The Examiner of your application in the USPTO has changed. To aid in correlating any papers for this application, all further correspondence regarding this application should be directed to Supervisory Patent Examiner Julie Wu.
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 .
Status of Claims
Claims 1, 4, 7, 9, 11-17, 22-24, and 27-28 are pending.
Claim 7 withdrawn from further consideration pursuant to 37 CFR 1.142(b) as being drawn to a nonelected species, there being no allowable generic or linking claim. Election was made without traverse in the reply filed on March 26, 2025.
Claims 1, 4, 5, 9, 11-17, 22-24, 27, and 28 are currently under prosecution.
Rejections Withdrawn
All previous rejections of claim 19 is moot in view of claim cancellation.
Previous rejection of 22, and 24 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35 U.S.C. 112 (pre-AIA ), second paragraph, as being indefinite for failing to particularly point out and distinctly is withdrawn in view of claim amendments.
Previous rejection of Claims 1 and 4 are rejected under 35 U.S.C. 103 as being unpatentable over WO2019/010224, Jones et al, published January 10, 2019, in view of US2017/0051035A1, Payne et al, published February 23, 2017 is withdrawn in view of claim amendments.
Previous rejection of claim 9 is rejected under 35 U.S.C. 103 as being unpatentable over WO2019/010224, Jones et al, published January 10, 2019, in view of US2017/0051035A1, Payne et al, published February 23, 2017, as applied to claims 1 and 4 above, and further in view of WO2013059593, Orentas et al, published April 25, 2013 in view of claim amendments.
Note: Upon further search and evaluation, previous indication of allowable subject matter cited in claims 5, 11-17, 23, 27 and 28 are withdrawn. The instant office actions contains new rejections.
New Objections/Rejections Necessitated by Claim amendments
Specification
The disclosure is objected to because it contains an embedded hyperlink and/or other form of browser-executable code. Applicant is required to delete the embedded hyperlink and/or other form of browser-executable code; references to websites should be limited to the top-level domain name without any prefix such as http:// or other browser-executable code. See MPEP § 608.01.
Specifically, page 16 of the instant specification recite a hyperlink.
Nucleotide and/or Amino Acid Sequence Disclosures
REQUIREMENTS FOR PATENT APPLICATIONS CONTAINING NUCLEOTIDE AND/OR AMINO ACID SEQUENCE DISCLOSURES
Items 1) and 2) provide general guidance related to requirements for sequence disclosures.
37 CFR 1.821(c) requires that patent applications which contain disclosures of nucleotide and/or amino acid sequences that fall within the definitions of 37 CFR 1.821(a) must contain a "Sequence Listing," as a separate part of the disclosure, which presents the nucleotide and/or amino acid sequences and associated information using the symbols and format in accordance with the requirements of 37 CFR 1.821 - 1.825. This "Sequence Listing" part of the disclosure may be submitted:
In accordance with 37 CFR 1.821(c)(1) via the USPTO patent electronic filing system (see Section I.1 of the Legal Framework for Patent Electronic System (https://www.uspto.gov/PatentLegalFramework), hereinafter "Legal Framework") as an ASCII text file, together with an incorporation-by-reference of the material in the ASCII text file in a separate paragraph of the specification as required by 37 CFR 1.823(b)(1) identifying:
the name of the ASCII text file;
ii) the date of creation; and
iii) the size of the ASCII text file in bytes;
In accordance with 37 CFR 1.821(c)(1) on read-only optical disc(s) as permitted by 37 CFR 1.52(e)(1)(ii), labeled according to 37 CFR 1.52(e)(5), with an incorporation-by-reference of the material in the ASCII text file according to 37 CFR 1.52(e)(8) and 37 CFR 1.823(b)(1) in a separate paragraph of the specification identifying:
the name of the ASCII text file;
the date of creation; and
the size of the ASCII text file in bytes;
In accordance with 37 CFR 1.821(c)(2) via the USPTO patent electronic filing system as a PDF file (not recommended); or
In accordance with 37 CFR 1.821(c)(3) on physical sheets of paper (not recommended).
When a “Sequence Listing” has been submitted as a PDF file as in 1(c) above (37 CFR 1.821(c)(2)) or on physical sheets of paper as in 1(d) above (37 CFR 1.821(c)(3)), 37 CFR 1.821(e)(1) requires a computer readable form (CRF) of the “Sequence Listing” in accordance with the requirements of 37 CFR 1.824.
If the "Sequence Listing" required by 37 CFR 1.821(c) is filed via the USPTO patent electronic filing system as a PDF, then 37 CFR 1.821(e)(1)(ii) or 1.821(e)(2)(ii) requires submission of a statement that the "Sequence Listing" content of the PDF copy and the CRF copy (the ASCII text file copy) are identical.
If the "Sequence Listing" required by 37 CFR 1.821(c) is filed on paper or read-only optical disc, then 37 CFR 1.821(e)(1)(ii) or 1.821(e)(2)(ii) requires submission of a statement that the "Sequence Listing" content of the paper or read-only optical disc copy and the CRF are identical.
Specific deficiencies and the required response to this Office Action are as follows:
Specific deficiency – Nucleotide and/or amino acid sequences appearing in the specification are not identified by sequence identifiers in accordance with 37 CFR 1.821(d).
Claim 4 recites (G4S)x and (G4S)3, both of which require sequence identifiers.
Paragraphs 0006 and 0053 of the instant specification recite (G4S)x and (G4S)3, both of which require sequence identifiers.
Paragraph 0073 of the instant specification recite (Gly4Ser)3, which requires a sequence identifier.
Required response – Applicant must provide:
A substitute specification in compliance with 37 CFR 1.52, 1.121(b)(3) and 1.125 inserting the required sequence identifiers, consisting of:
A copy of the previously-submitted specification, with deletions shown with strikethrough or brackets and insertions shown with underlining (marked-up version);
A copy of the amended specification without markings (clean version); and
A statement that the substitute specification contains no new matter.
Claim Rejections - 35 USC § 112
The following is a quotation of the first paragraph of 35 U.S.C. 112(a):
(a) IN GENERAL.—The specification shall contain a written description of the invention, and of the manner and process of making and using it, in such full, clear, concise, and exact terms as to enable any person skilled in the art to which it pertains, or with which it is most nearly connected, to make and use the same, and shall set forth the best mode contemplated by the inventor or joint inventor of carrying out the invention.
The following is a quotation of the first paragraph of pre-AIA 35 U.S.C. 112:
The specification shall contain a written description of the invention, and of the manner and process of making and using it, in such full, clear, concise, and exact terms as to enable any person skilled in the art to which it pertains, or with which it is most nearly connected, to make and use the same, and shall set forth the best mode contemplated by the inventor of carrying out his invention.
Claims 27 and 28 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.
The claimed invention. The instant claims are directed to a composition comprising a T lymphocyte or natural killer cell comprising a chimeric antigen receptor comprising a scFV that comprising a VL comprising SEQ ID NO:4 OR a VH comprising SEQ ID NO:8. The claims required the expression of the scFV be a functional antigen binding domain that is expressed on the cell surface.
State of the prior art. It is well established in the art that the formation of an intact antigen-binding site in an antibody usually requires the association of the complete heavy and light chain variable regions of a given antibody, each of which comprises three CDRs (or hypervariable regions) that provide the majority of the contact residues for the binding of the antibody to its target epitope (Almagro, Frontiers in Immunology, 2018:8, 1751; specifically page 3, “The IgG Molecule”; Figure 1). Sela-Culang (Frontiers in Immunology, 2013, 4:302) further teaches, “A major focus in analyzing the structural basis for [antigen] recognition has been in identifying the exact boundaries of the CDRs in a given [antibody]. It is a common practice to identify paratopes through the identification of CDRs” (page 3, left column, “CDRs Identification”).
Chiu (Antibodies, 2019, 8(55):1-80) teaches that the complementarity-determining regions (HCDRs 1-3 and LCDRs 1-3) determine antigen binding requiring specific sequences and orientation of those sequences to properly form tertiary structures that can recognize and bind antigens (page 4, 1.2.2 first and last paragraphs; figure 3). Chiu teaches that antibody modeling with known LCDRs 1-3, HCDR1 and HCDR2 could not predict HCDR3. Structure-Based antibody engineering is unable to predict antibody sequences (page 6, see 1.2.6, pages 10-11, see Section 2, in particular second paragraph of page 11). Chiu notes the advancement in antibody engineering but states it is still not possible to predict the point mutations that would improve affinity in both antibodies (page 51, lines 6-12).
Although the prior art teaches some understanding of the structural basis of antigen-antibody recognition, it is aptly noted that the art is characterized by a high level of unpredictability, since the skilled artisan still cannot accurately and reliably predict the consequences of amino acid substitutions, insertions, and deletions in the antigen-binding domains. Ni (The Protein Journal, 2024, 43:683-696) teaches, “Mutations, even one mutation, introduced in the CDRs through [somatic hypermutation] can change the binding properties and repertoire of antibodies. However, how just one-point mutation can dramatically change the recognition profiles of the antibody is still unclear” (Introduction). Furthermore, while affinity maturation techniques can result in differences in the CDRs of the antibody compared to its parental antibody, those techniques involve trial-and-error testing and the changes that maintain or improve affinity are unpredictable to those of ordinary skill in the art (Almagro, pages 3 and 6-7).
Press (WO2017161353A1) teaches 5 different CD20 scFVs or antibodies (figure 1; claim 18). These CD20 binding domains are comprised of a specific VH sequence paired with a specific VL sequence.
The art does not teach that any VH CDR sequences can pair with any VL CDR sequences to form an functional antigen binding domains.
Scope of species disclosed in original specification. The disclosure teaches and anti-CD20IFL, rituximab, comprising a VL comprising the amino acid sequences of SEQ ID NO:4 and VH comprising the amino acid of SEQ ID NO:8 (page 25). The instant specification does not teach an antigen binding domain comprising SEQ ID NO:4 that can pair with ANY VH sequence to form a functional antigen binding domain, nor an antigen binding domain comprising SEQ ID NO:8 that can pair with ANY VL sequence to form a functional antigen binding domain.
MPEP § 2163 states that 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. While the disclosure appears to describe one antibody (page 25), it does not permit a skilled artisan cannot envision the subgenus of VH domains that can pair with instant SEQ ID NO:4, nor the subgenus of VL domains that can pair with instant SEQ ID NO:8 to form a functional antigen binding domain of scFV as required by the instant claims.
In the absence of a representative number of species, the written description requirement for a claimed genus may be satisfied 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 claimed genus.
Accordingly, the disclosure only provides adequate written description for an scFV comprising SEQ ID NOs:4 and 8 that can form a functional antigen binding domain.
Conclusion. For all of the reasons presented above, one of skill in the art would not know which of the countless other antibodies encompassed by the highly general structural requirements of the claims would also possess the required formation of a function antigen binding domain of a scFV comprising a VL comprising SEQ ID NO:4 OR VH comprising SEQ ID NO:8. Given the lack of shared structural properties that provide the claimed binding activity, the limited number of species described, and the fact that the species that were described cannot be considered representative of the broad genus, the Applicant did not possess the full subgenus genus of antibodies as broadly claimed at the time the application was filed.
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.
Claims 1, 4, 9, 11, 12, 14-16, 27 and 28 are rejected under 35 U.S.C. 103 as being unpatentable over Ma et al. (WO2017222593A1) and Press (WO217161353A1).
Ma teaches a T cell or NK cell expressing a chimeric antigen receptor (CAR) comprising a CD8[Symbol font/0x61] signal peptide (L8) (page 34-35), attached to a scFV that binds to CD19 comprising a VH and VL domain, a hinge domain, transmembrane domain and 4-1BB and CD3[Symbol font/0x64] (figure 38A, 38B, and figure 39B). Ma teaches that IL-15 promotes T cell proliferation and enhances the T cell effector response, and increase generation of memory T cells (page 88, 1st paragraph). Ma teaches that expression of IL-15 with IL-15RA leads to effective action of IL-15[Symbol font/0x62][Symbol font/0x67] complex (page 88, 2nd-4th paragraphs). Ma teaches a T cell expressing a CAR that binds to CD19 or CD20 attached to a P2A self-cleavable linker to the C-terminus of the CAR that binds to CD19 and attach a IL-15-linkerIL-15sushi domain (CAR-P2A-IL15-linker-IL15sushi) (figure 59; page 88, 6th paragraph; page 89, 1st paragraph). Ma teaches that the scFv for the chimeric protein can also bind to CD20 (page 131, lines 18-21).
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Regarding claim 11, Ma further teaches T cell expressing a tandem CAR comprising CD19CAR and CD20CAR comprising: leader-anti-CD19scFV-Hinge-TM-4-1BB-CD3[Symbol font/0x64]-P2A-leader-CD20scFV-H-TM-CD28-CD3[Symbol font/0x64] (figure 15).
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Ma does not teach that the CAR is comprised of a G4S linker connecting the VH and VL domain of the scFV of the CAR, and the scFV is attached to a hinge, CH2 and Ch3 domain of IgG1. However, this deficiency is made up in Press.
Press generation of CD20 CAR to treat cancer overexpressing CD20 (page 4). Press teaches a CD20 CAR comprising an anti-CD20 scFV-hinge-CH2-CH3 domain-CD28 TM domain-CD28-41BB, CD3[Symbol font/0x78] intracellular signaling domains
(page 3, 3rd paragraph, page 19, last paragraph; example 15; figure 1), wherein the hinge, CH2, and CH3 are from IgG1 (same as instant SEQ ID NO:10) (page 32, last paragraph; example 15; figure 23A). Press teaches the linker connecting VH and VL of scFV is comprised of (Gly4Ser)5. Press teaches that the scFV can also comprise the VH and VL of rituximab (page 59, lines 1-3). As evidenced by the instant specification, rituximab is comprised of a VH and VL that is the same as instant SEQ ID NOs:4 and 8 (paragraphs 0098 and 00102). Press teaches that the CAR is effective at inducing IFN[Symbol font/0x67] and IL-2 production, and inducing specific lysis (Figure 8B and 8C). Press teaches that the hinge-CH2-CH3 spacers of the CAR enhances effector function (figures 22A and 22B; page 9).
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To generate CD8[Symbol font/0x61] leader sequence- anti-CD20 scFV-hinge-CH2-CH3 domain- CD28 TM domain-CD28-41BB-CD3[Symbol font/0x78]-P2A-IL15-linker-IL15sushi:
Regarding claim 1, 4, 9, 27 and 28, it would have been prima facie obvious to a person of ordinary skill in the art at the time the invention was filed to substitute the CAR (scFV that binds to CD20-CD28-4-1BB-CD3[Symbol font/0x64]) of the fusion protein comprising CD8[Symbol font/0x61] leader sequence-CAR-P2A-IL15-linker-IL15sushi that is expressed in a T cell or NK cell of Ma with the CAR comprising scFV (that comprises the same VH and VL sequences as instant SEQ ID NOs:4 and 8) that binds to anti-CD20 scFV-hinge-CH2-CH3 domain-CD28 TM domain-CD28-41BB-CD3[Symbol font/0x78] to generate a T cell or NK cell expressing a CD8[Symbol font/0x61] leader sequence- anti-CD20 scFV-hinge-CH2-CH3 domain-CD28 TM domain-CD28-41BB-CD3[Symbol font/0x78]-P2A-IL15-linker-IL15sushi in order to treat CD20 positive cancer cells. Ma teaches that addition of IL15 and IL15sushi to a CAR enhances the function of the T cell or NK cells by stimulating cellular proliferation, effector function, and formation of memory cells, and Press teaches that the CD20 CAR is effective at inducing T cell activation and inducing cellular lysis. Further, it would be obvious that the linker joining the VH and VL of the anti-CD20 scFV is comprised of (Gly4S)5 because Press teaches (Gly4S)5 as a preferred linker.
Regarding claims 27 and 28, it would be obvious to modify the anti-CD20 scFV of CD8[Symbol font/0x61] leader sequence- anti-CD20 scFV-hinge-CH2-CH3 domain-CD28 TM domain-CD28-41BB-CD3[Symbol font/0x78]-P2A-IL15-linker-IL15sushi to comprise the VH and VL of rituximab as taught by Press to generate CAR comprising a well characterized anti-CD20 antibody.
One of ordinary skill in the art would have a reasonable expectation of success for generating a T cell or NK cell expressing CD8[Symbol font/0x61] leader sequence- anti-CD20 scFV-hinge-CH2-CH3 domain-CD28 TM domain- CD28-41BB-CD3[Symbol font/0x78]-P2A-IL15-linker-IL15sushi, including anti-CD20 scFV of rituximab, because Ma teaches that addition of IL15-linker-IL15sushi enhances immune cell function, and Press teaches a T cell expressing CAR comprising a hinge-CH2-CH3 domains as spacers have enhanced effector function, and rituximab is a well described anti-CD20 antibody.
To generate CD8[Symbol font/0x61] leader-anti-CD19scFV-Hinge-TM-4-1BB-CD3[Symbol font/0x64]-P2A- CD8[Symbol font/0x61] leader sequence- anti-CD20 scFV-hinge-CH2-CH3 domain-CD28 TM domain-CD28-41BB-CD3[Symbol font/0x78]-P2A-IL15-linker-IL15sushi:
Regarding claims 11 and 12, it would be obvious to modify the T cell or NK cell expressing CD8[Symbol font/0x61] leader sequence- anti-CD20 scFV-hinge-CH2-CH3 domain-CD28 TM domain-CD28-41BB-CD3[Symbol font/0x78]-P2A-IL15-linker-IL15sushi of Ma and Press, to include an anti-CD19scFV-Hinge-TM-4-1BB-CD3[Symbol font/0x64]-P2A at the amino terminus to for a bispecific CAR as taught in Ma, to form a T-cell or NK cell that will aggressively target cancer cells expressing CD19 and CD20. Ma teaches a T cell or NK cell expressing two CAR linked by a P2A linker comprising CD8[Symbol font/0x61] leader-anti-CD19scFV-Hinge-TM-4-1BB-CD3[Symbol font/0x64]-P2A-leader-CD20scFV-H-TM-CD28-CD3[Symbol font/0x64], and the combined teachings of Ma and Press teaches CD8[Symbol font/0x61] leader sequence- anti-CD20 scFV-hinge-CH2-CH3 domain-CD28 TM domain-CD28-41BB-CD3[Symbol font/0x78]-P2A-IL15-linker-IL15sushi.
One of ordinary skill in the art would have a reasonable expectation of success for generating a T cell or NK cell expressing CD8[Symbol font/0x61] leader-anti-CD19scFV-Hinge-TM-4-1BB-CD3[Symbol font/0x64]-P2A- CD8[Symbol font/0x61] leader sequence- anti-CD20 scFV-hinge-CH2-CH3 domain-CD28 TM domain-CD28-41BB-CD3[Symbol font/0x78]-P2A-IL15-linker-IL15sushi, because Ma teaches a T cell or NK cell expressing a dual CAR comprising two CAR linked by a P2A linker to target multiple antigens on cancer cells.
Claim(s) 11-17 is/are rejected under 35 U.S.C. 103 as being unpatentable over over Ma et al. (WO2017222593A1) and Press (WO2017161353A1) as applied to claims 1 and 11 above, and further in view of Hwang WO2018124766 (US20190336533 is used as the English translation).
The teachings of Ma and Press are taught above. As discussed above, combined teachings of Ma and Press teaches a T cell expressing a dual CAR comprising CD8[Symbol font/0x61]leader-anti-CD19scFV-Hinge-TM-4-1BB-CD3[Symbol font/0x64]-P2A-CD8[Symbol font/0x61] leader sequence-anti-CD20 scFV-hinge-CH2-CH3 domain-CD28 TM domain-CD28-41BB-CD3[Symbol font/0x78]-P2A-IL15-linker-IL15sushi.
The combined teachings of Ma and Press does not teach that the dual CAR comprises CD16V-4-1BB-CD3[Symbol font/0x78].
Hwang teaches a CD16V-BBZ chimeric antigen receptor (CAR) comprising CD16V extracellular domain-CD8[Symbol font/0x61] hinge and TM-4-1BB and CD3[Symbol font/0x64] intracellular domain (paragraph 0114; Table 1). Hwang teaches that CD16V is a high affinity CD16 receptor that is a strong stimulator of NK cell activation (paragraph 0008). Hwang teaches that NK cells expressing the CD16V-BBZ CAR stimulated cell lysis (paragraph 0050; figure 1B) and against B cell lymphoma cells, Ramos cells, when it is treated with an antibody to Ramos cells (paragraph 0051; figure 1C)
Regarding claims 11-17, it would be obvious to substitute the first CAR of the chimeric antigen receptor comprising CD8[Symbol font/0x61]leader-anti-CD19scFV-Hinge-TM-4-1BB-CD3[Symbol font/0x64]-P2A-CD8[Symbol font/0x61] leader sequence-anti-CD20 scFV-hinge-CH2-CH3 domain-CD28 TM domain-CD28-41BB-CD3[Symbol font/0x78]-P2A-IL15-linker-IL15sushi of Ma and Press, with CD16V extracellular domain and expressing the CAR in NK cells of Hwang to generate a potent NK cells expressing a dual CAR that binds to Fc and CD20 to better treat B cell lymphoma. The combination of Ma and Press teaches a dual CAR comprising CD8[Symbol font/0x61]leader-anti-CD19scFV-Hinge-TM-4-1BB-CD3[Symbol font/0x64]-P2A-CD8[Symbol font/0x61] leader sequence-anti-CD20 scFV-hinge-CH2-CH3 domain-CD28 TM domain-CD28-41BB-CD3[Symbol font/0x78]-P2A-IL15-linker-IL15sushi, and Hwang teaches a NK cell expressing CD16V-BBZ CAR that potentially induces toxicity to B cell lymphoma cells.
One of ordinary skill in the art would have a reasonable expectation of success for generating an NK cell expressing CD8[Symbol font/0x61]leader-CD16V-Hinge-TM-4-1BB-CD3[Symbol font/0x64]-P2A- CD8[Symbol font/0x61] leader sequence- anti-CD20 scFV-hinge-CH2-CH3 domain-CD28 TM domain-CD28-41BB-CD3[Symbol font/0x78]-P2A-IL15-linker-IL15sushi, because Ma and Press that a T cell or NK cell expressing of a dual CAR that binds to CD19 and CD20 that is attached to IL-15, and Hwang teaches that NK cells expressing CD16V-BBZ CAR induces cytotoxicity against cancer cells.
Claim(s) 22 is/are rejected under 35 U.S.C. 103 as being unpatentable over Ma et al. (WO2017222593A1) and Press (WO2017161353A1) as applied to claims 1 and further in view of Cordoba (WO2018211244A1).
The teachings of Ma and Press are described above. The combined teachings of Ma and Press teach: CD8[Symbol font/0x61] leader sequence-anti-CD20 scFV-hinge-CH2-CH3 domain-CD28 TM domain- CD28-41BB-CD3[Symbol font/0x78]-P2A-IL15-linker-IL15sushi.
The combined teachings of Ma and Press does not teach that the linker joining -CD28-41BB-CD3[Symbol font/0x78]-P2A-IL15-linker-IL15sushi with the CD28 TM domain is comprised of the same sequence as instant SEQ ID NO:55. However this deficiency is made up in Cordoba.
Cordoba teaches an RL linker comprising SEQ ID NO:50 (same as instant SEQ ID NO:55) (page 49). Cordoba teaches a chimeric antigen receptor, SFGm R.V5_tag-CD22(2Ig)-CD19tm-RL-FRB-2A-FKBP12-L-CD148endo-2A-CAR, comprising the RL linker joining the CD19 transmembrane domain with the intracellular domain (example 1).
It would be obvious to substitute the linker that is joining the linker joining anti-CD20 scFV-hinge-CH2-CH3 domain-CD28 TM with the CD28-41BB-CD3[Symbol font/0x78]-P2A-IL15-linker-IL15sushi of the chimeric antigen receptor comprising CD8[Symbol font/0x61] leader sequence- anti-CD20 scFV-hinge-CH2-CH3 domain-CD28 TM domain-CD28-41BB-CD3[Symbol font/0x78]-P2A-IL15-linker-IL15sushi of Ma and Press, with the linker comprising SEQ ID NO:50 (same as instant SEQ ID NO:55) of Cordoba, to form an art equivalent chimeric antigen receptor. The combined teachings of Ma and Press teaches a chimeric antigen receptor comprising CD8[Symbol font/0x61] leader sequence-anti-CD20 scFV-hinge-CH2-CH3 domain-CD28 TM domain- CD28-41BB-CD3[Symbol font/0x78]-P2A-IL15-linker-IL15sushi, wherein there is a generic linker between the CD28 TM and CD28 domains, and Codoba teaches an RL linker that joins the TM domain of a CAR with the intracellular signaling domain.
One of ordinary skill in the art would have a reasonable expectation of success for generating a T cell expressing CD8[Symbol font/0x61] leader sequence-anti-CD20 scFV-hinge-CH2-CH3 domain-CD28 TM domain-RL-CD28-41BB-CD3[Symbol font/0x78]-P2A-IL15-linker-IL15sushi, because Cordoba teaches that the RL linker can be used to join the TM domain with the intracellular domain in a chimeric antigen receptor.
Claim(s) 23 is/are rejected under 35 U.S.C. 103 as being unpatentable over Ma (WO2017222593A1), Press (WO2017161353A1) as applied to claim 1 and further in view of Zhang (CN109957017A).
The teachings of Ma and Press are described above. The combined teachings of Ma and Press teaches: T cell expressing CD8[Symbol font/0x61] leader-anti-CD19scFV-Hinge-TM-4-1BB-CD3[Symbol font/0x64]-P2A-CD8[Symbol font/0x61] leader sequence-anti-CD20 scFV-hinge-CH2-CH3 domain-CD28 TM domain-CD28-41BB-CD3[Symbol font/0x78]-P2A-IL15-linker-IL15sushi.
The combined teachings of Ma and Press does not teach a dual CAR that binds to OX40. However this deficiency is made up in Zhang.
Zhang teaches a method of treating lymphoma comprised of administering an OX40 CAR (see “Background”), wherein the OX40 CAR is comprised of an OX40 scFV-CD8 hinge-CD8TM-CD28 and CD3[Symbol font/0x64] intracellular signaling domains (figure 1). Zhang teaches that lymphoma cells have a high expression of OX40 (see “summary of the invention”).
It would be obvious to substitute the first CAR of the chimeric antigen receptor comprising CD8[Symbol font/0x61] leader-anti-CD19scFV-Hinge-TM-4-1BB-CD3[Symbol font/0x64]-P2A- CD8[Symbol font/0x61] leader sequence-anti-CD20 scFV-hinge-CH2-CH3 domain-CD28 TM domain-CD28-41BB-CD3[Symbol font/0x78]-P2A-IL15-linker-IL15sushi of Ma and Press, with OX40-CAR of Zhang to generate a T cell expressing a dual CAR that binds to OX40 and CD20 to better treat B cell lymphoma. The combination of Ma and Press teaches a T cell expressing dual CAR comprising CD8[Symbol font/0x61] leader-anti-CD19scFV-Hinge-TM-4-1BB-CD3[Symbol font/0x64]-P2A- CD8[Symbol font/0x61] leader sequence- anti-CD20 scFV-hinge-CH2-CH3 domain-CD28 TM domain-CD28-41BB-CD3[Symbol font/0x78]-P2A-IL15-linker-IL15sushi that is used to treat lymphomas, and Zhang teaches a T cell expressing the OX40 CAR to treat lymphoma cells. One of ordinary skill in the art would have a reasonable expectation of success for generating a T cell expressing CD8[Symbol font/0x61]leader-OX40 scFV-CD8 hinge-CD8TM-CD28-CD3[Symbol font/0x64]-P2A- CD8[Symbol font/0x61] leader sequence- anti-CD20 scFV-hinge-CH2-CH3 domain-CD28 TM domain-CD28-41BB-CD3[Symbol font/0x78]-P2A-IL15-linker-IL15sushi, because Ma and Press teaches treating lymphoma with a T cell expressing of a dual CAR that binds to CD19 and CD20 that is attached to IL-15, and Zhang teaches OX40 CAR can be used to treat lymphomas.
Claim(s) 24 is/are rejected under 35 U.S.C. 103 as being unpatentable over Ma (WO2017222593A1), Press (WO2017161353A1) and Zhang (CN109957017A) as applied to claims 1 and 23 further in view of Cordoba (WO2018211244A1).
The combined teachings of Ma, Press and Zhang are described above. The combined teachings of Ma, Press and Zhang teaches: a T cell expressing CD8[Symbol font/0x61]leader-OX40 scFV-CD8 hinge-CD8TM-CD28-CD3[Symbol font/0x64]-P2A-CD8[Symbol font/0x61] leader sequence-anti-CD20 scFV-hinge-CH2-CH3 domain-CD28 TM domain-CD28-41BB-CD3[Symbol font/0x78]-P2A-IL15-linker-IL15sushi.
The combined teachings of Ma, Press and Zhang do not teach that the linker joining -CD28-41BB-CD3[Symbol font/0x78]-P2A-IL15-linker-IL15sushi with the CD28 TM domain is comprised of the same sequence as instant SEQ ID NO:55. However this deficiency is made up in Cordoba.
The teachings of Cordoba are described above.
It would be obvious to substitute the linker that is joining -CD28-41BB-CD3[Symbol font/0x78]-P2A-IL15-linker-IL15sushi with the CD28 TM domain of the chimeric antigen receptor comprising CD8[Symbol font/0x61]leader-OX40 scFV-CD8 hinge-CD8TM-CD28-CD3[Symbol font/0x64]-P2A- CD8[Symbol font/0x61] leader sequence-anti-CD20 scFV-hinge-CH2-CH3 domain- CD28 TM domain-CD28-41BB-CD3[Symbol font/0x78]-P2A-IL15-linker-IL15sushi of Ma, Press, and Zhang with the linker comprising SEQ ID NO:50 (same as instant SEQ ID NO:55) of Cordoba, to form an art equivalent chimeric antigen receptor. The combined teachings of Ma, Press, and Zhang teaches a chimeric antigen receptor comprising CD8[Symbol font/0x61]leader-OX40 scFV-CD8 hinge-CD8TM-CD28-CD3[Symbol font/0x64]-P2A- CD8[Symbol font/0x61] leader sequence- anti-CD20 scFV-hinge-CH2-CH3 domain-CD28 TM domain-CD28-41BB-CD3[Symbol font/0x78]-P2A-IL15-linker-IL15sushi, wherein a generic linker is located between the CD28 TM domain and CD28, and Codoba teaches an RL linker that joins the TM domain of a CAR with the intracellular signaling domain.
One of ordinary skill in the art would have a reasonable expectation of success for generating a T cell expressing CD8[Symbol font/0x61]leader-OX40 scFV-CD8 hinge-CD8TM-CD28-CD3[Symbol font/0x64]-P2A-CD8[Symbol font/0x61] leader sequence- anti-CD20 scFV-hinge-CH2-CH3 domain-CD28 TM domain-CD28-41BB-CD3[Symbol font/0x78]-P2A-IL15-linker-IL15sushi, because Cordoba teaches that the RL linker can be used to join the TM domain with the intracellular domain in a chimeric antigen receptor.
Conclusion
No claims allowed.
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/JULIE WU/Supervisory Patent Examiner, Art Unit 1643