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 .
1. The Election filed January 5, 2026 in response to the Office Action of November 5, 2025 is acknowledged. Applicant elected with traverse Group II and the species of:
F. immune cell (claim 14);
G. effector cell comprising a CAR having a targeting specificity in claim 15;
H. Not applicable claim 17;
I. effector cell comprising a CAR that is T cell specific (claim 18);
J. effector cell expressing cell surface exogenous IL-2 receptor (claim 19);
K. Not applicable claim 20;
L. cell comprises one or more exogenous polynucleotides integrated in a safe harbor locus of H11 (claim 22);
M. Not applicable claim 25;
N. therapeutic agent is an antibody (claims 29-31).
It is noted that although Applicants elected “immune cell” from claim 14 in species F, Applicants continued to elect a species in G, claim 15, wherein claim 15 is limited to the iPSC-derived effector cell of claim 14, and the language of claim 15 excludes the term “immune cell”. However, Examiner understands that iPSC-derived effector cells fall under the scope of immune cells, even if the language of claim 15 excludes the “immune cells”. In the interest of compact prosecution, Examiner has rejoined the species of iPSC-derived effector cell for examination. Consistent with rejoinder iPSC-derived effector cells and with Applicant’s species elections, the claims will be examined as drawn to the rejoined and elected species of:
F. immune cell that is an iPSC-derived effector cell (claim 14);
G. effector cell comprising a CAR having a targeting specificity in claim 15;
H. withdraw claim 17;
I. effector cell comprising a CAR that is T cell specific (claim 18);
J. effector cell expressing cell surface exogenous IL-2 receptor (claim 19);
K. withdraw claim 20;
L. cell comprises one or more exogenous polynucleotides integrated in a safe harbor locus of H11 (claim 22);
M. rejoin claim 25;
N. therapeutic agent is an antibody (claims 29-31).
2. Applicants argue that all of the claims depend from claim 1 and share the technical feature of claim 1. Applicants argue that the International Search Report indicates claim 1 is novel and inventive. Applicants argue that all of the claims share the special technical feature of claim 1 and should be examined together.
The arguments have been carefully considered but are not persuasive. The chimeric fusion receptor of claim 1 is not a special technical feature that makes a contribution over the prior art. See prior art rejections below (WO 2019/126748, Valamehr, and WO 2020/193506, Schamel) that teach or render obvious the special technical feature argued by Applicants. Thus, the “special technical feature” of claim 1 does not define a contribution over the prior art and the inventions lack unity. For these reasons, the restriction requirement is deemed to be proper and is therefore made FINAL.
3. Claims 1-42 are pending. Claims 1-13 and 32-42 have been withdrawn from further consideration by the examiner under 35 CFR 1.142(b) as being drawn to non-elected inventions. Claims 17, 20, 24, and 27 are withdrawn as being drawn to non-elected species. Claims 14-16, 18, 19, 21-23, 25, 26, 28-31 are currently under prosecution as drawn to the elected and rejoined species stated above.
Claim Objections
4. Claim 14 is objected to because of the following informalities: Claim 14 depends from claim 1 which is a non-elected invention. Examiner suggests incorporating the wording of claim 1 into claim 14. Appropriate correction is required.
Claim Rejections - 35 USC § 101
35 U.S.C. 101 reads as follows:
Whoever invents or discovers any new and useful process, machine, manufacture, or composition of matter, or any new and useful improvement thereof, may obtain a patent therefor, subject to the conditions and requirements of this title.
Section 33(a) of the America Invents Act reads as follows:
Notwithstanding any other provision of law, no patent may issue on a claim directed to or encompassing a human organism.
5. Claims 14-16, 18, 19, 22, 23, 26, 28-31 are rejected under 35 U.S.C. 101 and section 33(a) of the America Invents Act as being directed to or encompassing a human organism. See also Animals - Patentability, 1077 Off. Gaz. Pat. Office 24 (April 21, 1987) (indicating that human organisms are excluded from the scope of patentable subject matter under 35 U.S.C. 101). Claim 14 recites a cell or population of cells comprising a polynucleotide encoding the chimeric fusion receptor of claim 1, wherein the cell is a eukaryotic cell, animal cell, human cell, or immune cell which all encompass cells within in a human being, therefore encompass a transgenic human. Claim 26 recites a composition comprising the cell or population thereof and encompasses the composition of a human. Claim 28 recites the same composition with intended use “and one or more therapeutic agents”. The claim reasonably encompasses a human composition of the cells, wherein the human is holding a container of the therapeutic agent/ antibody.
Examiner Suggestion: Amend claim 14 to recite an isolated cell or isolated population of cells.
Claim Rejections - 35 USC § 112
The following is a quotation of 35 U.S.C. 112(b):
(b) CONCLUSION.—The specification shall conclude with one or more claims particularly pointing out and distinctly claiming the subject matter which the inventor or a joint inventor regards as the invention.
The following is a quotation of 35 U.S.C. 112 (pre-AIA ), second paragraph:
The specification shall conclude with one or more claims particularly pointing out and distinctly claiming the subject matter which the applicant regards as his invention.
6. Claim 31 is rejected under 35 U.S.C. 112(b) or 35 U.S.C. 112 (pre-AIA ), second paragraph, as being indefinite for failing to particularly point out and distinctly claim the subject matter which the inventor or a joint inventor (or for applications subject to pre-AIA 35 U.S.C. 112, the applicant), regards as the invention. Claim 31 recites a list of possible antibodies that serve as the therapeutic agent in the composition comprising the cell or population of cells thereof of claim 14, which encompasses a variety of cells (immune cells, feeder cell, iPSC, iPSC-derived effector cell, etc). However, after listing antibodies, claim 31 recites: “and wherein the iPSC-derived effector cell comprises a CD38 knockout, and optionally an expression of CD16 or a variant thereof”. The added limitation at the end of claim 31 renders the scope of the claimed invention unclear. Are the antibodies listed in claim 31 limited to iPSC-derived effector cells or can the antibodies be comprised with any of the cells listed in claim 14? The metes and bounds of the claimed invention cannot be determined.
7. Claims 28-31 are rejected under 35 U.S.C. 112(b) or 35 U.S.C. 112 (pre-AIA ), second paragraph, as being indefinite for failing to particularly point out and distinctly claim the subject matter which the inventor or a joint inventor (or for applications subject to pre-AIA 35 U.S.C. 112, the applicant), regards as the invention. Claim 28 recites: “A composition for therapeutic use comprising the cell or population thereof of claim 14, and one or more therapeutic agents.” The claim is unclear with regard to whether the therapeutic agent(s) are supposed to be comprised in the composition with the cells or if the agent(s) are existing separately. The metes and bounds of the claimed invention cannot be determined.
Claim Rejections - 35 USC § 102
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.
8. Claim(s) 14-16, 18, 19, 21-23, 25, 26, 28-31 are rejected under 35 U.S.C. 102(a)(1) and 35 U.S.C. 102(a)(2) as being anticipated by WO 2019/126748, Valamehr et al, published June 27, 2019, claiming priority to December 2017; as evidenced by the instant specification.
Valamehr teaches an immune cell or a population thereof, comprising a polynucleotide encoding a “chimeric fusion receptor” (CFR), wherein the CFR comprises and ectodomain receptor (i.e., of ectodomain of CD16), transmembrane domain (i.e., non-native TM domain derived from CD3, CD8a or CD28), costimulatory endodomain (i.e., non-native costimulatory domain derived from CD28), and signaling endodomain (i.e. non-native CD3ζ ITAM) ([20]; [128]; claims 5-7);
wherein the immune cell is an iPSC-derived NK effector cell or derivative NK cell progenitor ([16]; [26]; [41]; [51]; [236]; claims 1, 4, 10; Example 3);
wherein the cell also expresses a chimeric antigen receptor (CAR) with targeting specificity for an immune cell or tumor antigen ([17]; [22]; [23]; [26]; claim 8), wherein the CAR can also be considered a “chimeric fusion receptor”, wherein it comprises an ectodomain receptor, transmembrane domain comprising CD8a or CD28, and an endodomain (intracellular domain) comprising the native or modified ITAM of CD3ζ signaling domain and costimulatory domain comprising CD28, such as SEQ ID NO:13 (CD28- CD3ζITAM) ([133-138]); wherein the CAR ectodomain is an antigen recognition domain that targets immune cells or tumor antigens, and can be an antibody, scFv, single domain antibody or VHH ([133-134]), fragments which are not expected to contain endoplasmic reticulum retention (ERR) signals or endocytosis signals;
wherein the cell has therapeutic properties including:
(i) improved persistency and/or survival;
(ii) increased resistance to native immune cells;
(iii) increased cytotoxicity;
(iv) improved tumor penetration;
(v) enhanced or acquired ADCC;
(vi) enhanced ability in migrating, and/or activating or recruiting bystander immune cells, to tumor sites;
(vii) enhanced ability to reduce tumor immunosuppression;
(viii) improved ability in rescuing tumor antigen escape; and
(ix) reduced fratricide,
in comparison to its native counterpart cell obtained from peripheral blood, umbilical cord blood, or any other donor tissues ([19]; claim 4);
wherein the CAR is T cell specific ([21]; [229]; claim 8);
wherein the cell comprises a partial or full peptide of a cell surface expressed exogenous cytokine or a receptor, wherein the receptor is IL-2R ([24]; claim 9);
wherein the iPSC-derived NK effector cell is capable of recruiting, and/or migrating T cells to tumor sites, or is capable of reducing tumor immunosuppression in the presence of one or more checkpoint inhibitors ([25]; claim 10); and
wherein the cell comprises one or more exogenous polynucleotides integrated into a safe harbor locus that is H11 ([18]; [179]; [191]; [194-196]; [210]; [222]; claims 14-16; Example 1).
Valamehr further teaches a composition comprising the cell or population of cells; and the composition comprising the cell or cells and one or more therapeutic agents that is an antibody, wherein the antibody binds to checkpoint molecule PD-1, or is anti-CD20 ([27-28]; [169-178]; claims 17-21).
As evidenced by the instant specification, CD28 endodomain inherently does not contain any endoplasmic reticulum retention (ERR) signals or endocytosis signals ([134] “the CD28 wildtype endodomain does not have either ER retention or endocytosis motifs”), therefore the CD28 endodomain taught by Valamehr does not have ERR or endocytosis signals. Further, the CD28-CD3ζITAM endodoman taught by Valamehr, SEQ ID NO:13 ([138]), is 100% identical to instant endodoman SEQ ID NO:13 that appears to lack any ERR signals or endocytosis signals (see sequence alignment below).
The CD16 ectodomain and TM domains of the chimeric fusion receptor taught by Valamehr do not appear to contain ERR signals or endocytosis signals.
The ectodomain of the CAR, such as an antibody, scFv, single domain antibody, or VHH does not appear to contain ERR signals or endocytosis signals.
As stated above, the CD16 “chimeric fusion receptor” (CFR) and “chimeric antigen receptor” (CAR) of Valamehr comprise the same parts: ectodomain receptor/binding region-TM domain-endodoman (intracellular costimulatory/signaling domain), therefore either fall into the scope of the instantly claimed “chimeric fusion receptor”. Valamehr does not specifically teach that the entire chimeric fusion receptor (CD16 ectodomain-CD28 TM-CD28-CD3ζ endodomain) or entire CAR (antibody ectodomain-CD28 TM-CD28-CD3ζ endodomain) lacks ERR signals or endocytosis signals, however, the claimed chimeric fusion receptor (CFR) appears to be the same as the prior art CD16 chimeric fusion receptor and CAR, absent a showing of unobvious differences. The office does not have the facilities and resources to provide the factual evidence needed in order to establish that the product of the prior art does not possess the same material, structural and functional characteristics of the claimed product. In the absence of evidence to the contrary, the burden is on the applicant to prove that the claimed product is different from those taught by the prior art and to establish patentable differences. See In re Best 562F.2d 1252, 195 USPQ 430 (CCPA 1977) and Ex parte Gray 10 USPQ 2d 1922 (PTO Bd. Pat. App. & Int. 1989).
Sequence alignment of instant SEQ ID NO:13 with Valamehr SEQ ID NO:13 of endodomain CD28 costimulatory domain + CD3ζITAM:
(QY) = instant SEQ ID NO:13
(Db) = Valamehr SEQ ID NO:13
Result Query
No. Score Match Length DB ID Description
----------------------------------------------------------------------------
1 816 100.0 153 1 AASEQ2_02242026_185246
ALIGNMENTS
RESULT 1
AASEQ2_02242026_185246
Query Match 100.0%; Score 816; DB 1; Length 153;
Best Local Similarity 100.0%;
Matches 153; Conservative 0; Mismatches 0; Indels 0; Gaps 0;
Qy 1 RSKRSRLLHSDYMNMTPRRPGPTRKHYQPYAPPRDFAAYRSRVKFSRSADAPAYQQGQNQ 60
||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
Db 1 RSKRSRLLHSDYMNMTPRRPGPTRKHYQPYAPPRDFAAYRSRVKFSRSADAPAYQQGQNQ 60
Qy 61 LYNELNLGRREEYDVLDKRRGRDPEMGGKPRRKNPQEGLFNELQKDKMAEAFSEIGMKGE120
||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
Db 61 LYNELNLGRREEYDVLDKRRGRDPEMGGKPRRKNPQEGLFNELQKDKMAEAFSEIGMKGE120
Qy 121 RRRGKGHDGLFQGLSTATKDTFDALHMQALPPR 153
|||||||||||||||||||||||||||||||||
Db 121 RRRGKGHDGLFQGLSTATKDTFDALHMQALPPR 153
9. Claim(s) 14 and 26 are rejected under 35 U.S.C. 102(a)(1) and 35 U.S.C. 102(a)(2) as being anticipated by WO 2020/193506, Schamel et al, published October 1, 2020, claiming priority to March 2019; as evidenced by the instant specification.
Schamel teaches a composition comprising a T cell or population thereof, comprising and expressing a polynucleotide encoding a chimeric fusion receptor, also known as chimeric antigen receptor (CAR), with improved functionality, wherein the CAR comprises an antigen-binding ectodomain, a transmembrane (TM) domain, and an endodomain (intracellular domain);
wherein the antigen-binding ectodomain can be an antibody scFv (anti-CD19 scFv);
wherein the TM domain can be derived from CD8 or CD28;
wherein the endodomain comprises:
(i) a costimulatory domain such as derived from CD28 or 4-1BB;
(ii) a TCR-derived activation domain/primary cytoplasmic signaling sequence containing ITAM, such as CD3ε (CD3 epsilon); and
(iii) a second TCR-derived activation domain derived from CD3ζ (p. 2-9; claim 1-15);
wherein the CD3ε domain comprises a deletion of the endoplasmic reticulum retention sequence (deleting SEQ ID NO:3 NQRRI) (p. 8-9; 13-16; claim 6), for example, miniεRKζCAR and miniεAARKζCAR in Figure 2 lack the ERR signal:
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wherein the immune cell is a T cell transfected with a polynucleotide encoding the CAR (Experiment 1; Figure 4);
wherein the deletion of the ERR signal (deletion of SEQ ID NO:3) substantially increased the surface CAR expression (p. 17; Figure 4; Experiment 1); and
wherein T cell expressing miniεRKζCAR comprising the ERR signal deletion had significantly higher anti-tumor activity killing CD19-expressing cancer cells than T cells expressing the parental ζCAR (p. 19; Figure 5; Experiment 2).
As evidenced by the instant specification, CD28 endodomain inherently does not contain any endoplasmic reticulum retention (ERR) signals or endocytosis signals ([134] “the CD28 wildtype endodomain does not have either ER retention or endocytosis motifs”). Therefore, the CD28 endodomain taught by Schamel is not expected to contain ERR signals or endocytosis signals.
The CAR of Schamel comprises the same parts: ectodomain receptor/binding region-TM domain-endodoman (intracellular costimulatory/signaling domain) as the instantly claimed chimeric fusion receptor, therefore the CAR of Schamel falls into the scope of the instantly claimed “chimeric fusion receptor”. Schamel teaches a CAR comprising anti-CD19 scFv ectodomain - CD8 TM -41BB - CD3ε signaling domain lacking the ERR signal- CD3ζ signaling domain which do not appear to contain ERR signals or endocytosis signals. Schamel does not specifically teach that the entire CAR lacks ERR signals or endocytosis signals, however, the claimed chimeric fusion receptor (CFR) appears to be the same as the prior art CAR, absent a showing of unobvious differences. The office does not have the facilities and resources to provide the factual evidence needed in order to establish that the product of the prior art does not possess the same material, structural and functional characteristics of the claimed product. In the absence of evidence to the contrary, the burden is on the applicant to prove that the claimed product is different from those taught by the prior art and to establish patentable differences. See In re Best 562F.2d 1252, 195 USPQ 430 (CCPA 1977) and Ex parte Gray 10 USPQ 2d 1922 (PTO Bd. Pat. App. & Int. 1989).
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.
10. Claim(s) 14 and 26 are rejected under 35 U.S.C. 103 as being unpatentable over WO 2020/193506, Schamel et al, published October 1, 2020, claiming priority to March 2019.
Schamel teaches a composition comprising a T cell or population thereof, comprising and expressing a polynucleotide encoding a chimeric fusion receptor, also known as chimeric antigen receptor (CAR), with improved functionality, wherein the CAR comprises an antigen-binding ectodomain, a transmembrane (TM) domain, and an endodomain (intracellular domain);
wherein the antigen-binding ectodomain can be an antibody scFv (anti-CD19 scFv);
wherein the TM domain can be derived from CD8 or CD28;
wherein the endodomain comprises:
(i) a costimulatory domain such as derived from CD28 or 4-1BB;
(ii) a TCR-derived activation domain/primary cytoplasmic signaling sequence containing ITAM, such as CD3ε (CD3 epsilon); and
(iii) a second TCR-derived activation domain derived from CD3ζ (p. 2-9; claim 1-15);
wherein the CD3ε domain comprises a deletion of the endoplasmic reticulum retention sequence (deleting SEQ ID NO:3 NQRRI) (p. 8-9; 13-16; claim 6), for example, miniεRKζCAR and miniεAARKζCAR in Figure 2:
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430
778
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wherein the immune cell is a T cell transfected with a polynucleotide encoding the CAR (Experiment 1; Figure 4);
wherein the deletion of the ERR signal (SEQ ID NO:3) substantially increased the cell surface CAR expression (p. 17; Figure 4; Experiment 1); and
wherein T cell expressing miniεRKζCAR lacking the ERR signal had significantly higher anti-tumor activity killing CD19-expressing cancer cells than T cells expressing the parental ζCAR (p. 19; Figure 5; Experiment 2).
The CAR of Schamel comprises the same parts: ectodomain receptor/binding region-TM domain-endodoman (intracellular costimulatory/signaling domain) as the instantly claimed chimeric fusion receptor, therefore either falls into the scope of the instantly claimed “chimeric fusion receptor”. Schamel teaches a CAR comprising: anti-CD19 scFv ectodomain - CD8 TM - 41BB - CD3ε signaling domain lacking the ERR signal- CD3ζ signaling domain, all of which do not appear to contain ERR signals or endocytosis signals, however, Schamel does not explicitly state this.
It would have been prima facie obvious to one of ordinary skill in the art at the time the invention was filed to remove ERR signals from the CAR of Schamel. One would have been motivated to, and have a reasonable expectation of success to because: (1) Schamel suggests improving functionality of the CAR T cell by removing the ERR signal to enhance cell surface expression; (2) Schamel demonstrates successfully identifying and removing an ERR signal from the CAR; and (3) Schamel demonstrates that removing the ERR signal from the CAR results in a CAR T cell with substantially increased cell surface CAR expression and significantly higher anti-tumor activity killing cancer cells.
11. Claim(s) 28-30 is/are rejected under 35 U.S.C. 103 as being unpatentable over WO 2020/193506, Schamel et al, published October 1, 2020, claiming priority to March 2019 as applied to claims 14 and 26 above, and further in view of Cao et al (Frontiers in Oncology, 2019, 9:767, internet pages 1-11).
Schamel teaches a composition comprising a T cell expressing an anti-CD19 CAR lacking ERR signals, as set forth above. Schamel further teaches anti-CD19 CAR T cells are FDA approved for treatment of B-cell malignancies including lymphoma (p. 1), teaches utilizing their CAR T cells to treat cancer (claim 15); and demonstrates their CAR T cell successfully kills CD19-expressing cancer cells derived from lymphoma (Figures 6 and 9).
Schamel does not teach a composition of their CAR T cells and an anti-PD-1 antibody, nivolumab.
Cao teaches successfully combining anti-CD19 CAR T cells with nivolumab for the treatment of lymphoma which resulted in potent anti-lymphoma activity (abstract).
It would have been prima facie obvious to one of ordinary skill in the art at the time the invention was filed to add anti-PD-1 antibody nivolumab to the anti-CD19 CAR T cell composition of Schamel. One would have been motivated to, and have a reasonable expectation of success to because (1) Schamel suggests utilizing their anti-CD19 CAR T cell for the treatment of lymphoma, and recognizes anti-CD19 CAR T cells are FDA approved for the treatment of lymphoma; and (2) Cao teaches the addition of PD-1 antibody nivolumab to anti-CD19 CAR T cell therapy was effective in treating lymphoma, resulting in potent anti-lymphoma activity.
12. Claim(s) 28, 29, and 31 is/are rejected under 35 U.S.C. 103 as being unpatentable over WO 2020/193506, Schamel et al, published October 1, 2020, claiming priority to March 2019 as applied to claims 14 and 26 above, and further in view of Mihara et al (British Journal of Hematology, 2010, 151:37-46).
Schamel teaches a composition comprising a T cell expressing an anti-CD19 CAR lacking ERR signals, as set forth above. Schamel further teaches anti-CD19 CAR T cells are FDA approved for treatment of B-cell malignancies including lymphoma (p. 1), teaches utilizing their CAR T cells to treat cancer (claim 15); and demonstrates their CAR T cell successfully kills CD19-expressing cancer cells derived from lymphoma (Figures 6 and 9).
Schamel does not teach a composition of their CAR T cells and anti-CD20 antibody rituximab.
Mihara teaches successfully combining anti-CD19 CAR T cells with rituximab for the treatment of lymphoma which resulted in synergistic tumor-suppressing activity (abstract).
It would have been prima facie obvious to one of ordinary skill in the art at the time the invention was filed to add rituximab to the anti-CD19 CAR T cell composition of Schamel. One would have been motivated to, and have a reasonable expectation of success to because (1) Schamel suggests utilizing their anti-CD19 CAR T cell for the treatment of lymphoma, and recognizes anti-CD19 CAR T cells are FDA approved for the treatment of lymphoma; and (2) Mihara teaches the addition of rituximab to anti-CD19 CAR T cell therapy resulted in synergistic tumor-suppressing activity.
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.
13. Claims 14-16, 18, 19, 21-23, 25, 26, 28-31 are provisionally rejected on the ground of nonstatutory double patenting as being unpatentable over claims 1-52 of copending Application No. 18/250,737 (reference application). Although the claims at issue are not identical, they are not patentably distinct from each other because the copending application claims an overlapping population of immune cells expressing a chimeric fusion receptor comprising same features instantly claimed, additionally a therapeutic antibody, that render obvious the instantly claimed cell composition.
The copending application claims:
1. A cell or a population thereof, wherein the cell is an eukaryotic cell, an animal cell, a human cell, an immune cell, an induced pluripotent cell (iPSC), a clonal iPSC or a derivative cell differentiated therefrom, and wherein the cell comprises:
(i) a polynucleotide encoding a transgenic TCRα chain (tgTCRα); and
(ii) a polynucleotide encoding a transgenic TCRβ chain (tgTCRβ), wherein the tgTCRα chain and the tgTCRβ chain form an exogenous TCR complex (TCRexo) that recognizes a first tumor antigen; and optionally,
(iii) one or more additional exogenous polynucleotides comprising a polynucleotide encoding a chimeric antigen receptor (CAR) or an engager targeting at least a second tumor antigen.
2. The cell or population thereof of claim 1, wherein:
(i) the polynucleotide encoding the tgTCRα chain and the polynucleotide encoding the tgTCRβ chain are comprised in a bi-cistronic construct, and optionally wherein:
(a) the construct is inserted at a constant region of TCRα or TCRβ (TRAC or TRBC);
(b) the insertion of the construct disrupts expression of endogenous TCRα or TCRβ at the insertion site; and/or
(c) expression of the construct is driven by an endogenous promoter of TCR or an exogenous promoter; or
(ii) the polynucleotide encoding the CAR or the engager is inserted at TRAC or TRBC, and optionally wherein:
(a) the insertion of the polynucleotide encoding the CAR or the engager disrupts expression of the endogenous TCRα or TCRβ at the insertion site; and/or
(b) expression of the CAR or the engager is driven by an endogenous promoter of TCR or an exogenous promoter; or
(iii) the polynucleotides encoding the tgTCRα chain and the tgTCRβ chain, the CAR or the engager, or the one or more additional polynucleotides are inserted in one, or more safe harbor loci or selected gene loci.
3. The cell or population thereof of claim 2, (I) wherein the construct and the polynucleotide encoding the CAR or the engager are each inserted at a constant region of TCRα or TCRβ (TRAC or TRBC), but not at the same constant region, thereby disrupting expression of both endogenous TCRα and TCRβ, knocking out the endogenous TCR, and avoiding a mis-paired TCR comprising:
(a) the transgenic TCRα and the endogenous TCRβ, or
(b) the transgenic TCRβ and the endogenous TCRα;
or (II) wherein the construct and the polynucleotide encoding the CAR or the engager are each integrated at a locus comprising a safe harbor locus or a selected gene locus.
4. The cell or population thereof of claim 3, wherein:
(i) the safe harbor locus comprises at least one of AAVS1, CCR5, ROSA26, collagen, HTRP, H11, GAPDH, or RUNX1;
(ii) the selected gene locus is one of B2M, TAP1, TAP2, Tapasin, NLRC5, CIITA, RFXANK, RFX5, RFXAP, TCR, NKG2A, NKG2D, CD38, CD25, CD69, CD44, CD58, CD54, CD56, CD69, CD71, CIS, CBL-B, SOCS2, PD1, CTLA4, LAG3, TIM3, or TIGIT; and/or
(iii) the integration of the exogenous polynucleotides knocks out expression of the gene in the locus.
7. The cell of population thereof of claim 1, wherein the CAR is:
(i) T cell specific or NK cell specific;
(ii) a bi-specific antigen binding CAR;
(iii) a switchable CAR;
(iv) a dimerized CAR;
(v) a split CAR;
(vi) a multi-chain CAR;
(vii) an inducible CAR;
(viii) an inactivation CAR;
(ix) co-expressed with a partial or full peptide of a cell surface expressed exogenous cytokine and/or a receptor thereof, optionally in separate constructs or in a bi-cistronic construct;
(x) co-expressed with a checkpoint inhibitor, optionally in separate constructs or in a bi-cistronic construct.
8. The cell or population thereof of claim 1, wherein the engager comprises:
(i) a first binding domain recognizing an extracellular portion of CD3, CD28, CD5, CD16, CD64, CD32, CD33, CD89, NKG2C, NKG2D, or any functional variants thereof of the cell or a by-stander immune effector cell; and
(ii) a second binding domain targeting the second tumor antigen that is different from the first tumor antigen targeted by the exogenous TCR, and wherein the second binding domain of the engager is specific to any one of: B7H3, CD10, CD19, CD20, CD22, CD24, CD30, CD33, CD34, CD38, CD44, CD52, CD79a, CD79b, CD123, CD138, CD179b, CEA, CLEC12A, CS-1, DLL3, EGFR, EGFRvIII, EpCAM, FLT-3, FOLR1, FOLR3, GD2, gpA33, HER2, HM1.24, LGR5, MSLN, MCSP, MICA/B, Muc1, Muc16, PDL1, PSMA, PAMA, P-cadherin, ROR1, or VEGF-R2.
9. The cell or population thereof of claim 1, wherein the cell further comprises one or more of:
(i) CD38 knockout;
(ii) HLA-I deficiency and/or HLA-II deficiency;
(iii) introduced HLA-G or non-cleavable HLA-G, or knockout of one or both of CD58 and CD54;
(iv) a CD16 or a variant thereof;
(v) a chimeric fusion receptor (CFR);
(vi) a signaling complex comprising a partial or full peptide of a cell surface expressed exogenous cytokine and/or a receptor thereof;
(vii) at least one of the genotypes listed in Table 1;
(viii) deletion or disruption of at least one of B2M, CIITA, TAP1, TAP2, Tapasin, NLRC5, RFXANK, RFX5, RFXAP, TCR, NKG2A, NKG2D, CD25, CD69, CD44, CD56, CIS, CBL-B, SOCS2, PD1, CTLA4, LAG3, TIM3, and TIGIT; or
(ix) introduction or upregulation of at least one of HLA-E, 4-1BBL, CD3, CD4, CD8, CD16, CD47, CD113, CD131, CD137, CD80, PDL1, A2AR, Fc receptor, an antibody or functional variant or fragment thereof, a checkpoint inhibitor, and surface triggering receptor for coupling with an agonist.
10. The cell or population thereof of claim 9, wherein the CD16 or a variant thereof comprises at least one of:
(a) a high affinity non-cleavable CD16 (hnCD16);
(b) F176V and S197P in ectodomain domain of CD16;
(c) a full or partial ectodomain originated from CD64;
(d) a non-native (or non-CD16) transmembrane domain;
(e) a non-native (or non-CD16) intracellular domain;
a non-native (or non-CD16) signaling domain;
(g) a non-native stimulatory domain; and
(h) transmembrane, signaling, and stimulatory domains that are not originated from CD16, and are originated from a same or different polypeptide.
11. The cell or population thereof of claim 9, wherein the CFR comprises an ectodomain fused to a transmembrane domain, which is operatively connected to an endodomain, and wherein the ectodomain, transmembrane domain and the endodomain do not comprise any endoplasmic reticulum (ER) retention signals or endocytosis signals.
12. The cell or population thereof of claim 11, wherein:
(i) the ectodomain of the CFR comprises a full or partial length of an extracellular portion of a signaling protein comprising at least one of CD3ε, CD3γ, CD3δ, CD28, CD5, CD16, CD64, CD32, CD33, CD89, NKG2C, NKG2D, any functional variants, and a combination or a chimera thereof;
(ii) the ectodomain of the CFR initiates signal transduction upon binding to a selected agonist; or
(iii) the endodomain of the CFR comprises a cytotoxicity domain comprising at least a full length or a portion of CD3ζ, 2B4, DAP10, DAP12, DNAM1, CD137 (4-1BB), IL21, IL7, IL12, IL15, NKp30, NKp44, NKp46, NKG2C, or NKG2D polypeptide; and optionally wherein the endodomain further comprises one or more of:
(a) a co-stimulatory domain comprising a full length or a portion of CD2, CD27, CD28, CD40L, 4-1BB, OX40, ICOS, PD-1, LAG-3, 2B4, BTLA, DAP10, DAP12, CTLA-4, or NKG2D polypeptide, or any combination thereof;
(b) a co-stimulatory domain comprising a full length or a portion of CD28, 4-1BB, CD27, CD40L, ICOS, CD2, or combinations thereof;
(c) a persistency signaling domain comprising a full length or a portion of an endodomain of a cytokine receptor comprising IL7R, IL15R, IL18R, IL12R, IL23R, or combinations thereof; and/or
(d) a full or a partial intracellular portion of a receptor tyrosine kinase (RTK), a tumor necrosis factor receptor (TNFR), an EGFR or a FAS receptor.
16. The cell or population thereof of claims 1, wherein the cell has therapeutic properties comprising one or more of:
(i) increased cytotoxicity;
(ii) improved persistency and/or survival;
(iii) enhanced ability in migrating, and/or activating or recruiting bystander immune cells, to tumor sites;
(iv) improved tumor penetration;
(v) enhanced ability to reduce tumor immunosuppression;
(vi) improved ability in rescuing tumor antigen escape;
(vii) controlled apoptosis;
(viii) enhanced or acquired ADCC; and
(ix) ability to avoid fratricide,
in comparison to its counterpart primary cell obtained from peripheral blood, umbilical cord blood, or any other donor tissues without the same genetic edit(s).
17. The cell or population thereof of claim 1, wherein the derivative cell comprises a derivative CD34+ cell, a derivative hematopoietic stem and progenitor cell, a derivative hematopoietic multipotent progenitor cell, a derivative T cell progenitor, a derivative NK cell progenitor, a derivative T lineage cell, a derivative NKT lineage cell, a derivative NK lineage cell, a derivative B lineage cell, or a derivative effector cell having one or more functional features that are not present in a counterpart primary T, NK, NKT, and/or B cell.
18. The cell or population thereof of claim 1, wherein the derivative effector cell is a hematopoietic cell and comprises longer telomeres in comparison to its counterpart primary cell.
19. The cell or population thereof of claim 1, wherein the cell comprises one of the genotypes listed in Table 1; or wherein the cell comprises:
(i) (1) a CD19-CAR at TRAC locus, (2) a TRAC knockout, and (3) a MR1-TCR or a NYESO1-TCR, and optionally (4) a TRBC knockout;
(ii) (1) a BCMA-CAR and hnCD16 insertion at TRAC locus, (2) a TRAC knockout, and (3) a MR1-TCR or NYESO1-TCR, and optionally (4) a TRBC knockout; or
(iii) (1) a MICAS-CAR insertion at TRAC locus, (2) a TRAC knockout, (3) a hnCD16 insertion at CD38 locus, (4) a CD38 knockout, and (5) a MR1-TCR or NYESO1-TCR, and optionally (6) a TRBC knockout.
20. A composition comprising the cell or population thereof of claim 1.
21. The composition of claim 20, wherein the cell or population thereof comprises the iPSC derivative effector cell, and wherein the composition further comprises one or more therapeutic agents.
22. The composition of claim 21, wherein the one or more therapeutic agents comprise a peptide, a cytokine, a checkpoint inhibitor, an antibody or functional variant or fragment thereof, an engager, a mitogen, a growth factor, a small RNA, a dsRNA (double stranded RNA), mononuclear blood cells, feeder cells, feeder cell components or replacement factors thereof, a vector comprising one or more polynucleic acids of interest, a chemotherapeutic agent or a radioactive moiety, or an immunomodulatory drug (JIVED).
23. The composition of claim 22, wherein:
(a) the checkpoint inhibitor comprises:
(i) one or more antagonist checkpoint molecules comprising PD-1, PDL-1, TIM-3, TIGIT, LAG-3, CTLA-4, 2B4, 4-1BB, 4-1BBL, A2AR, BATE, BTLA, CD39, CD47, CD73, CD94, CD96, CD160, CD200, CD200R, CD274, CEACAM1, CSF-1R, Foxpl, GARP, HVEM, IDO, EDO, TDO, LAIR-1, MICA/B, NR4A2, MAFB, OCT-2, Rara (retinoic acid receptor alpha), TLR3, VISTA, NKG2A/HLA-E, or an inhibitory KIR;
(ii) one or more of atezolizumab, avelumab, durvalumab, ipilimumab, IPH4102, IPH43, IPH33, lirimumab, monalizumab, nivolumab, pembrolizumab, and their derivatives or functional equivalents; or
(iii) at least one of atezolizumab, nivolumab, and pembrolizumab; or
(b) the one or more therapeutic agents comprise one or more of venetoclax, azacitidine, and pomalidomide.
24. The composition of claim 22, wherein the antibody, or functional variant or fragment thereof comprises:
(a) anti-CD20, anti-CD22, anti-HER2, anti-CD52, anti-EGFR, anti-CD123, anti-GD2, anti-PDL1, and/or anti-CD38 antibody;
(b) one or more of rituximab, veltuzumab, ofatumumab, ublituximab, ocaratuzumab, obinutuzumab, ibritumomab, ocrelizumab, inotuzumab, moxetumomab, epratuzumab, trastuzumab, pertuzumab, alemtuzumab, cetuximab, dinutuximab, avelumab, daratumumab, isatuximab, MOR202, 7G3, CSL362, elotuzumab, and their humanized or Fc modified variants or fragments and their functional equivalents and biosimilars; or
(c) daratumumab, and wherein the derivative effector cell comprises a CD38 knockout, and optionally expresses CD16 or a variant thereof.
This is a provisional nonstatutory double patenting rejection because the patentably indistinct claims have not in fact been patented.
14. Claims 14-16, 18, 19, 21-23, 25, 26, 28-31 are provisionally rejected on the ground of nonstatutory double patenting as being unpatentable over claims 1-43, 46, 54, 56 of copending Application No. 18/250,733 (reference application). Although the claims at issue are not identical, they are not patentably distinct from each other because the copending application claims an overlapping population of immune cells expressing a chimeric fusion receptor comprising same features instantly claimed, additionally a therapeutic antibody, that render obvious the instantly claimed cell composition.
The copending application claims:
1. A cell or a population thereof, wherein (a) the cell comprises a polynucleotide encoding a recombinant cytokine signaling complex, and optionally a chimeric antigen receptor (CAR); (b) the cell is an eukaryotic cell, an animal cell, a human cell, an immune cell, a feeder cell, an induced pluripotent cell (iPSC), or a derivative cell differentiated therefrom; and (c) the cytokine signaling complex comprises (i) a full or partial cytokine and (ii) a full or partial IL7 receptor, IL2 receptor, IL4 receptor, IL9 receptor, IL21 receptor, or γC receptor.
2. The cell or population thereof of claim 1, wherein the cytokine signaling complex is co-expressed with the CAR in separate constructs or in a bi-cistronic construct.
3. The cell or population thereof of claim 1, wherein the iPSC is a clonal iPSC, a single cell dissociated iPSC, an iPSC cell line cell, or an iPSC master cell bank (MCB) cell; or wherein the derivative cell comprises (i) a derivative CD34+ cell, a derivative hematopoietic stem and progenitor cell, a derivative hematopoietic multipotent progenitor cell, a derivative T cell progenitor, a derivative NK cell progenitor, a derivative T lineage cell, a derivative NKT lineage cell, a derivative NK lineage cell, or a derivative B lineage cell; or (ii) a derivative effector cell having one or more functional features that are not present in a counterpart primary T, NK, NKT, and/or B cell.
5. The cell or population thereof of any one of claims 1-4, wherein the cell further comprises one or more of:
(i) CD38 knockout;
(ii) HLA-I deficiency and/or HLA-II deficiency;
(iii) introduced expression of HLA-G or non-cleavable HLA-G, or knockout of one or both of CD58 and CD54;
(iv) an exogenous CD16 or a variant thereof;
(v) a chimeric fusion receptor (CFR);
(vi) a partial or full peptide of a cell surface expressed exogenous cytokine and/or a receptor thereof;
(vii) at least one of the genotypes listed in Table 1;
(viii) deletion or disruption of at least one of B2M, CIITA, TAP1, TAP2, Tapasin, NLRC5, RFXANK, RFX5, RFXAP, TCR, NKG2A, NKG2D, CD25, CD69, CD44, CD56, CIS, CBL-B, SOCS2, PD1, CTLA4, LAG3, TIM3, and TIGIT; or
(ix) introduction of at least one of HLA-E, 4-1BBL, CD3, CD4, CD8, CD16, CD47, CD113, CD131, CD137, CD80, PDL1, A2AR, antigen-specific TCR, Fc receptor, an antibody or functional variant or fragment thereof, a checkpoint inhibitor, an engager, and surface triggering receptor for coupling with an agonist.
6. The cell or population thereof of claim 4, wherein the cell has therapeutic properties comprising one or more of:
(i) increased cytotoxicity;
(ii) improved persistency and/or survival;
(iii) enhanced ability in migrating, and/or activating or recruiting bystander immune cells, to tumor sites;
(iv) improved tumor penetration;
(v) enhanced ability to reduce tumor immunosuppression;
(vi) improved ability in rescuing tumor antigen escape;
(vii) controlled apoptosis;
(viii) enhanced or acquired ADCC; and
(ix) ability to avoid fratricide,
in comparison to its counterpart primary cell obtained from peripheral blood, umbilical cord blood, or any other donor tissues without the same genetic edit(s).
7. The cell or population thereof of claim 5, wherein the exogenous CD16 or a variant thereof comprises at least one of:
(a) a high affinity non-cleavable CD16 (hnCD16);
(b) F176V and S197P in ectodomain domain of CD16;
(c) a full or partial ectodomain originated from CD64;
(d) a non-native (or non-CD16) transmembrane domain;
(e) a non-native (or non-CD16) intracellular domain;
(f) a non-native (or non-CD16) signaling domain;
(g) a non-native stimulatory domain; and
(h) transmembrane, signaling, and stimulatory domains that are not originated from CD16, and are originated from a same or different polypeptide.
8. The cell of population thereof of claim 4, wherein the derivative effector cell comprises at least one of:
(a) improved relative cell expansion;
(b) increased percentage of CAR expression;
(c) increased CD69 expression; and
(d) decreased PD-1 expression,
in comparison to its counterpart cell without the cytokine signaling complex.
9. The cell of population thereof of claims 1, wherein the CAR is:
(i) T cell specific or NK cell specific;
(ii) a bi-specific antigen binding CAR;
(iii) a switchable CAR;
(iv) a dimerized CAR;
(v) a split CAR;
(vi) a multi-chain CAR;
(vii) an inducible CAR;
(viii) an inactivation CAR;
(ix) co-expressed with a checkpoint inhibitor, optionally in separate constructs or in a bi-cistronic construct;
(x) specific to at least one of CD19, BCMA, CD20, CD22, CD38, CD123, HER2, CD52, EGFR, GD2, MICA/B, MSLN, VEGF-R2, PSMA and PDL1; and/or
12. The cell or population thereof of claim 5, wherein the CFR comprises an ectodomain fused to a transmembrane domain, which is operatively connected to an endodomain, and wherein the ectodomain, transmembrane domain and the endodomain do not comprise any endoplasmic reticulum (ER) retention signals or endocytosis signals.
13. The cell or population thereof of claim 12, wherein the ectodomain of the CFR comprises a full or partial length of an extracellular portion of a signaling protein comprising at least one of CD3ε, CD3γ, CD3δ, CD28, CD5, CD16, CD64, CD32, CD33, CD89, NKG2C, NKG2D, any functional variants, and a combination or a chimera thereof.
14. The cell or population thereof of claim 12, wherein the ectodomain of the CFR initiates signal transduction upon binding to a selected agonist comprising at least a binding domain that is specific to an extracellular portion of CD3, CD28, CD5, CD16, CD64, CD32, CD33, CD89, NKG2C, NKG2D, or any functional variants thereof; or wherein the selected agonist comprises a binding domain specific to at least one tumor antigen comprising B7H3, BCMA, CD10, CD19, CD20, CD22, CD24, CD30, CD33, CD34, CD38, CD44, CD79a, CD79b, CD123, CD138, CD179b, CEA, CLEC12A, CS-1, DLL3, EGFR, EGFRvIII, EPCAM, FLT-3, FOLR1, FOLR3, GD2, gpA33, HER2, HM1.24, LGR5, MSLN, MCSP, MICA/B, PSMA, PAMA, P-cadherin, or ROR1.
15. The cell or population thereof of claims 12, wherein the endodomain of the CFR comprises a cytotoxicity domain comprising at least a full length or a portion of CD3ζ, 2B4, DAP10, DAP12, DNAM1, CD137 (4-1BB), IL21, IL7, IL12, IL15, NKp30, NKp44, NKp46, NKG2C, or NKG2D polypeptide; and optionally wherein the endodomain further comprises one or more of:
(i) a co-stimulatory domain comprising a full length or a portion of CD2, CD27, CD28, CD40L, 4-1BB, OX40, ICOS, PD-1, LAG-3, 2B4, BTLA, DAP10, DAP12, CTLA-4, or NKG2D polypeptide, or any combination thereof,
(ii) a co-stimulatory domain comprising a full length or a portion of CD28, 4-1BB, CD27, CD40L, ICOS, CD2, or combinations thereof,
(iii) a persistency signaling domain comprising a full length or a portion of an endodomain of a cytokine receptor comprising IL7R, IL15R, IL18R, IL12R, IL23R, or combinations thereof; and/or
(iv) a full or a partial intracellular portion of a receptor tyrosine kinase (RTK), a tumor necrosis factor receptor (TNFR), an EGFR or a FAS receptor.
17. The cell or population thereof of claims 1, wherein the cell comprises:
(i) one or more exogenous polynucleotides integrated in a safe harbor locus or a selected gene locus; or
(ii) more than two exogenous polynucleotides integrated in different safe harbor loci or two or more selected gene loci.
18. The cell or population thereof of claim 17, wherein the safe harbor locus comprises at least one of AAVS1, CCR5, ROSA26, collagen, HTRP, H11, GAPDH, or RUNX1; or wherein the selected gene locus is one of B2M, TAP1, TAP2, Tapasin, NLRC5, CIITA, RFXANK, RFX5, RFXAP, TCR, NKG2A, NKG2D, CD38, CD25, CD44, CD58, CD54, CD56, CD69, CD71, CIS, CBL-B, SOCS2, PD1, CTLA4, LAG3, TIM3, or TIGIT; and/or wherein the integration of the exogenous polynucleotides knocks out expression of the gene in the locus.
34. A composition comprising the cell or population thereof of claim 1.
36. A composition for therapeutic use comprising the iPSC derivative effector cell of claim 1, and one or more therapeutic agents.
37. The composition of claim 36, wherein the one or more therapeutic agents comprise a peptide, a cytokine, a checkpoint inhibitor, an antibody or functional variant or fragment thereof, a mitogen, a growth factor, a small RNA, a dsRNA (double stranded RNA), mononuclear blood cells, feeder cells, feeder cell components or replacement factors thereof, a vector comprising one or more polynucleic acids of interest, a chemotherapeutic agent or a radioactive moiety, or an immunomodulatory drug (IMiD).
38. The composition of claim 37, wherein:
(a) the checkpoint inhibitor comprises:
(i) one or more antagonist checkpoint molecules comprising PD-1, PDL-1, TIM-3, TIGIT, LAG-3, CTLA-4, 2B4, 4-1BB, 4-1BBL, A2AR, BATE, BTLA, CD39, CD47, CD73, CD94, CD96, CD160, CD200, CD200R, CD274, CEACAM1, CSF-1R, Foxpl, GARP, HVEM, IDO, EDO, TDO, LAIR-1, MICA/B, NR4A2, MAFB, OCT-2, Rara (retinoic acid receptor alpha), TLR3, VISTA, NKG2A/HLA-E, or inhibitory KIR;
(ii) one or more of atezolizumab, avelumab, durvalumab, ipilimumab, IPH4102, IPH43, IPH33, lirimumab, monalizumab, nivolumab, pembrolizumab, and their derivatives or functional equivalents; or
(iii) at least one of atezolizumab, nivolumab, and pembrolizumab; or
(b) the therapeutic agents comprise one or more of venetoclax, azacitidine, and pomalidomide.
39. The composition of claim 37, wherein the antibody, or functional variant or fragment thereof comprises:
(a) anti-CD20, anti-CD22, anti-HER2, anti-CD52, anti-EGFR, anti-CD123, anti-GD2, anti-PDL1, and/or anti-CD38 antibody;
(b) one or more of rituximab, veltuzumab, ofatumumab, ublituximab, ocaratuzumab, obinutuzumab, ibritumomab, ocrelizumab, inotuzumab, moxetumomab, epratuzumab, trastuzumab, pertuzumab, alemtuzumab, cetuximab, dinutuximab, avelumab, daratumumab, isatuximab, MOR202, 7G3, CSL362, elotuzumab, and their humanized or Fc modified variants or fragments and their functional equivalents and biosimilars; or
(c) daratumumab, and wherein the derivative effector cell comprises a CD38 knockout, and optionally an expression of CD16 or a variant thereof.
This is a provisional nonstatutory double patenting rejection because the patentably indistinct claims have not in fact been patented.
15. Claims 14-16, 18, 19, 21-23, 25, 26, 28-31 are provisionally rejected on the ground of nonstatutory double patenting as being unpatentable over claims 1-20, 23, 2830, 43, 46, 48-50, 61, 67-71 of copending Application No. 18/250,735 (reference application). Although the claims at issue are not identical, they are not patentably distinct from each other because the copending application claims an overlapping population of immune cells expressing a chimeric fusion receptor comprising the same features instantly claimed, and a therapeutic antibody, that render obvious the instantly claimed cell composition.
The copending application claims:
1. A cell or a population thereof, wherein the cell comprises a polynucleotide encoding a CAR targeting a B7H3 tumor antigen, wherein the CAR comprises a binding domain comprising:
(i) an amino acid sequence that is of at least about 99%, 98%, 96%, 95%, 90%, 85%, or 80% identity to SEQ ID NO: 36, 37, 38, 39, 40, or 41;
(ii) an amino acid sequence represented by a variant of SEQ ID NO: 36, and wherein the variant has one or more mutations at positions comprising 1, 40, 46, 79, 87, 88, 89, 97, 98, and 117 of SEQ ID NO: 36;
(iii) an amino acid sequence represented by a variant of SEQ ID NO: 36, wherein the variant has one or more substitutions comprising Q1E, T40A, E46V, G79L, K87R, P88A, D89E, V97A, S98R, and Q117L according to SEQ ID NO: 36; or
(iv) an amino acid sequence represented by any of SEQ ID NOs: 36, 37, 38, 39, 40, and 41; and
wherein the cell is an eukaryotic cell, an animal cell, a human cell, an immune cell, an induced pluripotent cell (iPSC), or a derivative cell differentiated therefrom.
2. The cell or a population thereof of claim 1, wherein the cell further comprises one or more polynucleotides encoding an engager, and optionally a CFR (chimeric fusion receptor), wherein the engager has a tumor antigen targeting specificity that is not B7H3.
4. The cell or a population thereof of claim 2, wherein
(i) the CFR comprises an ectodomain fused to a transmembrane domain, which is operatively connected to an endodomain, and wherein the ectodomain, transmembrane domain and the endodomain do not comprise any endoplasmic reticulum (ER) retention signals or endocytosis signals;
(ii) the CFR comprises an ectodomain that comprises a full or partial length of an extracellular portion of a signaling protein comprising at least one of CD3ε, CD3γ, CD3δ, CD28, CD5, CD16, CD64, CD32, CD33, CD89, NKG2C, NKG2D, any functional variants, and a combination or a chimera thereof;
(iii) the CFR comprises an ectodomain that initiates signal transduction upon binding to a selected agonist;
(iv) the CFR comprises an endodomain that comprises a cytotoxicity domain comprising at least a full length or a portion of CD3ζ, 2B4, DAP10, DAP12, DNAM1, CD137 (4-1BB), IL21, IL7, IL12, IL15, NKp30, NKp44, NKp46, NKG2C, or NKG2D polypeptide; and optionally wherein the endodomain further comprises one or more of:
(a) a co-stimulatory domain comprising a full length or a portion of CD2, CD27, CD28, CD40L, 4-1BB, OX40, ICOS, PD-1, LAG-3, 2B4, BTLA, DAP10, DAP12, CTLA-4, or NKG2D polypeptide, or any combination thereof;
(b) a co-stimulatory domain comprising a full length or a portion of CD28, 4-1BB, CD27, CD40L, ICOS, CD2, or any combination thereof;
(c) a persistency signaling domain comprising a full length or a portion of an endodomain of a cytokine receptor comprising IL7R, IL15R, IL18R, IL12R, IL23R, or combinations thereof; and/or
(d) a full or a partial intracellular portion of a receptor tyrosine kinase (RTK), a tumor necrosis factor receptor (TNFR), an EGFR or a FAS receptor; or
(iv) the CFR is co-expressed with the engager or the CAR in separate constructs or in a bicistronic expression cassette.
5. The cell or a population thereof of claim 1, wherein the cell further comprises one or more of:
(i) CD38 knockout;
(ii) HLA-I deficiency and/or HLA-II deficiency;
(iii) introduction of HLA-G or non-cleavable HLA-G, or knockout of one or both of CD58 and CD54;
(iv) an exogenous CD16 or a variant thereof.
6. The cell or a population thereof of claims 1, wherein the cell has therapeutic properties comprising one or more of:
(i) increased cytotoxicity;
(ii) improved persistency and/or survival;
(iii) enhanced ability in migrating, and/or activating or recruiting bystander immune cells, to tumor sites;
(iv) improved tumor penetration;
(v) enhanced ability to reduce tumor immunosuppression;
(vi) improved ability in rescuing tumor antigen escape;
(vii) controlled apoptosis;
(viii) enhanced or acquired ADCC; and
(ix) ability to avoid fratricide,
in comparison to its counterpart primary cell obtained from peripheral blood, umbilical cord blood, or any other donor tissues.
7. The cell or a population thereof of claim 6, wherein the exogenous CD16 or a variant thereof comprises at least one of:
(a) a high affinity non-cleavable CD16 (hnCD16);
(b) F176V and S197P in ectodomain domain of CD16;
(c) a full or partial ectodomain originated from CD64;
(d) a non-native (or non-CD16) transmembrane domain;
(e) a non-native (or non-CD16) intracellular domain;
(f) a non-native (or non-CD16) signaling domain;
(g) a non-native stimulatory domain; and
(h) transmembrane, signaling, and stimulatory domains that are not originated from CD16, and are originated from a same or different polypeptide.
8. The cell or a population thereof of claim 7, wherein the cell surface expressed exogenous cytokine or receptor thereof:
(a) comprises at least one of IL2, IL4, IL6, IL7, IL9, IL10, IL11, IL12, IL15, IL18, IL21, and its respective receptor(s); or
10. The cell or a population thereof of claim 1, wherein the cell comprises:
(i) one or more exogenous polynucleotides integrated in a safe harbor locus or a selected gene locus; or
(ii) more than two exogenous polynucleotides integrated in different safe harbor loci or two or more selected gene loci.
11. The cell or a population thereof of claim 10, wherein the safe harbor locus comprises at least one of AAVS1, CCR5, ROSA26, collagen, HTRP, H11, GAPDH, or RUNX1; and wherein the selected gene locus is one of B2M, TAP1, TAP2, Tapasin, NLRC5, CIITA, RFXANK, RFX5, RFXAP, TCR, NKG2A, NKG2D, CD38, CD25, CD69, CD44, CD58, CD54, CD56, CIS, CBL-B, SOCS2, PD1, CTLA4, LAG3, TIM3, or TIGIT; and/or wherein the integration of the exogenous polynucleotides knocks out expression of the gene in the locus.
13. The cell or a population thereof of claim 1, wherein the iPSC is a clonal iPSC, a single cell dissociated iPSC, an iPSC cell line cell, or an iPSC master cell bank (MCB) cell; or wherein the derivative cell comprises a derivative CD34+ cell, a derivative hematopoietic stem and progenitor cell, a derivative hematopoietic multipotent progenitor cell, a derivative T cell progenitor, a derivative NK cell progenitor, a derivative T lineage cell, a derivative NKT lineage cell, a derivative NK lineage cell, a derivative B lineage cell, or a derivative effector cell having one or more functional features that are not present in a counterpart primary T, NK, NKT, and/or B cell.
14. A composition comprising the cell or population thereof of claim 1.
15. A composition for therapeutic use comprising the derivative cell of claim 1, and one or more therapeutic agents.
16. The composition of claim 15, wherein the one or more therapeutic agents comprise a peptide, a cytokine, a checkpoint inhibitor, a mitogen, a growth factor, a small RNA, a dsRNA (double stranded RNA), mononuclear blood cells, feeder cells, feeder cell components or replacement factors thereof, a vector comprising one or more polynucleic acids of interest, an antibody, a chemotherapeutic agent or a radioactive moiety, or an immunomodulatory drug (IMiD).
17. The composition of claim 16, wherein:
(i) the checkpoint inhibitor comprises:
(a) one or more antagonists to checkpoint molecules comprising PD-1, PDL-1, TIM-3, TIGIT, LAG-3, CTLA-4, 2B4, 4-1BB, 4-1BBL, A2AR, BATE, BTLA, CD39, CD47, CD73, CD94, CD96, CD160, CD200, CD200R, CD274, CEACAM1, CSF-1R, Foxpl, GARP, HVEM, IDO, EDO, TDO, LAIR-1, MICA/B, NR4A2, MAFB, OCT-2, Rara (retinoic acid receptor alpha), TLR3, VISTA, NKG2A/ILA-E, or inhibitory KIR;
(b) one or more of atezolizunab, avelumab, durvalumab, ipilimumab, IPH4102, IPH43, IPH33, lirimumab, monalizumab, nivolumab, pembrolizumab, and their derivatives or functional equivalents;
(c) at least one of atezolizumab, nivolumab, and pembrolizumab; or
(ii) the therapeutic agents comprise one or more of venetoclax, azacitidine, and pomalidomide.
18. The composition of claim 16, wherein the antibody comprises:
(a) anti-CD20, anti-HER2, anti-CD52, anti-EGFR, anti-CD123, anti-GD2, anti-PDL1, and/or anti-CD38 antibody;
(b) one or more of rituximab, veltuzumab, ofatumumab, ublituximab, ocaratuzumab, obinutuzumab, trastuzumab, pertuzumab, alemtuzumab, cetuximab, dinutuximab, avelumab, daratumumab, isatuximab, MOR202, 7G3, CSL362, elotuzumab, and their humanized or Fc modified variants or fragments and their functional equivalents and biosimilars; or
(c) daratumumab, and wherein the derivative hematopoietic cells comprise derivative NK cells or derivative T cells comprising a CD38 knockout, and optionally an expression of exogenous CD16 or a variant thereof.
20. A composition comprising a cell or a population thereof, wherein the cell comprises one or more polynucleotides encoding a chimeric antigen receptor (CAR), an engager, and optionally a CFR (chimeric fusion receptor), wherein the CFR is optionally for engager coupling, and wherein the cell is an eukaryotic cell, an animal cell, a human cell, an immune cell, an induced pluripotent cell (iPSC), or a derivative cell differentiated therefrom.
28. The composition of claim 20, wherein the CFR comprises an ectodomain fused to a transmembrane domain, which is operatively connected to an endodomain, and wherein the ectodomain, transmembrane domain and the endodomain do not comprise any endoplasmic reticulum (ER) retention signals or endocytosis signals.
This is a provisional nonstatutory double patenting rejection because the patentably indistinct claims have not in fact been patented.
16. Any inquiry concerning this communication or earlier communications from the examiner should be directed to LAURA B GODDARD whose telephone number is (571)272-8788. The examiner can normally be reached Mon-Fri, 7am-3:30pm.
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/Laura B Goddard/Primary Examiner, Art Unit 1642