DETAILED ACTION
The present application, filed on or after March 16, 2013, is being examined under the first inventor to file provisions of the AIA .
A request for continued examination under 37 CFR 1.114, including the fee set forth in 37 CFR 1.17(e), was filed in this application after final rejection. Since this application is eligible for continued examination under 37 CFR 1.114, and the fee set forth in 37 CFR 1.17(e) has been timely paid, the finality of the previous Office action has been withdrawn pursuant to 37 CFR 1.114.
Applicant's submission filed on December 19, 2025 has been entered.
The claim listing filed on December 19, 2025 is acknowledged.
Claims 1-10 and 14-21 are canceled.
Claims 11-13 and 22-29 are pending and currently under investigation.
Priority
The instant application is a 371 of PCT/JP2020/029446 filed 07/31/2020 and claims foreign priority to JP2019-142358 filed 08/01/2019.
A translated copy of JP2019-142358 has not been filed. Therefore, it is not clear if the foreign priority document has adequate support for the instant claims.
In view of the applicant’s amendment filed on December 19, 2025, the rejection under 35 USC § 103 and the objection to the specification have been withdrawn and the following objections and rejections are set forth.
Claim Rejections - 35 USC § 112
Indefinite Language
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.
Claims 23, 25, 27, and 29 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.
Claims 23 and 27 recite “wherein the chimeric antigen receptor comprises a core domain comprising: a scFv domain comprising the heavy-chain variable region and the light-chain variable region” in lines 2-4. Claims 23 and 27 are dependent 11 and 13 (which is dependent on claim 12 which id dependent on claim 11), respectively. Claim 11 recites “a chimeric antigen receptor comprising a GD2-binding domain comprising: a heavy-chain variable region… a chimeric antigen receptor comprising a GD2-binding domain comprising: a heavy-chain variable region” in lines 2-8.
It is unclear if the core domain recited in claims 23 and 27 is in addition to the GD2-binding domain recited in claim 11 or if the GD2-binding domain comprises the core domain. Furthermore, if the GD2-binding domain comprises the core domain, it is also unclear if the scFv of the core domain is in addition to the heavy and light chain of the GD2-binding domain already recited in claim 11 or if the heavy and light chain of the scFv are the same heavy and light chain recited in claim 11. Meaning do the CARs of claims 23 and 27 comprise two or four variable domains.
Amending claims 23 and 27 to recite “wherein the chimeric antigen receptor comprises a core domain comprising: the GD2-binding domain as a scFv domain, the transmembrane domain, and the intracellular domain of the TCR” would obviate this part of the rejection.
Written Description
The following is a quotation of the first paragraph of 35 U.S.C. 112(a):
(a) IN GENERAL.—The specification shall contain a written description of the invention, and of the manner and process of making and using it, in such full, clear, concise, and exact terms as to enable any person skilled in the art to which it pertains, or with which it is most nearly connected, to make and use the same, and shall set forth the best mode contemplated by the inventor or joint inventor of carrying out the invention.
The following is a quotation of the first paragraph of pre-AIA 35 U.S.C. 112:
The specification shall contain a written description of the invention, and of the manner and process of making and using it, in such full, clear, concise, and exact terms as to enable any person skilled in the art to which it pertains, or with which it is most nearly connected, to make and use the same, and shall set forth the best mode contemplated by the inventor of carrying out his invention.
Claims 11-13 and 22-29 are rejected under 35 U.S.C. 112(a) or 35 U.S.C. 112 (pre-AIA ), first paragraph, as failing to comply with the written description requirement. The claim contains subject matter which was not described in the specification in such a way as to reasonably convey to one skilled in the relevant art that the inventor or a joint inventor, or for applications subject to pre-AIA 35 U.S.C. 112, the inventor(s), at the time the application was filed, had possession of the claimed invention.
The instant claims are drawn to a chimeric antigen receptor T-cell or chimeric antigen receptor NK-cell comprising a polynucleotide encoding a chimeric antigen receptor comprising a GD2-binding domain comprising: a heavy-chain variable region comprising: a heavy-chain CDR1 comprising the amino acid sequence of SEQ ID NO: 1, a heavy-chain CDR2 comprising the amino acid sequence of SEQ ID NO: 2, and a heavy-chain CDR3 comprising the amino acid sequence of SEQ ID NO: 3, and a light-chain variable region comprising: a light-chain CDR1 comprising the amino acid sequence of SEQ ID NO: 9, a light-chain CDR2 comprising the amino acid sequence of SEQ ID NO: 10, and a light-chain CDR3 comprising the amino acid sequence of SEQ ID NO: 11, wherein the chimeric antigen receptor comprises a transmembrane domain and an intracellular domain of a T-cell receptor (TCR), and wherein the chimeric antigen receptor T-cell or chimeric antigen receptor NK-cell has cytotoxic activity against at least one selected from the group consisting of blood cancer, lung cancer, colorectal cancer, ovarian cancer, breast cancer, stomach cancer, liver cancer, tongue cancer, thyroid cancer, kidney cancer, prostate cancer, uterine cancer, osteosarcoma, chondrosarcoma, rhabdomyosarcoma, melanoma, neuroblastoma, and bladder cancer; a pharmaceutical composition; and a method of treating a GD2-expressing cancer, the method comprising administering the pharmaceutical composition to a subject having at least one selected from the group consisting of blood cancer, lung cancer, colorectal cancer, ovarian cancer, breast cancer, stomach cancer, liver cancer, tongue cancer, thyroid cancer, kidney cancer, prostate cancer, uterine cancer, osteosarcoma, chondrosarcoma, rhabdomyosarcoma, melanoma, neuroblastoma, and bladder cancer.
The Applicant has disclosed several working examples that clearly demonstrate that the claimed GD2-targeting CAR T cells restrict their cytotoxic action to GD2-positive cells (e.g. see Examples 11-18 on pages 42-45). The cytotoxic action of the GD2-targeting CAR T cells was tested on GD2-positive cells, including GD2-positive Kelly cells (neuroblastoma cell line, examples 11 and 15), Hs578T-Luc cells (breast cancer cell line, example 13), D8 cells (example 16), and NCI-N417 cells (lung cancer, example 18); and GD-negative cells, including GD-negative SK-N-SH cells (neuroblastoma cell line, see example 12), BT549-Luc cells (breast cancer cell line, example 14), and C2 cells (thyroid cancer cell line, example 17). Cytotoxicity of the GD2-targeting CAR T cells was only observed in GD2-expressing cells. Also see Figures 20-27.
The Applicant has also disclosed that GD2 is known to be highly expressed in melanoma, neuroblastoma, glioblastoma, lung cancer, osteosarcoma, and leukemia (e.g. see page 1, [0003]).
Therefore, the disclosed the cytotoxicity of the claimed GD2 CAR T/NK cells against GD2-expressing cancer, not GD2 negative cancers.
When given the broadest reasonable interpretation in light of specification, the GD2 CAR T/NK cells of the instant invention encompass are those that have cytotoxic activity against any blood cancer, lung cancer, colorectal cancer, ovarian cancer, breast cancer, stomach cancer, liver cancer, tongue cancer, thyroid cancer, kidney cancer, prostate cancer, uterine cancer, osteosarcoma, chondrosarcoma, rhabdomyosarcoma, melanoma, neuroblastoma, and bladder cancer; and the method of treating a GD2-expressing cancer of the instant invention encompass treating any subject having any blood cancer, lung cancer, colorectal cancer, ovarian cancer, breast cancer, stomach cancer, liver cancer, tongue cancer, thyroid cancer, kidney cancer, prostate cancer, uterine cancer, osteosarcoma, chondrosarcoma, rhabdomyosarcoma, melanoma, neuroblastoma, and bladder cancer.
It is noted that the broadest claim (claim 11) does not indicate any specific structure for the genera of blood cancer, lung cancer, colorectal cancer, ovarian cancer, breast cancer, stomach cancer, liver cancer, tongue cancer, thyroid cancer, kidney cancer, prostate cancer, uterine cancer, osteosarcoma, chondrosarcoma, rhabdomyosarcoma, melanoma, neuroblastoma, and bladder cancer.
The guidelines for the Examination of Patent Applications Under the 35 U.S.C. 112, § 1 "Written Description" Requirement make clear that if a claimed genus does not show actual reduction to practice for a representative number of species, then the Requirement may be alternatively met by reduction to drawings, or by disclosure of relevant, identifying characteristics, i.e., structure or other physical and or chemical properties, by functional characteristics coupled with a known or disclosed correlation between function and structure, or by a combination of such identifying characteristics, sufficient to show the applicant was in possession of the genus (Federal Register, Vol. 66, No. 4, pages 1099-1111, January 5, 2001, see especially page 1106 column 3). In The Regents of the University of California v. Eli Lilly (43 USPQ2d 1398-1412) 19 F. 3d 1559, the court held that disclosure of a single member of a genus (rat insulin) did not provide adequate written support for the claimed genus (all mammalian insulins). In this same case, the court also noted:
“A definition by function, as we have previously indicated, does not suffice to define the genus because it is only an indication of what the gene does, rather than what it is. See Fiers, 984 F.2d at 1169-71, 25 USPQ2d at 1605-06 (discussing Amgen). It is only a definition of a useful result rather than a definition of what achieves that result. Many such genes may achieve that result. The description requirement of the patent statute requires a description of an invention, not an indication of a result that one might achieve if one made that invention. See In re Wilder, 736 F.2d 1516, 1521, 222 USPQ 369, 372-73 (Fed. Cir. 1984) (affirming rejection because the specification does “little more than outlin[e] goals appellants hope the claimed invention achieves and the problems the invention will hopefully ameliorate.”). Accordingly, naming a type of material generally known to exist, in the absence of knowledge as to what that material consists of, is not a description of that material.”
Philippova et al. 2024 (Front Immunol 2024, 15, 1-27, a reference of record) teach that GD2 is a surface tumor-associated antigen that is expressed by a wide range of tumors of neuroectodermal and epithelial origin, such as neuroblastoma, melanoma, glioma, retinoblastoma, medulloblastoma, small-cell lung cancer, various types of breast cancer and sarcoma, bladder cancer, colorectal cancer, and prostate cancer (e.g. see page 2, left column, second paragraph under “Introduction”).
It is noted that the art does not teach the expression of GD2 in ovarian cancer, stomach cancer, liver cancer, tongue cancer, thyroid cancer, kidney cancer, uterine cancer, or bladder cancer. Furthermore, the art also does not teach the expression of GD2 in ALL blood cancers, lung cancers, breast cancers, osteosarcomas, chondrosarcomas, rhabdomyosarcomas, melanomas, or neuroblastomas.
As noted above, the Applicant has disclosed examples of the cytotoxic function of the instantly claimed GD2 CAR T/NK cells against several GD2 positive cancer cell lines including neuroblastoma, breast cancer, and lung cancer, and their lack of cytotoxic function toward GD2 negative cancer cell lines including neuroblastoma, breast cancer, and thyroid cancer. Such a disclosure does not serve to provide sufficient written description of the claimed genera of blood cancer, lung cancer, colorectal cancer, ovarian cancer, breast cancer, stomach cancer, liver cancer, tongue cancer, thyroid cancer, kidney cancer, prostate cancer, uterine cancer, osteosarcoma, chondrosarcoma, rhabdomyosarcoma, melanoma, neuroblastoma, and bladder cancer that can be killed by the instantly claimed GD2 CAR T/NK cells or subjects having said cancers that would be susceptible to GD2 CAR T/NK cell therapy.
The disclosure does not identify any specific structural features or combination of features of the types of cancer which give rise to their ability to be killed by the instantly claimed GD2 CAR T/NK cells or subjects having said cancers that would be susceptible to GD2 CAR T/NK cell therapy. Additionally, there does not appear to be any reasonable shared structure present in the genera of recited cancers which gives rise to their ability to be killed by the GD2 CAR T/NK cells or subjects having said cancers that would be susceptible to GD2 CAR T/NK cell therapy. Ultimately, identifying the cancers simply on the basis of being able to be killed by the GD2 CAR T/NK cells or subjects having said cancers that would be susceptible to GD2 CAR T/NK cell therapy rather than by identifying the structure of the cancers, namely the expression of GD2, is generally insufficient to provide written description.
While the art teaches that GD2 is expressed in neuroblastoma, melanoma, glioma, retinoblastoma, medulloblastoma, small-cell lung cancer, various types of breast cancer and sarcoma, bladder cancer, colorectal cancer, and prostate cancer, it is silent on the expression of GD2 in ovarian cancer, stomach cancer, liver cancer, tongue cancer, thyroid cancer, kidney cancer, uterine cancer, or bladder cancer, or even ALL blood cancers, lung cancers, breast cancers, osteosarcomas, chondrosarcomas, rhabdomyosarcomas, melanomas, or neuroblastomas. The Applicant has even disclosed examples of GD2 negative neuroblastomas and breast cancers in the specification.
The claims are drawn to broad genera of cancers which are functionally defined by their ability to be killed by the instantly claimed GD2 CAR T/NK cells or would be susceptible to GD2 CAR T/NK cell therapy without reciting any corresponding structure expected to correlate with this ability as supported by Applicant’s disclosure. In view of the specification and the art, not all of the recited genera of cancers express GD2 and therefore a skilled artisan would not reasonably expect the instantly claimed GD2 CAR T/NK cells to have cytotoxicity toward any blood cancer, lung cancer, colorectal cancer, ovarian cancer, breast cancer, stomach cancer, liver cancer, tongue cancer, thyroid cancer, kidney cancer, prostate cancer, uterine cancer, osteosarcoma, chondrosarcoma, rhabdomyosarcoma, melanoma, neuroblastoma, and bladder cancer, which encompass those which do not express GD2 or the subjects having said cancers to be susceptible to GD2 CAR T/NK cell therapy.
Thus, there is insufficient written description for the breadth of blood cancers, lung cancers, colorectal cancers, ovarian cancers, breast cancers, stomach cancers, liver cancers, tongue cancers, thyroid cancers, kidney cancers, prostate cancers, uterine cancers, osteosarcomas, chondrosarcomas, rhabdomyosarcomas, melanomas, neuroblastomas, and bladder cancers that can be killed by a GD2 CAR T/NK cell or would be susceptible to GD2 CAR T/NK cell therapy as currently claimed, which are distinct and diverse and do not share a common structure that contributes to a common ability to be killed by a GD2 CAR T/NK cell or be susceptible to GD2 CAR T/NK cell therapy.
Therefore, in view of the breadth of the claims and the limited disclosure, artisans would reasonably conclude that applicant was not in possession of the full breadth of cancers that can be killed by the instantly claimed GD2 CAR T/NK cells or are susceptible to GD2 CAR T/NK cell therapy at the time the instant application was filed.
Amending claim 11 to recite: “wherein the chimeric antigen receptor T-cell or chimeric antigen receptor NK-cell has cytotoxic activity against a GD2-positive cancer” and claim 13 to recite: “a subject having a GD2 positive cancer” would obviate this part of the rejection.
Claim Rejections - 35 USC § 103
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 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 11-13, 22-24, and 26-28 are rejected under 35 U.S.C. 103 as being unpatentable over Golinelli et al. (US20210300990A1, a reference of record) in view of Mount et al. 2018 (Nat. Med. 24, 572–579, a reference of record).
Independent claim 11 is drawn to a chimeric antigen receptor T-cell or chimeric antigen receptor NK-cell comprising a polynucleotide encoding a chimeric antigen receptor comprising a GD2-binding domain comprising: a heavy-chain variable region comprising: a heavy-chain CDR1 comprising the amino acid sequence of SEQ ID NO: 1, a heavy-chain CDR2 comprising the amino acid sequence of SEQ ID NO: 2, and a heavy-chain CDR3 comprising the amino acid sequence of SEQ ID NO: 3, and a light-chain variable region comprising: a light-chain CDR1 comprising the amino acid sequence of SEQ ID NO: 9, a light-chain CDR2 comprising the amino acid sequence of SEQ ID NO: 10, and a light-chain CDR3 comprising the amino acid sequence of SEQ ID NO: 11, wherein the chimeric antigen receptor comprises a transmembrane domain and an intracellular domain of a T-cell receptor (TCR), and wherein the chimeric antigen receptor T-cell or chimeric antigen receptor NK-cell has cytotoxic activity against at least one selected from the group consisting of blood cancer, lung cancer, colorectal cancer, ovarian cancer, breast cancer, stomach cancer, liver cancer, tongue cancer, thyroid cancer, kidney cancer, prostate cancer, uterine cancer, osteosarcoma, chondrosarcoma, rhabdomyosarcoma, melanoma, neuroblastoma, and bladder cancer.
Dependent claim 12 is drawn to a pharmaceutical composition comprising the chimeric antigen receptor T-cell or the chimeric antigen receptor NK-cell of claim 11.
Dependent claim 13 is drawn to a method of treating a GD2-expressing cancer, the method comprising administering the pharmaceutical composition claim 12 to a subject having at least one selected from the group consisting of blood cancer, lung cancer, colorectal cancer, ovarian cancer, breast cancer, stomach cancer, liver cancer, tongue cancer, thyroid cancer, kidney cancer, prostate cancer, uterine cancer, osteosarcoma, chondrosarcoma, rhabdomyosarcoma, melanoma, neuroblastoma, and bladder cancer.
Dependent claims 22 and 26 limit the chimeric antigen receptor T-cell or chimeric antigen receptor NK-cell of claim 11 and the method of claim 13 to that wherein the binding capability of the chimeric antigen receptor to ganglioside GD1a, ganglioside GD1b, ganglioside GD3, ganglioside GM1, ganglioside GM3, ganglioside GT1b, or lactosylceramide is equal to or less than 1/2 of the binding capability of the chimeric antigen receptor to ganglioside GD2.
Dependent claims 23 and 27 limit the chimeric antigen receptor T-cell or chimeric antigen receptor NK-cell of claim 11 and the method of claim 13 to that wherein the chimeric antigen receptor comprises a core domain comprising: a scFv domain comprising the heavy-chain variable region and the light-chain variable region, the transmembrane domain, and the intracellular domain of the TCR.
Dependent claims 24 and 28 limit the chimeric antigen receptor T-cell or chimeric antigen receptor NK-cell of claim 23 and the method of claim 27 to that wherein the core domain further comprises an intracellular domain of a co-stimulator.
Golinelli et al. teach a GD2 CAR which comprises all of the CDRs recited in instant claim 11 (e.g. see SEQ ID NO: 3 spanning pages 13 and 14, “protein sequence for GD2 tCAR”). See sequence alignment below. Golinelli et al. also teach a polynucleotide sequence encoding the GD2 CAR (e.g. see SEQ ID NO: 2 spanning pages 12 and 13, “nucleotide sequence for GD2 tCAR”) and bifunctional cells comprising a permanent modification of the nucleus comprising a GD2 CAR molecule codified by at least one viral vector and inserted in said nucleus of said starting cells (e.g. see claim 19). Golinelli et al. further teach a construct expressing the GD2 CAR in which an anti-GD2 single-chain variable fragment (scFv) derived from an immunoglobulin M (IgM) is used as the antigen binding domain (e.g. see [0062] and Fig. 2a).
Alignment of Golinelli et al.’s SEQ ID NO: 3 and the instant CDRs (SEQ ID NOs: 1-3 and 9-11):
Query Match 52.7%; Score 145; DB 1; Length 335;
Best Local Similarity 24.2%;
Matches 51; Conservative 0; Mismatches 0; Indels 160; Gaps 5;
Qy 1 QSLLSSRTRKNY-----------------WAS--------------------------- 15
|||||||||||| |||
Db 46 QSLLSSRTRKNYLAWYQQKPGQSPKLLIYWASIRESGVPDRFTGSGSGTDFTLTISSVQA 105
Qy 16 --------KQSYNLRT-------------------------------------------- 23
||||||||
Db 106 EDLAVYYCKQSYNLRTFGGGTKLEIKGSTSGSGKPGSGEGSSKGEVQLQESGPGLVAPSQ 165
Qy 24 ---------GFSLPSYG-----------------IWAGGITN------------------ 39
|||||||| ||||||||
Db 166 SLSITCTVSGFSLPSYGVHWVRQPPGKGLEWLGVIWAGGITNYNSALMSRLTISKDNSKS 225
Qy 40 -------------------ARGGSDYDGFAY 51
||||||||||||
Db 226 QVFLKMNSLQTDDTAIYYCARGGSDYDGFAY 256
Golinelli et al. also teach that GD2 is expressed in many cancers and has restricted expression on normal tissues (e.g. see page 1, [0021]-[0022]). Therefore, GD2 represents a putative target for new therapeutic approaches, such as with anti-GD2 monoclonal antibodies and T-CAR lymphocytes (e.g. see page 1, [0023]-[0024]).
Golinelli et al. also teach some cancers that commonly express high levels of GD2 including lung microcitoma (lung cancer), melanoma, neuroblastoma, and bone (osteosarcoma and chondrosarcoma) and soft tissue (rhabdomyosarcoma) sarcomas (e.g. see [0021]). Golinelli et al. also teach that some breast cancer variants have been positive for GD2 (e.g. see [0022]).
The reference teachings differ from the instant invention by not teaching that the GD2 CAR-encoding polynucleotide is comprised in a T-cell; the CAR also comprises a transmembrane domain and an intracellular domain of a TCR; the CAR T cell is comprised in a pharmaceutical composition; or the CAR T cell is used in a method of treating a GD2-expressing cancer.
Mount et al. teach GD2-targeted CAR T cells incorporating a scFv derived from an anti-GD2 monoclonal antibody, a 4-1BB costimulatory domain, CD8 transmembrane domain (TM), and CD3ζ (intracellular domain of a TCR) (e.g. see paragraph spanning pages 572 and 573; page 580, right column, third paragraph; and figure 1e).
Mount et al. also teach that their GD2 CAR-T cell has potent antitumor efficacy in GD2-expressing cancer cells (e.g. see page 578, left column, third paragraph). Mount et al. teach that their GD2 CAR-T cell therapy displays substantial GD2-dependent killing at several effector to target ratios (Fig. 1f) and cytokine generation (Fig. 1g) (e.g. see paragraph spanning pages 572 and 573). In fact, Mount et al. teach that their GD2 CAR-T cell therapy did not produce a substantial cytokine response or induce cell killing when exposed to cancer cells that do not express GD2, providing evidence for therapeutic specificity of GD2-CAR T cells (e.g. see paragraph spanning pages 572 and 573).
Regarding claims 13, Mount et al. also teach a method of treating a GD2-expressing cancer in a subject having a GD2-expressing cancer with the GD2-CAR T cell (e.g. see paragraph spanning pages 580 and 581). Regarding claim 12, the CAR T cells were delivered in a concentration of 1×107 transduced cells in 200 µl of PBS (a pharmaceutical composition) through intravenous injection (e.g. see paragraph spanning pages 580 and 581).
It would have been prima facie obvious to one of ordinary skill in the art before the effective filing date of the claimed invention to have modified Golinelli et al. to incorporate the teachings of Mount et al. to include that the GD2 CAR-encoding polynucleotide is comprised in a T-cell; the CAR also comprises a transmembrane domain and an intracellular domain of a TCR; the CAR T cell is comprised in a pharmaceutical composition; and the CAR T cell is used in a method of treating a GD2-expressing cancer. This is because of the potent and GD2-dependent antitumor efficacy of the GD2 CAR-T cell taught by Mount et al.
Given the therapeutic specificity of GD2-CAR T cells incorporating a scFv derived from an anti-GD2 monoclonal antibody, a 4-1BB costimulatory domain, a CD8 TM, and the CD3ζ TCR intracellular domain as demonstrated by their potent antitumor efficacy in GD2-expressing cancer cells and not in cancer cells that do not express GD2 (Mount et al.); it would have been obvious to a skilled artisan to modify the GD2 CAR taught by Golinelli et al. to also comprise a transmembrane domain and an intracellular domain of a TCR and use the modified GD2 CAR in a T cell with a reasonable expectation of success. The GD2 CAR would be expected to transduce an intracellular T cell signal to activate the cytotoxic function of the T cell in a GD2-dependent manner.
Furthermore, given that the GD2 CAR T cell taught by Mount et al. was used in a pharmaceutical composition for treating a GD2-expressing cancer in a subject (Mount et al.) and GD2 is expressed in many cancers including lung microcitoma, melanoma, neuroblastoma, bone and soft tissue sarcomas, and breast cancer (Golinelli et al.); it would be obvious to a skilled artisan to also used the GD2 CAR T cell taught by Golinelli et al. in view of Mount et al. in a pharmaceutical composition for a method of treating a GD2-expressing cancer in a subject that has lung cancer, melanoma, neuroblastoma, osteosarcoma chondrosarcoma, rhabdomyosarcoma, and/or breast cancer with a reasonable expectation of success. The GD2 CAR T cell taught by Golinelli et al. in view of Mount et al. would be expected to have potent anti-tumor cytotoxicity toward these GD2-expressing cancers.
Regarding the limitations “wherein the chimeric antigen receptor T-cell or chimeric antigen receptor NK-cell has cytotoxic activity against at least one selected from the group consisting of blood cancer, lung cancer, colorectal cancer, ovarian cancer, breast cancer, stomach cancer, liver cancer, tongue cancer, thyroid cancer, kidney cancer, prostate cancer, uterine cancer, osteosarcoma, chondrosarcoma, rhabdomyosarcoma, melanoma, neuroblastoma, and bladder cancer” (claim 11) and “wherein the binding capability of the chimeric antigen receptor to ganglioside GD1a, ganglioside GD1b, ganglioside GD3, ganglioside GM1, ganglioside GM3, ganglioside GT1b, or lactosylceramide is equal to or less than 1/2 of the binding capability of the chimeric antigen receptor to ganglioside GD2” (claims 22 and 26), Golinelli et al. and Mount et al. are silent on these properties.
However, silence about a particular property does not necessarily constitute its absence. The office does not have the facilities and resources to provide the factual evidence needed in order to establish that there is a difference between the materials, i.e., that the claims are directed to new materials and that such a difference would have been considered unexpected by one of ordinary skill in the art, that is, the claimed subject matter, if new, is unobvious. In the absence of evidence to the contrary, the burden is on the Applicant to prove that the claimed materials are 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).
Although Golinelli et al. and Mount et al. are silent with regard to the cytotoxic and binding capability of the CAR as recited in claims 11, 22, and 26, it is noted that a compound and all of its properties are inseparable; they are one and the same thing (see In re Papesch, CCPA 137 USPQ 43; In re Swinehart and Sfiligoj, 169) USPQ 226 (CCPA 1971)). Therefore, in the absence of evidence to the contrary, the GD2 CAR T cell taught by Golinelli et al. in view of Mount et al. would necessarily have the claimed properties recited in claims 11, 22, and 26.
When a claim recites using an old composition or structure (e.g., GD2 CAR T cell) and the use is directed to a result or property of that composition or structure (properties recited in claims 11, 22, and 26) then the claim is anticipated. See MPEP 2112.02. Also, see Bristol-Myers Squibb Co. v. Ben Venue Laboratories, Inc. 58 USPQ2d 1508 (CA FC 2001); Ex parte Novitski 26 USPQ 1389 (BPAI 1993); Mehl/Biophile International Corp. V. Milgraum, 52 USPQ2d 1303 (Fed. Cir. 1999); Atlas Powder Co. V. IRECO, 51 USPQ2d 1943 (Fed. Cir. 1999).
The Courts have held that there is no requirement that those of ordinary skill in the art know of the inherent property. See MPEP 2131.01(d) and MPEP 2112 - 2113.
Nonetheless, regarding properties recited in claim 11, given that GD2 is expressed in many cancers GD2 including lung microcitoma (lung cancer), melanoma, neuroblastoma, bone (osteosarcoma and chondrosarcoma) and soft tissue (rhabdomyosarcoma) sarcomas, and breast cancer, and has restricted expression on normal tissues (Golinelli et al.); GD2 represents a putative target for new therapeutic approaches, such as with anti-GD2 T-CAR lymphocytes (Golinelli et al.); and the potent GD2-dependent antitumor efficacy of GD2 CAR-T cells (Mount et al.); it would be expected that the GD2 CAR-T cells taught by Golinelli et al. in view of Mount et al. to have cytotoxicity toward GD2-expressing cancers, such as those recited in claim 11.
Therefore, the invention as a whole was prima facie obvious to one of ordinary skill in the art at the time the invention was made, as evidenced by the references, especially in the absence of evidence to the contrary.
Applicant’s arguments have been fully considered but have not been found persuasive.
The Applicant argues that one of ordinary skill in the art would have been discouraged from modifying the TRAIL-GD2-tCAR therapy disclosed in Golinelli, which proved to exhibit a high cytotoxic effect targeting GD2, to GD2 CAR therapy, as suggested by the Office, because GD2 CAR therapy has been shown to have low cytotoxicity. The Applicant asserts that even if one skilled in the art would have engineered a complete GD2 CAR by modifying the GD2 tCAR taught in Golinelli to include an intracellular domain of a T-cell receptor (TCR), as suggested by the Office, which Applicant does not concede, the skilled person would not have had a reasonable expectation of success that a chimeric antigen receptor T-cell or chimeric antigen receptor NK-cell comprising such an engineered GD2 CAR would have the cytotoxic activity recited in the present claims.
The Applicant also argues that Mount does not teach or suggest that GD2 CAR can be effective against cancer in general because Mount only discloses that GD2 can be an immunotherapy target in H3-K27M* diffuse midline gliomas (DMG). The Applicant asserts that Mount only discloses that "[w]ith a cautious multidisciplinary clinical approach, GD2- targeted CAR T cell therapy for H3-K27M* diffuse midline gliomas of pons, thalamus and spinal cord could prove transformative for these lethal childhood cancers," which again does not indicate that GD2 CAR is effective against cancer in general.
The Applicant further argues that Fig. 1 of Mount shows that GD2 CAR is not effective in H3-WT GD2-negative diffuse intrinsic pontine glioma (DIPG) cells and that the H3-K27M mutation in gliomas may be associated with GD2 expression. The Applicant asserts that the H3-K27 mutation, especially the H3K27M variant, is known to be a key genetic driver in aggressive pediatric brain tumors, particularly DMG like DIPG. The Applicant, therefore, argues that it is unclear whether the H3-K27 mutation was known to be also associated with cancers other than gliomas at the time of the present application, and even if it was known, it is unclear whether the H3-K27 mutation- associated cancers, other than gliomas, also exhibited enhanced GD2 expression. Thus, the applicant argues that even in view of Mount, one of ordinary skill in the art would not have reasonably expected that GD2 CAR therapy would be effective against cancers other than gliomas.
Therefore the Applicant argues that for at least these reasons, Applicant submits that a person skilled in the art would not have been motivated to modify the TRAIL-GD2-tCAR therapy disclosed in Golinelli, which proved to exhibit a high cytotoxic effect targeting GD2, to GD2 CAR therapy, as suggested by the Office, with a reasonable expectation of success that it would be effective against GD2-positive cancers other than brain tumors, particularly in view of the teachings provided in WO 2012/033885 and the instant specification that CAR therapy targeting GD2 has a weak cytotoxic effect and low efficacy.
This is not found persuasive for the following reasons:
Contrary to the Applicant’s arguments that that one of ordinary skill in the art would have been discouraged from modifying the TRAIL-GD2-tCAR therapy disclosed in Golinelli, which proved to exhibit a high cytotoxic effect targeting GD2, to GD2 CAR therapy, because GD2 CAR therapy has been shown to have low cytotoxicity; note that Mount et al. teach a GD2 CAR T cell exhibited potent antitumor efficacy against GD2-expressing cancer cells. Furthermore, given the therapeutic specificity of GD2-CAR T cells incorporating a scFv derived from an anti-GD2 monoclonal antibody, a 4-1BB costimulatory domain, a CD8 TM, and the CD3ζ TCR intracellular domain as demonstrated by their potent antitumor efficacy in GD2-expressing cancer cells and not in cancer cells that do not express GD2; it would have been obvious to a skilled artisan to modify the GD2 CAR taught by Golinelli et al. also comprise a transmembrane domain and an intracellular domain of a TCR and use the modified GD2 CAR in a T cell with a reasonable expectation of success. The GD2 CAR would be expected to transduce an intracellular T cell signal to activate the cytotoxic function of the T cell in a GD2-dependent manner.
Regarding the Applicant’s argument that the skilled person would not have had a reasonable expectation of success that a chimeric antigen receptor T-cell or chimeric antigen receptor NK-cell comprising such an engineered GD2 CAR would have the cytotoxic activity recited in the present claims; it is noted that a compound and all of its properties are inseparable; they are one and the same thing (see In re Papesch, CCPA 137 USPQ 43; In re Swinehart and Sfiligoj, 169) USPQ 226 (CCPA 1971)). Therefore, in the absence of evidence to the contrary, the GD2 CAR T cell taught by Golinelli et al. in view of Mount et al. would necessarily have the cytotoxic activity recited in claim 11. The Courts have held that there is no requirement that those of ordinary skill in the art know of the inherent property. See MPEP 2131.01(d) and MPEP 2112 - 2113. Nonetheless, given that GD2 is expressed in many cancers GD2 including lung microcitoma (lung cancer), melanoma, neuroblastoma, bone (osteosarcoma and chondrosarcoma) and soft tissue (rhabdomyosarcoma) sarcomas, and breast cancer, and has restricted expression on normal tissues (Golinelli et al.); GD2 represents a putative target for new therapeutic approaches, such as with anti-GD2 T-CAR lymphocytes (Golinelli et al.); and the potent GD2-dependent antitumor efficacy of GD2 CAR-T cells (Mount et al.); it would be expected that the GD2 CAR-T cells taught by Golinelli et al. in view of Mount et al. would have cytotoxicity toward GD2-expressing cancers, such as those recited in claim 11.
Regarding the Applicant’s argument that Mount does not teach or suggest that GD2 CAR can be effective against cancer in general because Mount only discloses that GD2 can be an immunotherapy target in H3-K27M* diffuse midline gliomas (DMG); it is noted that Mount et al. teach that their GD2 CAR-T cell therapy displays substantial GD2-dependent killing and, in fact, does not produce a substantial cytokine response or induce cell killing when exposed to cancer cells that do not express GD2. Based on these teachings, a skilled artisan would reasonably expect the GD2 CAR T cell taught by Golinelli et al. in view of Mount et al. to have potent cytotoxicity against GD2-expressing cells in general. While Mount et al. specifically uses glioma in their study, it is simply an exemplary cancer to demonstrate the GD2-dependent therapeutic efficacy of their GD2 CAR T cell. It is noted that all that is required is a reasonable expectation of success, not absolute predictability of success. See In re O’Farrell, 853 F.2d 894,903 (Fed. Cir. 1988). Therefore, this does not discourage a skilled artisan from reasonably expecting that the GD2 CAR T cell would be effective against any cancer that expresses GD2.
Regarding the Applicant’s argument that it is unclear whether the H3-K27 mutation was known to be also associated with cancers other than gliomas at the time of the present application, and even if it was known, it is unclear whether the H3-K27 mutation-associated cancers, other than gliomas, also exhibited enhanced GD2 expression and thus, that even in view of Mount, one of ordinary skill in the art would not have reasonably expected that GD2 CAR therapy would be effective against cancers other than gliomas; it is noted that nowhere in the instant claims is the H3-K27 mutation recited. Thus, the Applicant’s arguments related to the H3-K27 mutation are not commensurate in scope with the claims. Nonetheless, as noted above, while Mount et al. specifically uses glioma in their study, it is simply an exemplary cell line to demonstrate the GD2-dependent therapeutic efficacy of their GD2 CAR T cell. While the H3-K27 mutation seems to dictate the expression of GD2 in gliomas, the H3-K27 mutation-GD2 expression relationship cannot be extrapolated to cancer in general. Thus, a cancer may express GD2 regardless of its H3-K27 mutation status. It is noted that all that is required is a reasonable expectation of success, not absolute predictability of success. See In re O’Farrell, 853 F.2d 894,903 (Fed. Cir. 1988). Therefore, so long as a cancer expresses GD2, there is no requirement to determine the H3-K27 mutation status or a connection between the H3-K27 mutation and GD2 expression for a skilled artisan to reasonably expect that the GD2 CAR T cell would be effective against said GD2-expressing cancer.
Therefore, the invention as a whole was prima facie obvious to one of ordinary skill in the art at the time the invention was made, as evidenced by the references, especially in the absence of evidence to the contrary.
Claims 11, 13, 23, 25, 27, and 29 are rejected under 35 U.S.C. 103 as being unpatentable over Golinelli et al. (US20210300990A1, a reference of record) in view of Mount et al. 2018 (Nat. Med. 24, 572–579, a reference of record), as applied to claims 11, 13, 23, and 27, and further in view of Golubovskaya et al. 2018 (Front Biosci, Landmark Ed, 23(12), 2245–2254, a reference of record), Knee et al. 2016 (European Journal of Cancer. 67; 1-10), and Liu et al. 2017 (Sci Rep 7, 2193, a reference of record).
Dependent claims 25 and 29 limit the chimeric antigen receptor T-cell or chimeric antigen receptor NK-cell of claim 23 and the method of claim 27, respectively, to that wherein the chimeric antigen receptor comprises a GITRL domain fused to the C-terminus of the core domain via a self-cleaving peptide domain.
The teachings of Golinelli et al. in view of Mount et al. pertaining to claims 11, 13, 23, and 27, and the rationale for combining them are outlined in the 103 rejection above.
The combined reference teachings do not teach that the chimeric antigen receptor comprises a GITRL domain fused to the C-terminus of the core domain via a self-cleaving peptide domain.
Golubovskaya et al. teach that while CAR T cell therapy using autologous T cells with a CAR against a tumor cell surface antigen demonstrates remarkable results against hematological cancers, several challenges remain to make CAR-T cells effective against solid tumors (e.g. see page 2246, left column, first paragraph under “introduction”). This is due to suppressive tumor microenvironment, suppressive checkpoint inhibitor signaling or inhibitory regulatory T cell (Treg signaling), angiogenesis, vasculogenesis, tumor associated macrophages (TAM), and other pathways in solid tumors (e.g. see page 2246, left column, first paragraph under “introduction”).
As a result, Golubovskaya et al. teach a CAR with a glucocorticoid-induced tumor necrosis factor receptor (GITR) co-stimulatory domain which is as effective as a CAR comprising a CD28 domain and in several cell lines is better than a CAR comprising a 41-BB domain (e.g. see page 2246, left column, second paragraph under “introduction”). Golubovskaya et al. teach that the GITR domain can be used for co-stimulation of CAR-T cells to produce CAR-T cells with similar or better functional activity than those without GITR (e.g. see page 2246, left column, second paragraph under “introduction”).
Golubovskaya et al. specifically teach a CAR construct designed with a GITR co-stimulatory domain introduced C-terminal to a core domain comprising an scFv, a TM, and a CD3 zeta domain (e.g. see “EGFR-CD3zeta-GITR” in figure 3A).
GITR is a member of the TNF superfamily proteins (such as 4-1BB, OX-40, CD40, CD27 and others) that is expressed at high levels on T reg cells, and is also expressed at a lower level on effector T cells, NK (natural killer) cells and other cells of the immune system (e.g. see page 2246, left column, second paragraph under “introduction”). GITR expression can be up-regulated upon activation of T cells and GITR can co-stimulate both CD4+ and CD8+ T cells. In addition, GITR can stimulate both Treg with inhibitory functions and effector T cells with stimulatory functions, thus mediating dual signaling in immune response that should be balanced (e.g. see page 2246, left column, second paragraph under “introduction”).
Golubovskaya et al. ultimately teach the novel function of the GITR co-stimulatory domain in regulating CAR-T cell activities against cancer cells that it is important for developing future cellular therapeutics (e.g. see page 2252, last paragraph under “discussion”).
Knee et al. teach that the engagement of GITR on T cells with agonist antibodies, recombinant GITRL or GITRL transfectants, following suboptimal TCR stimulation, enhances T cell activation by upregulating CD25, inducing IL-2 and IFNγ expression, and augmenting proliferation (e.g. see page 2, right column, first paragraph). Knee et al. also teach that GITR modulation shows compelling antitumor activity which is attributed both to its costimulatory role on CD4+ and CD8+ T cells as well as inhibition or depletion of intratumoral Tregs (e.g. see page 3, left column, second paragraph). The costimulatory function of GITR has been elucidated in several studies in which DTA-1 (an agonistic anti-GITR antibody) or GITRL-Fc clearly mediates CD8+ T cell expansion and cytokine production in vivo (e.g. see page 3, left column, third paragraph). DTA-1 further enhances the multifunctionality of CD8+ T cells in an adoptive T cell therapy model. Furthermore, there is a growing body of data indicating that GITR modulation enhances the Teff to Treg ratio, in part through its costimulatory role of enhancing the CD8+ T cell population, but also through its depletion of Tregs (e.g. see page 3, left column, third paragraph).
Knee et al. ultimately teach that the ability of GITR modulation to enhance the CD8/Treg ratio via two seemingly disparate mechanisms (Treg depletion and costimulation of Teff cells) provides a novel combination partner with checkpoint inhibitors to increase the response rate and duration of response (e.g. see page 8, left column, fourth paragraph).
Liu et al. teach that co-expression of multiple genes at a desired ratio is highly attractive for a broad array of basic research and biomedical applications including cellular reprogramming and expression of multiple subunits of complex multimeric proteins in gene therapy (e.g. see page 1, second paragraph). Strategies for multigene co-expression include introduction of multiple vectors, use of multiple promoters in a single vector, fusion proteins, proteolytic cleavage sites between genes, internal ribosome entry sites, and “self-cleaving” 2A peptides. 2A peptides are 18–22 amino-acid (aa)-long viral oligopeptides that mediate “cleavage” of polypeptides during translation in eukaryotic cells. Overall, 2A peptides lead to relatively high levels of downstream protein expression compared to other strategies for multi-gene co-expression, and they are small in size thus bearing a lower risk of interfering with the function of co-expressed genes. 2A peptides have also been successfully employed by several different groups for polycistronic and bi-cistronic multigene expression (e.g. see page 1, second paragraph).
It would have been prima facie obvious to one of ordinary skill in the art before the effective filing date of the claimed invention to have modified the combined teachings of Golinelli et al. in view of Mount et al., as applied to claims 11, 13, 23, and 27, and to incorporate the teachings of Golubovskaya et al., Knee et al., and Liu et al. to include that the CAR comprises a GITRL domain fused to the C-terminus of the core domain via a self-cleaving peptide domain. This is because that GITR modulation shows compelling antitumor activity which is attributed both to its costimulatory role on CD4+ and CD8+ T cells as well as inhibition or depletion of intratumoral Tregs (Knee et al.).
CAR constructs comprising C-terminal GITR have been described and GITR-comprising CARs have similar or better functional activity than those without GITR (Golubovskaya et al.). GITR is expressed at high levels on T reg cells and at a lower level on effector T cells (Golubovskaya et al.). GITR expression is up-regulated upon activation of T cells and GITR can co-stimulate both CD4+ and CD8+ T cells and stimulate both Treg with inhibitory functions and effector T cells with stimulatory functions (Golubovskaya et al. and Knee et al.).
The co-expression of multiple genes at a desired ratio is highly attractive for a broad array of basic research and biomedical applications (Liu et al.). Strategies to accomplish this include “self-cleaving” 2A peptide which mediate “cleavage” of polypeptides during translation in eukaryotic cells and lead to relatively high levels of downstream protein expression compared to other strategies for multi-gene co-expression (Liu et al.).
It is well known that the suppressive tumor microenvironment and suppressive checkpoint inhibitor signaling or inhibitory regulatory T cell (Treg signaling) limits the application of CAR-T cells against solid tumors (Golubovskaya et al.). Therefore, given that GITR is expressed on Treg and Teff cells and GITR modulation enhances the Teff/Treg ratio by depleting or inhibiting intratumoral Treg cells and co-stimulating Teff cells thereby enhancing T cell activation, proliferation, and, ultimately, antitumor activity (Golubovskaya et al. and Knee et al.); it would have been obvious to a skilled artisan, with the goal of enhancing the antitumor efficacy of the GD2 CAR T cell taught by Golinelli et al. in view of Mount et al. against solid tumors by limiting the suppressive tumor microenvironment and Treg signaling, to further modify the GD2 CAR construct to include a GITRL domain fused to the C-terminus of the core domain via a self-cleaving peptide domain with a reasonable expectation of success.
Golubovskaya et al. already teach a CAR construct comprising a C-terminal GITR co-stimulatory domain. It would have been obvious to a skilled artisan to modify this CAR construct to instead include a GITRL domain fused to the C-terminus of the CAR via a self-cleaving peptide domain. This is because, in the process of translating the polynucleotide encoding the CAR, the GITRL domain could be cleaved from the CAR and free to be expressed on the cell surface of the GD2 CAR T cell where it would engage GITR on intratumoral Treg cells, Teff cells, and also other GD2 CAR T cells. In view of Golubovskaya et al. and Knee et al., a skilled artisan would reasonably expect that this modulation of GITR would enhance the antitumor activity of the GD2 CAR T cells by depleting or inhibiting intratumoral Treg cells and co-stimulating Teff and GD2 CAR T cells.
It is noted that it would also be obvious to include the GITRL domain C-terminal to the CAR core domain so that no essential elements (TM or intracellular TCR domain) of the CAR are cleaved from the CAR by the self-cleaving peptide.
Combining prior art elements according to known methods to yield predictable results is obvious to one of ordinary skill in the art (see MPEP § 2143(A)). From the combined teachings of the references, it is apparent that one of ordinary skill in the art would have had a reasonable expectation of success in producing the claimed invention.
Therefore, the invention as a whole was prima facie obvious to one of ordinary skill in the art before the effective filing date of the claimed invention, as evidenced by the references, especially in the absence of evidence to the contrary.
Conclusion
No claim is allowed.
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/GRACE H LUNDE/Examiner, Art Unit 1641
/MISOOK YU/Supervisory Patent Examiner, Art Unit 1641