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 .
Applicant’s amendments filed on 4/8/2026 are acknowledged.
Claims 1-2, 6-12, 15, 18-20, 23-26, and 29 are pending.
Election/Restrictions
Applicant’s election without traverse of Invention Group I drawn to a chimeric antigen receptor wherein the antigen binding domain comprises an antibody specifically targeting CD7 in the reply filed on 4/9/2026 is acknowledged.
Claims 30-31 are cancelled by the Applicant as recited in page 1 of Applicant’s Remarks/Arguments due to being drawn to a non-elected method of using a chimeric antigen receptor for the preparation of a medicine. Election was made without traverse in the reply filed on 4/9/2026.
Applicant’s election without traverse of the species of a chimeric antigen receptor with an antigen binding region of an antiCD7 scFv comprising VH of SEQ ID NO:8, VL of SEQ ID No:7, and CDRs of SEQ ID NOs:1-6; a CD8alpha transmembrane domain; a intracellular signaling domain comprising 4-1BB, CD3zeta, and the yc chain intracellular region (e.g. SEQ ID NO:65); the second antigen is CD19 with the anti-CD19 scFv comprising VH of SEQ ID NO:57, VL of SEQ ID NO:56, and CDRs of SEQ ID NOs:44-49; the species of vector being a lentiviral vector; the species of engineered immune cell being a CD8+ T cell with suppressed or silenced expression of endogenous CD7 and TRAC (i.e. double knockout) and further expressing an immunosuppressive molecule that comprises an antigen binding region targeting PD-1 (e.g. PD-L1 extracellular domain); the species of pharmaceutical composition being a composition comprising the engineered immune cell of (c); the species of patient population and disease type being acute lymphoblastic leukemia in the reply filed on 4/9/2026 is acknowledged.
Claims 3-5, 13-14, 16-17, 21-22, and 27-28 have been cancelled by the Applicant as recited in the claim amendments filed on 4/9/2026.
As such claims 1-2, 6-12, 15, 18-20, 23-26, and 29 are currently under consideration as they read on the elected Invention Group I and species election the of a chimeric antigen receptor with an antigen binding region of an antiCD7 scFv comprising VH of SEQ ID NO:8, VL of SEQ ID No:7, and CDRs of SEQ ID NOs:1-6; a CD8alpha transmembrane domain; a intracellular signaling domain comprising 4-1BB, CD3zeta, and the yc chain intracellular region (e.g. SEQ ID NO:65); the second antigen being CD19 with the anti-CD19 scFv comprising VH of SEQ ID NO:57, VL of SEQ ID NO:56, and CDRs of SEQ ID NOs:44-49; the vector being a lentiviral vector; the engineered immune cell being a CD8+ T cell with suppressed or silenced expression of endogenous CD7 and TRAC (i.e. double knockout) and further expressing an immunosuppressive molecule that comprises an antigen binding region targeting PD-1 (e.g. PD-L1 extracellular domain); the pharmaceutical composition being a composition comprising the engineered immune cell of (c); the patient population and disease type being acute lymphoblastic leukemia.
Claim Interpretation
Claim 1 recites “wherein the antigen binding region comprises an antibody specifically targeting CD7” and claim 10 recites “wherein the antibody targeting a second antigen is an antibody targeting CD19”. When using broadest reasonable interpretation, the language utilized in the claims of “specifically targeting” and “targeting” opens up the claims to refer to any antibody that can directly bind to or target CD7 and CD19 AND any antibody that indirectly targets CD7 and CD19. However, in light of the specification, the Examiner is interpreting the claims to refer to the antibody specifically targeting CD7 as an anti-CD7 antibody and the antibody targeting CD19 as an anti-CD19 antibody.
Claim Objections
Claims are objected to because of the following informalities:
Claim 18 recites, “wherein the immune cell comprises suppressed or silenced expression of endogenous CD7”. Comprises is an open-ended transitional phrase that does not sufficiently describe the physical attributes of what a cell does and does not express. The Examiner recommends using “exhibits” instead of “comprises”, since “exhibits” more precisely describes the functional state of gene expression in a cell.
Claim 19 recites, “wherein the immune cell comprises suppressed or silenced expression..”. Comprises is an open-ended transitional phrase that does not sufficiently describe the physical attributes of what a cell does and does not express. The Examiner recommends using “exhibits” instead of “comprises”, since “exhibits” more precisely describes the functional state of gene expression in a cell.
Claim 20 recites, “wherein the immune cell comprises suppressed or silenced expression..”. Comprises is an open-ended transitional phrase that does not sufficiently describe the physical attributes of what a cell does and does not express. The Examiner recommends using “exhibits” instead of “comprises”, since “exhibits” more precisely describes the functional state of gene expression in a cell.
Claim 23 recites, “at least one TCR/CD3 gene selected from the group consisting of TRAC … least one MHC class II related gene selected from the group consisting of RFX5”. The recitation of “at least one” TCR/CD3 gene and MHC class II related gene contradicts the only one gene listed in the Markush group. The claim should recite, “… wherein the immune cell exhibits suppressed or silenced expression of endogenous CD7, one TCR/CD3 gene TRAC, and one MHC class II related gene RFX5.”.
Claim 29 recites, “A pharmaceutical composition the engineered immune cell according to claim 15” which should read “A pharmaceutical composition comprising the engineered immune cell according to claim 15”.
Appropriate correction is required.
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 10, 19, 20, and 23 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 10 recites the limitation "targeting a second antigen" in line 2. There is insufficient antecedent basis for this limitation in the claim.
Claim 19 recites the limitation “at least one TCR/CD3 gene; and the TCR/CD3 gene is TRAC” in lines 2-3. It is unclear whether the engineered immune cell exhibits suppressed or silenced expression of one OR more than one TCR/CD3 gene since the claim recites contradictory language of “at least one” and then selecting only one TCR/CD3 gene to be suppressed or silenced.
Claim 20 recites the limitation “at least one MHC class II related gene; and the MHC class II related gene is RFX5” in lines 2-4. It is unclear whether the engineered immune cell exhibits suppressed or silenced expression of one OR more than one MHC class II related gene since the claim recites contradictory language of “at least one” and then selecting only one MHC class II related gene to be suppressed or silenced.
Claim 23 recites the limitation “at least one TCR/CD3 gene selected from the group consisting of TRAC, and at least one MHC class II related gene selected from the group consisting of RFX5” in lines 3-4. It is unclear whether there is one OR more than one TCR/CD3 gene and MHC class II related gene exhibits suppressed or silenced expression since the claim recites contradictory language of “at least one… selected from the group consisting of” and only one gene is recited.
Appropriate correction is required.
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.
Written Description
Claims 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 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.
Applicant is in possession of: a chimeric antigen receptor comprising an antigen binding region comprises an antibody specifically targeting CD7 wherein the antibody targeting CD7 comprises a light chain variable region of SEQ ID NO:7 further comprising CDR-L1, -L2, and -L3 of SEQ ID NOs:1-3, respectively, and a heavy chain variable region of SEQ ID NO:8 further comprising CDR-H1, -H2, and -H3 of SEQ ID NOs:4-6, respectively; and wherein the antigen binding region comprises an antibody targeting a second antigen is an antibody targeting CD19 comprising a light chain variable region of SEQ ID NO:56 further comprising CDR-L1, -L2, and -L3 of SEQ ID NOs:44-46, respectively, and a heavy chain variable region of SEQ ID NO:57 further comprising CDR-H1, -H2, and -H3 of SEQ ID NOs:46-48, respectively; a CD8α transmembrane domain of SEQ ID NO:22; a CD3ζ primary signaling domain; a CD137 co-stimulatory domain; and a γc chain with 100% sequence identity to SEQ ID NO:65; a nucleic acid encoding a CAR comprising an antigen binding region comprises an antibody specifically targeting CD7 wherein the antibody targeting CD7 comprises a light chain variable region of SEQ ID NO:7 further comprising CDR-L1, -L2, and -L3 of SEQ ID NOs:1-3, respectively, and a heavy chain variable region of SEQ ID NO:8 further comprising CDR-H1, -H2, and -H3 of SEQ ID NOs:4-6, respectively; an engineered CD8+ T cell comprising a CAR comprising an antigen binding region comprises an antibody specifically targeting CD7 wherein the antibody targeting CD7 comprises a light chain variable region of SEQ ID NO:7 further comprising CDR-L1, -L2, and -L3 of SEQ ID NOs:1-3, respectively, and a heavy chain variable region of SEQ ID NO:8 further comprising CDR-H1, -H2, and -H3 of SEQ ID NOs:4-6, respectively; wherein the engineered immune cell comprises suppressed or silenced expression of endogenous CD7, TRAC (TCR/CD3 gene), and RFX5 (MHC class II related gene); wherein the engineered immune cell further expresses a PD-L1 immunosuppressive molecule with a PD-L1 immune cell antigen binding region of SEQ ID NO:69, a PDL1 transmembrane domain of SEQ ID NO:70, and a CD28 co-stimulatory domain of SEQ ID NO:26; and a pharmaceutical composition comprising a engineered CD8+ T cell comprising a CAR comprising an antigen binding region comprises an antibody specifically targeting CD7 wherein the antibody targeting CD7 comprises a light chain variable region of SEQ ID NO:7 further comprising CDR-L1, -L2, and -L3 of SEQ ID NOs:1-3, respectively, and a heavy chain variable region of SEQ ID NO:8 further comprising CDR-H1, -H2, and -H3 of SEQ ID NOs:4-6, respectively.
Applicant is not in possession of: A chimeric antigen receptor, comprising an antigen binding region, a transmembrane domain and an intracellular signaling region, wherein the antigen binding region comprises an antibody specifically targeting CD7, and the intracellular signaling region consists of at least one co-stimulatory domain, a primary signaling domain, and a γc chain or intracellular region thereof of claim 1; the chimeric antigen receptor according to claim 1, wherein the antibody of claim 2; the chimeric antigen receptor according to claim 1 of claim 6; the chimeric antigen receptor according to claim 1, wherein the antigen binding region further comprises an antibody targeting a second antigen, wherein the second antigen is CD19 of claim 9; a nucleic acid encoding the chimeric antigen receptor according to claim 1; an engineered immune cell, comprising the chimeric antigen receptor according to claim 1; the engineered immune cell according to claim 1 of claims 19-20 and 23-26; the immunosuppressive molecule comprising one or more immune cell antigen binding domains, a transmembrane domain, and at least one co-stimulatory domain of claim 24; the engineered immune cell of claim 24 wherein the immunosuppressive molecule of claim 25; the engineered immune cell of claim 24 wherein the immune cell antigen binding region is an antibody targeting an immune cell antigen of PD-1, a ligand of an immune cell antigen of PD-L1, or a combination thereof; and a pharmaceutical composition comprising the engineered immune cell according to claim 15 of claim 29.
The claims encompass a broad genus of CD7 specific chimeric antigen receptors (CARs), CD7 and CD19 specific CARs, a broad genus of nucleic acids encoding a broad genus of CD7 specific CAR, a broad genus of engineered immune cell expressing a broad genus of CD7 specific CARs and a broad genus of immunosuppressive molecules comprising a broad genus of antibodies targeting PD-1 and PD-L1, and a pharmaceutical composition comprising a broad genus of engineered immune cells expressing a broad genus of CD7 specific CARs. The skilled artisan cannot envision all the CAR, engineered immune cell, and pharmaceutical composition possibilities recited in the instant claims.
Consequently, conception cannot be achieved until a representative description of the structural and functional properties of the claimed invention has occurred, regardless of the complexity or simplicity of the method.
The specification must set forth the structural features that allow one of ordinary skill in the art to identify and produce the recited antibodies. In the instant case, definition by function does not suffice to define the genus because it is only an indication of what the antibodies do, rather than what they are.
It is well established in the art that it is highly unpredictable which changes in amino acid sequence can be made in complementarity determining regions (CDRs) of a parental antibody such that the derived antibody retains the binding specificity and affinity of the parent antibody. The art of Mariuzza et al. (PTO-892; page 2, Reference U) reviews the structural basis of antigen-antibody recognition and teaches that a naturally occurring antibody comprises light and heavy chains. The antigen-combining site of an antibody is a three-dimensional structure, which fully comprises six "complementarity-determining regions" (CDRs), three each from the light and heavy chains. The amino acid sequences of the CDRs are hypervariable, as the amino acid residues contained within the CDRs determine much of antibody's antigen-binding specificity. Of the amino acid residues of the antibody contacting the antigen, six are within the light chain, nine are within the heavy chain, and two are within the constant or nearly constant "framework" regions (In particular, whole document). As such, one of skill in the art would not know which of the recited CAR antibody variants and immunosuppressive molecule antibody variants would have the claimed function of binding to CD7, CD19, PD-1, and PD-L1 because each antibody comprises 6 CDRs together which determine the antibody's antigen-binding specificity.
It is expected that all of the heavy and light chain CDRs in their proper order and in the context of framework sequences which maintain their required conformation, are required in order to produce a protein having antigen-binding function and that proper association of heavy and light chain variable regions is required in order to form functional antigen binding sites. MacCallum, et al. (PT0-892; page 1, Reference X) analyzed many different antibodies for interactions with antigen and state that although CDR3 of the heavy and light chain dominate, a number of residues outside the standard CDR definitions make antigen contacts (see page 733, right column) and non- contacting residues within the CDRs coincide with residues as important in defining canonical backbone conformations (see page 735, left column). De Pascalis, et al. (PTO-892; page 1, Reference V) demonstrate that grafting of the CDRs into a human framework was performed by grafting CDR residues and maintaining framework residues that were deemed essential for preserving the structural integrity of the antigen binding site (see page 3079, right column). Although abbreviated CDR residues were used in the constructs, some residues in all 6 CDRs were used for the constructs (see page 3080, left column). Thus, it is unpredictable as to what amino acids can be changed in the original intact antibodies disclosed in the specification wherein the antibodies would still function. Thus, the skilled artisan cannot envision the detailed structure of the encompassed invention and therefore conception is not achieved until reduction to practice has occurred, regardless of the complexity or simplicity of the method of isolation.
It is well established in the art that the formation of an intact antigen-binding site generally requires the association of the complete heavy and light chain variable regions of a given antibody, each of which consists of three CDRs which provide the majority of the contact residues for the binding of the antibody to its target epitope. The amino acid sequences and conformations of each of the heavy and light chain CDRs are critical in maintaining the antigen binding specificity and affinity which is characteristic of the parent immunoglobulin. It is expected that all of the heavy and light chain CDRs in their proper order and in the context of framework sequences which maintain their required conformation, are required in order to produce a protein having antigen-binding function and that proper association of heavy and light chain variable regions is required in order to form functional antigen binding sites. Even minor changes in the amino acid sequences of the heavy and light variable regions, particularly in the CDRs, may dramatically affect antigen-binding function.
As evidenced by the art of Goel et al. (PTO-892; page 1, Reference W), Khan et al. (PTO-892; Page 2, Reference V) and Poosarla et al. (PTO-892; Page 2; Reference W), antibody specificity for a particular antigen does not correlate with any particular structure for the antibodies themselves. It was well known to those skilled in the art at the time the invention was made that minor structural differences among structurally related antibodies or compositions thereof could result in substantially different binding activities. Given the lack of guidance in the specification, it is unpredictable which antibodies with which structures would exhibit the recited functions. The specification does not describe a correlation between the structure of the antibodies themselves and their function of binding CD7, CD19, PD-1, and PD-L1 such that a skilled artisan would have known what antibody structures possess the claimed functions of binding CD7, CD19, PD-1, and PD-L1.
The specification does not describe a correlation between the CAR antibody structure and the function of binding CD7, CD19, PD-1, and PD-L1 such that a skilled artisan would have known what antibody variants possess the claimed function. "Possession may not be shown by merely describing how to obtain possession of members of the claimed genus or how to identify their common structural features" Ex parte Kubin (83 U.S.P.Q.2d 1410 (BPAI 2007)), at page 16. In this instant case, Applicants have not provided the requisite identifying structural features of the antibodies encompassed. "Without a correlation between structure and function, the claim does little more than define the claimed invention by function" supra, at page 17.
U.S. Court of Appeals for the Federal Circuit recently decided Amgen v. Sanofi, 872 F.3d 1367 (Fed. Cir. 2017) which concerned adequate written description for claims drawn to antibodies. The Federal Circuit explained in Amgen that when an antibody is claimed, 35 U.S.C. § l 12(a) requires adequate written description of the antibody itself. Amgen, 872 F.3d at 1378-79. The Amgen court expressly stated that the so-called "newly characterized antigen" test, which had been based on an example in USPTO- issued training materials and was noted in dicta in several earlier Federal Circuit decisions, should not be used in determining whether there is adequate written description under 35 U.S.C. § l 12(a) for a claim drawn to an antibody. Citing its decision in Ariad Pharmaceuticals, Inc. v. Eli Lilly & Co. , the court also stressed that the "newly characterized antigen" test could not stand because it contradicted the quid pro quo of the patent system whereby one must describe an invention in order to obtain a patent. Amgen, 872 F.3d at 1378-79, quoting Ariad Pharmaceuticals, Inc. v. Eli Lilly & Co., 598 F.3d 1336, 1345 (Fed. Cir. 2010). In view of the Amgen decision, adequate written description of a newly characterized antigen alone should not be considered adequate written description of a claimed antibody to that newly characterized antigen, even when preparation of such an antibody is routine and conventional. Id.
The specification does not provide adequate written description of the claimed invention. The legal standard for sufficiency of a patent's (or a specification's) written description is whether that description "reasonably conveys to the artisan that the inventor had possession at that time of the ... claimed subject matter", Vas-Cath, Inc. V. Mahurkar, 19 U.S.P.Q.2d 1111 (Fed. Cir. 1991). In the instant case, the specification does not convey to the artisan that the applicant had possession at the time of invention of the claimed invention. regarding description of the claimed invention, the specification
does not provide an adequate written description of the invention claimed herein. See The Regents of the University of California v. Eli Lilly and Company, 43 USPQ2d 1398,
1404-7 (Fed. Cir. 1997). In University of California v. Eli Lilly and Co., 39 U.S.P.Q.2d
1225 (Fed. Cir. 1995) the inventors claimed a genus of DNA species encoding insulin in
different vertebrates or mammals, but had only described a single species of cDNA
which encoded rat insulin. The court held that only the nucleic acids species described
in the specification (i.e. nucleic acids encoding rat insulin) met the description
requirement and that the inventors were not entitled to a claim encompassing a genus
of nucleic acids encoding insulin from other vertebrates, mammals or humans, id. at
1240. The Federal Circuit has held that if an inventor is "unable to envision the detailed
constitution of a gene so as to distinguish it from other materials . . . conception has not
been achieved until reduction to practice has occurred", Amgen, Inc. v. Chugai
Pharmaceutical Co, Ltd., 18 U.S.P.Q.2d 016 (Fed. Cir. 1991). Attention is also directed
to the decision of The Regents of the University of California v. Eli Lilly and Company
(CAFC, July 1997) wherein is stated: "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, 222 USPQ 369,
372-373 (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. Thus, as we have previously held, a cDNA is not
defined or described by the mere name "cDNA," even if accompanied by the name of
the protein that it encodes, but requires a kind of specificity usually achieved by means of the recitation of the sequence of nucleotides that make up the cDNA." See Fiers, 984
F.2d at 1171, 25 USPQ2d at 1606.
Additionally, claims 1-2, 6-12, 15, 18-20, 23-26, and 29 encompass a broad genus of CD7 specific CARs and dual CD7xCD19 bispecific CARs with a broad genus of transmembrane domains and intracellular signaling domains consisting of any co-stimulatory domain, any primary signaling domain, and any γc chain or an intracellular region thereof; engineered immune cells comprising these CARs; and pharmaceutical compositions comprising these CARs. Claims 24-26 encompass a broad genus of immunosuppressive molecules with a broad genus of immune cell antigen binding regions, transmembrane domains, and co-stimulatory domains. The skilled artisan cannot envision all the CAR, engineered immune cell, and pharmaceutical composition possibilities recited in the instant claims.
However, there does not appear to be an adequate written description in the specification as-filed of the essential structural features that provide the recited functions of “transmembrane domain”, “intracellular signaling domain consists of at least one-costimulatory domain, a primary signaling domain, and γc chain or an intracellular region thereof”, and “immunosuppressive molecule comprising one or more immune cell antigen binding regions, a transmembrane domain, and at least one co-stimulatory domain”. The Guidelines for the Examination of Patent Applications Under the 35 U.S.C. 112(a) or U.S.C 112, I 1 "Written Description" Requirement make clear that the written description requirement for a claimed genus may be satisfied through sufficient description of a representative number of species by actual reduction to practice, 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.
The specification (page 3, [0023]-[0024]) describes CARs to refer to an artificially constructed hybrid polypeptide with a basic structure including an antigen binding region, a transmembrane domain, at least one co-stimulatory domain, and a primary signaling domain. The specification (pages 7-10, Example 1) further describes the preferred embodiment of the claimed invention to include a CAR with a CD7 targeting antigen binding region, a CD19 antigen binding region, a CD8α transmembrane domain of SEQ ID NO:22, a CD3ζ primary signaling domain of SEQ ID NO:30, a co-stimulatory domain comprising either 4-1BB of SEQ ID NO:28 or CD28 of SEQ ID NO:26, and a γc chain of SEQ ID NO:63 or the intracellular region of SEQ ID NO:63. Thus only one example of a structure that represents a CAR with a transmembrane domain and an intracellular signaling domain comprising a co-stimulatory domain, a primary signaling domain, and a γc chain intracellular domain is given.
The specification (page 16, [0075]) additionally describes an immunosuppressive molecule to inhibit or reduce the immune response of immune cells such as NK cells and T cells thereby reducing the risk of HvG where the structure of the immunosuppressive molecule comprises one or more immune cell antigen binding domains, a transmembrane domain, and a costimulatory domain without a primary signaling domain. The specification (page 24-25, Examples 5-6, Table 3) describes the structure of 14 different immunosuppressive molecules and that the immunosuppressive molecules do not affect the killing activity of CAR-T cells and can significantly inhibit the killing effect of immune cells such as NK cells and T cells on CAR-T cells. However, there is no further description or examples of other immunosuppressive molecules that can perform the recited function of inhibiting or reducing the immune response of immune cells.
However, the specification fails to provide adequate written description support for a genus of CAR structures all with the function of “transmembrane domain”, “intracellular signaling domain consists of at least one-costimulatory domain, a primary signaling domain, and γc chain or an intracellular region thereof”, and a genus of immunosuppressive molecules comprising “one or more immune cell antigen binding regions, a transmembrane domain, and at least one co-stimulatory domain”. The claims are not supported by a description that satisfies 35 U.S.C. § 112(a) or 35 U.S.C. § 112, first paragraph. "[T]he test for sufficiency [of the written description] is whether the disclosure of the application relied upon reasonably conveys to those skilled in the art that the inventor had possession of the claimed subject matter as of the filing date." Ariad Phanns., Inc. V. Eli Lilly & Co., 598 F.3d 1336, 1351 (Fed. Cir. 2010) (en bane).
A "sufficient description of a genus requires the disclosure of either a representative number of species falling within the scope of the genus or structural features common to the members of the genus so that one of skill in the art can 'visualize or recognize' the members of the genus." Id. at 1350. "[A]n adequate written description requires a precise definition, such as by structure, formula, chemical name, physical properties, or other properties, of species falling within the genus sufficient to distinguish the genus from other materials." Id.
"[F]unctional claim language can meet the written description requirement when the art has established a correlation between structure and function." Id. "But merely drawing a fence around the outer limits of a purported genus is not an adequate substitute for describing a variety of materials constituting the genus and showing that one has invented a genus and not just a species." Id.
"A sufficient description of a genus requires the disclosure of either a representative number of species falling within the scope of the genus or structural features common to the members of the genus so that one of skill in the art can "visualize or recognize" the members of the genus" (AbbVie, 759 F.3d at 1297, reiterating Eli Lilly, 119 F.3d at 1568-69) (emphasis added).
The specification only discloses one example of a CAR comprising a transmembrane domain of SEQ ID NO:22 and an intracellular signaling region consisting of one co-stimulatory domain of SEQ ID NO:28, one primary signaling domain of SEQ ID NO:32, and one yc chain or intracellular region thereof which is SEQ ID NO: 63 with the intracellular region of SEQ ID NO: 65.
With respect to representative number of species, see AbbVic Deutschland GmbH & Co.V. Janssen Biotech, Inc. (Fed. Cir. 2014). Also, see MPEP 2163 II(A)(3)(a))(ii):
"A representative number of species means that the species which are adequately described are representative of the entire genus. Thus, when there is substantial variation within the genus, one must describe a sufficient variety of species to reflect the variation within the genus. A "representative number of species" means that the species which are adequately described are representative of the entire genus. Thus, when there is substantial variation within the genus, one must describe a sufficient variety of species to reflect the variation within the genus. See Abb Vie Deutschland GmbH & Co., KG V. Janssen Biotech, Inc., 759 F.3d 1285, 1300, 111 USPQ2d 1780, 1790 (Fed. Cir. 2014) (Claims directed to a functionally defined genus of antibodies were not supported by a disclosure that "only describe[d] one type of structurally similar antibodies" that "are not representative of the full variety or scope of the genus.")."
Satisfactory disclosure of a "representative number" depends on whether one of skill in the art would recognize that the applicant was in possession of the necessary common attributes or features possessed by the members of the genus in view of the species disclosed. For inventions in an unpredictable art, adequate written description of a genus which embraces widely variant species cannot be achieved by disclosing only one species within the genus. See, e.g., Eli Lilly, 119 F.3d at 1568, 43 USPQ2d at 1406. Instead, the disclosure must adequately reflect the structural diversity of the claimed genus, either through the disclosure of sufficient species that are "representative of the full variety or scope of the genus," or by the establishment of "a reasonable structure-function correlation." Such correlations may be established "by the inventor as described in the specification," or they may be "known in the art at the time of the filing date." See AbbVie, 759 F.3d at 1300-01, 111 USPQ2d 1780, 1790-91 (Fed. Cir. 2014) (Holding that claims to all human antibodies that bind IL-12 with a particular binding affinity rate constant (i.e., Koff) were not adequately supported by a specification describing only a single type of human antibody having the claimed features because the disclosed antibody was not representative of other types of antibodies in the claimed genus, as demonstrated by the fact that other disclosed antibodies had different types of heavy and light chains, and shared only a 50% sequence similarity in their variable regions with the disclosed antibodies.).
In the instant case, one example of a structure with the function of a CAR comprising a transmembrane domain and an intracellular signaling domain consisting of one co-stimulatory domain, one primary signaling domain, and one γc chain or an intracellular region thereof and fourteen examples of a structure with the function of an immunosuppressive molecule with an antigen binding region, a transmembrane domain, and a co-stimulatory domain are given, which does not sufficiently represent the broad genus of polypeptides of any length and sequence with this recited function.
Given the broadly claimed class of structures with the function of CAR comprising a transmembrane domain and an intracellular signaling domain consisting of one co-stimulatory domain, one primary signaling domain, and one γc chain or an intracellular region thereof and an immunosuppressive molecule with an antigen binding region, a transmembrane domain, and a co-stimulatory domain, and in the absence of sufficient disclosure of relevant identifying characteristics for the broadly claimed class of polypeptides encompassed by the claims, the patentee must establish "a reasonable structure-function correlation" either within the specification or by reference to the knowledge of one skilled in the art with functional claims. AbbVie Deutschland GmbH & Co. V. Janssen Biotech, Inc. (Fed. Cir. 2014), MPEP 2163.
In the instant case, Applicant has not provided sufficient structure identifying characteristics or a reasonable structure-function correlation between a peptide's sequence and the function of CAR comprising a transmembrane domain and an intracellular signaling domain consisting of one co-stimulatory domain, one primary signaling domain, and one γc chain or an intracellular region thereof and an immunosuppressive molecule with an antigen binding region, a transmembrane domain, and a co-stimulatory domain, other than to list one specific structure with this function. The instant specification provides no guidance on how to generate other polypeptides with the function of CAR comprising a transmembrane domain and an intracellular signaling domain consisting of one co-stimulatory domain, one primary signaling domain, and one γc chain or an intracellular region thereof and an immunosuppressive molecule with an antigen binding region, a transmembrane domain, and a co-stimulatory domain, or how to distinguish between polypeptides with this function from ones without. Other than the recited CAR structure in Example 1 of the specification and the recited immunosuppressive molecule structures recited in Examples 5-6 and Table 3 of the specification, undue experimentation would be required to produce the invention commensurate with the scope of the claims from the written disclosure alone.
As such, there is insufficient written description of the required kind of structure
identifying information about the corresponding makeup of the claimed CAR and immunosuppressive molecule structures to demonstrate possession.
Enablement
Claims 1 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.
While being enabled for: a chimeric antigen receptor comprising an antigen binding region comprises an antibody specifically targeting CD7 wherein the antibody targeting CD7 comprises a light chain variable region of SEQ ID NO:7 further comprising CDR-L1, -L2, and -L3 of SEQ ID NOs:1-3, respectively, and a heavy chain variable region of SEQ ID NO:8 further comprising CDR-H1, -H2, and -H3 of SEQ ID NOs:4-6, respectively; and wherein the antigen binding region comprises an antibody targeting a second antigen is an antibody targeting CD19 comprising a light chain variable region of SEQ ID NO:56 further comprising CDR-L1, -L2, and -L3 of SEQ ID NOs:44-46, respectively, and a heavy chain variable region of SEQ ID NO:57 further comprising CDR-H1, -H2, and -H3 of SEQ ID NOs:46-48, respectively; a CD8α transmembrane domain of SEQ ID NO:22; a CD3ζ primary signaling domain of SEQ ID NO:30; a CD137 co-stimulatory domain of SEQ ID NO:28; and a γc chain with 100% sequence identity to SEQ ID NO:65; a nucleic acid encoding a CAR comprising a CD8α transmembrane domain of SEQ ID NO:22, a CD3ζ primary signaling domain of SEQ ID NO:30, a CD137 co-stimulatory domain of SEQ ID NO:28, a γc chain with 100% sequence identity to SEQ ID NO:65, and an antigen binding region comprises an antibody specifically targeting CD7 wherein the antibody targeting CD7 comprises a light chain variable region of SEQ ID NO:7 further comprising CDR-L1, -L2, and -L3 of SEQ ID NOs:1-3, respectively, and a heavy chain variable region of SEQ ID NO:8 further comprising CDR-H1, -H2, and -H3 of SEQ ID NOs:4-6, respectively; an engineered CD8+ T cell comprising a CAR comprising CD8α transmembrane domain of SEQ ID NO:22; a CD3ζ primary signaling domain of SEQ ID NO:30; a CD137 co-stimulatory domain of SEQ ID NO:28; and a γc chain with 100% sequence identity to SEQ ID NO:65, and an antigen binding region comprises an antibody specifically targeting CD7 wherein the antibody targeting CD7 comprises a light chain variable region of SEQ ID NO:7 further comprising CDR-L1, -L2, and -L3 of SEQ ID NOs:1-3, respectively, and a heavy chain variable region of SEQ ID NO:8 further comprising CDR-H1, -H2, and -H3 of SEQ ID NOs:4-6, respectively; wherein the engineered immune cell comprises suppressed or silenced expression of endogenous CD7, TRAC (TCR/CD3 gene), and RFX5 (MHC class II related gene); wherein the engineered immune cell further expresses a PD-L1 immunosuppressive molecule with a PD-L1 immune cell antigen binding region of SEQ ID NO:69, a PDL1 transmembrane domain of SEQ ID NO:70, and a CD28 co-stimulatory domain of SEQ ID NO:26; and a pharmaceutical composition comprising a engineered CD8+ T cell comprising a CAR comprising CD8α transmembrane domain of SEQ ID NO:22; a CD3ζ primary signaling domain of SEQ ID NO:30; a CD137 co-stimulatory domain of SEQ ID NO:28; and a γc chain with 100% sequence identity to SEQ ID NO:65, and an antigen binding region comprises an antibody specifically targeting CD7 wherein the antibody targeting CD7 comprises a light chain variable region of SEQ ID NO:7 further comprising CDR-L1, -L2, and -L3 of SEQ ID NOs:1-3, respectively, and a heavy chain variable region of SEQ ID NO:8 further comprising CDR-H1, -H2, and -H3 of SEQ ID NOs:4-6, respectively;
The specification does not provide enablement for: A chimeric antigen receptor, comprising an antigen binding region, a transmembrane domain and an intracellular signaling region, wherein the antigen binding region comprises an antibody specifically targeting CD7, and the intracellular signaling region consists of at least one co-stimulatory domain, a primary signaling domain, and a γc chain or intracellular region thereof of claim 1; the chimeric antigen receptor according to claim 1, wherein the antibody of claim 2; the chimeric antigen receptor according to claim 1 of claim 6; the chimeric antigen receptor according to claim 1, wherein the antigen binding region further comprises an antibody targeting a second antigen, wherein the second antigen is CD19 of claim 9; the chimeric antigen receptor according to claim 9, wherein the antibody of claim 10; the chimeric antigen receptor according to claim 10 of claim 11; a nucleic acid encoding the chimeric antigen receptor according to claim 1 of claim 12; an engineered immune cell, comprising the chimeric antigen receptor according to claim 1 of claim 15; the engineered immune cell according to claim 1 of claims 18-20 and 23-26; the immunosuppressive molecule comprising one or more immune cell antigen binding domains, a transmembrane domain, and at least one co-stimulatory domain of claim 24; the engineered immune cell of claim 24 wherein the immunosuppressive molecule of claim 25; the engineered immune cell of claim 24 wherein the immune cell antigen binding region is an antibody targeting an immune cell antigen of PD-1, a ligand of an immune cell antigen of PD-L1, or a combination thereof; and a pharmaceutical composition comprising the engineered immune cell according to claim 15 of claim 29.
Factors to be considered in determining whether undue experimentation is required to practice the claimed invention are summarized In re Wands (858 F2d 731, 737, 8 USPQ2d 1400, 1404 (Fed. Cir. 1988)). The factors most relevant to this rejection are the scope of the claim, the amount of direction or guidance provided, the lack of sufficient working examples, the unpredictability in the art and the amount of experimentation required to enable one of skill in the art to practice the claimed invention.
The breadth of the claims encompass CARs comprising any transmembrane domain and any intracellular signaling domain including any co-stimulatory domain, any primary signaling domain, and any γc chain or intracellular region thereof including nucleic acids encoding these CARs, engineered immune cells expressing these CARs, and pharmaceutical compositions comprising these CARs. The breadth of the claims also encompass engineered immune cells with any immunosuppressive molecule with any immune cell antigen binding region, any transmembrane domain and any co-stimulatory domain. Using broadest reasonable interpretation, the immunosuppressive molecules also encompasses CARs without primary signaling domains and the immune cell antigen binding domain encompasses all antigens that are found in or on any immune cell.
The scope of the claims encompass hundreds of thousands if not millions of CAR structure possibilities and immunosuppressive molecule structure possibilities that perform the recited function of a “chimeric antigen receptor” and “immunosuppressive molecule”.
The specification (Example 1 and 4) describes the preparation of a dual-target UCAR-T cell (CAR7X19 T cells) comprising a CD8α signal peptide (SEQ ID NO:36), an anti-CD7 scFv (SEQ ID NO:12), an anti-CD19 scFv (SEQ ID NO:58), a CD8α hinge domain (SEQ ID NO:38), a CD8α transmembrane domain (SEQ ID NO:22), a 4-1BB intracellular region (SEQ ID NO:28), a CD3ζ intracellular signaling domain (SEQ ID NO:32), and a γc intracellular region (SEQ ID NO:65) where the CAR7X19 T cells had significantly increased specific killing activity and cytokine release in vitro. The specification (Examples 5-6) additionally describes the killing activity of a CD7 CAR T cell expressing B2M and PDL1 immunosuppressive molecules (No.10 and 14) in a TCR/CD7/CIITA triple knockout T cell. However, there are no other working examples of other CARs with other transmembrane domains, other intracellular signaling domains (including primary signaling domain, co-stimulatory domain, and γc chain or intracellular region thereof) AND other immunosuppressive molecules with other antigen binding regions, other transmembrane domains, and other co-stimulatory domains.
The art of Jayaramen et al (PTO-892; page 3, Reference U; “Jayaramen”) teaches each module of the CAR structure influences CAR function both independently and synergistically. For example, choosing the right cytoplasmic domain can augment the changes in signal due to reduced affinity of the scFv (Jayaramen; Section 6, Conclusions and outstanding questions). Additionally, the number and type of co-stimulatory signals as well as their order and proximity to the membrane are critical parameters affecting CAR function and efficacy (Jayaramen; Section 5, Cytoplasmic Domain). Jayaramen also teaches appropriate compositional and structural design of CARs reduces off-target effects and enhances tumor eradication and persistence while small variations in these CAR modules and characteristics can be critical functional determinants (Jayaramen; Section 1, Introduction).
The art of Britannica (PTO-892; page 3, Reference V) teaches antigens to be any foreign material that binds specifically to a receptor molecule made by lymphocytes including those that do and do not evoke an immune response (Britannica; page 1). The art of Funk et al (PTO-892; page 2, Reference W) teaches the specific components of an inhibitory CAR (iCAR) that comprise CARs without a primary signaling domain can impact the efficacy of the iCAR and CAR-T cell including the antigen binding domain, the transmembrane domain, and the intracellular domain (Funk; Figure 1; page 984; page 991, right column, paragraph 2).
The prior art does not appear to provide any evidence as to the treatment of the full scope of the claims of any as such, not any CAR and immunosuppressive molecule can have any structure including nucleic acids encoding said CAR, engineered immune cells comprising said CARs and immunosuppressive molecules and pharmaceutical compositions comprising said CARs and perform their recited functions without undue experimentation.
Reasonable correlation must exist between the scope of the claims and scope of the enablement set forth. In view of the quantity of experimentation necessary, the lack of working examples, the unpredictability in the art, the lack of sufficient guidance in the specification, and the breadth of the claims, it would take undue trials and errors to make and use the encompassed CARs and immunosuppressive molecules, nucleic acids encoding said CARs, engineered immune cells comprising said CAR and immunosuppressive molecules, and pharmaceutical compositions comprising said engineered immune cell comprising said CAR.
Priority
This application is a 371 of PCT/CN/2021/135963 effectively filed on 12/7/2021 and claims foreign priority to CN 202110147730.4 effectively filed on 2/3/2021.
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.
Claims 1-2, 9, 12, 15, 18-19 and 29 are rejected under 35 U.S.C. 102(a)(2) as being anticipated by U.S. Patent Application Number 2023/0113157 A1 (PTO-892; page 1, Reference C; "Ge").
Ge teaches that CD19 CAR-T cells have shown promising clinical results in treating patients with cancer with most clinical trials using autologous CAR-T cell infusion to prevent graft versus host disease (GVHD); however, some patients’ T cells are not sufficiently effective even after CAR redirection which promotes the modification of allogeneic donor T cells (Ge; [0001]-[0002]). TO address this, Ge teaches an engineered CD8+ T cell comprising a chimeric antigen receptor (CAR) with a first antigen binding domain targeting an immune cell antigen CD7 and a second antigen binding domain targeting a disease-associated antigen CD19 (Ge; Abstract; Figs. 1-7; [0101]-[0102]; Example 1). Ge additionally teaches that endogenous CD7 of the engineered immune cell is inactivated or suppressed along with the TRAC gene to increase the successful expression of the CD7/CD19 Dual CAR in the T cell and killing potential in vitro and in vivo (Ge; Example 1; Figs. 2A-B, 3A-B, 5A-C, 6, 7A-B). Additionally, Ge teaches the expression of MHC class I and/or class II gene may be suppressed, knocked out, or partially knocked out to reduce T cell killing activity and keep anti-NK killer (Ge; [0018]; [00152]). Ge also teaches the engineered immune cell to also express an enhancer moiety capable of enhancing PD-1 activity (Ge; [0019]; [0024]; [00217]).
Regarding claim 1, Ge teaches A chimeric antigen receptor, comprising an antigen binding region, a transmembrane domain and an intracellular signaling region, wherein the antigen binding region comprises an antibody specifically targeting CD7, and the intracellular signaling region consists of at least one co-stimulatory domain, a primary signaling domain, and a yc chain or intracellular region thereof (Ge; Abstract; [0101]-[0102]; Fig.1-7; Example 1).
Regarding claim 2, Ge teaches wherein the antibody is selected from the group consisting of IgG, Fab, Fab', F(ab')2, Fd, Fd', Fv, scFv, sdFv, linear antibody, single domain antibody, nanobody and diabody; the transmembrane domain is a transmembrane domain of protein CD8; the primary signaling domain is a signaling domain of protein CD3ζ; or the at least one co-stimulatory domain is CD137 (Ge; Abstract; [0011]; [0100]-[0102]; Fig.1-7; Example 1).
Regarding claim 9, Ge teaches wherein the antigen binding region further comprises an antibody targeting a second antigen, wherein the second antigen is CD19 (Ge; Abstract; [0100]-[0102]; Fig.1-7; Example 1).
Regarding claim 12, Ge teaches a nucleic acid encoding the chimeric antigen receptor according to claim 1 (Ge; [0121]-[0122]; Example 1).
Regarding claim 15, Ge teaches an engineered immune cell, comprising the chimeric antigen receptor according to claim 1 (Ge; [087]; Example 1).
Regarding claim 18, Ge teaches wherein the immune cell comprises suppressed or silenced expression of endogenous CD7 (Ge; [0017]; Example 1.2; Fig 2A-B and 3C).
Regarding claim 19, Ge teaches wherein the immune cell comprises suppressed or silenced expression of at least one TCR/CD3 gene and the TCR/CD3 gene is TRAC (Ge; [0017]; Example 1.2; Fig 2A-B and 3C).
Regarding claim 29, Ge teaches a pharmaceutical composition the engineered immune cell according to claim 15, and one or more pharmaceutically acceptable excipients (Ge; [0234]; Example 1).
The reference teachings anticipate the claimed invention.
Claim Rejections - 35 USC § 103
The following is a quotation of 35 U.S.C. 103 which forms the basis for all obviousness rejections set forth in this Office action:
A patent for a claimed invention may not be obtained, notwithstanding that the claimed invention is not identically disclosed as set forth in section 102, if the differences between the claimed invention and the prior art are such that the claimed invention as a whole would have been obvious before the effective filing date of the claimed invention to a person having ordinary skill in the art to which the claimed invention pertains. Patentability shall not be negated by the manner in which the invention was made.
The factual inquiries for establishing a background for determining obviousness under 35 U.S.C. 103 are summarized as follows:
1. Determining the scope and contents of the prior art.
2. Ascertaining the differences between the prior art and the claims at issue.
3. Resolving the level of ordinary skill in the pertinent art.
4. Considering objective evidence present in the application indicating obviousness or nonobviousness.
Claims 1 and 6 are rejected under 35 U.S.C. 103 as being unpatentable over U.S. Patent Application Number 2023/0113157 A1 (PTO-892; page 1, Reference C; "Ge") in view of U.S. Patent Application Number 2018/0312570 A1 (PTO-892; page 1, Reference B; “Pulé”).
Ge teaches that CD19 CAR-T cells have shown promising clinical results in treating patients with cancer with most clinical trials using autologous CAR-T cell infusion to prevent graft versus host disease (GVHD); however, some patients’ T cells are not sufficiently effective even after CAR redirection which promotes the modification of allogeneic donor T cells (Ge; [0001]-[0002]). To address this, Ge teaches an engineered CD8+ T cell comprising a chimeric antigen receptor (CAR) with a first antigen binding domain targeting an immune cell antigen CD7 and a second antigen binding domain targeting a disease-associated antigen CD19 (Ge; Abstract; Figs. 1-7; [0101]-[0102]; Example 1). Ge additionally teaches that endogenous CD7 of the engineered immune cell is inactivated or suppressed along with the TRAC gene to increase the successful expression of the CD7/CD19 Dual CAR in the T cell and killing potential in vitro and in vivo (Ge; Example 1; Figs. 2A-B, 3A-B, 5A-C, 6, 7A-B). Additionally, Ge teaches the expression of MHC class I and/or class II gene may be suppressed, knocked out, or partially knocked out to reduce T cell killing activity and keep anti-NK killer (Ge; [0018]; [00152]). Ge also teaches the engineered immune cell to also express an enhancer moiety capable of enhancing PD-1 activity (Ge; [0019]; [0024]; [00217]).
However, Ge does not teach wherein the yc chain has at least 95% sequence identity to SEQ ID NO:65.
Pulé does teach that CAR T cells have been successful in treating liquid tumors, but treatment of solid tumors is more challenging due to an immunosuppressive microenvironment which is hostile to T cells, so there is an unmet need for alternative CAR T cells that facilitate engraftment and expansion of T cells (Pulé; [0006]-[0007]). Pulé teaches that an endodomain that comprises a cytokine receptor endodomain (the common γ-chain) and an intracellular T cell signaling domain (CD3zeta) can overcoming the immunosuppressive microenvironment (the common γ-chain as set forth in reference SEQ ID NO:1 is 100% sequence identical to the instant γc region as set forth in instant SEQ ID NO:65) (Pulé; [0011]; [0015]; [0026]-[0027]; Figures 2-5). Pulé teaches that 4th generation CAR systems with the common γ-chain exhibited increased proliferation/survival in vitro when compared to equivalent CAR systems lacking cytokine receptor endodomains (Pulé; Examples 3-4).
It would have been prima facie obvious to a person of ordinary skill in the art, before the effective filing date of the claimed invention, to have modified the dual CD7/CD19 CAR of Ge with the common yc chain (Reference SEQ ID NO:1) of Pulé with reasonable expectation of success. One of ordinary skill in the art would have been motivated to have combined the CD7/CD19 CAR of Ge with the common y chain (Reference SEQ ID NO:1) of Pulé since Ge teaches there is an unmet need to improve CAR T cell persistence in subjects and Pulé teaches enhances CAR systems with the common y chain exhibited increased proliferation/survival in vitro when compared to CAR systems lacking cytokine receptor endodomains. Therefore, a person of ordinary skill in the art would have been motivated to combine the CD7/CD19 CAR of Ge with the common y chain (Reference SEQ ID NO:1) of Pulé to yield predictable results of enhancing CAR T cell proliferation and survival and improve patient outcomes.
From the combined teachings of the reference, 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 at the time the invention was made, as evidenced by the reference, especially in the absence of evidence to the contrary.
Claims 1 and 7-8 are rejected under 35 U.S.C. 103 as being unpatentable over U.S. Patent Application Number 2023/0113157 A1 (PTO-892; page 1, Reference C; "Ge") in view of WO 2020/102589 A1 (PTO-892; page 1, Reference N; "Ismail").
Ge teaches that CD19 CAR-T cells have shown promising clinical results in treating patients with cancer with most clinical trials using autologous CAR-T cell infusion to prevent graft versus host disease (GVHD); however, some patients’ T cells are not sufficiently effective even after CAR redirection which promotes the modification of allogeneic donor T cells (Ge; [0001]-[0002]). TO address this, Ge teaches an engineered CD8+ T cell comprising a chimeric antigen receptor (CAR) with a first antigen binding domain targeting an immune cell antigen CD7 and a second antigen binding domain targeting a disease-associated antigen CD19 (Ge; Abstract; Figs. 1-7; [0101]-[0102]; Example 1). Ge additionally teaches that endogenous CD7 of the engineered immune cell is inactivated or suppressed along with the TRAC gene to increase the successful expression of the CD7/CD19 Dual CAR in the T cell and killing potential in vitro and in vivo (Ge; Example 1; Figs. 2A-B, 3A-B, 5A-C, 6, 7A-B). Additionally, Ge teaches the expression of MHC class I and/or class II gene may be suppressed, knocked out, or partially knocked out to reduce T cell killing activity and keep anti-NK killer (Ge; [0018]; [00152]). Ge also teaches the engineered immune cell to also express an enhancer moiety capable of enhancing PD-1 activity (Ge; [0019]; [0024]; [00217]).
However, Ge does not teach the antibody targeting CD7 to comprise CD-L1 as set forth in SEQ ID NO:1, CDR-L2 as set forth in SEQ ID NO: 2, CDR-L3 as set forth in SEQ ID NO: 3, CDR-Hl as set forth in SEQ ID NO: 4, CDR-H2 as set forth in SEQ ID NO: 5 and CDR-H3 as set forth in SEQ ID NO: 6 of instant claim 7; and wherein the antibody targeting CD7 comprises a light chain variable region having at least 95% sequence identity to an amino acid sequence selected from the group consisting of SEQ ID NO: 7 and a heavy chain variable region having at least 95% sequence identity to an amino acid sequence selected from the group consisting of SEQ ID NO: 8 of instant claim 8.
Ismail teaches there is a need to expand CAR T cell therapy to treat T-cell acute lymphocytic leukemia (T-ALL) since treatment options for these patients remains limited to intensive chemotherapy and hematopoietic stem cell transplant (Ismail; [0004]). Ismail teaches an engineered T cell with a CD7 targeting CAR to overcome this limitation as CD7 is highly expressed in T-ALL and CD7 CAR T cells can induce T cells to exert specific cytotoxicity against T cell malignancies (Ismail; [00101]). Ismail teaches the anti-CD7 CAR is used in combination with downregulation of expression of CD7 on the effector T cells to prevent fratricidal effect exerted by the corresponding anti-CD7 CAR leading to greater T cell recovery after CAR expression as compared to cells that retained CD7 and more effective cytotoxicity against T leukemia/lymphoma cells (The reference anti-CD7 scFv based on the 3A1F antibody comprises a heavy chain variable region of reference SEQ ID NO:34 which is 100% sequence identical to instant SEQ ID NO:8 further comprising instant CDRH1-3 as set forth in instant SEQ ID NOs:4-6; and further comprises a light chain variable region of reference SEQ ID NO:35 which is 100% sequence identical to instant SEQ ID NO:7 further comprising reference VL CDR1-3 as set forth in reference SEQ ID NOs:50-52 which are 100% sequence identical to instant CDRL1-L3 as set forth in instant SEQ ID NOs:1-3) (the reference anti-CD7 (3A1F) CAR of Reference SEQ ID NO:30 comprises 100% of instant CD7 VH and VL domains as set forth in instant SEQ ID NOs:8 and 7, respectively, further comprising 100% of instant VH CDRs of instant SEQ ID NOs:4-6 and instant VL CDRs of instant SEQ ID NOs:1-3) (Ismail; [00101]; Figure 44; Example 1).
It would have been prima facie obvious to a person of ordinary skill in the art, before the effective filing date of the claimed invention, to have modified the dual CD7/CD19 CAR of Ge with the CD7 CAR of Ismail with reasonable expectation of success. One of ordinary skill in the art would have been motivated to have combined the dual CD7/CD19 CAR of Ge with the CD7 CAR antibody sequences with suppressed expression endogenous of CD7 of Ismail since Ismail teaches the suppression of endogenous CD7 prevent fratricidal effect exerted by the corresponding anti-CD7 CAR leading to greater T cell recovery after CAR expression. Therefore, a person of ordinary skill in the art would have been motivated to combine the dual CD7/CD19 CAR of Ge with the CD7 antibody sequences and suppression of endogenous CD7 of Ismail to yield predictable results of reducing fratricidal effects and increase T cell recovery after CAR expression.
From the combined teachings of the reference, 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 at the time the invention was made, as evidenced by the reference, especially in the absence of evidence to the contrary.
Claims 1 and 10-11 are rejected under 35 U.S.C. 103 as being unpatentable over U.S. Patent Application Number 2023/0113157 A1 (PTO-892; page 1, Reference C; "Ge") in view of U.S. Patent Application Number 2020/0040096 A1 (PTO-892; page 1, Reference A; “Forman”).
Ge teaches that CD19 CAR-T cells have shown promising clinical results in treating patients with cancer with most clinical trials using autologous CAR-T cell infusion to prevent graft versus host disease (GVHD); however, some patients’ T cells are not sufficiently effective even after CAR redirection which promotes the modification of allogeneic donor T cells (Ge; [0001]-[0002]). TO address this, Ge teaches an engineered CD8+ T cell comprising a chimeric antigen receptor (CAR) with a first antigen binding domain targeting an immune cell antigen CD7 and a second antigen binding domain targeting a disease-associated antigen CD19 (Ge; Abstract; Figs. 1-7; [0101]-[0102]; Example 1). Ge additionally teaches that endogenous CD7 of the engineered immune cell is inactivated or suppressed along with the TRAC gene to increase the successful expression of the CD7/CD19 Dual CAR in the T cell and killing potential in vitro and in vivo (Ge; Example 1; Figs. 2A-B, 3A-B, 5A-C, 6, 7A-B). Additionally, Ge teaches the expression of MHC class I and/or class II gene may be suppressed, knocked out, or partially knocked out to reduce T cell killing activity and keep anti-NK killer (Ge; [0018]; [00152]). Ge also teaches the engineered immune cell to also express an enhancer moiety capable of enhancing PD-1 activity (Ge; [0019]; [0024]; [00217]).
However, Ge does not teach wherein the antibody targeting a second antigen of CD19 comprises a CDR-L1 as set forth in SEQ ID NO: 44, CDR-L2 as set forth in SEQ ID NO: 45, CDR-L3 as set forth in SEQ ID NO: 46, CDR-Hl as set forth in SEQ ID NO: 47, CDRH2 as set forth in SEQ ID NO: 48 and CDR-H3 as set forth in SEQ ID NO: 49 of instant claim 10; and wherein the antibody targeting CD 19 comprises a light chain variable region having at least 95% sequence identity to the amino acid sequence as set forth in SEQ ID NO: 56 and a heavy chain variable region having at least 95% sequence identity to the amino acid sequence as set forth in SEQ ID NO: 57 of instant claim 11.
Forman does teach adoptive immunotherapy using CAR expressing T cell as a promising cancer treatment, but therapeutic approach is highly dependent on the optimal molecular design of the CAR and impacts immunological rejection and clearance by the host (Forman; [0003]-[0005]). Forman teaches altering the design of the CAR addresses the immunological rejection and clearance of the cells meant to provide therapeutic benefit to patients (Forman; [0008]-[0009]). Forman teaches the CD19 antigen binding region remains constant across the mutant CD19 CARs with modifications in the immunoglobulin Fc region or the CH2 region resulting in impaired binding to an FcR (The reference CD19R light chain of reference SEQ ID NO:1 is 100% sequence identical to instant CD19 light chain of SEQ ID NO:56 which further comprises 100% of instant CDR-L1-L3 of instant SEQ ID NOs:44-46; and reference CD19R heavy chain of reference SEQ ID NO:2 is 100% sequence identical to instant CD19 light chain of instant SEQ ID NO:57 which further comprises 100% of instant CDR-H1-H3 as set forth in instant SEQ ID NOs:47-49) (Forman; Abstract; [0027]-[0028]; Example 1). Forman teaches modifications to the immunological Fc region and CH2 region can result in improved T cell persistence and anti-tumor efficacy (Forman; Example 1).
It would have been prima facie obvious to a person of ordinary skill in the art, before the effective filing date of the claimed invention, to have modified the dual CD7/CD19 CAR of Ge with the CD19R CAR antibody sequences of Forman with reasonable expectation of success. One of ordinary skill in the art would have been motivated to have combined the dual CD7/CD19 CAR of Ge with the CD19 CAR antibody sequences of Forman since Forman teaches the CD19 CAR antibody is displays increased persistence and anti-tumor efficacy with CAR design modifications. Therefore, a person of ordinary skill in the art would have been motivated to combine the CD7/CD19 CAR of Ge with the CD19 CAR antibody sequences of Forman to yield predictable results of increased CAR T cell persistence and anti-tumor efficacy.
From the combined teachings of the reference, 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 at the time the invention was made, as evidenced by the reference, especially in the absence of evidence to the contrary.
Claims 15, 20, and 23 are rejected under 35 U.S.C. 103 as being unpatentable over U.S. Patent Application Number 2023/0113157 A1 (PTO-892; page 1, Reference C; "Ge") in view of U.S. Patent Number 12577283 B2 (PTO-892; page 1, Reference D; “Bethune”).
Ge teaches that CD19 CAR-T cells have shown promising clinical results in treating patients with cancer with most clinical trials using autologous CAR-T cell infusion to prevent graft versus host disease (GVHD); however, some patients’ T cells are not sufficiently effective even after CAR redirection which promotes the modification of allogeneic donor T cells (Ge; [0001]-[0002]). To address this, Ge teaches an engineered CD8+ T cell comprising a chimeric antigen receptor (CAR) with a first antigen binding domain targeting an immune cell antigen CD7 and a second antigen binding domain targeting a disease-associated antigen CD19 (Ge; Abstract; Figs. 1-7; [0101]-[0102]; Example 1). Ge additionally teaches that endogenous CD7 of the engineered immune cell is inactivated or suppressed along with the TRAC gene to increase the successful expression of the CD7/CD19 Dual CAR in the T cell and killing potential in vitro and in vivo (Ge; Example 1; Figs. 2A-B, 3A-B, 5A-C, 6, 7A-B). Additionally, Ge teaches the expression of MHC class I and/or class II gene may be suppressed, knocked out, or partially knocked out to reduce T cell killing activity and keep anti-NK killer (Ge; [0018]; [00152]). Ge also teaches the engineered immune cell to also express an enhancer moiety capable of enhancing PD-1 activity (Ge; [0019]; [0024]; [00217]).
However, Ge does not teach wherein the immune cell comprises suppressed or silenced expression of at least one MHC class II related gene, and the MHC class II related gene is RFX5 of instant claim 20; and wherein the immune cell comprises suppressed or silenced expression of endogenous CD7, at least one TCR/CD3 gene selected from the group consisting of TRAC and at least one MHC class II related gene selected from the group consisting of RFX5 of instant claim 23.
However, Bethune teaches improvements to allogeneic cell therapies that provide increased persistence of the administered cells to mitigate rejection by the host or recipient (Bethune; Abstract; [0007]-[0008]). Bethune teaches the improvements to be directed towards engineering immune cells to have silenced or suppressed one or more of TAP2, NLRC5, p2m, TRAC, CIITA, RFX5, RFXAP and RFXANK which can result in selective killing of T cells lacking MHC in both autologous and alloreactive contexts and improve therapeutic outcomes for patients (Bethune; [0007]-[0008]). Bethune specifically teaches TRAC/RFX5 double knockout T cells were minimally killed by allogeneic NK cells and when transduced with a CD19 CAR, the T cells displayed reduction of host CD8 T cell expansion suggesting effective mitigation of allogeneic CD8 T cell recognition by reducing MHC-I expression on CD19 CAR T cells, higher T cell counts suggesting CAR T cells with reduced MHC-I expression were superior in mitigating allogeneic T cell rejection (Bethune; Examples 6-7; Example 10-11 [0227]-[0231]; Fig. 15A-B, 16, 22B). Bethune also teaches the CD19 CAR T cells with TRAC/RFX5 double KO also demonstrated better anti-tumor efficacy (Bethune; Example 11-12; Fig. 22C).
It would have been prima facie obvious to a person of ordinary skill in the art, before the effective filing date of the claimed invention, to have modified the engineered immune cell with a CD7/TRAC double KO of Ge with the CD8+ T cell with TRAC/RFX5 double KO of Bethune with reasonable expectation of success. One of ordinary skill in the art would have been motivated to have combined the engineered immune cell with CD7/TRAC double KO of Ge with the CD8+ T cell with TRAC/RFX5 double KO of Bethune since Ge teaches the CD7/TRAC double KO increases the successful expression of the CD7/CD19 dual CAR in the T cell and killing potential in vitro and in vivo and Bethune teaches the TRAC/RFX5 double KO increases the persistence and killing potential of a CD19 CAR T cell. Therefore, it would have been obvious to a person of ordinary skill in the art to combine the CD7/TRAC double KO immune cell of Ge with the TRAC/RFX5 double KO of Bethune to yield predictable results of effectively mitigating allogeneic CD8 T cell recognition by reducing MHC-I expression on the CAR T cell to increase CAR T cell persistence and anti-tumor efficacy.
From the combined teachings of the reference, 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 at the time the invention was made, as evidenced by the reference, especially in the absence of evidence to the contrary.
Claims 15 and 24-26 are rejected under 35 U.S.C. 103 as being unpatentable over U.S. Patent Application Number 2023/0113157 A1 (PTO-892; page 1, Reference C; "Ge") in view of Liao et al (PTO-892; page 2, Reference U; “Liao”).
Ge teaches that CD19 CAR-T cells have shown promising clinical results in treating patients with cancer with most clinical trials using autologous CAR-T cell infusion to prevent graft versus host disease (GVHD); however, some patients’ T cells are not sufficiently effective even after CAR redirection which promotes the modification of allogeneic donor T cells (Ge; [0001]-[0002]). To address this, Ge teaches an engineered CD8+ T cell comprising a chimeric antigen receptor (CAR) with a first antigen binding domain targeting an immune cell antigen CD7 and a second antigen binding domain targeting a disease-associated antigen CD19 (Ge; Abstract; Figs. 1-7; [0101]-[0102]; Example 1). Ge additionally teaches that endogenous CD7 of the engineered immune cell is inactivated or suppressed along with the TRAC gene to increase the successful expression of the CD7/CD19 Dual CAR in the T cell and killing potential in vitro and in vivo (Ge; Example 1; Figs. 2A-B, 3A-B, 5A-C, 6, 7A-B). Additionally, Ge teaches the expression of MHC class I and/or class II gene may be suppressed, knocked out, or partially knocked out to reduce T cell killing activity and keep anti-NK killer (Ge; [0018]; [00152]). Ge also teaches the engineered immune cell to also express an enhancer moiety capable of enhancing PD-1 activity (Ge; [0019]; [0024]; [00217]).
Ge does not teach the engineered immune cell to further express an immunosuppressive molecule, wherein the immunosuppressive molecule comprises one or more immune cell antigen binding regions, a transmembrane domain and at least one co-stimulatory domain of instant claim 24; wherein the immunosuppressive molecule does not comprise a primary signaling domain of instant claim 25; and wherein the immune cell antigen binding region is an antibody targeting an immune cell antigen, a ligand of an immune cell antigen, or a combination thereof; the immune cell antigen is PD-1; and the ligand of the immune cell antigen is PD-L1 of instant claim 26.
However, Liao does teach that on-target off-tumor toxicity impedes the clinical application of CAR T cells in the treatment of solid tumors and that PD-L1 is an interesting target to explore as a universal target for designing chimeric costimulatory receptor ligand (CCRs) and as a switch to turn the immune brake into immune accelerator since it is preferentially overexpressed on multiple tumors and minimally expressed on normal tissue (Liao; Abstract; page 2, Introduction; page 6, left column, paragraph 2). Liao teaches the design of a dual targeting CAR (CD19/HER2) and a universal CCR specific for PD-L1 which is constructed of a human PD-L1 scFv, a transmembrane domain and a signaling domain of CD28 (Liao; pages 2-3, CAR and CCR designs; Fig. 1A-B). Liao teaches that dual targeted CAR-T cells exhibited increased proliferation capacity when equipped with PD-L1 CCR, exerted cytotoxicity against tumor associated antigen (TAA)+ tumor cells but spared TAA- PD-L1+ cell in vitro, displayed vigorous anti-tumor activity against PD-L1+ tumor xenografts, and improved anti-tumor activity of low affinity CAR T cells in vitro (Liao; Abstract; pages 7-11). Therefore, Liao teaches PD-L1 CCR in combination with dual-targeted CAR-T cells can be used to reduce the risk of on-target off-tumor toxicity while retaining their potent antitumor efficacy in the treatment of PD-L1+ tumors (Liao; Abstract).
Therefore, it would have been prima facie obvious to a person of ordinary skill in the art, before the effective filing date of the claimed invention, to have modified the engineered immune cell of Ge with the PD-L1 CCR of Liao with reasonable expectation of success. One of ordinary skill in the art would have been motivated to have combined the engineered immune cell of Ge with the PD-L1 CCR of Liao since Ge teaches there is a need to design more effective CAR T cells to prevent GVHD and Liao teaches the PD-L1 CCR in combination with a dual targeting CAR enhances the cytokine release and proliferation in vitro and provided more effective treatment. Therefore, it would have been obvious to a person of ordinary skill in the art to combine the engineered immune cell of Ge with the PD-L1 CCR of Liao to yield predictable results of effectively enhancing CAR T cell proliferation and more effectively treat patients.
From the combined teachings of the reference, 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 at the time the invention was made, as evidenced by the reference, especially in the absence of evidence to the contrary.
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.
Claims 1-2, 7-9, 12, 15, and 18 are provisionally rejected on the ground of nonstatutory double patenting as being unpatentable over claims 4 and 6-17 of copending Application No. 18/861,000 (reference application) (“‘000”). Although the claims at issue are not identical, they are not patentably distinct from each other because '000 teaches in reference claim 4 a method for knocking out the CD7 gene in vitro; wherein the cell is a CD4+CD8+ T cell, a CD4+ T cell, a CD8+ T cell, a memory T cell, a naïve T cell, a γδ T cell, or an αβ-T cell of reference claim 7; wherein the immune cell is introduced with a nucleic acid encoding a chimeric antigen receptor of reference claim 8; wherein the chimeric antigen receptor comprises a ligand binding domain, a transmembrane domain, a co-stimulatory domain, and a primary signaling domain, wherein the ligand binding domain comprises a CD7-targeting antibody or antigen binding fragment thereof of reference claims 9-10; wherein the CD7-targeting antibody or antigen binding fragment thereof comprises a light chain variable region sequence having at least 95%, 97%, 99%, or 100% sequence identity to the amino acid sequence as set forth in SEQID NO:12 and a heavy chain variable region sequence having at least 95%, 97%, 99%, or 100% sequence identity to the amino acid sequence as set forth in SEQ ID NO:13 of reference claim 11 (Reference light chain variable region sequence of SEQ ID NO:12 is 100% sequence identical to instant SEQ ID NO:7 further comprising 100% of instant CDR-L1, -L2, and -L3 of SEQ ID NOs:1-3, respectively; Reference heavy chain variable region sequence of SEQ ID NO:13 is 100% sequence identical to instant SEQ ID NO:8 further comprising 100% of instant CDR-H1, -H2, and -H3 of SEQ ID NOs:4-6, respectively); wherein the transmembrane domain is CD8α of reference claim 12; wherein the costimulatory domain is a co-stimulatory signaling domain of protein CD137 of reference claim 13; wherein the primary signaling domain is a signaling domain of a CD3ζ of reference claim 14; an engineered immune cell obtained by the method of reference claim 6 wherein the CD7 gene is knocked out of reference claim 15; wherein the engineered immune cell further comprises suppressed or silenced expression of at least one gene selected from the group consisting of: TRAC…RFX5 of reference claim 16.
Therefore ‘000 anticipates instant claims 1-2, 7-9, 12, 15, and 18. This is a provisional nonstatutory double patenting rejection because the patentably indistinct claims have not in fact been patented.
Claims 1 and 6 are provisionally rejected on the ground of nonstatutory double patenting as being unpatentable over claims 4 and 8-10 of copending Application No. 18/861,000 (“000”) in view of U.S. Patent Application Number US 2018/0312570 A1 (PTO-892; Reference B; “Pulé”).
‘000 has been discussed above. The claimed invention differs from ‘000 with respect to instant claim 6 wherein the γc chain has at least 95% sequence identity to SEQ ID NO: 63 or 65.
However, Pulé does teach that CAR T cells have been successful in treating liquid tumors, but treatment of solid tumors is more challenging due to an immunosuppressive microenvironment which is hostile to T cells, so there is an unmet need for alternative CAR T cells that facilitate engraftment and expansion of T cells (Pulé; [0006]-[0007]). Pulé teaches that an endodomain that comprises a cytokine receptor endodomain (the common γ-chain) and an intracellular T cell signaling domain (CD3zeta) can overcoming the immunosuppressive microenvironment (the common γ-chain as set forth in reference SEQ ID NO:1 is 100% sequence identical to the instant γc region as set forth in instant SEQ ID NO:65) (Pulé; [0011]; [0015]; [0026]-[0027]; Figures 2-5). Pulé teaches that 4th generation CAR systems with the common γ-chain exhibited increased proliferation/survival in vitro when compared to equivalent CAR systems lacking cytokine receptor endodomains (Pulé; Examples 3-4).
It would have been prima facie obvious to a person of ordinary skill in the art, before the effective filing date of the claimed invention, to have modified the CD7-specific CAR of ‘000 with the common yc chain (Reference SEQ ID NO:1) of Pulé with reasonable expectation of success. One of ordinary skill in the art would have been motivated to have combined the CD7-specific CAR of ‘000 with the common y chain (Reference SEQ ID NO:1) of Pulé since Pulé teaches enhanced CAR systems with the common y chain exhibited increased proliferation/survival in vitro when compared to CAR systems lacking cytokine receptor endodomains. Therefore, a person of ordinary skill in the art would have been motivated to combine the CD7-specific CAR of ‘000 with the common y chain (Reference SEQ ID NO:1) of Pulé to yield predictable results of enhancing CAR T cell proliferation and survival and improve patient outcomes.
This is a provisional nonstatutory double patenting rejection.
Claims 1, 10-11 and 29 are provisionally rejected on the ground of nonstatutory double patenting as being unpatentable over claims 4 and 8-10 of copending Application No. 18/861,000 (“000”) in view of U.S. Patent Application Number 2023/0113157 A1 (PTO-892; Reference C; "Ge") and U.S. Patent Application Number 2020/0040096 A1 (PTO-892; Reference A; “Forman”).
‘000 has been discussed above. The claimed invention differs from ‘000 with respect to instant claim 10 wherein the antibody targeting a second antigen is an antibody targeting CD19 comprising: CDR-L1 as set forth in SEQ ID NO: 44, CDR-L2 as set forth in SEQ ID NO:45, CDR-L3 as set forth in SEQ ID NO: 46, CDR-H1 as set forth in SEQ ID NO: 47, CDR-H2 as set forth in SEQ ID NO: 48 and CDR-H3 as set forth in SEQ ID NO: 49; instant claim 11 wherein the antibody targeting CD19 comprises a light chain variable region having at least 95% sequence identity to the amino acid sequence as set forth in SEQ ID NO: 56 and a heavy chain variable region having at least 95% sequence identity to the amino acid sequence as set forth in SEQ ID NO: 57; A pharmaceutical composition the engineered immune cell according to claim 15, and one or more pharmaceutically acceptable excipients of instant claim 29.
However, Ge teaches that CD19 CAR-T cells have shown promising clinical results in treating patients with cancer with most clinical trials using autologous CAR-T cell infusion to prevent graft versus host disease (GVHD); however, some patients’ T cells are not sufficiently effective even after CAR redirection which promotes the modification of allogeneic donor T cells (Ge; [0001]-[0002]). To address this, Ge teaches an engineered CD8+ T cell comprising a chimeric antigen receptor (CAR) with a first antigen binding domain targeting an immune cell antigen CD7 and a second antigen binding domain targeting a disease-associated antigen CD19 (Ge; Abstract; Figs. 1-7; [0101]-[0102]; Example 1). Ge additionally teaches that endogenous CD7 of the engineered immune cell is inactivated or suppressed along with the TRAC gene to increase the successful expression of the CD7/CD19 Dual CAR in the T cell and killing potential in vitro and in vivo (Ge; Example 1; Figs. 2A-B, 3A-B, 5A-C, 6, 7A-B). Additionally, Ge teaches the expression of MHC class I and/or class II gene may be suppressed, knocked out, or partially knocked out to reduce T cell killing activity and keep anti-NK killer (Ge; [0018]; [00152]). Ge also teaches the engineered immune cell to also express an enhancer moiety capable of enhancing PD-1 activity (Ge; [0019]; [0024]; [00217]). Ge additionally teaches the dual CD7/CD19 CAR in a pharmaceutical composition (Ge; [0234]-[0238]; Example 1).
Forman does teach adoptive immunotherapy using CAR expressing T cell as a promising cancer treatment, but therapeutic approach is highly dependent on the optimal molecular design of the CAR and impacts immunological rejection and clearance by the host (Forman; [0003]-[0005]). Forman teaches altering the design of the CAR addresses the immunological rejection and clearance of the cells meant to provide therapeutic benefit to patients (Forman; [0008]-[0009]). Forman teaches the CD19 antigen binding region remains constant across the mutant CD19 CARs with modifications in the immunoglobulin Fc region or the CH2 region resulting in impaired binding to an FcR (The reference CD19R light chain of reference SEQ ID NO:1 is 100% sequence identical to instant CD19 light chain of SEQ ID NO:56 which further comprises 100% of instant CDR-L1-L3 of instant SEQ ID NOs:44-46; and reference CD19R heavy chain of reference SEQ ID NO:2 is 100% sequence identical to instant CD19 light chain of instant SEQ ID NO:57 which further comprises 100% of instant CDR-H1-H3 as set forth in instant SEQ ID NOs:47-49) (Forman; Abstract; [0027]-[0028]; Example 1). Forman teaches modifications to the immunological Fc region and CH2 region can result in improved T cell persistence and anti-tumor efficacy (Forman; Example 1). Forman additionally teaches the population of T cells being a part of a pharmaceutically acceptable composition (Forman; [0063]; Example 1).
It would have been prima facie obvious to a person of ordinary skill in the art, before the effective filing date of the claimed invention, to have combined the CD7-specific CAR of ‘000 with the CD7/CD19 dual CAR of Ge with the CD19R CAR antibody sequences of Forman with reasonable expectation of success. One of ordinary skill in the art would have been motivated to have combined the CD7-specific CAR of ‘000 with the CD7/CD19 dual CAR of Ge with the CD19 CAR antibody sequences of Forman since Ge teaches a CD7/CD19 dual CAR can help increase effectiveness of patient’s T cells after CAR redirection and when expressed in a CD7/TRAC double knockout CD8+ T cell, the CAR displayed increased expression and killing potential in vitro and in vivo. Additionally, Forman teaches the CD19 CAR antibody displays increased persistence and anti-tumor efficacy with CAR design modifications. Therefore, a person of ordinary skill in the art would have been motivated to combine the CD7-specific CAR of ‘000 with the CD7/CD19 CAR of Ge with the CD19 CAR antibody sequences of Forman to yield predictable results of increased CAR T cell persistence and anti-tumor efficacy.
It would have been prima facie obvious to a person of ordinary skill in the art, before the effective filing date of the claimed invention, to have combined CD7-specific CAR of ‘000 with the pharmaceutical composition comprising the CAR of Ge with reasonable expectation of success. One of ordinary skill in the art would have been motivated to combine the CD7-specific CAR of ‘000 with the pharmaceutical composition of Ge in order to successfully deliver the CD7-CAR T cells to a patient.
This is a provisional nonstatutory double patenting rejection.
Claims 15, 20, and 23 are provisionally rejected on the ground of nonstatutory double patenting as being unpatentable over claims 4, 6-10, and 15-17 of copending Application No. 18/861,000 (“000”) in view of U.S. Patent Number 12577283 B2 (PTO-892; Reference D; “Bethune”).
‘000 has been discussed above. The claimed invention differs from ‘000 in respect to instant claim 20 wherein the immune cell comprises suppressed or silenced expression of at least one MHC class II related gene, and the MHC class II related gene is RFX5; and instant claim 23 wherein the immune cell comprises suppressed or silenced expression of endogenous CD7, at least one TCR/CD3 gene selected from the group consisting of TRAC and at least one MHC class II related gene selected from the group consisting of RFX5.
However, Bethune teaches improvements to allogeneic cell therapies that provide increased persistence of the administered cells to mitigate rejection by the host or recipient (Bethune; Abstract; [0007]-[0008]). Bethune teaches the improvements to be directed towards engineering immune cells to have silenced or suppressed one or more of TAP2, NLRC5, p2m, TRAC, CIITA, RFX5, RFXAP and RFXANK which can result in selective killing of T cells lacking MHC in both autologous and alloreactive contexts and improve therapeutic outcomes for patients (Bethune; [0007]-[0008]). Bethune specifically teaches TRAC/RFX5 double knockout T cells were minimally killed by allogeneic NK cells and when transduced with a CD19 CAR, the T cells displayed reduction of host CD8 T cell expansion suggesting effective mitigation of allogeneic CD8 T cell recognition by reducing MHC-I expression on CD19 CAR T cells, higher T cell counts suggesting CAR T cells with reduced MHC-I expression were superior in mitigating allogeneic T cell rejection (Bethune; Examples 6-7; Example 10-11 [0227]-[0231]; Fig. 15A-B, 16, 22B). Bethune also teaches the CD19 CAR T cells with TRAC/RFX5 double KO also demonstrated better anti-tumor efficacy (Bethune; Example 11-12; Fig. 22C).
It would have been prima facie obvious to a person of ordinary skill in the art, before the effective filing date of the claimed invention, to have modified the engineered immune cell with a CD7/TRAC double KO of ‘000 with the CD8+ T cell with TRAC/RFX5 double KO of Bethune with reasonable expectation of success. One of ordinary skill in the art would have been motivated to combine the engineered immune cell with CD7/TRAC double KO of ‘000 with the CD8+ T cell with TRAC/RFX5 double KO of Bethune since Bethune teaches the TRAC/RFX5 double KO increases the persistence and killing potential of a CD19 CAR T cell. Therefore, it would have been obvious to a person of ordinary skill in the art to combine the engineered immune cell with CD7/TRAC double KO of ‘000 with the TRAC/RFX5 double KO of Bethune to yield predictable results of effectively mitigating allogeneic CD8 T cell recognition by reducing MHC-I expression on the CAR T cell to increase CAR T cell persistence and anti-tumor efficacy.
This is a provisional nonstatutory double patenting rejection.
Claims 15 and 24-26 are provisionally rejected on the ground of nonstatutory double patenting as being unpatentable over claims 4, 6-10, and 15 of copending Application No. 18/861,000 (“000”) in view of Liao et al (PTO-892; page 2, Reference U; “Liao”).
‘000 has been discussed above. The claimed invention differs from ‘000 in respect to instant claim 24 the engineered immune cell to further express an immunosuppressive molecule, wherein the immunosuppressive molecule comprises one or more immune cell antigen binding regions, a transmembrane domain and at least one co-stimulatory domain; wherein the immunosuppressive molecule does not comprise a primary signaling domain of instant claim 25; and wherein the immune cell antigen binding region is an antibody targeting an immune cell antigen, a ligand of an immune cell antigen, or a combination thereof; the immune cell antigen is PD-1; and the ligand of the immune cell antigen is PD-L1 of instant claim 26.
However, Liao does teach that on-target off-tumor toxicity impedes the clinical application of CAR T cells in the treatment of solid tumors and that PD-L1 is an interesting target to explore as a universal target for designing chimeric costimulatory receptor ligand (CCRs) and as a switch to turn the immune brake into immune accelerator since it is preferentially overexpressed on multiple tumors and minimally expressed on normal tissue (Liao; Abstract; page 2, Introduction; page 6, left column, paragraph 2). Liao teaches the design of a dual targeting CAR (CD19/HER2) and a universal CCR specific for PD-L1 which is constructed of a human PD-L1 scFv, a transmembrane domain and a signaling domain of CD28 (Liao; pages 2-3, CAR and CCR designs; Fig. 1A-B). Liao teaches that dual targeted CAR-T cells exhibited increased proliferation capacity when equipped with PD-L1 CCR, exerted cytotoxicity against tumor associated antigen (TAA)+ tumor cells but spared TAA- PD-L1+ cell in vitro, displayed vigorous anti-tumor activity against PD-L1+ tumor xenografts, and improved anti-tumor activity of low affinity CAR T cells in vitro (Liao; Abstract; pages 7-11). Therefore, Liao teaches PD-L1 CCR in combination with dual-targeted CAR-T cells can be used to reduce the risk of on-target off-tumor toxicity while retaining their potent antitumor efficacy in the treatment of PD-L1+ tumors (Liao; Abstract).
Therefore, it would have been prima facie obvious to a person of ordinary skill in the art, before the effective filing date of the claimed invention, to have modified the engineered immune cell of ‘000 with the PD-L1 CCR of Liao with reasonable expectation of success. One of ordinary skill in the art would have been motivated to have combined the engineered immune cell of ‘000 with the PD-L1 CCR of Liao since Liao teaches the PD-L1 CCR in combination with a dual targeting CAR enhances the cytokine release and proliferation of the CAR construct in vitro and provided more effective treatment. Therefore, it would have been obvious to a person of ordinary skill in the art to combine the engineered immune cell of ‘000 with the PD-L1 CCR of Liao to yield predictable results of effectively enhancing CAR T cell proliferation and more effectively treat patients.
This is a provisional nonstatutory double patenting rejection.
Claims 1-2, 9-12, and 19-20 are provisionally rejected on the ground of nonstatutory double patenting as being unpatentable over claims 4 and 7-16 of copending Application No. 18/861,006 (reference application) (“‘006”). Although the claims at issue are not identical, they are not patentably distinct from each other because '006 teaches in reference claim 4 a method for knocking out the CIITA gene in vitro; wherein the cell is a CD8+ T cell of reference claims 6-7; wherein the immune cell is introduced with a nucleic acid encoding a chimeric antigen receptor of reference claim 8; wherein the chimeric antigen receptor comprises a ligand binding domain, a transmembrane domain, a co-stimulatory domain, and a primary signaling domain, wherein the ligand binding domain comprises one or more of CD7, CD19 of reference claim 9; wherein the ligand binding domain comprises a CD19/CD22-targeting antigen or antigen binding fragment thereof of reference claim 10; wherein the CD19-targeting antibody or antigen binding fragment thereof comprises a light chain variable region sequence having at least 95%, 97%, 99%, or 100% sequence identity to the amino acid sequence as set forth in SEQ ID NO:28, and a heavy chain variable region sequence having at least 95%, 97%, 99%, or 100% sequence identity to the amino acid sequence as set forth in SEQ ID NO:29 (The reference light chain variable region sequence of reference SEQ ID NO:28 is 100% sequence identical to instant CD19 light chain of SEQ ID NO:56 which further comprises 100% of instant CDR-L1-L3 of instant SEQ ID NOs:44-46; and reference CD19 heavy chain region sequence of reference SEQ ID NO:29 is 100% sequence identical to instant CD19 light chain of instant SEQ ID NO:57 which further comprises 100% of instant CDR-H1-H3 as set forth in instant SEQ ID NOs:47-49); wherein the transmembrane domain is CD8α of reference claim 12; wherein the costimulatory domain is a co-stimulatory signaling domain of protein CD137 of reference claim 13; wherein the primary signaling domain is a signaling domain of a CD3ζ of reference claim 14; an engineered immune cell obtained by the method of reference claim 6 wherein the CIITA gene is knocked out of reference claim 15; wherein the engineered immune cell further comprises suppressed or silenced expression of at least one gene selected from the group consisting of: TRAC…RFX5 of reference claim 16.
Therefore ‘006 anticipates instant claims 1-2, 9-12, and 15. This is a provisional nonstatutory double patenting rejection because the patentably indistinct claims have not in fact been patented.
Claims 1 and 6 are provisionally rejected on the ground of nonstatutory double patenting as being unpatentable over claims 4 and 6-9 of copending Application No. 18/861,006 (“’006”) in view of U.S. Patent Application Number US 2018/0312570 A1 (PTO-892; Reference B; “Pulé”).
‘006 has been discussed above. The claimed invention differs from ‘006 with respect to instant claim 6 wherein the γc chain has at least 95% sequence identity to SEQ ID NO: 63 or 65.
However, Pulé does teach that CAR T cells have been successful in treating liquid tumors, but treatment of solid tumors is more challenging due to an immunosuppressive microenvironment which is hostile to T cells, so there is an unmet need for alternative CAR T cells that facilitate engraftment and expansion of T cells (Pulé; [0006]-[0007]). Pulé teaches that an endodomain that comprises a cytokine receptor endodomain (the common γ-chain) and an intracellular T cell signaling domain (CD3zeta) can overcoming the immunosuppressive microenvironment (the common γ-chain as set forth in reference SEQ ID NO:1 is 100% sequence identical to the instant γc region as set forth in instant SEQ ID NO:65) (Pulé; [0011]; [0015]; [0026]-[0027]; Figures 2-5). Pulé teaches that 4th generation CAR systems with the common γ-chain exhibited increased proliferation/survival in vitro when compared to equivalent CAR systems lacking cytokine receptor endodomains (Pulé; Examples 3-4).
It would have been prima facie obvious to a person of ordinary skill in the art, before the effective filing date of the claimed invention, to have modified the CD7/CD19-specific CAR of ‘006 with the common yc chain (Reference SEQ ID NO:1) of Pulé with reasonable expectation of success. One of ordinary skill in the art would have been motivated to have combined the CD7/CD19-specific CAR of ‘006 with the common y chain (Reference SEQ ID NO:1) of Pulé since Pulé teaches enhanced CAR systems with the common y chain exhibited increased proliferation/survival in vitro when compared to CAR systems lacking cytokine receptor endodomains. Therefore, a person of ordinary skill in the art would have been motivated to combine the CD7/CD19-specific CAR of ‘006 with the common y chain (Reference SEQ ID NO:1) of Pulé to yield predictable results of enhancing CAR T cell proliferation and survival and improve patient outcomes.
This is a provisional nonstatutory double patenting rejection.
Claims 1-2, 7-8, 15, 18-20, 23 and 29 are provisionally rejected on the ground of nonstatutory double patenting as being unpatentable over claims 4 and 6-17 of copending Application No. 18/861,006 (“’006”) in view of WO 2020/102589 A1 (PTO-892; Reference N; "Ismail") and U.S. Patent Application Number 2023/0113157 A1 (PTO-892; Reference C; "Ge").
‘006 has been discussed above. The claimed invention differs from ‘006 with respect to instant claim 7 wherein the antibody targeting CD7 comprises CDR-L1 as set forth in SEQ ID NO: 1, CDR-L2 as set forth in SEQ ID NO: 2, CDR-L3 as set forth in SEQ ID NO: 3, CDR-Hl as set forth in SEQ ID NO: 4, CDR-H2 as set forth in SEQ ID NO: 5 and CDR-H3 as set forth in SEQ ID NO: 6; instant claim 8 wherein the antibody targeting CD7 comprises a light chain variable region having at least 95% sequence identity to an amino acid sequence selected from the group consisting of SEQ ID NO:7, and a heavy chain variable region having at least 95% sequence identity to an amino acid sequence selected from the group consisting of SEQ ID NO:8; and instant claim 15 an engineered immune cell, comprising the chimeric antigen receptor according to claim 1; wherein the immune cell comprises suppressed or silenced expression of endogenous CD7 of instant claim 18; and a pharmaceutical composition the engineered immune cell according to claim 15, and one or more pharmaceutically acceptable excipients of instant claim 29.
However, Ismail teaches there is a need to expand CAR T cell therapy to treat T-cell acute lymphocytic leukemia (T-ALL) since treatment options for these patients remains limited to intensive chemotherapy and hematopoietic stem cell transplant (Ismail; [0004]). Ismail teaches an engineered T cell with a CD7 targeting CAR to overcome this limitation as CD7 is highly expressed in T-ALL and CD7 CAR T cells can induce T cells to exert specific cytotoxicity against T cell malignancies (Ismail; [00101]). Ismail teaches the anti-CD7 CAR is used in combination with downregulation of expression of CD7 on the effector T cells to prevent fratricidal effect exerted by the corresponding anti-CD7 CAR leading to greater T cell recovery after CAR expression as compared to cells that retained CD7 and more effective cytotoxicity against T leukemia/lymphoma cells (The reference anti-CD7 scFv based on the 3A1F antibody comprises a heavy chain variable region of reference SEQ ID NO:34 which is 100% sequence identical to instant SEQ ID NO:8 further comprising instant CDRH1-3 as set forth in instant SEQ ID NOs:4-6; and further comprises a light chain variable region of reference SEQ ID NO:35 which is 100% sequence identical to instant SEQ ID NO:7 further comprising reference VL CDR1-3 as set forth in reference SEQ ID NOs:50-52 which are 100% sequence identical to instant CDRL1-L3 as set forth in instant SEQ ID NOs:1-3) (the reference anti-CD7 (3A1F) CAR of Reference SEQ ID NO:30 comprises 100% of instant CD7 VH and VL domains as set forth in instant SEQ ID NOs:8 and 7, respectively, further comprising 100% of instant VH CDRs of instant SEQ ID NOs:4-6 and instant VL CDRs of instant SEQ ID NOs:1-3) (Ismail; [00101]; Figure 44; Example 1).
Ge teaches that CD19 CAR-T cells have shown promising clinical results in treating patients with cancer with most clinical trials using autologous CAR-T cell infusion to prevent graft versus host disease (GVHD); however, some patients’ T cells are not sufficiently effective even after CAR redirection which promotes the modification of allogeneic donor T cells (Ge; [0001]-[0002]). To address this, Ge teaches an engineered CD8+ T cell comprising a chimeric antigen receptor (CAR) with a first antigen binding domain targeting an immune cell antigen CD7 and a second antigen binding domain targeting a disease-associated antigen CD19 (Ge; Abstract; Figs. 1-7; [0101]-[0102]; Example 1). Ge additionally teaches that endogenous CD7 of the engineered immune cell is inactivated or suppressed along with the TRAC gene to increase the successful expression of the CD7/CD19 Dual CAR in the T cell and killing potential in vitro and in vivo (Ge; Example 1; Figs. 2A-B, 3A-B, 5A-C, 6, 7A-B). Additionally, Ge teaches the expression of MHC class I and/or class II gene may be suppressed, knocked out, or partially knocked out to reduce T cell killing activity and keep anti-NK killer (Ge; [0018]; [00152]). Ge also teaches the engineered immune cell to also express an enhancer moiety capable of enhancing PD-1 activity (Ge; [0019]; [0024]; [00217]). Ge additionally teaches the dual CD7/CD19 CAR in a pharmaceutical composition (Ge; [0234]-[0238]; Example 1).
It would have been prima facie obvious to a person of ordinary skill in the art, before the effective filing date of the claimed invention, to have modified the dual CD19/CD22 CAR of ‘006 with the CD7 CAR antibody sequences of Ismail with the motivation to design a dual CD7/CD19 CAR of Ge with reasonable expectation of success. One of ordinary skill in the art would have been motivated to have swapped the CD22 antibody binding domain of ‘006 with the CD7 antibody binding domain of Ismail since Ismail teaches CD7 is highly expressed in T-ALL and CD7 specific CAR T cells can induce T cells to exert specific cytotoxicity against T cell malignancies and Ge teaches combining CD19 and CD7 antibodies on a CAR can more effectively treat patients. Therefore, a person of ordinary skill in the art would have been motivated to swap the CD22 antibody domain of ‘006 with the CD7 antibody binding domain of Ismail to yield a CD7/CD19 dual CAR in order to more effectively treat patients with T-ALL.
It would have been prima facie obvious to a person of ordinary skill in the art, before the effective filing date of the claimed invention, to have modified the engineered immune cell with CIITA/TRAC/RFX5 knocked out of ‘006 with the engineered immune cell expressing the CD7 CAR with CD7/TRAC knocked out of Ismail with reasonable expectation of success. One of ordinary skill in the art would have been motivated to knock out CD7 of Ismail instead of knocking out CIITA of ‘006 since Ismail teaches suppression of endogenous CD7 prevent fratricidal effect exerted by the corresponding anti-CD7 CAR leads to greater T cell recovery after CD7-CAR expression. Therefore, a person of ordinary skill in the art would have been motivated to combine the engineered CD8+ T cell of with CIIITA/TRAC/RFX5 knockout of ‘006 with the engineered immune cell expressing CD7-specific CAR with suppression or silencing of endogenous CD7 of Ismail to yield predictable results of reducing fratricidal effects and increase T cell recovery after CAR expression.
It would have been prima facie obvious to a person of ordinary skill in the art, before the effective filing date of the claimed invention, to have combined the CD7/CD19 dual CAR in a pharmaceutical composition of Ge with the CD19 antibody sequences of ‘006, with the CD7 antibody sequences of Ismail with reasonable expectation of success. One of ordinary skill in the art would have been motivated to combine the CD7/CD19 dual CAR in a pharmaceutical composition of Ge with the CD19 antibody sequences of ‘006, with the CD7 antibody sequences of Ismail in order to successfully deliver the CD7-CAR T cells to a patient.
This is a provisional nonstatutory double patenting rejection.
Claims 15 and 24-26 are provisionally rejected on the ground of nonstatutory double patenting as being unpatentable over claims 4, 6-9, and 15-17 of copending Application No. 18/861,006 (“’006”) in view of U.S. Patent Application Number 2023/0113157 A1 (PTO-892; page 1, Reference C; "Ge") and WO 2020/102589 A1 (PTO-892; page 1, Reference N; "Ismail") in further view of Liao et al (PTO-892; page 2, Reference U; “Liao”).
‘006, Ge, and Ismail have been discussed above. The claimed invention differs from ‘006, Ge, and Ismail with respect to instant claim 24 wherein the engineered immune cell further expressing an immunosuppressive molecule, wherein the immunosuppressive molecule comprises one or more immune cell antigen binding regions, a transmembrane domain and at least one co-stimulatory domain; instant claim 25 wherein the immunosuppressive molecule does not comprise a primary signaling domain; and instant claim 26 wherein the immune cell antigen binding region is an antibody targeting an immune cell antigen, a ligand of an immune cell antigen, or a combination thereof; the immune cell antigen is PD-1; and the ligand of the immune cell antigen is PD-L1.
However, Liao does teach that on-target off-tumor toxicity impedes the clinical application of CAR T cells in the treatment of solid tumors and that PD-L1 is an interesting target to explore as a universal target for designing chimeric costimulatory receptor ligand (CCRs) and as a switch to turn the immune brake into immune accelerator since it is preferentially overexpressed on multiple tumors and minimally expressed on normal tissue (Liao; Abstract; page 2, Introduction; page 6, left column, paragraph 2). Liao teaches the design of a dual targeting CAR (CD19/HER2) and a universal CCR specific for PD-L1 which is constructed of a human PD-L1 scFv, a transmembrane domain and a signaling domain of CD28 (Liao; pages 2-3, CAR and CCR designs; Fig. 1A-B). Liao teaches that dual targeted CAR-T cells exhibited increased proliferation capacity when equipped with PD-L1 CCR, exerted cytotoxicity against tumor associated antigen (TAA)+ tumor cells but spared TAA- PD-L1+ cell in vitro, displayed vigorous anti-tumor activity against PD-L1+ tumor xenografts, and improved anti-tumor activity of low affinity CAR T cells in vitro (Liao; Abstract; pages 7-11). Therefore, Liao teaches PD-L1 CCR in combination with dual-targeted CAR-T cells can be used to reduce the risk of on-target off-tumor toxicity while retaining their potent antitumor efficacy in the treatment of PD-L1+ tumors (Liao; Abstract).
Therefore, it would have been prima facie obvious to a person of ordinary skill in the art, before the effective filing date of the claimed invention, to have modified the engineered immune cell of ‘006 and Ge with the PD-L1 CCR of Liao with reasonable expectation of success. One of ordinary skill in the art would have been motivated to have combined the engineered immune cell of ‘006 and Ge with the PD-L1 CCR of Liao since Liao teaches the PD-L1 CCR in combination with a dual targeting CAR enhances the cytokine release and proliferation of the CAR construct in vitro and provided more effective treatment for patients. Therefore, it would have been obvious to a person of ordinary skill in the art to combine the engineered immune cell of ‘100 with the PD-L1 CCR of Liao to yield predictable results of effectively enhancing CAR T cell proliferation and more effectively treat patients.
This is a provisional nonstatutory double patenting rejection.
Claims 1-2, 7, 9, 12, 15, 18-20, 23-24, and 29 are provisionally rejected on the ground of nonstatutory double patenting as being unpatentable over claims 1-12, and 16-17 of copending Application No. 18/034,177 (reference application) (“‘177”). Although the claims at issue are not identical, they are not patentably distinct from each other because ‘177 teaches in reference claim 1 an engineered immune cell, (1) expressing a chimeric antigen receptor comprising an antigen-binding region, the antigen binding region comprising an anti-CD7 antibody; and (2) having suppressed or silenced expression of endogenous CD7, at least one TCR/CD3 gene, and at least one MHC-II related gene; wherein the chimeric antigen receptor comprises the anti_CD7 antibody, a transmembrane domain, and an intracellular signaling domain of reference claim 2; wherein the anti-CD7 antibody comprises CDR-L1, -CDR-L2, and CDR-L3 as set forth in SEQ ID NOs:1, 2, and 3, respectively, and CDR-H12, CDR-H2, and CDR-H3 as set forth in SEQ ID NOs:4, 5, and 6, respectively of reference claim 3 (Reference SEQ ID NOs:1-6 are 100% sequence identical to instant SEQ ID NOs:1-6); wherein the antigen-binding region of the chimeric antigen receptor further comprises an antibody targeting a second antigen, or a functional fragment thereof, wherein the second antigen is CD19 of reference claim 4; wherein the chimeric antigen receptor comprises an anti-CD7 antibody and an anti-CD19 antibody of reference claim 5; wherein the transmembrane domain is a transmembrane domain of CD8α of reference claim 6; wherein the intracellular signaling domain is an intracellular region of CD3ζ of reference claim 7; wherein the chimeric antigen receptor further comprises at least one costimulatory domain which is an intracellular region of CD137 (4-1BB) of reference claim 8; wherein the TCR/CD3 gene is TRAC of reference claim 9; wherein the MHC-II related gene is RFX5 of reference claim 10; wherein the engineered immune cell has suppressed or silenced expression of endogenous CD7, at least one TCR/CD3 gene of TRAC, and at least one MHC class II gene of RFX5 of refer3ence claim 11; wherein the engineered immune cell further expresses a NK inhibitory molecule, and the NK inhibitory molecule comprises one or more NK inhibitory ligands, a transmembrane domain, and at least one co-stimulatory domain of reference claim 12; wherein the NK inhibitory ligand is an antibody targeting a NK inhibitory receptor or a functional fragment thereof of reference claim 13; a pharmaceutical composition comprising the engineered immune cell according to reference claim 1, and one or more pharmaceutically acceptable carriers of reference claim 17.
Therefore, ‘177 anticipates instant claims 1-2, 7, 9, 12, 15, 18-20, 23-24, and 29. This is a provisional nonstatutory double patenting rejection because the patentably indistinct claims have not in fact been patented.
Claims 1 and 6 are provisionally rejected on the ground of nonstatutory double patenting as being unpatentable over claims 1-2 of copending Application No. 18/034,177 (“’177”) in view of U.S. Patent Application Number US 2018/0312570 A1 (PTO-892; Reference B; “Pulé”).
‘177 has been discussed above. The claimed invention differs from ‘177 with respect to instant claim 6 wherein the γc chain has at least 95% sequence identity to SEQ ID NO: 63 or 65.
However, Pulé does teach that CAR T cells have been successful in treating liquid tumors, but treatment of solid tumors is more challenging due to an immunosuppressive microenvironment which is hostile to T cells, so there is an unmet need for alternative CAR T cells that facilitate engraftment and expansion of T cells (Pulé; [0006]-[0007]). Pulé teaches that an endodomain that comprises a cytokine receptor endodomain (the common γ-chain) and an intracellular T cell signaling domain (CD3ζ) can overcoming the immunosuppressive microenvironment (the common γ-chain as set forth in reference SEQ ID NO:1 is 100% sequence identical to the instant γc region as set forth in instant SEQ ID NO:65) (Pulé; [0011]; [0015]; [0026]-[0027]; Figures 2-5). Pulé teaches that 4th generation CAR systems with the common γ-chain exhibited increased proliferation/survival in vitro when compared to equivalent CAR systems lacking cytokine receptor endodomains (Pulé; Examples 3-4).
It would have been prima facie obvious to a person of ordinary skill in the art, before the effective filing date of the claimed invention, to have modified the CD7/CD19-specific CAR of ‘106 with the common yc chain (Reference SEQ ID NO:1) of Pulé with reasonable expectation of success. One of ordinary skill in the art would have been motivated to have combined the CD7/CD19-specific CAR of ‘106 with the common y chain (Reference SEQ ID NO:1) of Pulé since Pulé teaches enhanced CAR systems with the common y chain exhibited increased proliferation/survival in vitro when compared to CAR systems lacking cytokine receptor endodomains. Therefore, a person of ordinary skill in the art would have been motivated to combine the CD7/CD19-specific CAR of ‘177 with the common y chain of reference SEQ ID NO:1 of Pulé to yield predictable results of enhancing CAR T cell proliferation and survival and improve patient outcomes.
This is a provisional nonstatutory double patenting rejection.
Claims 1 and 8 are provisionally rejected on the ground of nonstatutory double patenting as being unpatentable over claims 1-3 of copending Application No. 18/034,177 (“’177”) in view of WO 2020/102589 A1 (PTO-892; Reference N; "Ismail").
‘177 has been discussed above. The claimed invention differs from ‘177 with respect to instant claim 8 wherein the antibody targeting CD7 comprises a light chain variable region having at least 100% sequence identity to an amino acid sequence of SEQ ID NO:7, and a heavy chain variable region having at least 95% sequence identity to an amino acid sequence of SEQ ID NO:8.
However, Ismail teaches there is a need to expand CAR T cell therapy to treat T-cell acute lymphocytic leukemia (T-ALL) since treatment options for these patients remains limited to intensive chemotherapy and hematopoietic stem cell transplant (Ismail; [0004]). Ismail teaches an engineered T cell with a CD7 targeting CAR to overcome this limitation as CD7 is highly expressed in T-ALL and CD7 CAR T cells can induce T cells to exert specific cytotoxicity against T cell malignancies (Ismail; [00101]). Ismail teaches the anti-CD7 CAR is used in combination with downregulation of expression of CD7 on the effector T cells to prevent fratricidal effect exerted by the corresponding anti-CD7 CAR leading to greater T cell recovery after CAR expression as compared to cells that retained CD7 and more effective cytotoxicity against T leukemia/lymphoma cells (The reference anti-CD7 scFv based on the 3A1F antibody comprises a heavy chain variable region of reference SEQ ID NO:34 which is 100% sequence identical to instant SEQ ID NO:8 further comprising instant CDRH1-3 as set forth in instant SEQ ID NOs:4-6; and further comprises a light chain variable region of reference SEQ ID NO:35 which is 100% sequence identical to instant SEQ ID NO:7 further comprising reference VL CDR1-3 as set forth in reference SEQ ID NOs:50-52 which are 100% sequence identical to instant CDRL1-L3 as set forth in instant SEQ ID NOs:1-3) (the reference anti-CD7 (3A1F) CAR of Reference SEQ ID NO:30 comprises 100% of instant CD7 VH and VL domains as set forth in instant SEQ ID NOs:8 and 7, respectively, further comprising 100% of instant VH CDRs of instant SEQ ID NOs:4-6 and instant VL CDRs of instant SEQ ID NOs:1-3) (Ismail; [00101]; Figure 44; Example 1).
It would have been prima facie obvious to a person of ordinary skill in the art, before the effective filing date of the claimed invention, to have modified the dual CD7/CD19 CAR of ‘177 with the CD7 CAR light chain and heavy chain antibody sequences of Ismail with reasonable expectation of success. One of ordinary skill in the art would have been motivated to have modify the CD7 CDRL1-3 and CDRH1-3 amino acid sequences of ‘177 with the CD7 heavy and light chain variable region amino acid sequences of Ismail since Ismail teaches CD7 is highly expressed in T-ALL and CD7 specific CAR T cells, specifically the CD7-specific CARs with can induce T cells to exert specific cytotoxicity against T cell malignancies. Therefore, a person of ordinary skill in the art would have been motivated to modify the CD7/CD19 dual CAR of ‘177 with the heavy and light chain variable region amino acid sequences of Ismail to yield a CD7/CD19 dual CAR to yield predictable results of more specifically targeting CD7 for T cells to exert specific cytotoxicity against T cell malignancies and more effectively treat patients with T cell malignancies.
This is a provisional nonstatutory double patenting rejection.
Claims 1 and 10-12 are provisionally rejected on the ground of nonstatutory double patenting as being unpatentable over claims 1-2 and 4-5 of copending Application No. 18/034,177 (“’177”) in view of U.S. Patent Application Number 2020/0040096 A1 (PTO-892; Reference A; “Forman”).
‘177 has been discussed above. The claimed invention differs from ‘177 with respect to instant claim 10 wherein CDR-L1 as set forth in SEQ ID NO: 44, CDR-L2 as set forth in SEQ ID NO: 45, CDR-L3 as set forth in SEQ ID NO: 46, CDR-Hl as set forth in SEQ ID NO: 47, CDRH2 as set forth in SEQ ID NO: 48 and CDR-H3 as set forth in SEQ ID NO: 49; instant claim 11 wherein the antibody targeting CD 19 comprises a light chain variable region having at least 95% sequence identity to the amino acid sequence as set forth in SEQ ID NO: 56; and a heavy chain variable region having at least 95% sequence identity to the amino acid sequence as set forth in SEQ ID NO: 57; and instant claim 12 a nucleic acid encoding the chimeric antigen receptor according to instant claim 1.
However, Forman does teach adoptive immunotherapy using CAR expressing T cell as a promising cancer treatment, but therapeutic approach is highly dependent on the optimal molecular design of the CAR and impacts immunological rejection and clearance by the host (Forman; [0003]-[0005]). Forman teaches altering the design of the CAR addresses the immunological rejection and clearance of the cells meant to provide therapeutic benefit to patients (Forman; [0008]-[0009]). Forman teaches the CD19 antigen binding region remains constant across the mutant CD19 CARs with modifications in the immunoglobulin Fc region or the CH2 region resulting in impaired binding to an FcR (The reference CD19R light chain of reference SEQ ID NO:1 is 100% sequence identical to instant CD19 light chain of SEQ ID NO:56 which further comprises 100% of instant CDR-L1-L3 of instant SEQ ID NOs:44-46; and reference CD19R heavy chain of reference SEQ ID NO:2 is 100% sequence identical to instant CD19 light chain of instant SEQ ID NO:57 which further comprises 100% of instant CDR-H1-H3 as set forth in instant SEQ ID NOs:47-49) (Forman; Abstract; [0027]-[0028]; Example 1). Forman teaches modifications to the immunological Fc region and CH2 region can result in improved T cell persistence and anti-tumor efficacy (Forman; Example 1). Forman additionally teaches the population of T cells being a part of a pharmaceutically acceptable composition (Forman; [0063]; Example 1).
It would have been prima facie obvious to a person of ordinary skill in the art, before the effective filing date of the claimed invention, to have combined the CD7/CD19 dual CAR of ‘177 with the CD19R CAR heavy and light chain variable sequences of Forman with reasonable expectation of success. One of ordinary skill in the art would have been motivated to have combined the CD7/CD19 dual CAR of ‘177 with the CD19R CAR heavy and light chain variable sequences of Forman since Forman teaches the CD19 CAR antibody displays increased persistence and anti-tumor efficacy with CAR design modifications. Therefore, a person of ordinary skill in the art would have been motivated to combine the CD7/CD19 dual CAR of ‘177 with the CD19R CAR heavy and light chain variable sequences of Forman to yield predictable results of increased CAR T cell persistence and anti-tumor efficacy.
This is a provisional nonstatutory double patenting rejection.
Claims 15 and 24-26 are provisionally rejected on the ground of nonstatutory double patenting as being unpatentable over claims 1-2 and 12-16 of copending Application No. 18/034,177 (“’177”) in view of Liao et al (PTO-892; page 2, Reference U; “Liao”).
‘177 has been discussed above. The claimed invention differs from ‘177 with respect to instant claim 24 wherein the engineered immune cell further expressing an immunosuppressive molecule, wherein the immunosuppressive molecule comprises one or more immune cell antigen binding regions, a transmembrane domain and at least one co-stimulatory domain; instant claim 25 wherein the immunosuppressive molecule does not comprise a primary signaling domain; and instant claim 26 wherein the immune cell antigen binding region is an antibody targeting an immune cell antigen, a ligand of an immune cell antigen, or a combination thereof; the immune cell antigen is PD-1; and the ligand of the immune cell antigen is PD-L1.
However, Liao does teach that on-target off-tumor toxicity impedes the clinical application of CAR T cells in the treatment of solid tumors and that PD-L1 is an interesting target to explore as a universal target for designing chimeric costimulatory receptor ligand (CCRs) and as a switch to turn the immune brake into immune accelerator since it is preferentially overexpressed on multiple tumors and minimally expressed on normal tissue (Liao; Abstract; page 2, Introduction; page 6, left column, paragraph 2). Liao teaches the design of a dual targeting CAR (CD19/HER2) and a universal CCR specific for PD-L1 which is constructed of a human PD-L1 scFv, a transmembrane domain and a signaling domain of CD28 (Liao; pages 2-3, CAR and CCR designs; Fig. 1A-B). Liao teaches that dual targeted CAR-T cells exhibited increased proliferation capacity when equipped with PD-L1 CCR, exerted cytotoxicity against tumor associated antigen (TAA)+ tumor cells but spared TAA- PD-L1+ cell in vitro, displayed vigorous anti-tumor activity against PD-L1+ tumor xenografts, and improved anti-tumor activity of low affinity CAR T cells in vitro (Liao; Abstract; pages 7-11). Therefore, Liao teaches PD-L1 CCR in combination with dual-targeted CAR-T cells can be used to reduce the risk of on-target off-tumor toxicity while retaining their potent antitumor efficacy in the treatment of PD-L1+ tumors (Liao; Abstract).
Therefore, it would have been prima facie obvious to a person of ordinary skill in the art, before the effective filing date of the claimed invention, to have modified the engineered immune cell of ‘177 with the PD-L1 CCR of Liao with reasonable expectation of success. One of ordinary skill in the art would have been motivated to have combined the engineered immune cell of ‘177 with the PD-L1 CCR of Liao since Liao teaches the PD-L1 CCR in combination with a dual targeting CAR enhances the cytokine release and proliferation of the CAR construct in vitro and provided more effective treatment. Therefore, it would have been obvious to a person of ordinary skill in the art to combine the engineered immune cell of ‘177 with the PD-L1 CCR of Liao to yield predictable results of effectively enhancing CAR T cell proliferation and more effectively treat patients by reducing on-target off-tumor toxicity.
This is a provisional nonstatutory double patenting rejection.
Claims 1-2, 6, 9, 15, 18-19, and 29 are provisionally rejected on the ground of nonstatutory double patenting as being unpatentable over claims 1, 3, 5-7, and 17 of copending Application No. 17/802,242 ("'242") in view of U.S. Patent Application Number 2023/0113157 A1 (PTO-892; Reference C; "Ge").
‘242 teaches in reference claim 1 a chimeric antigen receptor comprising an antigen-binding region, a transmembrane domain, a co-stimulatory domain, an intracellular signaling domain, and an additional signaling domain, wherein: the additional signaling domain consists of the intracellular region of a γc chain; the intracellular signaling domain is the signaling domain of CD3ζ; and the co-stimulatory domain is the co-stimulatory signaling domain of 4-1BB; wherein the co-stimulatory domain, the intracellular signaling domain, and the additional signaling region are arranged in order of distance from a cell membrane of from nearest to farthest; wherein the amino acid sequence of the intracellular region of the γc chain is as represented by SEQ ID NO:16 (Reference SEQ ID NO:16 is 100% sequence identical to instant SEQ ID NO:65) of reference claim 3; wherein the antigen-binding domain is selected from the group consisting of monoclonal antibody, polyclonal antibody, recombinant antibody, human antibody, humanized antibody, murine antibody, and chimeric antibody of reference claim 5; wherein the antigen binding region binds to a target selected from the group consisting of: CD19 of reference claim 6; wherein the transmembrane domain is a transmembrane domain of a protein selected from the group consisting of: CD3ζ subunit of reference claim 7; a pharmaceutical composition comprising the chimeric antigen receptor according to reference claim 1 and one or more pharmaceutically acceptable excipients of reference claim 17.
‘242 does not teach wherein the antigen binding region comprises an antibody specifically targeting CD7 of instant claim 1; a nucleic acid encoding the chimeric antigen receptor of instant claim 1 of instant claim 12; an engineered immune cell comprising the chimeric antigen receptor of instant claim 1 of instant claim 15; wherein the immune cell comprises suppressed or silenced expression of endogenous CD7 of instant claim 18; and wherein the immune cell comprises suppressed or silenced expression of at least one TCR/CD3 gene and the TCR/CD3 gene is TRAC of instant claim 19.
However, Ge teaches that CD19 CAR-T cells have shown promising clinical results in treating patients with cancer with most clinical trials using autologous CAR-T cell infusion to prevent graft versus host disease (GVHD); however, some patients’ T cells are not sufficiently effective even after CAR redirection which promotes the modification of allogeneic donor T cells (Ge; [0001]-[0002]). To address this, Ge teaches an engineered CD8+ T cell comprising a chimeric antigen receptor (CAR) with a first antigen binding domain targeting an immune cell antigen CD7 and a second antigen binding domain targeting a disease-associated antigen CD19 (Ge; Abstract; Figs. 1-7; [0101]-[0102]; Example 1). Ge additionally teaches that endogenous CD7 of the engineered immune cell is inactivated or suppressed along with the TRAC gene to increase the successful expression of the CD7/CD19 Dual CAR in the T cell and killing potential in vitro and in vivo (Ge; Example 1; Figs. 2A-B, 3A-B, 5A-C, 6, 7A-B). Additionally, Ge teaches the expression of MHC class I and/or class II gene may be suppressed, knocked out, or partially knocked out to reduce T cell killing activity and keep anti-NK killer (Ge; [0018]; [00152]). Ge also teaches the engineered immune cell to also express an enhancer moiety capable of enhancing PD-1 activity (Ge; [0019]; [0024]; [00217]). Ge additionally teaches the dual CD7/CD19 CAR in a pharmaceutical composition (Ge; [0234]-[0238]; Example 1).
It would have been prima facie obvious to a person of ordinary skill in the art, before the effective filing date of the claimed invention, to have modified the CD19 CAR of ‘242 with the dual CD7/CD19 CAR expressed in an engineered CD8+ T cell CD7/TRAC double knockout of Ge with reasonable expectation of success. One of ordinary skill in the art would have been motivated to have modify the CD19 CAR of ‘242 with the dual CD7/CD19 CAR expressed in an engineered CD8+ T cell CD7/TRAC double knockout of Ge since Ge teaches targeting both CD7 and CD19 can increase the effectiveness of patient’s T cells after CAR redirection and suppressing or silencing endogenous CD7 and TRAC can increase expression of the CD7/CD19 dual CAR and increase the killing potential of the CAR when expressed in a T cell. Therefore, a person of ordinary skill in the art would have been motivated to modified the CD19 CAR of ‘242 with the dual CD7/CD19 CAR expressed in an engineered CD8+ T cell with CD7/TRAC double knockout of Ge to yield a predictable result of producing a functional dual CD7/CD19 CAR in a CD8+ T cell with silenced CD7 and TRAC expression that can increase the effectiveness of a patient’s T cells and increase the CAR T cell’s killing potential.
This is a provisional nonstatutory double patenting rejection.
Claims 1 and 7-8 are provisionally rejected on the ground of nonstatutory double patenting as being unpatentable over claim 1 of copending Application No. 17/802,242 ("'242") in view of Ge (see above) as applied above in further view of WO 2020/102589 A1 (PTO-892; Reference N; "Ismail").
‘242 and Ge have been discussed above. The claimed invention differs from ‘242 and Ge with respect to instant claim 7 wherein the antibody targeting CD7 comprises CDR-L1 as set forth in SEQ ID NO: 1, CDR-L2 as set forth in SEQ ID NO: 2, CDR-L3 as set forth in SEQ ID NO: 3, CDR-Hl as set forth in SEQ ID NO: 4, CDR-H2 as set forth in SEQ ID NO: 5 and CDR-H3 as set forth in SEQ ID NO: 6; and instant claim 8 wherein the antibody targeting CD7 comprises a light chain variable region having at least 95% sequence identity to an amino acid sequence selected from the group consisting of SEQ ID NO: 7, and a heavy chain variable region having at least 95% sequence identity to an amino acid sequence selected from the group consisting of SEQ ID NO: 8.
However, Ismail teaches there is a need to expand CAR T cell therapy to treat T-cell acute lymphocytic leukemia (T-ALL) since treatment options for these patients remains limited to intensive chemotherapy and hematopoietic stem cell transplant (Ismail; [0004]). Ismail teaches an engineered T cell with a CD7 targeting CAR to overcome this limitation as CD7 is highly expressed in T-ALL and CD7 CAR T cells can induce T cells to exert specific cytotoxicity against T cell malignancies (Ismail; [00101]). Ismail teaches the anti-CD7 CAR is used in combination with downregulation of expression of CD7 on the effector T cells to prevent fratricidal effect exerted by the corresponding anti-CD7 CAR leading to greater T cell recovery after CAR expression as compared to cells that retained CD7 and more effective cytotoxicity against T leukemia/lymphoma cells (The reference anti-CD7 scFv based on the 3A1F antibody comprises a heavy chain variable region of reference SEQ ID NO:34 which is 100% sequence identical to instant SEQ ID NO:8 further comprising instant CDRH1-3 as set forth in instant SEQ ID NOs:4-6; and further comprises a light chain variable region of reference SEQ ID NO:35 which is 100% sequence identical to instant SEQ ID NO:7 further comprising reference VL CDR1-3 as set forth in reference SEQ ID NOs:50-52 which are 100% sequence identical to instant CDRL1-L3 as set forth in instant SEQ ID NOs:1-3) (the reference anti-CD7 (3A1F) CAR of Reference SEQ ID NO:30 comprises 100% of instant CD7 VH and VL domains as set forth in instant SEQ ID NOs:8 and 7, respectively, further comprising 100% of instant VH CDRs of instant SEQ ID NOs:4-6 and instant VL CDRs of instant SEQ ID NOs:1-3) (Ismail; [00101]; Figure 44; Example 1).
It would have been prima facie obvious to a person of ordinary skill in the art, before the effective filing date of the claimed invention, to have modified the CD19 CAR of ‘242 with the CD7/CD19 dual CAR of Ge with the CD7 CAR light chain and heavy chain antibody sequences of Ismail with reasonable expectation of success. One of ordinary skill in the art would have been motivated to have modify the CD19 CAR of ‘242 with the CD7/CD19 dual CAR of Ge with the CD7 heavy and light chain variable region amino acid sequences of Ismail since Ge teaches targeting both CD7 and CD19 can increase the effectiveness of patient’s T cells after CAR redirection and Ismail teaches CD7 is highly expressed in T-ALL and CD7 specific CAR T cells, specifically the CD7-specific CARs with can induce T cells to exert specific cytotoxicity against T cell malignancies. Therefore, a person of ordinary skill in the art would have been motivated to modify the CD19 CAR of ‘242 with the CD7/CD19 dual CAR of Ge with the CD7 CAR heavy and light chain variable region amino acid sequences of Ismail to yield a CD7/CD19 dual CAR to yield predictable results of more specifically targeting CD7 for T cells to exert specific cytotoxicity against T cell malignancies and more effectively treat patients with T cell malignancies.
This is a provisional nonstatutory double patenting rejection.
Claims 1 and 10-11 are provisionally rejected on the ground of nonstatutory double patenting as being unpatentable over claims 1 and 6 of copending Application No. 17/802,242 ("'242") in view of Ge (see above) as applied above in further view of U.S. Patent Application Number 2020/0040096 A1 (PTO-892; Reference A; “Forman”).
‘242 and Ge have been discussed above. The claimed invention differs from ‘242 and Ge in respect to instant claim 10 wherein the antibody targeting a second antigen is an antibody targeting CD19 comprising: CDR-L1 as set forth in SEQ ID NO: 44, CDR-L2 as set forth in SEQ ID NO: 45, CDR-L3 as set forth in SEQ ID NO: 46, CDR-Hl as set forth in SEQ ID NO: 47, CDRH2 as set forth in SEQ ID NO: 48 and CDR-H3 as set forth in SEQ ID NO: 49; and instant claim 11 wherein the antibody targeting CD 19 comprises a light chain variable region having at least 95% sequence identity to the amino acid sequence as set forth in SEQ ID NO: 56, and a heavy chain variable region having at least 95% sequence identity to the amino acid sequence as set forth in SEQ ID NO: 57.
However, Forman does teach adoptive immunotherapy using CAR expressing T cell as a promising cancer treatment, but therapeutic approach is highly dependent on the optimal molecular design of the CAR and impacts immunological rejection and clearance by the host (Forman; [0003]-[0005]). Forman teaches altering the design of the CAR addresses the immunological rejection and clearance of the cells meant to provide therapeutic benefit to patients (Forman; [0008]-[0009]). Forman teaches the CD19 antigen binding region remains constant across the mutant CD19 CARs with modifications in the immunoglobulin Fc region or the CH2 region resulting in impaired binding to an FcR (The reference CD19R light chain of reference SEQ ID NO:1 is 100% sequence identical to instant CD19 light chain of SEQ ID NO:56 which further comprises 100% of instant CDR-L1-L3 of instant SEQ ID NOs:44-46; and reference CD19R heavy chain of reference SEQ ID NO:2 is 100% sequence identical to instant CD19 light chain of instant SEQ ID NO:57 which further comprises 100% of instant CDR-H1-H3 as set forth in instant SEQ ID NOs:47-49) (Forman; Abstract; [0027]-[0028]; Example 1). Forman teaches modifications to the immunological Fc region and CH2 region can result in improved T cell persistence and anti-tumor efficacy (Forman; Example 1).
It would have been prima facie obvious to a person of ordinary skill in the art, before the effective filing date of the claimed invention, to have modified the CD19 CAR of ‘242 with the dual CD7/CD19 CAR of Ge with the CD19R CAR antibody sequences of Forman with reasonable expectation of success. One of ordinary skill in the art would have been motivated to have combined the CD19 CAR of ‘242 with the dual CD7/CD19 CAR of Ge with the CD19 CAR antibody sequences of Forman since Forman teaches the CD19 CAR antibody is displays increased persistence and anti-tumor efficacy with CAR design modifications and Ge teaches targeting both CD7 and CD19 can increase the effectiveness of patient’s T cells after CAR redirection. Therefore, a person of ordinary skill in the art would have been motivated to combine the CD19 CAR of ‘242 with the CD7/CD19 CAR of Ge with the CD19 CAR antibody sequences of Forman to yield predictable results of increased CAR T cell persistence and anti-tumor efficacy.
This is a provisional nonstatutory double patenting rejection.
Claims 15, 20, and 23 are provisionally rejected on the ground of nonstatutory double patenting as being unpatentable over claim 1 of copending Application No. 17/802,242 ("'242") in view of Ge (see above) as applied above in further view of Bethune et al (PTO-892; Reference D; "Bethune").
‘242 and Ge have been discussed above. The claimed invention differs from ‘242 and Ge with respect to instant claim 20 wherein the immune cell comprises suppressed or silenced expression of at least one MHC class II related gene, and the MHC class II related gene is RFX5; and instant claim 23 wherein the immune cell comprises suppressed or silenced expression of endogenous CD7, at least one TCR/CD3 gene selected from the group consisting of TRAC and at least one MHC class II related gene selected from the group consisting of RFX5.
However, Bethune teaches improvements to allogeneic cell therapies that provide increased persistence of the administered cells to mitigate rejection by the host or recipient (Bethune; Abstract; [0007]-[0008]). Bethune teaches the improvements to be directed towards engineering immune cells to have silenced or suppressed one or more of TAP2, NLRC5, p2m, TRAC, CIITA, RFX5, RFXAP and RFXANK which can result in selective killing of T cells lacking MHC in both autologous and alloreactive contexts and improve therapeutic outcomes for patients (Bethune; [0007]-[0008]). Bethune specifically teaches TRAC/RFX5 double knockout T cells were minimally killed by allogeneic NK cells and when transduced with a CD19 CAR, the T cells displayed reduction of host CD8 T cell expansion suggesting effective mitigation of allogeneic CD8 T cell recognition by reducing MHC-I expression on CD19 CAR T cells, higher T cell counts suggesting CAR T cells with reduced MHC-I expression were superior in mitigating allogeneic T cell rejection (Bethune; Examples 6-7; Example 10-11 [0227]-[0231]; Fig. 15A-B, 16, 22B). Bethune also teaches the CD19 CAR T cells with TRAC/RFX5 double KO also demonstrated better anti-tumor efficacy (Bethune; Example 11-12; Fig. 22C).
It would have been prima facie obvious to a person of ordinary skill in the art, before the effective filing date of the claimed invention, to have modified the immune cell expressing a CAR of ‘242 with the dual CD7/CD19 CAR T engineered CAR T cell with CD7/TRAC double KO of Ge with the CD8+ T cell with TRAC/RFX5 double KO of Bethune with reasonable expectation of success. One of ordinary skill in the art would have been motivated to combine immune cell expressing a CAR of ‘242 with the dual CD7/CD19 CAR T engineered CAR T cell with CD7/TRAC double KO of Ge with the CD8+ T cell with TRAC/RFX5 double KO of Bethune since Ge teaches the CD7/TRAC double KO increases the successful expression of the CD7/CD19 dual CAR in the T cell and killing potential in vitro and in vivo and teaches Bethune teaches the TRAC/RFX5 double KO increases the persistence and killing potential of a CD19 CAR T cell. Therefore, it would have been obvious to a person of ordinary skill in the art to combine the immune cell expressing a CAR of ‘242 with the dual CD7/CD19 CAR T engineered CAR T cell with CD7/TRAC double KO of Ge with the CD8+ T cell with TRAC/RFX5 double KO of Bethune to yield predictable results of effectively mitigating allogeneic CD8 T cell recognition by reducing MHC-I expression on the CAR T cell to increase CAR T cell persistence and anti-tumor efficacy.
This is a provisional nonstatutory double patenting rejection.
Claims 15 and 24-26 are provisionally rejected on the ground of nonstatutory double patenting as being unpatentable over claim 1 of copending Application No. 17/802,242 ("'242") in view of Ge (see above) as applied above in further view of Liao et al (PTO-892; page 2, Reference U; "Liao").
‘242 and Ge have been discussed above. The claimed invention differs from ‘242 and Ge with respect to instant claim 24 the engineered immune cell to further express an immunosuppressive molecule, wherein the immunosuppressive molecule comprises one or more immune cell antigen binding regions, a transmembrane domain and at least one co-stimulatory domain; wherein the immunosuppressive molecule does not comprise a primary signaling domain of instant claim 25; and wherein the immune cell antigen binding region is an antibody targeting an immune cell antigen, a ligand of an immune cell antigen, or a combination thereof; the immune cell antigen is PD-1; and the ligand of the immune cell antigen is PD-L1 of instant claim 26.
However, Liao does teach that on-target off-tumor toxicity impedes the clinical application of CAR T cells in the treatment of solid tumors and that PD-L1 is an interesting target to explore as a universal target for designing chimeric costimulatory receptor ligand (CCRs) and as a switch to turn the immune brake into immune accelerator since it is preferentially overexpressed on multiple tumors and minimally expressed on normal tissue (Liao; Abstract; page 2, Introduction; page 6, left column, paragraph 2). Liao teaches the design of a dual targeting CAR (CD19/HER2) and a universal CCR specific for PD-L1 which is constructed of a human PD-L1 scFv, a transmembrane domain and a signaling domain of CD28 (Liao; pages 2-3, CAR and CCR designs; Fig. 1A-B). Liao teaches that dual targeted CAR-T cells exhibited increased proliferation capacity when equipped with PD-L1 CCR, exerted cytotoxicity against tumor associated antigen (TAA)+ tumor cells but spared TAA- PD-L1+ cell in vitro, displayed vigorous anti-tumor activity against PD-L1+ tumor xenografts, and improved anti-tumor activity of low affinity CAR T cells in vitro (Liao; Abstract; pages 7-11). Therefore, Liao teaches PD-L1 CCR in combination with dual-targeted CAR-T cells can be used to reduce the risk of on-target off-tumor toxicity while retaining their potent antitumor efficacy in the treatment of PD-L1+ tumors (Liao; Abstract).
Therefore, it would have been prima facie obvious to a person of ordinary skill in the art, before the effective filing date of the claimed invention, to have modified the immune cell expressing a CAR of ‘242 with the PD-L1 CCR of Liao with reasonable expectation of success. One of ordinary skill in the art would have been motivated to have combined the engineered immune cell of ‘242 with the dual CD7/CD19 targeting CAR expressed in an engineered immune cell of Ge with the PD-L1 CCR of Liao since Ge teaches there is a need to design more effective CAR T cells to prevent GVHD Liao teaches the PD-L1 CCR in combination with a dual targeting CAR enhances the cytokine release and proliferation of the CAR construct in vitro and provided more effective treatment. Therefore, it would have been obvious to a person of ordinary skill in the art to combine the engineered immune cell of ‘242 with the dual CD7/CD19 targeting CAR expressed in an engineered immune cell of Ge with the PD-L1 CCR of Liao to yield predictable results of effectively enhancing CAR T cell proliferation and more effectively treat patients.
Conclusion
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/LEAH ELIZABETH STEIN/Examiner, Art Unit 1641
/NORA M ROONEY/Primary Examiner, Art Unit 1641
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