim 1, “CAR-that specifically” should not include the dash line.
Regarding claim 4, “PEG” needs to be defined.
Regarding claim 15, “scFV” needs to be defined.
Appropriate correction is required.
Claim Rejections - 35 USC § 112
The following is a quotation of 35 U.S.C. 112(d):
(d) REFERENCE IN DEPENDENT FORMS.—Subject to subsection (e), a claim in dependent form shall contain a reference to a claim previously set forth and then specify a further limitation of the subject matter claimed. A claim in dependent form shall be construed to incorporate by reference all the limitations of the claim to which it refers.
The following is a quotation of pre-AIA 35 U.S.C. 112, fourth paragraph:
Subject to the following paragraph [i.e., the fifth paragraph of pre-AIA 35 U.S.C. 112], a claim in dependent form shall contain a reference to a claim previously set forth and then specify a further limitation of the subject matter claimed. A claim in dependent form shall be construed to incorporate by reference all the limitations of the claim to which it refers.
Claim 14 is rejected under 35 U.S.C. 112(d) or pre-AIA 35 U.S.C. 112, 4th paragraph, as being of improper dependent form for failing to further limit the subject matter of the claim upon which it depends, or for failing to include all the limitations of the claim upon which it depends. Claim 14 recites the same features of claim 12, wherein the cell comprises a chimeric antigen receptor (CAR) that recognizes the amphiphilic ligand. Thus claim 14 does not further limit claim 12 upon which it depends. Applicant may cancel the claim(s), amend the claim(s) to place the claim(s) in proper dependent form, rewrite the claim(s) in independent form, or present a sufficient showing that the dependent claim(s) complies with the statutory requirements.
Claim Rejections - 35 USC § 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(s) 1-3, 5-6, 8-16 are rejected under 35 U.S.C. 102(a)(1) as being anticipated by Jensen, WO/2018/148224 A1, published on 08/16/2018 (herein after referred to as Jensen WO’224).
Regarding claim 1, Jensen WO’224 teaches a method of treating a tumor (Paragraph 0091, page 293, “ methods of treatment, inhibition, or amelioration of cancer in mouse models of cancer” ) comprising,
introducing a membrane-inserting amphiphilic ligand into tumor of a subject in need of treatment (Paragraph 0092, page 293, “ Mice with mutations in the MSH2 and/or MLH1 genes” are “susceptible to developing gastrointestinal cancer and tumors” and these “mice were given the FL-PLE” [FL is fluorescein and PLE is phospholipid ether])
followed by administering an engineered immune cell expressing a CAR-that specifically binds to the amphiphilic ligand (Paragraph 0092, page 293 CAR “T cells expressing CARs that are specific for the target moiety” and “mice were given the FL-PLE followed by the CAR T cell […] after FL-PE administration”).
Jensen WO’224 demonstrates that the FL-PLE amphiphilic ligand is able to integrate in several in vitro tumor models (Paragraph 0098, page 295, “FL- PLE is able to integrate into multiple cancers: Be2 (neuroblastoma), U87 (glioblastoma), and daoy (medulloblastoma)”; Figure 7A). Jensen WO’224 also teaches that the CAR T cells that specifically recognize FL-PLE are able to target the FL-PLE in an in vivo CAR T tumor model (Paragraph 0100, page 296, “the antiFL CAR T cell was able to activate and slow down the engraftment of the tumor at a 10:1 E:T (effector to target ratio)”; Figure 10).
Regarding claim 2, Jensen WO’224 teaches all the limitations in claim 1 above and a fluorescein isothiocyanate lipid amphiphile ligand (Paragraph 0098, page 295, “FL- PLE is able to integrate into multiple cancers: Be2 (neuroblastoma), U87 (glioblastoma), and daoy (medulloblastoma)).
Regarding claim 3, Jensen WO’224 teaches all the limitations in claim 1 above and the engineered immune cell expressing a CAR that specifically binds to the amphiphilic ligand is a fluorescein isothiocyanate lipid amphiphile ligand (Paragraph 0099, page 296 “antiFL CAR T cells recognize the FL moiety of the FL-PLE, which was integrated into the plasma membrane of target cells [K562 tumor cell line]”; Figures 9A-C).
Regarding claim 5 and 6, Jensen WO’224 teaches all the limitations of claim 1 above and that the membrane-inserting amphiphilic ligand is introduced into the tumor by intratumoral injection (claim 5) and administering the engineered immune cell expressing a CAR that specifically binds to the amphiphilic ligand comprises systemic infusion of the engineered immune cell into the subject (claim 6) (Paragraph 0002, line 4-5; "synthetic compounds and CAR T cells are administered to a subject by intravenous or locoregional administration").
Regarding claim 8, Jensen WO’224 teaches all the limitations of claim 1 above and the tumor of a subject in need of treatment is a solid tumor (Paragraph 0105, “ the target cell is a target cell of a solid tumor”).
Regarding claim 9, Jensen WO’224 teaches all the limitations of claim 1 above and a therapeutic compound conjugated to an amphiphilic poly(ethylene glycol)-lipid (Paragraph 0006, “hapten, which is a target moiety, comprises [list examples of therapeutic drugs e.g.] morphine, metaxon”; Paragraph 0004 “the spacer comprises a PEG spacer”).
Regarding claim 10, Jensen WO’224 teaches all the limitations of claim 1 above and a frequency of intratumoral injection is equal or less than about once every 6 days (Paragraph 0092, “FL-PLE’s may be then redosed weekly or biweekly”).
Regarding claim 11, Jensen WO’224 teaches all the limitations of claim 1 above and the engineered immune cell expressing a CAR comprises a CD28 costimulatory domain (Paragraph 0033, “the CAR comprises a co-stimulatory domain. […] the co-stimulatory domain is CD28”).
Regarding claim 12, Jensen WO’224 teaches an engineered immune cell expressing a CAR that specifically binds to a membrane-inserted amphiphilic ligand of a tumor cell (Paragraph 0099, page 296 “antiFL CAR T cells recognize the FL moiety of the FL-PLE, which was integrated into the plasma membrane of target cells [K562 tumor cell line]”; Figures 9A-C).
Regarding claim 13, Jensen WO’224 teaches all the limitations of claim 12 above and the limitation “membrane-inserting amphiphilic ligand is a fluorescein isothiocyanate lipid amphiphile ligand” (Paragraph 0099, page 296, “antiFL CAR T cells recognize the FL moiety of the FL-moiety of the FL-PLE”).
Regarding claim 14 and 15, Jensen WO’224 teaches all the limitations of claim 12 above and the limitations “a chimeric antigen receptor that recognizes the amphiphilic ligand” (claim 14) and “chimeric antigen receptor comprises amphiphilic-ligand specific scFV” (claim 15) (Paragraph 0085, page 279, "The chimeric antigen receptor can comprise an antibody, antibody fragment, scFV or other binding moiety that is specific for the target moiety").
Regarding claim 16, Jensen WO’224 teaches all the limitations of claim 12 above and the limitation “a CD28 costimulatory domain” (Paragraph 0033 "the CAR comprises a co-stimulatory domain. [...] the co-stimulatory domain is CD28").
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 4 and 17 are rejected under 35 U.S.C. 103 as being unpatentable over Jensen, WO/2018/148224 A1, published on 08/16/2018 (herein after referred to as Jensen WO’224) as applied to claim 1 and 12 above, and further in view of Kolb, US 2018/0028647, published 02/01/2018 (herein after referred to as Kolb US’647)
Regarding claim 4, Jensen WO’224 teaches the limitations of claim 1 as described above. While Jensen WO’224 teaches the administration of an amphiphilic ligand into a tumor and an immune cell that expressed a CAR that binds to the amphiphilic ligand, Jensen WO’224 does not teach that the amphiphilic ligand comprises 1,2-distearoyl-sn-glycero-2-phosphoethanolamine-PEG-FITC (claim 4). Jensen WO’224 teaches that different phospholipids can be substituted on the ligand and that the amphiphilic ligand is a lipid that has a polar head group and a hydrophobic group wherein the polar head group comprises a phosphoethanolamine group (Paragraph 0005).
Kolb US’647 teaches a membrane-inserting amphiphilic ligand comprises 1,2-distearoyl-sn-glycero-3-phosphoethanolamine-PEG-FITC (Paragraph 0006, "composition that comprises a lipid [...] where the polar head group comprises a [...] phosphoethanolamine group [...]; a spacer comprises a PEG spacer; a target moiety that is a fluorescein"). Kolb teaches compositions and methods for treating cancer using amphiphilic compounds that include phospholipids such as 1,2-diacyl-sn-glycero-3-phosphoethanolamine" (Paragraph 0296, line 1-2). Kolb teaches that the amphiphilic compounds increase stability of targeted anti-cancer agents, and minimize their premature breakdown before reaching their targeted site (Paragraph 0007). In addition, Kolb teaches that the compositions can be used prior to or in conjunction [...] adoptive T cell therapy (Paragraph 0388) like CAR T cells (Paragraph 0390).
It would have been obvious to a person of ordinary skill of the art to substitute the phosphoether lipid ligand in Jensen with the 1,2-distearoyl-sn-glycero-3-phosphoethanolamine in Kolb to increase stability of the anti-cancer agents and minimize breakdown before reaching their target site. The simple substitution of one known element for another is likely to be obvious when predictable results are achieved. See KSR International Co. v. Teleflex Inc., 550 U.S. 398, 415-421, USPQ2d 1385, 1395 – 97 (2007) (see MPEP § 2143, B.).
Regarding claim 17, Jensen WO’224 teaches the limitations of claim 12 as described above. While Jensen WO’224 teaches the administration of an amphiphilic ligand into a tumor and an immune cell that expressed a CAR that binds to the amphiphilic ligand, Jensen WO’224 does not teach that the amphiphilic ligand comprises 1,2-distearoyl-sn-glycero-2-phosphoethanolamine-PEG-FITC (claim 12). However, Jensen WO’224 teaches that different phospholipids can be substituted on the ligand and that the amphiphilic ligand is a lipid that has a polar head group and a hydrophobic group wherein the polar head group comprises a phosphoethanolamine group (Paragraph 0005).
Kolb US’647 teaches a membrane-inserting amphiphilic ligand comprises 1,2-distearoyl-sn-glycero-3-phosphoethanolamine-PEG-FITC (Paragraph 0006, "composition that comprises a lipid [...] where the polar head group comprises a [...] phosphoethanolamine group [...]; a spacer comprises a PEG spacer; a target moiety that is a fluorescein"). Kolb teaches compositions and methods for treating cancer using amphiphilic compounds that include phospholipids such as 1,2-diacyl-sn-glycero-3-phosphoethanolamine" (Paragraph 0296, line 1-2). Kolb teaches that the amphiphilic compounds increase stability of targeted anti-cancer agents, and minimize their premature breakdown before reaching their targeted site (Paragraph 0007). In addition, Kolb teaches that the compositions can be used prior to or in conjunction [...] adoptive T cell therapy (Paragraph 0388) like CAR T cells (Paragraph 0390). It would have been obvious to a person of ordinary skill of the art to substitute the phosphoether lipid ligand in Jensen with the 1,2-distearoyl-sn-glycero-3-phosphoethanolamine in Kolb to increase stability of the anti-cancer agents and minimize breakdown before reaching their target site. The simple substitution of one known element for another is likely to be obvious when predictable results are achieved. See KSR International Co. v. Teleflex Inc., 550 U.S. 398, 415-421, USPQ2d 1385, 1395 – 97 (2007) (see MPEP § 2143, B.).
Claim 7 is rejected under 35 U.S.C. 103 as being unpatentable over Jensen, WO/2018/148224 A1, published on 08/16/2018 (herein after referred to as Jensen WO’224) as applied to claim 1 above, and further in view of Ma et al. (Ma L, Dichwalkar T, Chang JYH, Cossette B, Garafola D, Zhang AQ, Fichter M, Wang C, Liang S, Silva M, Kumari S, Mehta NK, Abraham W, Thai N, Li N, Wittrup KD, Irvine DJ. Enhanced CAR-T cell activity against solid tumors by vaccine boosting through the chimeric receptor. Science. 2019 Jul 12;365(6449):162-168. doi: 10.1126/science.aav8692.) and in further view of van der Burg et al. (van der Burg SH, Arens R, Ossendorp F, van Hall T, Melief CJ. Vaccines for established cancer: overcoming the challenges posed by immune evasion. Nat Rev Cancer. 2016 Apr;16(4):219-33. doi: 10.1038/nrc.2016.16. Epub 2016 Mar 11. PMID: 26965076.).
Jensen WO’224 teaches the limitations of claim 1 as discussed above. However, Jensen does not teach introducing the membrane-inserting amphiphilic ligand into dendritic cells in lymph nodes of the subject by subcutaneous injection (claim 7).
Ma et al. teaches a membrane-inserting amphiphilic ligand comprising 1,2-distearoyl-sn-glycero-3-phosphoethanolamine-PEG-FITC ("FITC-poly(ethylene glycol) (PEG)–1,2-distearoyl-sn-glycero-3-phosphoethanolamine (amph-FITC; Fig. 1B)", page 1, column 3, line 3).
In this research article by Ma et al. which was published before the effective filing date of the instant application, the authors teach a method of enhancing CAR-T cell activity against solid tumors by vaccine boosting through the chimeric receptor (title and abstract). Ma et al. teaches a method of introducing the membrane-inserting amphiphilic ligand into dendritic cells in the lymph nodes by subcutaneous injection (page 1, column 3, paragraph 2; Fig. 2B, CD11c+cells with anti-FITC reporter). They further teach that the amphiphilic ligand can partition into membranes of resident antigen presenting cells (APCs), thereby cosplaying the amphiphile ligand (amph-ligand) from the APC surface together with the native cytokine-receptor costimulation and that the ligand strategy safely expands CAR T-cells in vivo, while increasing their functionality and enhancing anti-tumor activity in multiple models of solid tumors (page 1, column 2, paragraph 2).
Van der Burg et al. describes that a challenge in adoptive T cell therapy known in the art is that immune suppression and immune escape mechanisms in tumor microenvironments may impact sustained T cell effector function (page 219, column 2, paragraph 2 "failed to ensure that these T cells could home to tumors and/or exert their function within the tumour"). van der Burg et al. then teaches a common strategy to increase efficacy of adoptive T cell therapy (ACT) is to utilize vaccination of the target antigen to stimulate dendritic cells (DCs) for optimal T cell activation (page 219, column 1, paragraph 1). van der Burg et al. teaches that the DCs are key antigen-presenting cells (APCs) to deliver signals (antigenic signals through the T cell receptor, co-stimulatory molecules and inflammatory cytokines) to T cells to expand and differentiate into effector and memory T cells (page 222, box 3). Van der Burg et al. also provides examples of studies that demonstrated therapeutic cancer vaccines in ACT can help induce and enlarge the pool of tumour-specific T cells, kick-start tumour infiltration and the induction of neoantigen-specific T cell responses in situ, and sustain T cell activation (page 229, column 2, paragraph 2).
It would have been obvious to a person of ordinary skill in the art before the effective filing date of the invention to improve the method of treating cancer using the CAR T cell and the amphiphilic ligand taught by Jensen WO'224's disclosure by utilizing a vaccine strategy of introducing the amphiphilic ligand into DCs in the lymph nodes by subcutaneous injection as described by Ma et al. The common vaccine strategy to insert the ligand to DCs would predictably improve CAR-T cell activation to the amphiphilic ligand, its expansion, increased functionality, and anti-tumor activity as suggested by van der Burg et al. See KSR International Co. v. Teleflex Inc., 550 U.S. 398, 415-421, USPQ2d 1385, 1395 – 97 (2007) (see MPEP § 2143, C.).
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 1-6, 8, 9, 11, and 12-17 are rejected on the ground of nonstatutory double patenting as being unpatentable over claims 1-5 of U.S. Patent No. 12,453,777 issued on 10/28/2025 (herein after referred to as USPat’777) in view of Jensen, WO/2018/148224 A1, published on 08/16/2018 (herein after referred to as Jensen WO’224) as applied to claims above, and further in view of Kolb, US 2018/0028647, published 02/01/2018 (herein after referred to as Kolb US’647) and as evidenced by Zhang et al. (Zhang C, Liu J, Zhong JF, Zhang X. Engineering CAR-T cells. Biomark Res. 2017 Jun 24;5:22. doi: 10.1186/s40364-017-0102-y. PMID: 28652918; PMCID: PMC5482931). Although the claims at issue are not identical, they are not patentably distinct from each other because they contain overlapping subject matter.
Regarding instant claim 1, USPat’777 claim 1 teaches a method of stimulating an immune response to a target cell population or a target issue in a subject, the method comprising administering a composition to the subject, wherein the composition comprises an amphiphilic ligand 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.
Regarding instant claim 2, USPat’777 claim 1 recites an amphiphilic conjugate comprising a CAR ligand wherein the CAR ligand is fluorescein isothiocyanate (FITC).
Regarding instant claim 3, USPat’777 claim 1 recites an immune cell comprising a CAR, wherein the CAR comprises an extracellular domain comprising a target-binding domain that binds to FITC. USPat’777 claim 2 recites a CAR further comprises a transmembrane domain and an intracellular signaling domain.
Regarding instant claim 4, USPat’777 claim 1 recites an amphiphilic conjugate comprising a lipid, wherein the lipid is 1,2-distearoyl-sn-glycero-3-phosphoethanolamine (DSPE).
Instant claim 5 recites membrane-inserting amphiphilic ligand is introduced into the tumor by intratumoral injection. However, USPat’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 of administering a composition to the subject but does not recite an intratumoral injection of the amphiphilic ligand. Jensen WO’224 teaches that the amphiphilic ligand can be administered intratumorally. It would have been obvious for a person ordinary skill in the art to administer the amphiphilic ligand intratumorally because Jensen WO’224 recites that route of administration of the ligand can be intratumoral (Paragraph 0002, line 4-5; "synthetic compounds and CAR T cells are administered to a subject by intravenous or locoregional administration").
Instant claim 6 recites administering the engineered immune cell expressing a CAR that specifically binds to the amphiphilic ligand comprises systemic infusion of the engineered immune cell into the subject. USPat’777 claim 1 recites a subject comprising an immune cell comprising a CAR but does not recite a systemic infusion of the engineered immune cell into the subject. Jensen WO’224 teaches a method step wherein the CAR T cells are administered to a subject by intravenous administration (Paragraph 0002, line 4-5 “synthetic compounds and CAR T cells are administered to a subject by intravenous or locoregional administration"). It would have been obvious to a person of ordinary skill in the art to administer the engineered immune cell by systemic infusion using Jensen WO’224 disclosure.
Instant claim 8 recites the tumor of a subject in need of treatment is a solid tumor. USPat’777 claim 1 recites a method of stimulating an immune response to a target cell population or a target tissue in a subject but does not recite a solid tumor. Jensen WO’224 teaches the tumor of a subject in need of treatment is a solid tumor (Paragraph 0105, “ the target cell is a target cell of a solid tumor”). It would have been obvious to a person skilled in the art to conclude that the target tissue in the subject in USPat’777 includes solid tumors.
Instant claim 9 recites a therapeutic compound conjugated to an amphiphilic poly(ethylene glycol)-lipid. The therapeutic compounds are recited in USPat’777 wherein 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 (claim 4) and the amphiphilic ligand conjugate binds albumin under physiological conditions (claim 5). Jensen WO’224 teaches all of the limitations of instant claim 1 and different haptens conjugated to amphiphilic ligands which include oligonucleotides (page 23, e.g. “guanine”) and albumin (Paragraph 0009, “a target moiety , such as fluorescein, is an albumin , a mutant albumin, or fragment thereof”). It would have been obvious to a person of skilled in the art to substitute different therapeutic compounds to conjugate with the amphiphilic ligand.
Instant claim 11 recites the engineered immune cell expressing a CAR comprises a CD28 costimulatory domain. USPat’777 claim 3 recites a CAR further comprises one or more co-stimulatory domains but does not recite CD28 costimulatory domain. Jensen WO’224 teaches the engineered immune cell expressing a CAR comprises a CD28 costimulatory domain (Paragraph 0033, “the CAR comprises a co-stimulatory domain. […] the co-stimulatory domain is CD28”). It would have been obvious to a person of ordinary skill in the art to include CD28 as the costimulatory domain in instant claim 11 in the one or more co-stimulatory domains in USPat’777 claim 3.
Regarding instant claim 12, USPat’777 claim 1 recites an immune cell comprising a CAR, wherein the CAR comprises an extracellular domain comprising a target-binding domain that binds to FITC wherein the composition that is administered to the subject 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 and the CAR ligand is fluorescein isothiocyanate (FITC).
Regarding instant claim 13, USPat’777 claim 1 recites an amphiphilic ligand conjugate comprising a lipid, a CAR ligand wherein the CAR ligand is fluorescein isothiocyanate (FITC).
Regarding instant claim 14, USPat’777 claim 1 recites a CAR comprising an extracellular domain comprising a target-binding domain that binds to FITC wherein the amphiphilic ligand conjugate comprises a CAR ligand wherein the CAR ligand is fluorescein isothiocyanate (FITC).
Regarding instant claim 15, USPat’777 claim 1 recites a CAR comprising an extracellular domain comprising a target-binding domain that binds to FITC wherein the amphiphilic ligand conjugate comprises a CAR ligand wherein the CAR ligand is fluorescein isothiocyanate (FITC) . Instant claim 15 claims an scFV which is known in the art to be a part of the extracellular domain of the CAR. CARs include three parts: an extracellular antigen recognition domain of the single-chain Fragment variant (scFV) derived from an antibody, a transmembrane domain and an intracellular T cell activation domain of CD3ζ (Zhang C, Liu J, Zhong JF, Zhang X. Engineering CAR-T cells. Biomark Res. 2017 Jun 24;5:22. doi: 10.1186/s40364-017-0102-y. PMID: 28652918; PMCID: PMC5482931.).
Regarding instant claim 16, USPat’777 claim 3 recites a CAR further comprises one or more co-stimulatory domains.
Regarding instant claim 17, USPat’777 claim 1 recites 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 and the CAR ligand is fluorescein isothiocyanate (FITC).
Claim 1 - 4, 7, 11-14, 16, and 17 are provisionally rejected on the ground of nonstatutory double patenting as being unpatentable over claims 77, 83, 85, 86, 87, 89, 91, 92, 96, 97, 99-101 of copending Application No. 18/339,230 (App’230, claim set filed on 04/01/2025) in view of Ma et al., 2019. Although the claims at issue are not identical, they are not patentably distinct from each other because they contain overlapping subject matter.
Copending App’230 claim 77 recites a method of activating, expanding or increasing proliferation of chimeric antigen receptor-T (CAR-T) cells in a subject, 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 CAR ligand binds to the CAR of the CAR-T cells.
Dependent claims of the copending application further include more specific embodiments of the membrane-inserting amphiphilic ligand (claims 77, 92), comprising a 1,2-diastearoyl-sn-glycero-3-phosphoethanolamine-PEG-FITC (claim 83, 85, 86, 87), the engineered immune cell expressing a CAR (claim 77, 96), and a CAR comprising a costimulatory domain (claim 89). The copending application also teaches that the subject has cancer (claim 97).
Furthermore, the copending App’230 claim 91 and 92 recite the amphiphilic ligand conjugate is trafficked to lymph nodes and the amphiphilic ligand conjugate is inserted into membrane of antigen presenting cells upon trafficking to the lymph nodes. However, App’230 claim 91 and 92 does not teach the introduction of the amphiphilic ligand conjugate to dendritic cell in lymph nodes of the subject by subcutaneous injection. Ma et al. teaches a membrane-inserting amphiphilic ligand comprising 1,2-distearoyl-sn-glycero-3-phosphoethanolamine-PEG-FITC ("FITC-poly(ethylene glycol) (PEG)–1,2-distearoyl-sn-glycero-3-phosphoethanolamine (amph-FITC; Fig. 1B)", page 1, column 3, line 3) and a method of introducing the membrane-inserting amphiphilic ligand into dendritic cells in the lymph nodes by subcutaneous injection (page 1, column 3, paragraph 2; Fig. 2B, CD11c+cells with anti-FITC reporter). It would have been obvious to the person of ordinary skill in the art to use subcutaneous injection of the ligand to introduce the ligand to the membrane of the antigen presenting cells such as dendritic cells that are trafficked to lymph nodes as described by Ma et al.
Claims 99-101 in App’230 are currently withdrawn as of 04/01/2025 but they are provisionally rejected under the ground of nonstatutory double patenting in the event the application becomes active later on in the prosecution such as a rejoinder. Claims 99-101 in App’230 are drawn to 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 of 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, wherein the CAR ligand binds to the CAR of the CAR-T cells. Claims 100-101 claims that the immune responses is a T-cell mediated immune response or an anti-tumor immune response and that the target cell population or target tissue is tumor cells or tumor tissue.
This is a provisional nonstatutory double patenting rejection.
Conclusion
No claims are allowed.
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/LAM THUY VI TRAN HO/Examiner, Art Unit 1647 /JOANNE HAMA/Supervisory Patent Examiner, Art Unit 1647