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 .
The Election filed July 28, 2025, in response to the Office Action of February 26, 2025, is acknowledged and has been entered. Applicants elected without traverse the species of Antigen Recognition Domain comprising the binding target of Human ASGR1 isoform a, the antigen recognition domain wherein the antigen recognition domain comprises CDR1, CDR2, and CDR3 regions comprising SEQ ID NOs: 11, 12, and 13, respectively, and the amino acid sequence of SEQ ID NO: 74. Applicant also elected without traverse a species of Chimeric Antigen Receptor (CAR) comprising the hinge domain of CD8alpha hinge domain, the transmembrane domain of CD8alpha transmembrane domain, the co-stimulatory domain of CD28 signaling domain, the intracellular signaling domain of CD3 signaling domain, or any homologs thereof, the amino acid of SEQ ID NO: 151, and the endodomain, wherein the endodomain does not comprise a STAT3 association motif. Claims 1-27 and 29-31 are pending and currently under prosecution.
Claim Rejections - 35 USC § 112
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 1-7, 11-27, and 29-31 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(s) contains subject matter which was not described in the specification in such a way as to reasonably convey to one skilled in the relevant art that the inventor or a joint inventor, or for pre-AIA the inventor(s), at the time the application was filed, had possession of the claimed invention. This is a WRITTEN DESCRIPTION rejection.
The claims are drawn an engineered regulatory T cell (Treg) comprising a chimeric antigen receptor (CAR), wherein the CAR comprises an antigen recognition domain which specifically binds to asialoglycoprotein receptor (ASGR), a pharmaceutical composition, and a method of inducing tolerance to a liver transplant in a subject, which comprises the step of administering to the subject an engineered Treg. Thus, the claims identify the antigen recognition domain which binds asialogylcoprotein receptor (ASGR) by function only. No antigen binding protein structure is recited.
Claims 11 and 18 recite that the antigen recognition domain comprises an amino acid sequence that has at least about 90% identity to SEQ ID NO:74 or SEQ ID NO:151. These claims encompass a partial sequence of the antigen recognition domain, wherein the antigen recognition domain can comprise any sequence variations or mutations anywhere in up to 10% of the claimed sequence, including in the CDR regions critical to the antigen binding function claimed.
With regards to an antigen recognition domain which binds asialoglycoprotein receptor (ASGR), the instant specification discloses:
(page 14, line 25) The "antigen recognition domain" as used herein refers to the extracellular part of the CAR that defines the antigen-binding capability of the CAR. In certain aspects of the invention, the25 antigen recognition domain provides the CAR with the ability to bind to a liver-specific antigen, preferably asialoglycoprotein receptor (ASGR). Thus, the antigen recognition
domain targets a liver-specific antigen, preferably ASGR.
(page 14, line 30) A liver-specific antigen is one which is preferentially expressed in liver tissue e.g. in hepatocytes, parenchymal cells, kupffer cells, stellate cells, and/or liver sinusoidal endothelial cells. Suitably, a liver-specific antigen is an antigen which has higher expression levels in liver tissue (e.g. in at least one of hepatocytes, parenchymal cells, kupffer cells, stellate cells, and liver sinusoidal endothelial cells) as compared to other tissues. For example, a liver-specific antigen may be an antigen which has expression levels at least 10% higher, at least 20% higher, at least 30% higher, at least 40% higher, at least 50% higher, at least 100% higher, at least 200% higher, at least 300% higher, at least 400% higher, at least 500% higher, or at least 1000% higher compared to expression levels in other tissues. Preferably, a liver specific-antigen is one which is only expressed in liver tissue, i.e. is not detectably expressed in other tissues.
(page 15, line 15) Preferably, the antigen recognition domain specifically binds to asialoglycoprotein receptor (ASGR). Most preferably, the antigen recognition domain binds to human ASGR. In some embodiments, the antigen recognition domain binds to both human ASGR and ASGR from other animals, e.g. mouse ASGR. Suitably, the antigen recognition domain may bind specifically to human ASGR.
(page 21, line 15) Preferably, the antigen recognition domain is, or is derived from, an antibody (Ab). An antibody-derived antigen recognition domain can be a fragment of an antibody or a genetically engineered product of one of more fragments of the antibody, which fragment is involved in binding with the antigen. Examples include a camelid antibody (VHH), an antigen-binding fragment (Fab), a variable region (Fv), a single chain antibody (scFv), a
single-domain antibody (sdAb), a heavy chain variable region (VH), a light chain variable
region (VL), and a complementarity determining region (CDR). In preferred embodiments, the antigen recognition domain is a single chain antibody (scFv) or a single-domain antibody (sdAb). Most preferably, the antigen recognition domain is a single-domain antibody (sdAb).
The specification discloses producing anti-ASGR1 CAR constructs comprising a single-domain antibody (sdAb) binding ASGR1, including CAR sequence SEQ ID NO:151 that comprises SEQ ID NO:74 and CDR SEQ ID NOs:11, 12, and 13:
Example 1 Design of Anti-ASGR1 CAR Constructs
Chimeric antigen receptors (CAR) were designed comprising: an antigen recognition domain derived from a single-domain antibody (sdAb) known to specifically bind to ASGR; a transmembrane domain (TM) derived from CD28 (aa 153 to 179); and an intracellular signalling domain comprising the signalling domains of CD3ζ and CD28. Exemplary constructs are shown below and in FIG. 1.
The specification discloses an antigen recognition domain is, or is derived from an antibody wherein the antibody comprises one or more CDR regions, selected from SEQ ID NOs: 11-73, or derivatives thereof and functions to bind ASGR. Thus, the instant specification discloses a number of anti-ASGR antigen recognition domains that function as claimed. The specification fails to disclose all of the structural sequences required of an anti-ASGR antigen recognition domain to possess the function of binding ASGR and inducing tolerance to a liver transplant in a subject.
To provide adequate written description and evidence of possession of the claimed anti-ASGR antigen recognition domain genus, the instant specification can structurally describe representative anti-ASGR antigen recognition domains that function to bind ASGR and induce tolerance to a liver transplant, or describe structural features common to the members of the genus, which features constitute a substantial portion of the genus. Alternatively, the specification can show that the claimed invention is complete by disclosure of sufficiently detailed, relevant identifying characteristics, functional characteristics when coupled with a known or disclosed correlation between function and structure, or some combination of such characteristics (see University of California v. Eli Lilly and Co., 119 F.3d 1559, 43 USPQ2d 1398 (Fed. Cir. 1997) and Enzo Biochem, Inc. V. Gen-Probe Inc.). A disclosure that does not adequately describe a product itself logically cannot adequately describe a method of using that product.
Although Applicants may argue that it is possible to screen for anti-ASGR antigen binding domains that bind ASGR and function as claimed, the court found in (Rochester v. Searle, 358 F.3d 916, Fed Cir., 2004) that screening assays are not sufficient to provide adequate written description for an invention because they are merely a wish or plan for obtaining the claimed chemical invention. “As we held in Lilly, “[a]n adequate written description of a DNA … ‘requires a precise definition, such as by structure, formula, chemical name, or physical properties,’ not a mere wish or plan for obtaining the claimed chemical invention.” 119 F.3d at 1566 (quoting Fiers, 984 F.2d at 1171). For reasons stated above, that requirement applies just as well to non-DNA (or RNA) chemical inventions.” Knowledge of screening methods provides no information about the structure of any future binding proteins or antibodies yet to be discovered that may function as claimed. The ASGR antigen provides no information about the structure of an antigen recognition domain that binds to it.
In this case, the only factor present in the claims is a recitation of the protein function: “an antigen recognition domain which specifically binds to asialoglycoprotein receptor (ASGR),” “inducing tolerance to a liver transplant in a subject,” and “treating and/or preventing liver transplant rejection, liver graft-versus-host disease (GvHD), an autoimmune liver disease, or an inflammatory liver disorder.” The claims broadly encompass any antigen recognition domain that binds to ASGR and functions as claimed. The instant specification fails to describe structural features common to the members of the genus, which features constitute a substantial portion of the genus because the instant specification discloses only a number of antigen recognition domains that bind ASGR. A definition by function does not suffice to define the genus because it is only an indication of what the antigen binding protein does, rather than what it is. Other than for an antigen recognition domain comprising all six CDR SEQ ID NOs selected from SEQ ID NOs 11-73, the specification fails to provide any structural features coupled to the claimed functional characteristics.
Applicants have not established any reasonable structure-function correlation with regards to the sequences in the variable domains or CDRs that can be altered and still maintain ASGR binding function and induce tolerance to a liver transplant in a subject. The instant claims attempt to claim every protein that would achieve a desired result (i.e., bind ASGR and induce tolerance to a liver transplant in a subject), wherein the instant specification does not describe sufficient representative examples to support the full scope of the claims. Given the well-known high level of polymorphism of binding proteins and antibody CDR sequences and structure, the skilled artisan would not have been in possession of the vast repertoire of antigen binding proteins and required to practice the claimed antigen recognition domain and methods claimed. Therefore, one could not readily envision members of the broadly claimed genus.
Given the lack of representative examples to support the full scope of the claimed anti-ASGR antigen recognition domains and those used in the claimed methods, and lack of reasonable structure-function correlation with regards to the unknown sequences in the proteins or variable domains or CDRs that provide ASGR-binding function and inducing tolerance to a liver transplant function, the present claims lack adequate written description. Thus, the specification does not provide an adequate written description of anti-ASGR antigen recognition domains that is required to practice the claimed invention. Since the specification fails to adequately describe the product to which the claimed method uses, it also fails to adequately describe the method.
Examiner Suggestion: Amend independent claim 1 to recite the structure critical to the anti-ASGR antigen recognition domain function, that is, an anti-ASGR antigen recognition single antibody domain comprising all three CDR SEQ ID NOs:11, 12, and 13, critical to performing the claimed functions.
Claims 29-31 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 enablement requirement. The claim(s) contains subject matter which was not described in the specification in such a way as to enable one skilled in the art to which it pertains, or with which it is most nearly connected, to make and/or use the invention.
The claims are drawn to a method for preventing liver transplant rejection, liver graft-versus-host disease (GvHD), an autoimmune liver disease, or an inflammatory liver disorder in a subject, the methods comprising the step of administering the engineered Treg according to claim 1.
The specification discloses the sequences and formulations of an engineered regulatory T cell (Treg) comprising a chimeric antigen receptor (CAR), wherein the CAR comprises an antigen recognition domain which specifically binds to asialoglycoprotein receptor (ASGR), but does not disclose any examples of the claimed Treg preventing diseases. The instantly claimed Treg is not predictably expected to, and is not enabled to prevent cancer, disorders, or diseases as claimed.
Regarding the prevention of disease, the specification lacks the critical steps necessary in presenting some type of predictable response in a population of hosts deemed necessary to prevent disease. Reasonable guidance with respect to preventing any disease relies on quantitative analysis from defined populations which have been successfully pre-screened and are predisposed to particular types of disease or have had disease. The essential element towards the validation of a preventive therapeutic is the ability to test the drug on subjects monitored in advance of clinical disease and link those results with subsequent histological confirmation of the presence or absence of disease. This irrefutable link between antecedent drug and subsequent knowledge of the prevention of the cancer/disease is the essence of a valid preventive agent. All of this underscores the criticality of providing workable examples which are not disclosed in the specification.
Examiner Suggestion: Delete the word “preventing” from claims 29-31.
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.
Claims 1-18, 22-27 are rejected under 35 U.S.C. 103 as being unpatentable over EP3228702A1 (WO2016086813), Wang et al, published November 10, 2017 in view of “Chimeric Antigen Receptor (CAR) Treg: A Promising Approach to Inducing Immunological Tolerance,” Zhang et al, published October 12, 2018; as evidenced by NCBI NP_001662.1, asialoglycoprotein receptor 1 isoform a [Homo sapiens], printed September 2025.
Regarding claims 1 and 2, Wang teaches a chimeric antigen receptor T lymphocyte specifically recognizing ASGPR1 (Claim 1). ASGPR1 is a synonym for ASGR1. Wang teaches T lymphocyte-based adoptive immunotherapy, wherein a chimeric antigen receptor immune effector cell expresses a chimeric antigen receptor that binds to ASGPR1 [0002].
With regard to claims 3-4, Wang teaches the ASGPR1 antigen recognition domain binds to human ASGPR1 SEQ ID NO:8 (Example 1). As evidenced by NCBI NP_001662.1 that is 100% to SEQ ID NO:8, SEQ ID NO:8 represents human asialoglycoprotein receptor 1 isoform a. Therefore, the ASGPR1 antigen recognition domain taught by Wang binds to human asialoglycoprotein receptor 1 isoform a.
Regarding claims 6 and 7, Wang teaches the chimeric antigen receptor comprises an anti-ASGPR1 single chain antibody (Claims 4 and 5).
Regarding claims 5 and 8-11, Wang teaches an ASGPR fusion protein comprising SEQ ID NO 24 which comprises instantly claimed CDR SEQ ID NOs 11, 12, and 13, and the instantly claimed amino acid sequence SEQ ID NO: 74 (see sequence alignments below). Given Wang teaches the ASGPR1 antigen recognition domain comprises the same sequences instantly claimed, it is expected it comprises the same antigen affinity claimed.
Regarding claim 12, Wang teaches the chimeric antigen receptor comprises a transmembrane domain and an intracellular signaling domain, as well as a hinge domain and a co-stimulatory domain ([0003][0046-0047]).
Regarding claim 13, Wang teaches the chimeric antigen receptor comprises a hinge domain, CD8alpha, which is a flexible region [0046].
Regarding claim 14, Wang teaches the chimeric antigen receptor comprises a transmembrane domain selected from CD8 and CD28 and in one embodiment, specifically CD8alpha [0046].
Regarding claim 15, Wang teaches the chimeric antigen receptor comprises a co-stimulatory molecule domain CD28 (Claim 5, [0003].
Regarding claim 16, Wang teaches the chimeric antigen receptor comprises an intracellular signaling domain CD3zeta [0037].
Regarding claim 17, Wang teaches the chimeric antigen receptor comprises a CD8a hinge domain, a CD28 transmembrane domain, a CD28 signaling domain, and the CD3 zeta signaling domain ([0037][0046-0047]).
Regarding claim 18, Wang teaches construction of the ASGPR plasmid with a mcherry nucleic acid fragments with F2A (a self-cleaving peptide) and a CD8 signal peptide [0070].
Regarding claims 22-24, Wang does not teach the presence of any Stat5 association motif, Stat3 association motif, a JAK1- or JAK2- binding motif, or endodomain comprising instant SEQ ID NO:133, therefore they are absent.
Regarding claim 27, Wang teaches administering the CAR T cell in a saline pharmaceutical composition to treat cancer in vivo (Example 7). Wang teaches administering the chimeric antigen receptor immune effector cell to treat liver cancer (Claim 7).
Wang does not teach the engineered CAR T lymphocyte is a regulatory T cell (Treg). Zhang remedies this deficiency.
Zhang teaches engineering Treg with antigen-specificity via transfection of viral vectors encoding chimeric antigen receptors (CARs). Zhang teaches Tregs can be modified with CARs to have the advantage of widespread applications in transplantation and autoimmunity. Zhang also teaches CAR T-regs are less dependent on IL-2 (page 1). Zhang teaches an ex vivo-generated Tregs were used in a major pilot study where most patients developed liver transplant tolerance (page 2, paragraph 2).
Regarding claims 25 and 26, Zhang teaches a major subset of Tregs is defined by stable expression of CD25 and FoxP3 (page 2, paragraph 1). Zhang also teaches generating CAR Tregs where murine FoxP3 was co-expressed with the CAR to differentiate from CD4+ T cells (page 5, paragraph 2).
It would have been prima facie obvious to one of ordinary skill in the art to engineer a Treg cell comprising an antigen recognition domain which specifically binds to asiaglycoprotein receptor (ASGR).
One of ordinary skill in the art would have been motivated to and have a reasonable expectation of success given: 1) Wang teaches modifying T lymphocytes to express a chimeric antigen receptor that binds to ASGR for treatment of liver cancer, and 2) Zhang teaches the advantages of using Treg cells in place of T lymphocytes and generating Treg CARs for immunotherapy, often used in transplant and liver disorders.
Instantly claimed SEQ ID NO: 74 aligned to SEQ ID NO: 24 of EP3228702A1
RESULT 6
BDB14957
ID BDB14957 standard; protein; 556 AA.
AC BDB14957;
DT 28-JUL-2016 (first entry)
DE MCherry-F2A-ASGPR-CD28a-CD28b-CD137 fusion protein, SEQ ID 24.
KW ASGPR1; CD137; CD28 protein; T cell surface glycoprotein CD28;
KW asialoglycoprotein receptor 1; cancer; cell therapy; cytostatic;
KW gastrointestinal-gen.; hepatotropic; liver tumor; therapeutic.
OS Synthetic.
OS Unidentified.
CC PN WO2016086813-A1.
CC PD 09-JUN-2016.
CC PF 30-NOV-2015; 2015WO-CN095938.
PR 04-DEC-2014; 2014CN-10736009.
CC PA (CARS-) CARSGEN THERAPEUTICS LTD.
CC PI Wang H, Cai X, Zhao H, Song B, Chen Y, Zhu Y;
DR WPI; 2016-345130/43.
PS Example 2; SEQ ID NO 24; 29pp; Chinese.
SQ Sequence 556 AA;
Query Match 100.0%; Score 630; Length 556;
Best Local Similarity 100.0%;
Matches 120; Conservative 0; Mismatches 0; Indels 0; Gaps 0;
Qy 1 EVQLLESGGGLVQPGGSLRLSCAASGFTFEKYAMAWVRQAPGKGLEWVSRISARGVTTYY 60
||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
Db 282 EVQLLESGGGLVQPGGSLRLSCAASGFTFEKYAMAWVRQAPGKGLEWVSRISARGVTTYY 341
Qy 61 ADSVKGRFTISRDNSKNTLYLQMNSLRAEDTAVYYCAKHKRHEHTRFDSWGQGTLVTVSS 120
||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
Db 342 ADSVKGRFTISRDNSKNTLYLQMNSLRAEDTAVYYCAKHKRHEHTRFDSWGQGTLVTVSS 401
Instantly claimed SEQ ID NO: 11-12-13 aligned to SEQ ID NO: 24 of EP3228702A1
RESULT 9
BDB14957
ID BDB14957 standard; protein; 556 AA.
AC BDB14957;
DT 28-JUL-2016 (first entry)
DE MCherry-F2A-ASGPR-CD28a-CD28b-CD137 fusion protein, SEQ ID 24.
KW ASGPR1; CD137; CD28 protein; T cell surface glycoprotein CD28;
KW asialoglycoprotein receptor 1; cancer; cell therapy; cytostatic;
KW gastrointestinal-gen.; hepatotropic; liver tumor; therapeutic.
OS Synthetic.
OS Unidentified.
CC PN WO2016086813-A1.
CC PD 09-JUN-2016.
CC PF 30-NOV-2015; 2015WO-CN095938.
PR 04-DEC-2014; 2014CN-10736009.
CC PA (CARS-) CARSGEN THERAPEUTICS LTD.
CC PI Wang H, Cai X, Zhao H, Song B, Chen Y, Zhu Y;
DR WPI; 2016-345130/43.
CC PT New double chimeric antigen receptor-targeted immune effector cell
CC PT capable of expressing chimeric receptors recognizing glypican-3 and
CC PT asialoglycoprotein receptor 1, useful in preparation of medicine for
CC PT treating liver cancer.
CC PS Example 2; SEQ ID NO 24; 29pp; Chinese.
SQ Sequence 556 AA;
Query Match 80.7%; Score 106.5; Length 556;
Best Local Similarity 31.2%;
Matches 25; Conservative 0; Mismatches 0; Indels 55; Gaps 2;
Qy 1 EKYAMA--------------RISARGVT-------------------------------- 14
|||||| ||||||||
Db 311 EKYAMAWVRQAPGKGLEWVSRISARGVTTYYADSVKGRFTISRDNSKNTLYLQMNSLRAE 370
Qy 15 ---------HKRHEHTRFDS 25
|||||||||||
Db 371 DTAVYYCAKHKRHEHTRFDS 390
Instantly claimed SEQ ID NO: 74 aligned to SEQ ID NO: 874 of WO2011086143A2
RESULT 1
AZK15894
(NOTE: this sequence has 2 duplicates in the database searched.
See complete list at the end of this report)
ID AZK15894 standard; protein; 120 AA.
AC AZK15894;
DT 18-AUG-2011 (first entry)
DE Anti-mouse ASGPR variable kappa chain dAb protein, SEQ:874.
KW ASGPR receptor; ASGR protein; Asialoglycoprotein receptor;
KW antibody production; antibody therapy; antiinflammatory;
KW antimicrobial-gen.; cytostatic; domain antibody; drug delivery;
OS Homo sapiens.
OS Synthetic.
CC PN WO2011086143-A2.
CC PD 21-JUL-2011.
CC PF 13-JAN-2011; 2011WO-EP050420.
PR 14-JAN-2010; 2010US-0294942P.
CC PA (GLAX ) GLAXO GROUP LTD.
CC PI Dunlevy G, Holmes S, Hong Z, Sepp A, Walker A;
DR WPI; 2011-J40160/50.
CC PS Disclosure; SEQ ID NO 874; 250pp; English.
SQ Sequence 120 AA;
Query Match 100.0%; Score 630; Length 120;
Best Local Similarity 100.0%;
Matches 120; Conservative 0; Mismatches 0; Indels 0; Gaps 0;
Qy 1 EVQLLESGGGLVQPGGSLRLSCAASGFTFEKYAMAWVRQAPGKGLEWVSRISARGVTTYY 60
||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
Db 1 EVQLLESGGGLVQPGGSLRLSCAASGFTFEKYAMAWVRQAPGKGLEWVSRISARGVTTYY 60
Qy 61 ADSVKGRFTISRDNSKNTLYLQMNSLRAEDTAVYYCAKHKRHEHTRFDSWGQGTLVTVSS 120
||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
Db 61 ADSVKGRFTISRDNSKNTLYLQMNSLRAEDTAVYYCAKHKRHEHTRFDSWGQGTLVTVSS 120
Claims 1 and 20-21 are rejected under 35 U.S.C. 103 as being unpatentable over EP3228702A1 (WO2016086813), Wang et al, published November 10, 2017 in view of “Chimeric Antigen Receptor (CAR) Treg: A Promising Approach to Inducing Immunological Tolerance,” Zhang et al, published October 12, 2018 as applied to claims 1-18 and 22-27 above, and further in view of “A novel chimeric antigen receptor containing a JAK-STAT signaling domain mediates superior antitumor effects,” Kagoya et al, published February 5, 2018.
The teachings of the combined references are set forth above. The combined references do not teach the engineered Treg wherein the CAR comprises an endodomain which comprises a STAT5 association motif and a JAK1-and/or a JAK2-binding motif, and a JAK3-binding motif. Kagoya remedies this deficiency.
Kagoya teaches constructing CD19-specific chimeric antigen receptor constructs to induce JAK-STAT pathway activation. Kagoya teaches adding Box 1 motif, Box 2 motif, and a STAT5-binding domain into the chimeric antigen receptor (Figure 1d). Kagoya teaches that the engineered CAR-T cells showed antigen-dependent activation of the JAK kinase and of the STAT3 and STAT5 transcription factors signaling pathways, and demonstrated superior antitumor effects (page 352, column 1).
It would have been prima facie obvious to one of ordinary skill in the art to engineer a Treg cell comprising a chimeric antigen receptor comprising an antigen recognition domain which binds ASGR, and wherein the CAR comprises and endodomain which comprises a STAT5 association motif, and a JAK1-and/or a JAK2-binding motif and a JAK3-binding motif.
One would have been motivated and have a reasonable expectation of success given: 1) The combined references teach engineering a Treg cell comprising a chimeric antigen receptor to treat liver cancer, and 2) Kagoya demonstrates successfully improving antitumor effects through activation of the JAK/STAT pathway by adding JAK and STAT5 binding domains to the CAR. One would have been motivated to make this change to the chimeric antigen receptor taught by the combined references in order to improve the anti-tumor effect of the cancer therapy.
Claims 1 and 29-31 are rejected under 35 U.S.C. 103 as being unpatentable over EP3228702A1 (WO2016086813), Wang et al, published November 10, 2017 in view of “Chimeric Antigen Receptor (CAR) Treg: A Promising Approach to Inducing Immunological Tolerance,” Zhang et al, published October 12, 2018 as applied to claims 1-18 and 22-27 above, and further in view of “A Pilot Study of Operational Tolerance With a Regulatory T-Cell-Based Cell Therapy in Living Donor Liver Transplantation,” Todo et al, published 2016.
The combined references teach an engineered regulatory T cell (Treg) comprising a chimeric antigen receptor (CAR), wherein the CAR comprises an antigen recognition domain which specifically binds to asiaglycoprotein receptor (ASGR). The combined references do not teach a pharmaceutical composition comprising an engineered Treg, and do not teach the methods taught in claims 29-31. Todo remedies these deficiencies.
Regarding claim 29, Todo teaches a pilot study aiming to induce tolerance after liver transplantation using a novel regulatory T-cell-based cell therapy. Todo teaches administering Treg-based therapy to 10 adult patients suffering from end-stage liver failure for various causes (Table 1), with clinical trial registration number UMIN-000015789.
Regarding claims 30 and 31, Todo teaches administering the Treg therapy to patients with primary sclerosing cholangitis as well as patients with liver cirrhosis caused by alcohol and viral hepatitis (Table 1). Todo teaches all the patients who received the Treg therapy ended up with normal liver function and histology (page 640, paragraph 1).
It would have been prima facie obvious to one of ordinary skill in the art to administer to a subject an engineered Treg in a method to induce tolerance to a liver transplant.
One would have been motivated to and have a reasonable expectation of success given: 1) The combined references teach an engineered Treg cell comprising a chimeric antigen receptor (CAR) to treat liver cancer, 2) Todo demonstrates successfully using Treg cell therapy to induce operational tolerance in liver transplantation in a number of patients. One would have been motivated to use the Treg cell taught by the combined references in the method taught by Todo.
Conclusion
Conclusion: Claims 1-27 and 29-31 are rejected.
Any inquiry concerning this communication or earlier communications from the examiner should be directed to NADA AHMED MAHMOUD ELMANSY whose telephone number is (571)270-0810. The examiner can normally be reached Monday-Friday 9am-5pm EST.
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/NADA AHMED MAHMOU ELMANSY/Examiner, Art Unit 1646
/Laura B Goddard/Primary Examiner, Art Unit 1642