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 .
Claim Status
Claims 9, 12, 16-17, 22-65 are cancelled.
Claims 11, 13, 15, 18-19, 21 are amended.
Claims 66-68 are new.
Claims 1-8, 10-11, 13-15, 18-21, 66-68 are examined on the merits.
Priority
This application is a national stage application of international Patent Application No. PCT/US22/13947, filed 01/26/2022, which claims priority from U.S. Provisional Application 63142347, filed 01/27/2021.
Election/Restrictions
Applicants’ election without traverse of the species in the reply filed on 04/22/2026 is acknowledged.
Species 1: SEQ ID NO: 51
Species 2: SEQ ID NO: 12
Species 3: SEQ ID NO: 5
Species 4: SEQ ID NO: 49
Upon further consideration Species Election for Species 4 is withdrawn.
Claim Objections
Claim 20 is objected to because of the following informalities: reciting an abbreviation without spelling out what the abbreviation is in the first instance (MND).
Appropriate correction is required.
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 6, 11, 13, 20, 66 and 68 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.
Claim 6 requires the provision of a genus of functional variants of FKBP-rapamycin complex binding domain (FRB domain); and of a genus of functional variants of FK506 binding protein domain (FKBP). The claim encompasses any number of mutations of any type, such as an insertion, deletion or substitution, as long as the variants have FKBP-rapamycin binding domain and FK506 binding protein domain. Thus, the claim encompasses the provision of a large genus of nucleotide sequences that must function as FKBP-rapamycin binding domain and FK506 binding protein domain.
Claim 11 requires the provision of genus of anti-CD19 scFv sequences sharing at least 80% sequence identity to SEQ ID NOs: 51 (elected species). A claim of a genus of antibody fragments defined by an identity as low as 80% encompasses a large number of potential amino acid modifications across the complementary determining regions (CDRs). The specification does not provide a written description indicating which specific position substitutions preserve antigen-binding affinity for CD19. Thus, the claim encompasses a large number of substitutions, as long as the fragments bind CD19.
Claim 66 requires the provision of a genus of functional variants of FKBP-rapamycin complex binding domain (FRB domain); and of a genus of functional variants of FK506 binding protein domain (FKBP). The claim encompasses any number of mutations of any type, such as an insertion, deletion or substitution, as long as the variants have FKBP-rapamycin binding domain and FK506 binding protein domain. Thus, the claim encompasses the provision of a large genus of nucleotide sequences that must function as FKBP-rapamycin binding domain and FK506 binding protein domain.
Claim 68 requires the provision of genus of anti-CD19 scFv sequences comprising at least 91% sequence identity to SEQ ID NO: 63. A claim of a genus of antibody fragments defined by an identity as low as 91% encompasses a large number of potential amino acid modifications across the complementary determining regions (CDRs). The specification does not provide a written description indicating which specific position substitutions preserve antigen-binding affinity for CD19. Thus, the claim encompasses a large number of substitutions, as long as the fragments bind CD19.
To provide adequate written description and evidence of possession of a claimed genus, the specification must provide sufficient distinguishing identifying characteristics of the genus. The factors to be considered include disclosure of a complete or partial structure, physical and/or chemical properties, functional characteristics, structure/function correlation, and any combination thereof.
The specification envisions a viral particle comprising a vector genome comprising a polynucleotide sequence encoding an anti-CD19 chimeric antigen receptor, wherein the viral particle transduces immune cells in vivo (e.g., paragraph 0008). The specification envisions the viral particle comprises a polynucleotide sequence encoding a multipartite cell-surface receptor comprising a FKBP-rapamycin complex binding domain (FRB domain) or a functional variant thereof; and the polynucleotide comprises a polynucleotide sequence encoding a FK506 binding protein domain (FKBP) or a functional variant thereof (e.g., paragraph 0013). The specification envisions the viral particle comprises a sequence in 5' to 3' order on a polycistronic transcript: the polynucleotide sequence encoding the multipartite cell-surface receptor and the polynucleotide sequence encoding the anti-CD19 chimeric antigen receptor (e.g., paragraph 0017). the viral particle comprises a sequence in 5' to 3' order on a polycistronic transcript: the polynucleotide sequence encoding the anti-CD 19 chimeric antigen receptor and the polynucleotide sequence encoding the multipartite cell-surface receptor, and/or wherein the anti-CD19 chimeric antigen receptor shares at least 80%, 90%, 95%, or 100% identity to SEQ ID NO: 51, 79, 89, 121, or 122 (e.g., paragraph 0018). The specification envisions The complementary determining regions (CDR) of this scFv are RASQDISKYLN, (CDR-Ll; SEQ ID NO: 138), HTSRLHS (CDR-L2; SEQ ID NO: 139), QQGNTLPYT (CDR-L3; SEQ ID NO: 140), DYGV (CDR-Hl; SEQ ID NO: 141), VIWGSETTYYNSALKS (CDR-H2; SEQ ID NO: 142), HYYYGGSY AMDY (CDR-H3; SEQ ID NO: 143). In some embodiments, the viral particle comprises a polynucleotide encoding a CAR whose extracellular domain comprises an aCD19 scFv having these CDRs,
wherein optionally the aCD19 scFv shares at least 75%, at least 80%, at least 85%, at least 90%, at least 95%, at least 99%, or 100% identity to SEQ ID NO: 51 (e.g., paragraph 0404). The specification envisions the viral particle comprises a nucleic acid encoding the extracellular domain of a CAR comprising an aCD19 scFv that shares at least 75%, at least 80%, at least 85%, at least 90%, at least 95%, at least 99%, or 100% identity to SEQ ID NO: 63 (e.g., paragraph 0408). The specification envisions the viral envelope comprises an anti-CD3 single-chain variable fragment exposed on the surface and/or conjugated to the surface of the viral envelope (e.g., paragraph 0022). The specification envisions the viral envelope comprises a Cocal glycoprotein exposed on the surface and/or conjugated to the surface of the viral envelope (e.g., paragraph 0023).
The specification discloses a lentiviral particle surface engineered with transgene plasmid containing the anti-CD19 CAR in addition to the Rapamycin-Activated Cell-surface Receptor (RACR) component with the CMV promotor and aCD3-Cocal surface envelope proteins (SEQ ID NO: 129) (RACRaCD19CMV-aCD3-Cocal) (e.g., paragraph [0669]; Examples 2 and 7).
The examples described in the specification do not meet the limitation of the rejected claims containing a functional variant thereof of FKBP-rapamycin complex binding domain (FRB domain) and functional variants thereof of FK506 binding protein domain. The specification only provides data for FKBP-rapamycin complex binding domain (FRB domain). This is not representative of the very large variations allowed by the claims, there is insufficient guidance provided indicating any of the elements that are critical to the functioning of the FKBP-rapamycin complex binding domain (FRB domain) variants or the FK506 binding protein domain variants, thus it cannot be determined which amino acid can be changed without disrupting the function of the FRB domain variant; thus, further experimentation would be required to determine which variants of e.g., FRB domain and FK506 binding protein domain are functional and which are not.
Furthermore, the examples described in the specification do not meet the limitation of the rejected claim, having at least 80% identity of its amino acid sequence to SEQ ID NO 51. The specification only provides data for the anti-CD19 antibody. This specie is not representative of a very large variations allow by the claim, there is insufficient guidance provided indicating the amino acids that are critical to the binding to CD19, so it cannot be determined which amino acids can be changed without disrupting the function of the anti-CD19 antibody; thus, further experimentation would be required to determine which variants of the anti-CD19 antibody are functional and which are not. In addition, examples described in the specification do not meet the limitation of the rejected claim, having at least 91% identity of nucleotide sequence to SEQ ID NO 63. The specification only provides data for the anti-CD19 antibody. This specie is not representative of a very large variations allow by the claim, there is insufficient guidance provided indicating the amino acids that are critical to the binding to CD19, so it cannot be determined which amino acids can be changed without disrupting the function of the anti-CD19 antibody; thus, further experimentation would be required to determine which variants of the anti-CD19 antibody are functional and which are not.
The prior art does not appear to offset the deficiencies of the instant specification in that it does not describe functional variants of FKBP- rapamycin complex binding domain (FRB domain); and functional variants of FK506 binding protein domain (FKBP). Leung et al. (JCI Insight, 2019, cited as reference 1 on IDS filed 11/20/2023) teaches T cell activation remains antigen dependent but can only be achieved in the presence of a dimerizing drug, rapamycin. Studies performed in vitro and in xenograft mouse models illustrate equivalent to superior antitumor potency compared with currently used CAR designs, and at rapamycin concentrations well below immunosuppressive levels (e.g., abstract). Leung discloses that the antigen recognition subunit contains an N-terminal CD19-targeting scFv (clone FMC63) fused to the FK506-binding protein (FKPB12) and a CD4 transmembrane domain. The physically separated signaling subunit contains the FKBP-rapamycin binding (FRB*) domain from the human mTOR complex fused to the CD8α transmembrane domain, followed by the cytoplasmic signaling domains of 4-1BB and CD3ζ (e.g., paragraph 3rd, page 3; Fig. 1A). Wu et al. (Science, 2015, cited as reference 2 on IDS filed 11/20/2023) discloses a set of structurally well-defined heterodimerizing components: the FK506 binding protein (FKBP) domain and the T2089L mutant of FKBP-rapamycin binding domain (FRB*) that heterodimerize in the presence of the rapamycin analog AP21967, which has less immunosuppressive activity than does rapamycin (e.g., paragraph 1st, left column, page 5; Fig. 2).
Furthermore, the prior art does not appear to offset the deficiencies of the instant specification in that it does not describe functional variants of anti-CD19 antibody. Kugler et al. (Protein Engineering, Design & Selection, 2009) teaches that a single-chain Fv (scFv) fragment derived from the murine antibody 4G7, specific for human lymphocyte CD19, was engineered for stability and expression in Escherichia coli in view of future use as a therapeutic protein. Two orthogonal knowledge-based procedures. In one approach, we designed a mutant with 14 single amino-acid substitutions predicted to correct destabilizing residues in the 4G7-wt sequence to create 4G7-mut. In the second variant, the murine CDRs were grafted to the human acceptor framework huVk3-huVH3, with 11 additional point mutations introduced to obtain a better match between CDR graft and acceptor framework, to arrive at 4G7-graft. Compared to 4G7-wt, 4G7-mut showed greater thermodynamic stability in guanidinium chloride-induced equilibrium denaturation experiments and somewhat greater stability in human serum. The loop graft maintained the comparatively high stability of the murine loop donor, but did not improve it further (e.g., abstract). Kugler teaches comparison of the biophysical properties of an scFv derived from the murine monoclonal antibody 4G7 (4G7-wt) both to those of a variant in which a number of destabilizing features in the 4G7 framework have been repaired by point mutations (4G7-mut) and to those of a variant in which the CDRs of 4G7 have been grafted to the frameworks of the most stable human consensus domains, huVk3 and huVH3 (4G7-graft) (e.g., paragraph 2nd, right column, page 145).
Given the very large genus of sequences encompassed by
the rejected claims, and given the limited description provided
by the prior art and specifications regarding their common sequence motifs/structures, the skilled artisan would not have been able to envision a sufficient number of specific embodiments that meet the functional limitations of the claims: functional variants of FKBP- rapamycin complex binding domain (FRB domain); functional variants of FK506 binding protein domain (FKBP); and to describe the broadly claimed genus of anti-CD19 sequences with 80% or 91% identity with SEQ ID NOS: 51 and 63 respectively.
Therefore, the skilled artisan would have reasonably concluded applicants were not in possession of the claimed invention for claims 6, 11, 13, 20, 66 and 68.
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.
Claim 21 is 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 21 recites sequence identity in relation to SEQ ID NOs: 49, 75, 87. However, SEQ ID NOs 49, 75, 87 are disclosed in the specification as amino acid sequence, while the claim refers to the “vector genome”. Calculating the percentage of sequence identity directly between a polynucleotide sequence and an amino acid sequence is impossible. Therefore, it is not possible to determine the scope and metes and bounds of claim 21.
Claim Rejections - 35 USC § 102
In the event the determination of the status of the application as subject to AIA 35 U.S.C. 102 and 103 (or as subject to pre-AIA 35 U.S.C. 102 and 103) is incorrect, any correction of the statutory basis (i.e., changing from AIA to pre-AIA ) for the rejection will not be considered a new ground of rejection if the prior art relied upon, and the rationale supporting the rejection, would be the same under either status.
The following is a quotation of 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.
Claims 1-5, 7-8, 14-15 are rejected under 35 U.S.C. 102(a)(1) as being anticipated by Scharenberg et al. (“Scharenberg”, US 2022/0017920 A1, cited as reference 27 on IDS filed 09/18/2025; with priority date Nov. 21, 2018, Provisional application 62/770,421 [‘421]).
Regarding claim 1-3 Scharenberg teaches intravenous or intratumoral injection of a lentiviral particle adapted for transduction and expansion of tumor-infiltrating lymphocytes in vivo (e.g., abstract; 421 at paragraphs [0002], [0037]). Scharenberg teaches the lentiviral particle comprises a targeting agent or the nucleic acid vector encodes a targeting agent. Exemplary targeting agents include antibodies and chimeric antigen receptors ("CAR"). The CAR used in the present disclosure in some embodiments comprises a binding domain which is specific for B-cells, e.g., specific for a CD-marker that can be found on B-cell lymphoma such as CD19 (e.g., paragraph [0093]); ‘421 at paragraph [0088]).
Regarding claim 4, Scharenberg teaches surface-engineered lentiviral particles that can be generated using multicistronic vectors designed to express a plurality of polypeptides, namely a fusion glycoprotein or functional variant thereof and one or more non-viral proteins capable of viral surface display (e.g., paragraph [0006]); 421 at paragraph [0005]) (It reads on multipartite cell-surface receptor).
Regarding claim 5, Scharenberg teaches that resistance to rapamycin may be conferred by a polynucleotide sequence encoding the protein domain FRB, found in the m TOR domain and known to be the target of the FKBP-rapamycin complex (e.g., paragraph [0075]); 421 at paragraph [0072]). Scharenberg teaches the lentiviral particle facilitates selective expansion of target cells by conferring resistance to an immunosuppressive drug to transduced cells. A lentiviral vector system that comprises any of the nucleic sequences that confer resistance to an immunosuppressive drug known in the art. Examples of immunosuppressive drugs include, without limitation, rapamycin (e.g., paragraph [0076]; ‘421 at paragraph [0072]) (It reads on FKBP-rapamycin complex is induced by rapamycin).
Regarding claim 7, Scharenberg teaches a transfer plasmid VT103, which contains a model payload comprising a 2A-linked open reading frame encoding two proteins that form a dimeric cytokine receptor, a third protein that confers partial resistance to the immunosuppressive agent rapamycin under the control of MND promoter (e.g., paragraph [0034]; Fig. 3B [see below]; ‘421 at paragraph [00123]) (It reads on multipartite a rapamycin-activated cell-surface receptor).
Fig. 3B: MND promoter-Receptor Component-Immunosuppression resistance-marker
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Regarding claim 8, Scharenberg teaches the lentiviral vector system
of the present disclosure further comprises a nucleic acid sequence (e.g., on the transfer plasmid) that provides resistance to an immunosuppressive drug (e.g., paragraph [0075]; 21 at paragraph [0071]).
Regarding claims 14-15, Scharenberg teaches the non-viral proteins
capable of viral surface display comprise one or more non-viral proteins selected from a transmembrane-domain fusion of a single chain variable fragment (scFv) specific for human CD3 (anti-CD3 scFv) (e.g., paragraph [0013]; ‘421 at paragraph [0012]). Scharenberg teaches envelop plasmids encoding CMV.VSVG (pMD2.8), CMV.Cocal, or MND.Cocal were generated. In each case the fusion glycoprotein (G protein) of the virus, either vesicular stomatitis Indiana virus (VSV) or Coca! virus, was placed under the control of a strong promoter, either the CMV promoter or the MND promoter (e.g., paragraph [0130]); ‘421 at paragraph 00123]).
Claim Rejections - 35 USC § 103
In the event the determination of the status of the application as subject to AIA 35 U.S.C. 102 and 103 (or as subject to pre-AIA 35 U.S.C. 102 and 103) is incorrect, any correction of the statutory basis (i.e., changing from AIA to pre-AIA ) for the rejection will not be considered a new ground of rejection if the prior art relied upon, and the rationale supporting the rejection, would be the same under either status.
The following is a quotation of 35 U.S.C. 103 which forms the basis for all obviousness rejections set forth in this Office action:
A patent for a claimed invention may not be obtained, notwithstanding that the claimed invention is not identically disclosed as set forth in section 102, if the differences between the claimed invention and the prior art are such that the claimed invention as a whole would have been obvious before the effective filing date of the claimed invention to a person having ordinary skill in the art to which the claimed invention pertains. Patentability shall not be negated by the manner in which the invention was made.
The factual inquiries for establishing a background for determining obviousness under 35 U.S.C. 103 are summarized as follows:
1. Determining the scope and contents of the prior art.
2. Ascertaining the differences between the prior art and the claims at issue.
3. Resolving the level of ordinary skill in the pertinent art.
4. Considering objective evidence present in the application indicating obviousness or nonobviousness.
Claims 6, 10-11, 13, 20 and 66 are rejected under 35 U.S.C. 103 as being unpatentable over Scharenberg et al. (“Scharenberg”, US 2022/0017920 A1, cited as reference 27 on IDS filed 09/18/2025; with priority date Nov. 21, 2018, Provisional application 62/770,421 [‘421]) as applied to claims 1-5, 7-8, 14-15 above, and further in view of Brogdon et al. (“Brogdon”, WO 2015/090229 A1).
The teachings of Scharenberg et al. are described above and applied as before.
Scharenberg teaches a protein that confers partial resistance to the immunosuppressive agent rapamycin under the control of MND promoter (e.g., paragraph [0034]; Fig. 3B [see above]).
Scharenberg does not teach the vector genome comprises a polynucleotide sequence encoding a multipartite cell-surface receptor comprising a FKBP- rapamycin complex binding domain (FRB domain) or a functional variant thereof; and the polynucleotide comprises a polynucleotide sequence encoding a FK506 binding protein domain (FKBP), as required by the instant claims. Scharenberg does not teach the 5' to 3' order on a polycistronic transcript: the polynucleotide sequence encoding the multipartite cell- surface receptor and the polynucleotide sequence encoding the anti-CD19 chimeric antigen receptor, as required by the instant claim. Scharenberg does not teach the vector genome comprises, in 5' to 3' order on a polycistronic transcript: the polynucleotide sequence encoding the anti-CD19 chimeric antigen receptor and the polynucleotide sequence encoding the multipartite cell-surface receptor, as required by the instant claims. However, this is cured by Brogdon.
Regarding claim 6, Brogdon teaches compositions and methods relating to regulatable chimeric antigen receptors (RCARs), where the intracellular signaling or proliferation of the RCAR can be controlled to optimize the use of an RCAR-expressing cell to provide an immune response, are provided. RCAR can comprise a dimerization switch that, upon the presence of a dimerization molecule, can couple an intracellular signaling domain to an extracellular recognition element, e.g., an antigen binding domain, an inhibitory counter ligand binding domain, or costimulatory ECD domain (e.g., abstract). Brogdon teaches the FKBP-FRB based switch comprises a switch domain comprising a FRB binding fragment or analog of FKBP and a switch domain comprising an FKBP binding fragment or analog of FRB, and the FKBP binding fragment or analog of FRB comprises one or more mutations which enhances the formation of a complex between an FKBP switch domain, an FRB switch domain, and the dimerization molecule (e.g., line 10, page 23; Fig. 5 [see below]).
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Regarding claim 10, Brogdon teaches unless otherwise indicated, when members or elements of an RCAR are described herein, the order can be as provided, but other orders are included as well. In other words, in an embodiment, the order is as set out in the text, but in other embodiments, the order can be different (e.g., line 15, page 2). Brogdon teaches a vector system comprising one or more vectors, comprising nucleic acid encoding a RCAR described herein. In an embodiment, all of the elements of a RCAR are encoded on a single vector (e.g., line 21, page 86) (it reads on a vector genome can comprises in 5’ to 3’ order the multipartite surface receptor and anti-CD19 or anti-CD19 and multipartite surface receptor, as required by the claims).
Regarding claim 11, Brogdon teaches the arrangement of RCAR elements on a single nucleic acid vector (from 5’ to 3’ anti-CD19-and the multipartite receptor) (e.g., lines [3]-[11]; Fig. 22 and 23).
Regarding claim 13, Brogdon teaches the use of an inducible
promoter provides a molecular switch capable of turning on expression of the polynucleotide sequence which is operatively linked when such expression is desired, or turning off the expression when expression is not desired. Examples of inducible promoters include, but are not limited to a metallothionine promoter, a glucocorticoid promoter, a progesterone promoter, and a tetracycline promoter. Sequence encoding various elements of an RCAR can be disposed on the same nucleic acid molecule, e.g., the same plasmid or vector, e.g., viral vector, e.g., lentiviral vector. E.g., both (i) sequence encoding an antigen binding member and (ii) sequence encoding an intracellular signaling member, can be present on the same nucleic acid, e.g., vector. Production of the corresponding proteins can be achieved, e.g., using separate promoters, or by the use of a bicistronic transcription product (e.g., lines [13]-[25]).
Regarding claim 66, Brogdon teaches the FKBP-FRB based switch comprises a switch domain comprising a FRB binding fragment or analog of FKBP and a switch domain comprising an FKBP binding fragment or analog of FRB, and the FKBP binding fragment or analog of FRB comprises one or more mutations which enhances the formation of a complex between an FKBP switch domain, an FRB switch domain, and the dimerization molecule (e.g., line 10, page 23; Fig. 5). Brogdon teaches the arrangement of RCAR elements on a single nucleic acid vector (from 5’ to 3’ anti-CD19-and the multipartite receptor) (e.g., lines [3]-[11]; Fig. 22 and 23). Brogdon teaches unless otherwise indicated, when members or elements of an RCAR are described herein, the order can be as provided, but other orders are included as well. In other words, in an embodiment, the order is as set out in the text, but in other embodiments, the order can be different (e.g., line 15, page 2).
It would have been obvious to one of ordinary skill in the art before the effective filing date of the claimed invention to incorporate the FKBP binding protein domain taught by Brogdon into the a lentiviral particle adapted for transduction and expansion of tumor-infiltrating lymphocytes in vivo, comprising a polynucleotide encoding a chimeric antigen receptors against CD19 and a sequence encoding the protein domain FRB taught by Scharenberg, because both references taught of conferring resistance to rapamycin by transduced immune cells, a person of ordinary skill in the art would have reasonable expectation of success in utilizing Brogdon’s FKBP binding protein domain in Scharenberg’ lentivirus particle for targeting CD19.
One would have been motivated to make such a modification in order to receive the expected benefit of develop a lentivirus particle carrying a vector encoding an-CD19 antibody, a FKBP binding domain and a FRB domain that can dimerize in presence of rapamycin coupling an intracellular signaling domain to an extracellular recognition element, e.g., an antigen binding domain as taught by Brogdon.
Claim 18 is rejected under 35 U.S.C. 103 as being unpatentable over Scharenberg et al. (“Scharenberg”, US 2022/0017920 A1, cited as reference 27 on IDS filed 09/18/2025; with priority date Nov. 21, 2018, Provisional application 62/770,421 [‘421]) as applied to claims 1-5, 7-8, 14-15 above, and further in view of Maus et al. (“Maus”, WO2018132508 A1).
The teachings of Scharenberg et al. are described above and applied as before.
Scharenberg does not teach that the viral envelope comprises an anti-CD3 single-chain variable fragment sequence that shares at least 80% identity to SEQ ID NO 12. However, this is cured by Maus.
Maus teaches the T cell target molecule expressed on the surface of an aAPC includes but is not limited to CD19. Any T cell target molecule expressed on the aAPC can be targeted by a chimeric antigen receptor CAR (e.g., line 14, page 27). Maus teaches SQ ID NO 27 that has 98.4% similarity to SEQ ID NO 12 of the instant claim.
It would have been obvious to one of ordinary skill in the art before the effective filing date of the claimed invention to substitute the specific anti-CD3 scvf sequence taught by Maus into the lentivirus envelop taught by Scharenberg, because both references taught of targeting immune cells using anti-CD3 scvf antibodies, a person of ordinary skill in the art would have reasonable expectation of success in utilizing Maus’ anti-CD3 (SEQ ID NO 27) in Scharenberg’ lentivirus envelop.
One would have been motivated to make such a modification in order to receive the expected benefit of optimizing targeting T cell expressing CD3.
Claim 19 is rejected under 35 U.S.C. 103 as being unpatentable over Scharenberg et al. (“Scharenberg”, US 2022/0017920 A1; with priority date Nov. 21, 2018, Provisional application 62/770,421 [‘421]) as applied to claims 1-5, 7-8, 14-15 above, and further in view of Charneau et al. (“Charneau”, US 8,420,104 B2).
The teachings of Scharenberg et al. are described above and applied as before.
Scharenberg does not teach the viral envelope comprises a Cocal glycoprotein sequence that shares at least 80% identity to SEQ ID NO 5. However, this is cured by Charneau.
Charneau teaches the design of gene transfer vectors and especially provides lentiviral gene transfer vectors suitable for either a unique administration or, for iterative administration in a host, and to their medicinal application. These vectors may be used to elicit an immune response to prevent or to treat a pathogenic state, including
cancers (e.g., abstract). Charneau teaches SEQ ID NO 16 that has 100% similarity to SEQ ID NO 5 of the instant claim.
It would have been obvious to one of ordinary skill in the art before the effective filing date of the claimed invention to incorporate the specific Cocal sequence taught by Charneau (SEQ ID NO 16) into the viral envelop taught by Scharenberg, because both Scharenberg and Charneau teach lentiviral delivery systems utilizing Cocal envelop protein, a person of ordinary skill in the art would have had a reasonable expectation of success in utilizing Charneau’s Cocal sequence (SEQ ID NO 16) in Scharenberg’s lentivirus.
One would have been motivated to make such a modification in order to receive the expected benefit of developing vectors suitable for either a unique administration or, for iterative administration in a host, and to their medicinal application as taught by Charneau.
Claim 21 is rejected under 35 U.S.C. 103 as being unpatentable over Scharenberg et al. (“Scharenberg”, US 2022/0017920 A1, cited as reference 27 on IDS filed 09/18/2025; with priority date Nov. 21, 2018, Provisional application 62/770,421 [‘421]) as applied to claims 1-5, 7-8, 14-15 above, and further in view of Schneider et al. (“Schneider”, WO 2020/181164 A1).
The teachings of Scharenberg et al. are described above and applied as before.
Scharenberg does not teach the vector genome shares at least 80% identity to SEQ ID NO 87. However, this is cured by Schneider.
Schneider teaches methods of treating or preventing cancer in a subject, and methods of making self-driving surface antigen-regulated promoter-therapeutic payload constructs in T-cells are also disclosed (e.g., abstract). Schneider teaches CAR-based surface antigen-regulated inducible promoter-therapeutic payload is provided wherein the encoded extracellular antigen binding domain comprises at least one single chain variable fragment of an antibody that binds to CD19 (e.g., paragraph 1st, page 7). Schneider teaches CAR LTG1563 with a dominant negative version of inhibitory TGF-beta receptor comprising the amino acid sequence as set forth in SEQ ID NO: 104 (e.g., paragraph 1st, page 58). Schneider teaches SEQ ID NO 104 that has 88.3% similarity with SEQ ID NO 87 of the instant claim.
It would have been obvious to one of ordinary skill in the art before the effective filing date of the claimed invention to modify the teachings of Scharenberg to incorporate the vector genome construct taught by Schneider (comprising SEQ ID NO 104) into the viral particle delivery system of Scharenberg, because Scharenberg and Schneider apply to engineered vector constructs for targeting CD19 in cancer therapy, a person of ordinary skill in the art would have had a reasonable expectation of success in packaging Schneider’s vector genome (SEQ ID NO 104) within Scharenberg lentivirus.
One would have been motivated to make such a modification in order to receive the expected benefit of developing a construct comprising additional auxiliary components comprising dominant negative receptors lacking the intracellular signaling domains of either TGFBRII as taught by Schneider.
Claim 67 is rejected under 35 U.S.C. 103 as being unpatentable over Scharenberg et al. (“Scharenberg”, US 2022/0017920 A1, cited as reference 27 on IDS filed 09/18/2025; with priority date Nov. 21, 2018, Provisional application 62/770,421 [‘421]) as applied to claims 1-5, 7-8, 14-15 above, and further in view of Wong et al. (“Wong”, US 2019/0144550 A1).
The teachings of Scharenberg et al. are described above and applied as before.
Scharenberg does not teach a 41BB sequence at least 95% identity to SEQ ID NO 65. However, this is cured by Wong.
Wong teaches that the intracellular signaling domain of a CAR according to the invention is responsible for intracellular signaling following the binding of extracellular ligand binding domain to the target resulting in the activation of the immune cell and immune response. The intracellular signaling domain has the ability to activate of at least one of the normal effector functions of the immune cell in which the CAR is expressed (e.g., paragraph 0112). Wong teaches the intracellular signaling domain of a CAR of the invention comprises a part of co-stimulatory molecule selected from the group consisting of a fragment of 41BB (e.g., paragraph 0114). Wong teaches SEQ ID NO 204 (amino acid sequence) that has 100% similarity to the amino acid sequence of the translated SEQ ID NO 65 of the instant claim.
Alignment of SEQ ID NO 65 (translation) vs SQ ID NO 204:
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It would have been obvious to one of ordinary skill in the art before the effective filing date of the claimed invention to substitute the 41BB sequence taught by Scharenberg with the 41BB (SEQ ID NO 204) taught by Wong, because the genetic code’s degeneracy and codon optimization techniques are routine and predictable in molecular biology, a person of ordinary skill in the art would have had a reasonable expectation of success in generating nucleotide variants of at least 95% sequence identity to SEQ ID NO 65, while maintaining 100% translation identity to 41BB intracellular domain.
One would have been motivated to make such a modification in order to receive the expected benefit of utilizing the 41BB sequence as an intracellular signaling domain of a CAR, responsible for intracellular signaling following the binding of extracellular ligand binding domain to the target resulting in the activation of the immune cell and immune response as taught by Wong.
Claim 68 is rejected under 35 U.S.C. 103 as being unpatentable over Scharenberg et al. (“Scharenberg”, US 2022/0017920 A1, cited as reference 27 on IDS filed 09/18/2025; with priority date Nov. 21, 2018, Provisional application 62/770,421 [‘421]) as applied to claims 1-5, 7-8, 14-15 above, and further in view of Brudno et al. (“Brudno”, Nat. Med., 2020).
The teachings of Scharenberg et al. are described above and applied as before.
Scharenberg does not teach an anti-CD19 scvf sequence with at least 91% identical to SEQ ID NO 63. However, this is cured by Brudno.
Brudno discloses results from the first-in-humans trial of Hu19-CD828Z T cells. Compared results with Hu19-CD828Z-expressing T cells and results from a previous clinical trial that tested T cells expressing an anti-CD19 CAR designated FMC63–28Z (e.g., paragraph 2nd, page 3). Brudno teaches FMC63-CD828Z (GenBank accession number MN702884) (e.g., paragraph 2nd, page 21). The FMC63-CD828Z amino acid sequence has 100% similarity to the translated protein encoded by SEQ ID NO 63 of the instant claim (see below). While the native nucleotide sequence of Brudnos’s FMC63-CD828Z shares 82% sequence similarity with SEQ ID NO 63, it encodes the identical anti-CD19 scFv amino acid sequence.
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It would have been obvious to one of ordinary skill in the art before the effective filing date of the claimed invention to substitute the anti-CD19 scFv sequence taught by Scharenberg with the anti-CD19 (FMC63-CD828Z) taught by Brudno, because the genetic code’s degeneracy and codon optimization techniques are routine and predictable in molecular biology, a person of ordinary skill in the art would have had a reasonable expectation of success in generating nucleotide variants at least 91% sequence identity to SEQ ID NO 63, while maintaining 100% translation identity to the target protein.
One would have been motivated to make such a modification in order to receive the expected benefit of utilizing the validated FMC63-derived anti-CD19 scFv amino acid sequence taught by Brudno due to its efficacy in clinical trials.
Conclusion
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/JULIO WASHINGTON GOMEZ RODRIGUEZ/Examiner, Art Unit 1637
/Jennifer Dunston/Supervisory Patent Examiner, Art Unit 1637
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