Notice of Pre-AIA or AIA Status
The present application, filed on or after March 16, 2013, is being examined under the first inventor to file provisions of the AIA .
The amendment filed on 7/26/2023 is acknowledged.
Claims 1-12 are pending and currently under consideration.
Information Disclosure Statement
The references disclosed in IDS filed on 7/26/2023 have been considered by the
examiner.
Specification
The disclosure is objected to because of the following informalities:
Page 10, lines 14-18 recites, “For BCMA scFv contained in bispecific CAR, the BCMA scFv derived from clone 4C8 (R. Berahovich, et al., CAR-T Cells Based on Novel BCMA Monoclonal Antibody Block Multiple Myeloma Cell Growth. Cancers (Basel) 10 (2018).) is used, and the amino acid sequence of which is shown in SEQ ID NO: 2.”. SEQ ID NO:2 represents the amino acid sequence of the light chain variable region of CS1 (scFv1), not the BCMA scFv (see claim 3). The Applicant is required to identify the correct sequence identification number that is derived from clone 4C8.
Appropriate correction is required.
Claim Objections
Claim 11 is objected to because of the following informalities:
Claim 11 recites "
Appropriate correction is required.
Claim Rejections - 35 USC § 101
35 U.S.C. 101 reads as follows:
Whoever invents or discovers any new and useful process, machine, manufacture, or composition of matter, or any new and useful improvement thereof, may obtain a patent therefor, subject to the conditions and requirements of this title.
Claim 9 is rejected under 35 U.S.C. 101 because the claimed invention is directed to non-statutory subject matter. The claim(s) does/do not fall within at least one of the four categories of patent eligible subject matter because claim 9 is directed towards the "use" of the CAR of claim 1 and merely recites intended use with no action steps of a proper method claim (see MPEP 2173.05(q)).
Claim Rejections - 35 USC § 112
The following is a quotation of the first paragraph of 35 U.S.C. 112(a):
(a) IN GENERAL.—The specification shall contain a written description of the invention, and of the manner and process of making and using it, in such full, clear, concise, and exact terms as to enable any person skilled in the art to which it pertains, or with which it is most nearly connected, to make and use the same, and shall set forth the best mode contemplated by the inventor or joint inventor of carrying out the invention.
The following is a quotation of the first paragraph of pre-AIA 35 U.S.C. 112:
The specification shall contain a written description of the invention, and of the manner and process of making and using it, in such full, clear, concise, and exact terms as to enable any person skilled in the art to which it pertains, or with which it is most nearly connected, to make and use the same, and shall set forth the best mode contemplated by the inventor of carrying out his invention.
Written Description
Claims 1-13 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.
Claims 1-13 encompass a broad genus of bispecific chimeric antigen receptor (CAR) with a broad genus of CS1 and BCMA antigen binding domains or antibodies that is expressed in a broad genus of engineered immune cell that is used in a method of treating a broad genus of diseases. The claims encompass all variants of CS1-BCMA bispecific CARs, all variants of engineered immune cells expressing the CS1-BCMA bispecific CAR, and all variants of diseases treated with CS1-BCMA bispecific CAR.
The specification (pages 10-12, Figures 3-4) describes the chimeric antigen receptor (CAR) of the present invention to be a second-generation CAR, including an extracellular domain, a transmembrane domain, and an intracellular domain. The extracellular domain includes a target-specific binding element (also called antigen binding domain). The intracellular domain includes a costimulatory signal transduction region and a zeta chain part. The costimulatory signal transduction region refers to a part of intracellular domain including costimulatory molecules. Additionally, a linker may be incorporated between the extracellular and transmembrane domains of the CAR, or between the cytoplasmic and transmembrane domains of the CAR. The linker refers to any oligopeptide or polypeptide that plays the role of connecting the transmembrane domain to the extracellular domain or cytoplasmic domain of the polypeptide chain. The linker may comprise 0 to 300 amino acids, preferably 2 to 100 amino acids and most preferably 3 to 50 amino acids. Additionally, the CAR can contain a signal peptide derived from CD8 with a hinge region derived from CD8 and a transmembrane region derived from CD28 (page 3). Additionally, a preferred embodiment of the present invention is a second-generation CAR vector targeting CS1 and BCMA as shown in Figure 3 with a CD8 signal peptide sequence, a CS1 antigen binding domain, a linker, a BCMA antigen binding domain, a hinge domain, a transmembrane domain, a 4-1BB costimulatory domain, and a CD3zeta cytoplasmic signaling sequence AND an amino acid sequence depicted in Figure 4.
The specification (page 22-25) describes example 1 of a CS1-BCMA CAR vector including a CS1-BCMA scFv fragment, 41BB costimulatory domain, and a CD3zeta activating domain. The specification (pages 24-25) describes in examples 5-7, the when the CS1-BCMA CAR vector is transduced into T cells from donors, the resulting CAR T cells specifically killed CS1 positive cells and blocked the growth of multiple myeloma RPMI8226 xenograft tumors. However, there are no other examples of other variant structures of CS1-BCMA bispecific chimeric antigen receptors. The specification has not adequately described a “bispecific antibody chimeric antigen receptor” or a sufficient number of adequate examples of a “bispecific chimeric antigen receptor”. Therefore, the skilled artisan cannot envision all the CAR structural variants recited in the instant claims.
The art of Schettini et al (PTO-892; page 1, Reference X) teaches CAR-T cell therapy has shown unprecedent efficacy in several hematologic malignancies as the T cells are engineered to express CARs specifically directed against the tumor surface antigen of interest which is cancer subtype specific due to tumor heterogeneity and plasticity leading to tumor escape base don loss of TSA expression (Schettini; page 2, paragraph 2).
Additionally, the art of Sun et al (PTO-892; page 2, Reference U) describes that CAR T cell therapy is limited by the selection and heterogeneity of target tumor antigens. Antigen expression varies between tumor types and patients and tumors can lack specific antigens (Sun, page 4, right column, paragraph 2). Therefore, the broad genus of T cells expressing a broad genus of cancer targeting chimeric antigen receptor cannot be used in a method to treat any cancer. The CAR T-cell needs to be cancer subtype specific. Sun also teaches the various specific structural components of a CAR construct to include the antigen recognition domain, transduction domain (i.e. CD3epsilon), and co-stimulatory domain(s) (i.e. CD28, 4-1BB, and/or OX40) (Sun, page 2, left column, paragraph 3). CAR designs can impact CAR T cell persistence, enhance cell-killing capacity, and anti-tumor response, and improve selective and specific recognition (Sun, page 2, right column, paragraph 1).
As such, there is insufficient written description of the required kind of structure identifying information about the corresponding structure of the claimed CS1-BCMA bispecific CAR to demonstrate possession.
Regarding the broad genus of CS1 and BCMA antigen binding domains or antibodies, the specification (page 10) describes the BCMA scFV contained in bispecific CAR to be derived from clone 4C8 which is shown in SEQ ID NO:2 and the CS1 scFv contained in bispecific CAR to be derived from the C1 antibody 7A8D5 from Promab which is shown in SEQ ID NO:1. Additionally, the specification (pages 2-3, Figure 2) describes the CS1 scFv1 with a heavy chain and light chain variable regions as shown in SEQ ID NOs:1-2, respectively, and the BCMA scFv2 with a heavy chain and light chain variable regions as shown in SEQ ID NOs:4-5, respectively. The specification (page 22-25) describes example 1 of a CS1-BCMA CAR vector including a CS1-BCMA scFv fragment, 41BB costimulatory domain, and a CD3zeta activating domain. The specification describes in examples 5-7, the when the CS1-BCMA CAR vector is transduced into T cells from donors, the resulting CAR T cells specifically killed CS1 positive cells and blocked the growth of multiple myeloma RPMI8226 xenograft tumors. However, there are no other examples of other sequence variants of CS1 and BCMA. The specification has not adequately described a bispecific CAR wherein one of scFv1 and scFv2 is an antigen binding domain targeting CS1 and the other is an antigen binding domain targeting BCMA. The specification does not provide sufficient number of representative examples of a bispecific CS1-BCMA CAR. Therefore, the skilled artisan cannot envision all the antibody variants 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.
As outlined in Amgen Inc. v. Sanofi, 598 U.S. 594 (2023), broad antibody genus claims must be supported either by a sufficient number of representative species or common structural features that define the genus. Disclosure of only one or a few antibody species is insufficient where the claim encompasses a large and structurally diverse genus.
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 inventions.
The claims encompass antibodies with variants of the recited amino acid
sequences. The claims recite variable region sequences containing amino acids not
found in the antibodies that were actually produced in the examples in the specification
which actually bind to the recited CS1 sequences in claim 3 and BCMA sequences in
claim 3. The claims recite combinations of antibody variable regions wherein the combinations encompass antibodies other than the specific antibodies produced in the examples in the specification which actually bind the CS1 in claim 3 and BCMA in
claim 3. The claims recites a CS1-BCMA bispecific CAR without any structure.
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. (PTO-892; Page 1, Reference W)
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 U) demonstrates 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.
Adequate written description requires more than a mere statement that it is part
of the invention and a reference to a potential method of isolating it. In the instant
application, the amino acid sequence itself or isolated protein is required. See Fiers v.
Revel, 25 USPQ 2d 160 I at 1606 (CAFC 1993) and Amgen Inc. V. Chugai
Pharmaceutical Co. Lts., 18 USPQ2d 1016. In view of the aforementioned problems
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.
As such, there is insufficient written description of the required kind of structure
identifying information about the corresponding makeup of the claimed antigen binding domains to demonstrate possession.
Regarding the broad genus of “engineered immune cell” expressing the CS1-BCMA bispecific CAR of claim 1, the specification (page 5) describes a preferred embodiment of the present invention wherein the immune cell is derived from a human or non-human mammal such as a mouse and that the cell comprises is a CAR-T cell or CAR-NK cell. Additionally, the specification describes Examples 1 and 5 (page 22 and 24) where the CS1-BCMA bispecific CAR was effectively transduced into T cells and Example 7 (page 25) describes the CS1-BCMA CAR T cells blocking the growth of multiple myeloma RPMI8226 xenograft tumor growth. However, the specification does not describe any other engineered immune cell or provide examples of engineered immune cells expressing the CS1-BCMA CAR besides a T cell. Therefore, the skilled artisan cannot envision all the engineered immune cell possibilities recited in the instant claims.
The art of Jassaud et al (PTO-892; page 1, Reference V) teaches various immune cells that can be used for CAR-based therapies including innate immune cells such as natural killer (NK) cells, macrophages, invariant NK T cells, γδ T cells, dendritic cells, and neutrophils with the most extensive research being performed in NK cells and macrophages (Jassaud; Abstract; page 97, right column, paragraph 4; page 98, right column, paragraph 2). Each immune cell has its own unique mechanism of action against the target cell where T cells rely on antigen-specific recognition to target malignant cells and induces an adaptive immune response whereas NK cells and macrophages possess antigen-independent cytotoxicity and are not constrained by MHC restriction and induce an innate immune response (Jassaud; page 98, right column, paragraph 1). Jassaud et al further teaches that choice of immune cell type itself needs to be tailored to disease and tumor context including CAR-NK cells may be suited for hematological malignancies and metastatic tumors due to their strong cytotoxicity and reduced risk of GvHD whereas CAR-M cells are more advantageous in solid tumors due to their capacity to remodel the TME (Jassaud; page 112, right column, paragraph 1). Therefore, the engineered immune cell needs to be strategically picked in order to maximize its anti-disease and anti-tumor mechanisms and improve a patient’s response to the CAR-engineered immune cell therapy.
Regarding the CS1-BCMA bispecific CAR immune cell used to treat a broad genus of diseases, the specification (pages 17-18) describes the CAR-T can treat all cancers that express the antigen wherein the cancers include tumors that have not been vascularized or have basically, not been vascularized, and tumors that have been vascularized. The cancers may include non-solid tumors (such as hematological tumors, e.g., leukemia and lymphoma) or may include solid tumors. The types of cancer treated with the CAR of the present invention include, but are not limited to, carcinomas, blastocytomas, and sarcomas, and certain leukemic or lymphoid malignancies, benign and malignant tumors, and malignant tumors, such as sarcomas, carcinomas, and melanoma. It also includes adult tumors/cancers and pediatric tumors/cancers. Hematological cancers include leukemia, including acute leukemia (such as acute lymphocytic leukemia, acute myeloid leukemia, acute myelogenous leukemia and myeloblastic, premyelocytic, granulo-monocytic, monocytic and erythroleukemia), chronic leukemia (such as chronic myeloid (granulocytic) leukemia, chronic myelogenous leukemia and chronic lymphocytic leukemia), polycythemia vera, lymphoma, Hodgkin's disease, non-Hodgkin's lymphoma (painless and high-grade forms), multiple myeloma, Waldenstrom's macroglobulinemia, heavy chain disease, myelodysplastic syndrome, hairy cell leukemia and spinal cord dysplasia. A solid tumor may be benign or malignant. Different types of solid tumors are named after the cell types that form them (such as sarcomas, carcinomas, and lymphomas). Examples of solid tumors such as sarcomas and carcinomas include fibrosarcoma, mucinous sarcoma, liposarcoma mesothelioma, lymphoid malignant tumor, pancreatic carcinoma and ovarian carcinoma. In a preferred embodiment, the treatable cancer is CS1 and/or BCMA positive tumor such as multiple osteosarcoma, etc. Additionally, the specification (page 25) describes Example 7 where the CS1-BCMA CAR T cell is effectively blocked the growth of multiple myeloma RPMI8226 xenograft tumor. However, the specification does not describe examples of treating other diseases besides multiple myeloma using the bispecific CS1-BCMA CAR. This is not deemed to be predicative of response for all diseases to the claimed methods of treating a disease with the CS1-BCMA bispecific CAR as there is no correlation between the structure of the CS1-BCMA bispecific CAR and their ability to treat the genus of diseases claimed.
The specification does not reasonably convey possession of the full scope of a disease encompassed by the claims. Absent a limiting species for the term “disease”, the terms open up the claimed invention to all diseases. The skilled artisan cannot envision all of the diseases treated with CS1-BCMA specific CAR recited in the instant claims.
The art of Schettini et al (PTO-892; Reference U) teaches CAR-T cell therapy
has shown unprecedent efficacy in several hematologic malignancies as the T cells are
engineered to express CARs specifically directed against the tumor surface antigen of
interest which is cancer subtype specific due to tumor heterogeneity and plasticity
leading to tumor escape based on loss of TSA expression (Schettini; page 2, paragraph 2).
Additionally, the art of Sun et al (PTO-892; Reference V) describes that CAR T
cell therapy is limited by the selection and heterogeneity of target tumor antigens.
Antigen expression varies between tumor types and patients and tumors can lack
specific antigens (Sun, page 4, right column, paragraph 2). Therefore, the broad genus
of engineered immune cells expressing a broad genus of CS1-BCMA bispecific CAR
cannot be used in a method to treat any cancer or any disease.
The art of O’Neal (PTO-892; page 2, Reference V) teaches that expression of CS1 is uniformly high on myeloma cells and its expression within normal tissue is restricted to the hematopoietic system and includes mature NK cells, dendritic cells, plasma cells, and some T-cells while not being expressed on hematopoietic stem cells making it an ideal target for multiple myeloma (O’Neal; page 1, left column, paragraph 2). The art of Dogan (PTO-892; Reference XX) further teaches that BCMA is expressed in various hematological malignancies and is important in regulating B-cell proliferation and survival (Dogan; Abstract; page 1, left column, paragraph 1). Dogan further teaches that BCMA expression has been studied extensively in multiple myeloma and BCMA can be targeted to achieve anti-tumor effects in MM patients (Dogan; page 1, left column, paragraph 1). Therefore, the CS1-BCMA bispecific CAR cannot be used to treat any disease.
Claim 1-13 do not meet the requirements of 35 U.S.C. 112(a) for written description as they are currently written.
Enablement
Claims 1-13 rejected under 35 U.S.C. 112(a) or 35 U.S.C. 112 (pre-AIA ), first paragraph, because the specification, while being enabling for : a CS1-BCMA-41BB-CD3 bispecific CAR-T cell with the CS1 scFv1 with a heavy and light chain variable region as shown in SEQ ID NOs:1-2, respectively, and the BCMA scFv2 with a heavy and light chain variable region as shown in SEQ ID NOs:4-5, respectively; a pharmaceutical formulation comprising the CS1-BCMA-41BB-CD3 bispecific CAR-T cell; a method of preparing the CS1-BCMA-41BB-CD3 bispecific CAR-T cell; and a method of treating multiple myeloma comprising administering an effective amount of the CS1-BCMA-41BB-CD3 bispecific CAR-T cell, does not reasonably provide enablement for a “bispecific chimeric antigen receptor with the structure of Formula I”, “an engineered immune cell expressing the CAR”, “a method for the preparation of an engineered immune cell expressing the CAR”, “a method of treating a disease”, or “use of the CAR of claim 1, nucleic acid molecule encoding the CAR, the vector comprising the nucleic acid molecule, or the immune cell expressing the CAR in preparation of a drug or formulation for preventing cancer or tumor”. The specification does not enable any person skilled in the art to which it pertains, or with which it is most nearly connected, to use the invention commensurate in scope with these claims. The specification disclosure does not enable one skilled in the art to practice the invention without undue amount of experimentation.
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 specification (pages 21-22) provides sufficient teachings only for the enablement of a CS1-BCMA-41BB-CD3 bispecific CAR-T cell wherein the CS1 scFv1 has a heavy and light chain variable region as shown in SEQ ID NOs:1-2, respectively, and the BCMA scFv2 has a heavy and light chain variable regions as shown in SEQ ID NOs:4-5, respectively. The specification (pages 21-23, example 1) provides sufficient teachings for the method of preparing the CS1-BCMA-41BB-CD3 bispecific CAR T-cell.
The specification is not enabled for the “bispecific chimeric antigen receptor with the structure of Formula I”, “an engineered immune cell expressing the CAR”, or “a method for the preparation of an engineered immune cell expressing the CAR”.
The breadth of the instant claims encompass all CS1-BCMA bispecific CARs with the structure of Formula I and all variants of engineered immune cells encoding the CS1-BCMA bispecific CAR.
The art of Sun et al (PTO-892; page 2, Reference U) teaches the various specific structural components of a CAR construct to include the antigen recognition domain, transduction domain (i.e. CD3epsilon), and co-stimulatory domain(s) (i.e. CD28, 4-1BB, and/or OX40) (Sun, page 2, left column, paragraph 3). CAR designs can impact CAR T cell persistence, enhance cell-killing capacity, and anti-tumor response, and improve selective and specific recognition (Sun, page 2, right column, paragraph 1). Additionally, Sun et al teaches CAR T cell therapy is limited by the selection and heterogeneity of target tumor antigens. Antigen expression varies between tumor types and patients and tumors can lack specific antigens (Sun, page 4, right column, paragraph 2).
The art of Jassaud et al (PTO-892; page 1, Reference V) teaches various immune cells that can be used for CAR-based therapies including innate immune cells such as natural killer (NK) cells, macrophages, invariant NK T cells, γδ T cells, dendritic cells, and neutrophils with the most extensive research being performed in NK cells and macrophages (Jassaud; Abstract; page 97, right column, paragraph 4; page 98, right column, paragraph 2). Each immune cell has its own unique mechanism of action against the target cell where T cells rely on antigen-specific recognition to target malignant cells and induces an adaptive immune response whereas NK cells and macrophages possess antigen-independent cytotoxicity and are not constrained by MHC restriction and induce an innate immune response (Jassaud; page 98, right column, paragraph 1). Jassaud further teaches that choice of immune cell type itself needs to be tailored to disease and tumor context including CAR-NK cells may be suited for hematological malignancies and metastatic tumors due to their strong cytotoxicity and reduced risk of GvHD whereas CAR-M cells are more advantageous in solid tumors due to their capacity to remodel the TME (Jassaud; page 112, right column, paragraph 1).
The prior art does not appear to provide any evidence as to treatment of the full scope of instant claims 1-13 of any as such, CS1-BCMA bispecific CARs can include various alternatives to the functional domains not limited to the amino acid sequence differences of the CS1 and BCMA scFv and the engineered immune cells encoding the CS1-BCMA bispecific CAR needs to be chosen based on disease and tumor context.
In view of the quantity of experimentation necessary, the limited working examples, the unpredictability of 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 claimed CS1-BCMA bispecific CAR and the engineered immune cell encoding the CS1-BCMA bispecific CAR
Furthermore, the specification (pages 23-25, Examples 2-7) provides sufficient teachings for the method of treating multiple myeloma comprising administering an effective amount of the CS1-BCMA-41BB-CD3 bispecific CAR-T cell.
The specification is not enabled for “a method of treating a disease”, or “use of the CAR of claim 1, nucleic acid molecule encoding the CAR, the vector comprising the nucleic acid molecule, or the immune cell expressing the CAR in preparation of a drug or formulation for preventing cancer or tumor”.
The breadth of the instant claims encompass treating all diseases with the CS1-BCMA bispecific CAR.
The art of O’Neal (PTO-892; page 2, Reference V) teaches that expression of CS1 is uniformly high on myeloma cells and its expression within normal tissue is restricted to the hematopoietic system and includes mature NK cells, dendritic cells, plasma cells, and some T-cells while not being expressed on hematopoietic stem cells making it an ideal target for multiple myeloma (O’Neal; page 1, left column, paragraph 2). The art of Dogan (PTO-892; page 2, Reference W) further teaches that BCMA is expressed in various hematological malignancies and is important in regulating B-cell proliferation and survival (Dogan; Abstract; page 1, left column, paragraph 1). Dogan further teaches that BCMA expression has been studied extensively in multiple myeloma and BCMA can be targeted to achieve anti-tumor effects in MM patients (Dogan; page 1, left column, paragraph 1). Therefore, the CS1-BCMA bispecific CAR cannot treat any disease and needs to be disease specific.
PDQ (PTO-892; page 3, Reference U) teaches that prevention of cancer can be accomplished by avoiding a carcinogen, pursuing a healthy lifestyle or dietary practices, medical interventions (e.g. chemoprevention) or surgical procedures, or early detection strategies (PDQ; page 1; paragraph 4). Of the chemoprevention, only several have proven benefit including selective estrogen receptor modulators, finasteride, and COX-2 inhibitors (PDQ; page 12, paragraphs 1-4). Additionally, Amiri et al (PTO-892; page 2, Reference X) teaches that CAR T cells as cancer treatments directed against tumor specific antigens, not expressed on normal cells (Amiri; page 3, right column, paragraph 1). Although CAR T cells have found success in treating patients and improving outcomes, they cannot currently be used as a means to prevent the development or the recurrence of cancer due to severe side effects, toxicity of treatment, and inefficacy of treatment (Amiri; page 2, left column, paragraph 3)
The specification fails to provide guidance as to how to prevent (100% prevention) cancer using any of the recited CS1-BCMA bispecific CARs. The art is highly unpredictable as what will be a therapy for cancer, so it would require an undue amount of experimentation for one of ordinary skill in the art to practice the claimed invention commensurate in the scope with the claims. The invention may encompass a pharmaceutical composition which treats cancer, but the specification does not disclose how to totally prevent cancer using the recited composition. The specification does not adequately teach how to effectively prevent cancer. The specification does not teach how to extrapolate data from the in vitro and in vivo studies to the development of effective in vivo prevention studies, commensurate with the scope of the claimed invention. There must be rigorous correlation of biological activity between the disclosed in vitro activity and an in vivo effectiveness to establish the CS1-BCMA bispecific CAR can be used to prevent cancer.
Although, the specification describes in vitro experiments, there is no correlation on this record between the in vitro studies and the preventing of cancer in currently available form for humans or animals. It is not enough to rely on in vitro studies where, as here, a person having ordinary skill in the art has no basis for perceiving those studies as constituting recognized screening procedures with clear relevance to efficacy in humans or animals (emphasis added). Ex parte Maas, 9 USPQ2d 1746
The prior art does not appear to provide any evidence as to treatment of the full scope of instant claims 1-13 of any as such, not any disease can be prevented and/or treated with any engineered immune cell expressing any CS1-BCMA bispecific chimeric antigen receptor without undue experimentation.
In view of the quantity of experimentation necessary, the limited working examples, the unpredictability of 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 claimed CS1-BCMA bispecific CAR for use in preventing cancer and in methods of treating diseases.
Substantiating evidence may be in the form of animal tests, which constitute recognized screening procedures with clear relevance to efficacy in humans. See Ex parte Krepelka, 231 USPQ 746 (Board of Patent Appeals and Interferences 1986) and cases cited therein. Ex parte Maas, 9 USPQ2d 1746.
Reasonable correlation must exist between the scope of the claims and scope of the enablement set forth. In view of experimentation necessary the limited working examples, the nature of the invention, the state of the prior art, the unpredictability of the art and the breadth of the claims, it would take undue trials and errors to practice the claimed invention.
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.
Claim(s) 1-2, 5-13 is/are rejected under 35 U.S.C. 102(a)(2) as being anticipated by WO 2019241358 A2 (PTO-892; Reference N; "Chen").
Chen teaches a CS1-BCMA bispecific CAR-T cell that can be used for the treatment of BCMA+ cancers including multiple myeloma (MM) since BCMA and CS1 are two surface proteins found on MM cells, but there are limitations associated with CS1 and BCMA CAR-T cells including CS1 causing T cell fratricide, outgrowth of both BCMA+ and BCMA- tumor cells demonstrating insufficient efficacy and susceptibility to antigen escape (Chen; see Figure 1B, Abstract; [0002]-[0008]; [0038]-[0039]; [0061]; [0288], see Example 1). For these reasons, Chen teaches there is a necessity to fine tune CAR signaling in response to CS1 in order to achieve therapeutic efficacy against tumor cells without eliminating T cells and there is a need for more effective therapies treating MM (Chen; [0002]-[0003]) Chen teaches the method of preparing CS1-BCMA bispecific CAR T-cells that can then be further administered to a subject in need via a pharmaceutical formulation (Chen; [0002]).
Regarding claim 1, Chen teaches a bispecific chimeric antigen receptor (CAR) wherein the structure of the chimeric antigen receptor contains a signal peptide sequence, a flexible linker (reference SEQ ID NO:146), a hinge region, a transmembrane domain (reference SEQ ID NO: 99), a costimulatory signal domain (reference SEQ ID NO:77), a CD3ζ cytoplasmic signaling sequence derived from CD3ζ (reference SEQ ID NO:120), one of scFv1 and scFv2 is an antigen binding domain targeting CS1 and the other is an antigen binding domain targeting BCMA (Chen; see Figure 1B, Abstract; [0004]-[0008]; [0038]-[0039]; [0061]; [0288], see Example 1).
Regarding claim 2, Chen teaches wherein the scFv1 is the antigen binding domain targeting CS1, and the scFv2 is the antigen binding domain targeting BCMA (Chen; page 27, [0061]).
Regarding claim 5, Chen teaches a nucleic acid molecule encoding the CAR of claim 1 (Chen; [0004]; [0049]]).
Regarding claim 6, Chen teaches a vector comprising the nucleic acid molecule of claim 5 (Chen; [0004]); [0049]).
Regarding claim 7, Chen teaches an engineered immune cell expressing the CAR of claim 1 (Chen; [0004]; [0050]; [0290], see Example 1).
Regarding claim 8, Chen teaches a formulation comprising the CAR of claim 1, nucleic acid encoding the CAR, the vector comprising the nucleic acid, or the immune cell expressing the CAR and a pharmaceutically acceptable carrier, diluent, or excipient (Chen; [0052], [0242]).
Regarding claim 9, Chen teaches the CAR of claim 1 being used in preparation of a drug or formulation for preventing and/or treating cancer or tumor (Chen; [0053]; [0056]; [0059]).
Regarding claim 10, Chen teaches a method of preparation of an engineered immune cell expressing the CAR of claim 1, which comprises the following steps of: providing an immune cell to be modified; and transferring the nucleic acid or a vector comprising the nucleic acid into the immune cell to obtain an engineered cell (Chen; [0290, [0295]], see Example 1)
Regarding claim 11, Chen teaches a method of treating a disease, comprising administering an appropriate amount of the immune cell of claim 7 to a subject in need of treatment (Chen; [0053]; [0056]; [0059])
Regarding claim 12, Chen teaches the disease is a cancer or a tumor (Chen; [0053]; [0056]; [0059]; [0239]; [0241]).
Regarding claim 13, Chen teaches the tumor is a CS1 and/or BCMA positive tumor (Chen; see Figure 4C-D, 9A-D; [0008]; [00315]; [0324]).
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.
Claim(s) 1 and 3-4 are rejected under 35 U.S.C. 103 as being unpatentable over WO 2019241358 A2 (PTO-892; Reference N; "Chen") in view of US 12540195 B2 (PTO-892; Reference B; “Wu”) and US 20210015870 A1 (PTO-892; Reference A; “Wu_2”).
Chen teaches a CS1-BCMA bispecific CAR-T cell that can be used for the treatment of BCMA+ cancers including multiple myeloma (MM) since BCMA and CS1 are two surface proteins found on MM cells, but there are limitations associated with CS1 and BCMA CAR-T cells including CS1 causing T cell fratricide, outgrowth of both BCMA+ and BCMA- tumor cells demonstrating insufficient efficacy and susceptibility to antigen escape (Chen; see Figure 1B, Abstract; [0002]-[0008]; [0038]-[0039]; [0061]; [0288], see Example 1). For these reasons, Chen teaches there is a necessity to fine tune CAR signaling in response to CS1 in order to achieve therapeutic efficacy against tumor cells without eliminating T cells and there is a need for more effective therapies treating MM (Chen; [0002]-[0003]). Chen teaches the CS1-BCMA bispecific CAR to have a structure of CS1 scFv1 – (G4S)4 linker (reference SEQ ID NO: 146) – BCMA scFv2 – hinge domain (SEQ ID NO:96) – transmembrane domain (reference SEQ ID NO: 99) – a costimulatory signal domain (reference SEQ ID NO:77) – a CD3ζ cytoplasmic signaling sequence derived from CD3ζ (reference SEQ ID NO:120). Specifically for the hinge domain, Chen teaches that the hinge domain provides structural flexibility and spacing to flank polypeptide regions and includes regions derived from CD8 and other receptors that provide a similar function (Chen; [0150]).
Chen also teaches the method of preparing CS1-BCMA bispecific CAR T-cells that can then be further administered via a pharmaceutical formulation for the treatment of cancer specifically of CS1 and BCMA positive myeloma or lymphoma (Chen; [0002]; [0056]).
However, Chen does not teach the CAR comprising CS1 scFv1 with a heavy chain variable region of SEQ ID NO:1 and a light chain variable region of SEQ ID NO:2 and a BCMA scFv2 with a heavy chain variable region of SEQ ID NO:4 and a light chain variable region of SEQ ID NO:5 . Additionally, Chen does not teach the amino acid sequence of the CAR as shown in SEQ ID NO:3.
Wu teaches chimeric antigen receptor (CAR) T-cells being an efficient approach to immunotherapy where the reprogrammed engineered T cells can proliferate and persist in the patient as a “living drug” (Wu; page 1, left column, paragraph 3). Wu teaches CS1 being overexpressed in multiple myeloma patients and represents a cancer specific target for CAR T-cell therapy (Wu; page 1, right column, paragraphs 4-5). Wu teaches a CAR structure of: CD8 leader sequence – CS1 scFv – CD8 hinge – CD28 transmembrane – CD28 or 4-1BB costimulatory domain – CD3ζ intracellular signaling domain (Wu; see Figure 3; page 15, column 3, paragraphs 9-11). Wu teaches the CS1 scFv with heavy chain variable region of SEQ ID NO:4 and a light chain variable region of SEQ ID NO:5 that are separated by a 3XG4S linker (reference SEQ ID NO: 6) (reference SEQ ID NO:4-5 are 100% match in sequence and length to instant SEQ ID NO:1-2, the heavy and light chain variable regions of the instant CS1 scFv) (Wu; page 15, column 3, paragraphs 7-8). This CS1 CAR T cell can be used to as a therapeutic agent against hematological cancer cells overexpressing CS1 (Wu; page 15, column 4, paragraph 6-7). Wu further teaches the CS1 CAR can be stably integrated into a T cell and when used for treatment in NSG1 mice injected MM1S cells, prolonged survival compared to Mock-CAR-T-cells (Wu; see page 20-21, example 15; see page 21, Example 22).
Wu also teaches CS1 and BCMA are often overexpressed in multiple myeloma and are both targets used for CAR-T cell therapy and can be used for more effective therapy of multiple myeloma (Wu; page 16, paragraph 13-14). Wu teaches the structure of a CS1-BCMA bispecific CAR T cell; CD8 leader– CS1 scFv – linker – BCMA scFv – CD8 hinge – CD28 transmembrane – CD28 or 4-1BB costimulatory domain – CD3ζ intracellular signaling domain (Wu; see Figure 4).
Wu_2 teaches chimeric antigen receptor (CAR) T-cells being an efficient approach to immunotherapy where the reprogrammed engineered T Cells can proliferate and persist in the patient as a “living drug” (Wu_2; [0005]). Wu_2 teaches BCMA is a cell surface receptor mainly expressed in mature B lymphocytes and in most cases multiple myeloma making it a target for CAR T-cells (Wu_2; [0008]; [0039]). Wu_2 teaches a BCMA CAR-T cell that can significantly decrease MM tumor growth indicating the BCMA CAR T cell can treat patients with MM (Wu_2; [0039]-[0040]). Wu_2 teaches the BCMA scFv with a heavy chain variable region of SEQ ID NO:6 and a light chain variable region of SEQ ID NO:7 separated by a 3XG4S linker (reference SEQ ID NO:8) (Reference SEQ ID NO: 7 is a 100% match in sequence and in length to the instant SEQ ID NO:5. Reference SEQ ID NO: 6 is a 99.2% match in sequence and in length to the instant SEQ ID NO:4; see sequence alignment below) (Wu_2; [0028]; see Example 2). Wu_2 additionally teaches the BCMA scFv use with another tumor antigen for generation of bispecific CARs including BCMA-CS1 (Wu_2; [0044]).
It would have been prima facie obvious to one of ordinary skill, in the art before the effective filing date, to have modified the CS1-BCMA bispecific CAR T cell and the method of treating cancer with the CS1-BCMA bispecific CAR T cell of Chen with the CS1 heavy chain variable region and light chain variable regions of reference SEQ ID NO:4-5 of Wu with reasonable expectation of success.
One of ordinary skill in the art would have been motivated to make this modification before the effective filing date of the instant invention since Chen teaches targeting both CS1 and BCMA in a CAR T cell can overcome limitations of CAR T cell therapy including T cell fratricide and antigen escape and targeting both CS1 and BCMA provides a fine-tuned approach to treating patients with MM. Wu teaches CS1 being overexpressed in MM patients and that the reference CS1 CAR T cell can be used as a therapeutic agent against cancer cells and prolong a patient’s survival. Wu also teaches that CS1 and BCMA can be used together in a bispecific CAR T cell to provide a more effective therapy for MM.
Therefore, it would have been obvious to combine the CS1-BCMA bispecific CAR of Chen with the specific CS1 heavy and light chain variable regions (reference SEQ ID NO:4-5) of Wu according to known methods to yield predictable results to improve therapy options for MM patients and prolong their response to treatment.
It would have been prima facie obvious to one of ordinary skill in the art, before the effective filing date, to have modified the CS1-BCMA bispecific CAR T cell and the methods of treating cancer with the CS1-BCMA bispecific CAR T cells of Chen with the BCMA heavy chain variable region and light chain variable regions of reference SEQ ID NO:6-7 of Wu_2 with reasonable expectation of success.
One of ordinary skill in the art would have been motivated to make this modification before the effective filing date of the instant invention since Chen teaches targeting both CS1 and BCMA in a CAR T cell can overcome limitations of CAR T cell therapy including T cell fratricide and antigen escape and targeting both CS1 and BCMA provides a fine-tuned approach to treating patients with MM. Wu_2 teaches that BCMA is overexpressed in MM patients and can be an effective treatment as a target for CAR T cells as the reference BCMA CAR T cell significantly decreased tumor growth in vivo.
Therefore, it would have been obvious to combine the CS1-BCMA bispecific antibody of Chen with the specific BCMA heavy and light chain variable regions (SEQ ID NO:6-7, respectively) of Wu_2 according to known methods to yield predictable results to improve therapy options for MM patients and prolong their response to treatment.
Additionally, regarding reference SEQ ID NO:6 of Wu_2, it has a 99.2% match to instant SEQ ID NO:4 of the BCMA arm of the CAR T cell:
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One of ordinary skill in the art would have been motivated to make this modification before the effective filing date of the instant invention since Wu_2 teaches the reference BCMA CAR T cell being an effective treatment for patients with MM and can be used in combination with CS1 in a bispecific CAR T cell and Chen teaches the CS1-BCMA bispecific antibody being able to overcome limitations associated with CAR T cell therapy including T cell fratricide and antigen escape.
Therefore, it would have been obvious to combine the reference BCMA scFv with heavy chain variable region of SEQ ID NO:6 of Wu_2 with the CS1-BCMA bispecific antibody of Chen since reference SEQ ID NO:6 is nearly identical to instant SEQ ID NO:4 and both variants retain and perform the same function as taught by Wu_2. Removing or changing one C-terminal amino acid is routine modification that one of ordinary skill in the art would expect to have little to no effect on the overall protein structure and function with no unexpected results occurring from the amino acid deletion.
Regarding claim 4 reciting the CAR of claim 1 wherein the amino acid sequence of the CAR is as shown in SEQ ID NO:3, it would have been prima facie obvious to one of ordinary skill in the art, before the effective filing date, to have modified the CS1-BCMA bispecific CAR amino acid sequence with specific structural elements of CS1 scFv1 – (G4S)4 linker (reference SEQ ID NO: 146) – BCMA scFv2 – hinge domain (SEQ ID NO:96) – transmembrane domain (reference SEQ ID NO: 99) – a costimulatory signal domain (reference SEQ ID NO:77) – a CD3ζ cytoplasmic signaling sequence derived from CD3ζ (reference SEQ ID NO:122) of Chen with the CS1 heavy and light chain amino acid sequences (reference SEQ ID NO:4-5) in the CAR amino acid sequence as shown in reference SEQ ID NO: 18 of Wu with the BCMA heavy and light chain amino acid sequences (reference SEQ ID NO:6-7) in the CAR amino acid sequence as shown in SEQ ID NO:15 of Wu_2 resulting in instant SEQ ID NO:3 with reasonable expectation of success.
One of ordinary skill in the art would have been motivated to make this modification before the effective filing date of the instant invention since Chen teaches the amino acid sequences of all of the functional domains present in the instant SEQ ID NO:3 in reference SEQ ID NO:77, 96, 99, 122, and 146, Wu teaches the CS1 scFv in a CAR vector with the same CAR functional domains as Chen, and Wu_2 teaches the BCMA scFv in a CAR vector with the same CAR functional domains as Chen. When the amino acid sequences of Chen, Wu, and Wu_2 are combined, the resulting amino acid sequence is as shown below (98.1% match to instant SEQ ID NO:3):
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In regards to the 98.1% difference between sequences, the 98.1% difference occurs in the hinge domain with an amino acid substitution in position 538 from of serine in reference sequence to cysteine in instant SEQ ID NO:3 and in the linker sequences (positions 386, 507-509, and 549-550) between functional domains. It is well established in the art that certain amino acid substitutions can be introduced into a protein sequence without significantly altering its structure or function, such as conservative amino acid substitutions (i.e. serine to cysteine). One skilled in the art would recognize that an amino acid substitution is considered routine optimization to identify variant sequences with optimized properties especially when within linker sequences between functional domains. In regards to the hinge domain, Chen teaches that the hinge domain provides structural flexibility and spacing to flank polypeptide regions and variants of the CD8 hinge are viable options that provide a similar function.
Therefore, it would have been obvious to combine the CS1-BCMA bispecific CAR with a hinge domain (SEQ ID NO:96) – transmembrane domain (reference SEQ ID NO: 99) – a costimulatory signal domain (reference SEQ ID NO:77) – a CD3ζ cytoplasmic signaling sequence derived from CD3ζ (reference SEQ ID NO:120) of Chen with the specific CS1 heavy and light chain variable regions (reference SEQ ID NO:4-5) of Wu with the BCMA heavy chain variable region and light chain variable regions of reference SEQ ID NO:6-7 of Wu_2 to yield predictable results of a stable, functional CS1-BCMA CAR vector with a structurally flexible hinge domain.
Therefore, the invention as a whole was prima facie obvious to one of ordinary skill in the art at the time the invention was made, as evidenced by the references, especially in the absence of evidence on the contrary.
Conclusion
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/LEAH ELIZABETH STEIN/ Examiner, Art Unit 1641
/NORA M ROONEY/ Primary Examiner, Art Unit 1641