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 .
Claims Status
Claim(s) 3-4,6,11,14,19,25,27,41,63,66,68-69,99,105,107,153,156-157 and 169 is/are currently pending and presented for examination on the merits.
Specification
The use of trade name(s) or mark(s) used in commerce (e.g., Thermo Fisher, Gibco, BioLegend, Cell Signaling, IncuCyte), has been noted in this application. The term should be accompanied by the generic terminology; furthermore the term should be capitalized wherever it appears or, where appropriate, include a proper symbol indicating use in commerce such as ™, SM , or ® following the term.
Although the use of trade names and marks used in commerce (i.e., trademarks, service marks, certification marks, and collective marks) are permissible in patent applications, the proprietary nature of the marks should be respected and every effort made to prevent their use in any manner which might adversely affect their validity as commercial marks.
Claim Interpretation
Claim 3 recites “a method of preparing a population of immune cells…”, but the specification does not define what “preparing” means. The phrase “preparing a population of immune cells” is interpreted as “expanding a population of immune cells” for the purposes of examination.
Claim Rejections - 35 USC § 112(a)
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 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.
Claim(s) 99 is/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.
Claimed Invention
Claim(s) 99, are drawn to a method of preparing a chimeric polypeptide comprising a ROR1-binding protein comprising at least 60% amino acid sequence of SEQ ID NO:86. Instant SEQ ID NO:86 is the amino acid sequence of a chimeric antigen receptor (CAR) that binds ROR1 (§0499; table 14).
Breadth of Claims
The invention as disclosed in claim(s) 99 recite(s) “…the chimeric polypeptide comprises an amino acid sequence having at least about 60% sequence identity to the amino acid sequence as set forth in SEQ ID NO: 86.”. The claim(s) encompass a genus of heavy and/or light chain variable regions comprising variability (e.g., 60% identical) in both the heavy and/or light chain variable regions which are claimed as having the function of specifically binding to ROR1. This means that the variability in sequence identity can also occur in the CDRs, the domains that are critical for the antibody binding to its target, which one of ordinary skill in the art would understand to result in unpredictable binding characteristics with no reasonable expectation of maintaining ROR1 antigen binding. Additionally, the instant disclosure does not provide an adequate number of species of the claimed genus nor does the disclosure provide a structure-function correlation that would allow for a person of ordinary skill in the art to envision what variation can occur to the light and heavy chains, particularly in the CDR regions, such that the obtained structure would result in the claimed functions.
Scope of Disclosed Species
The anti-ROR1 CARs in the Applicant disclosure Table 14 with 100% sequence identity in the CDR regions of the heavy and light chain variable regions represents the anti-CD30 CAR that the applicant was in possession of at the time of filing. It is noted that there would be support for 100% identity of the full complement of the six CDRs together with some percentages of identity in the framework region that would have been predictable.
State of the Prior Art
At the time of filing, WO 2015/066551 A2 (hereinafter “WO551”) taught anti-ROR1 CARs were recognized in the art as a cancer therapy [e.g., paras 0002-0006, 32, 0075]. WO551 further taught various separate species of ROR1-directed CARs as cancer therapies, and cites three known anti-ROR1 scFvs (with different CDRs) called R12, R11, and 2A2 and further species “a number of additional antibodies specific for ROR1 are known to those of skill in the art” [e.g., paras 0032, 0075, 0077, 0089-0090]. Therefore, the prior art demonstrates that the binding of ROR1 is possible by various ROR1-directed CARs with different patient outcomes. The prior art does not teach a known structure activity relationship for HCDR1-3 and LCDR1-3 in a ROR1-directed CAR that would allow prediction of CDR residues that specifically bind to ROR1.
Further, at the time of filing, antibody and CAR functionality were known to depend on the entire structure, particularly a full complement of six CDRs. It is understood by one of ordinary skill in the art that that mutation to CDRs is unpredictable and that each construct requires function testing.
Sela-Culang, Kunik, and Ofran (Fron. Immuno., Vol. 4, Article 302, Oct. 2013), hereinafter “Sela-Culang”, reviews the structural basis of antibody-antigen recognition in the state of the art. Naturally occurring antibodies have six hypervariable loops are commonly termed complementary determining regions (CDRs) and are widely assumed to be responsible for antigen recognition [e.g., pg. 1, abstract; pg. 3, “The Role of CDRs and their Definition”]. A person of ordinary skill in the art would understand that although the above basics of antibody-antigen binding are known, that the specifics of antibody structure (e.g., within the CDRs) that underlie the antigen recognition are not well characterized [e.g., pg. 1, “The Motivations for…”].
Further, Herold et al. (Nature Scientific Reports, 7:12276, 25 Sep 2017), hereinafter “Herold”, teaches that it should be emphasized that there is no correlation between experimentally determined change in antibody binding affinity and a given mutation and additionally that no such correlation is expected because antigen binding is “affected by each CDR loop differently” and changes thereto “can in principle affect antigen binding affinity in an unpredictable way” [e.g., pg. 14, paragraph 2]. Further, Herold asserts that multiple determinants regulate antigen affinity and the interactions with CDRs are complex [e.g., pg. 14, paragraph 3].
Thus, making changes to the CDR sequence of a CAR T sequence is a highly unpredictable process and one skilled in the art could not a priori make any predications regarding such mutations with any reasonable expectation of success nor envisage the breadth of structurally unrelated CDR combinations that would still possess the required function(s).
Conclusion
As indicated by the art, a full complement of 6 CDRs are required for antigen binding and one cannot predict which CDR residues may be changed and still result in a CAR that binds ROR1. Written description can be met if the claims recite the minimal structure that is needed to perform the function recited in the claims. Above, the art indicates that the 6 CDRs in a CAR antigen-binding domain are the minimal structure that binds to a target antigen. Specifically, Applicant claim(s) 99 would need to recite the 6 CDRs in the CAR that bind ROR1, without variability in the sequences thereof.
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.
This application currently names joint inventors. In considering patentability of the claims the examiner presumes that the subject matter of the various claims was commonly owned as of the effective filing date of the claimed invention(s) absent any evidence to the contrary. Applicant is advised of the obligation under 37 CFR 1.56 to point out the inventor and effective filing dates of each claim that was not commonly owned as of the effective filing date of the later invention in order for the examiner to consider the applicability of 35 U.S.C. 102(b)(2)(C) for any potential 35 U.S.C. 102(a)(2) prior art against the later invention.
Claim(s) 3-4, 6, 11, 14, 19, 25, 27, 63, 105, 107, 153, 156, and 157 is/are rejected under 35 U.S.C. 103 as being unpatentable over WO 2019/118902 A2 (hereinafter “WO902”), in view of Vodnala et al. (Science 363, 1417 (2019) 29 March 2019; hereinafter “Vodnala”).
Regarding instant claims 3-4, 6, 14, 25, 105, 107, 153, WO902 teaches T cell compositions and methods for inhibiting T cell exhaustion [e.g., title, abstract]. WO902 further teaches engineering CAR T cells to overexpress an AP-1 factor (e.g., c-Jun) enhanced expansion (e.g., preparing) potential, diminished terminal differentiation (e.g., increased stemness; different phenotypic immune cell marker expression), increased functional capacity, and improved antitumor activity (e.g., improved function) [e.g., pg. 3, lines 7-9]. WO902 further teaches c-Jun expression is overexpressed/increased in engineered immune cells [e.g., fig 22C; pg. 4, lines 4-14, 23-33; pg. 17 lines 8-11; pg. 34, lines 14-33; pg. 35, lines 29-32; examples 11, 14]. WO902 teaches the engineered T cells co-express c-Jun and a ROR-1 binding CAR [e.g., claims 6, 17, 37; pg. 5, lines 13-23; pg. 48, lines 18-27]. WO902 teaches the CAR T cells are maintained in CD3/CD28 Dynabeads (e.g., CD3/CD28 agonist) and AIMV media [e.g., pg. 63, “CAR T cell production”], but the potassium concentration of the media is proprietary.
Regarding instant claim 11, WO902 further teaches the increased c-Jun CAR T cells display increased functionality and/or activity including enhanced killing capacity [e.g., pg. 7, lines, 8-14].
Regarding instant claim 19, WO902 further teaches immune cells have been modified with an exogenous polynucleotide encoding the ROR-1 binding CAR and the c-Jun polypeptide [e.g., pg. 4, lines 5-15].
Regarding instant claims 27, 63, WO902 further teaches the CAR comprises an scFv and a transmembrane domain [e.g., pg. 5, lines 24-33].
Regarding instant claims 156-157, WO902 further teaches a pharmaceutical composition comprising the c-Jun+/anti-ROR-1 CAR T cells and a pharmaceutically acceptable carrier [e.g., pg. 23, lines 5-16; pg. 43, lines 20-29; pg. 61, lines 1-11]. WO902 further teaches a method of treating a tumor comprising administration of the CAR T cell composition to a cancer subject (e.g., a subject in need thereof) [e.g., pg. 8, lines 29-33; pg. 10, lines 15-20; “Methods of Treatment”].
WO902 does not expressly teach (1) the c-Jun+/anti-ROR-1 CAR T cells are cultured in media comprising greater than 5 mM of potassium; (2) a population of immune cells prepared by the method (e.g., the c-Jun+/anti-ROR-1 CAR T cells cultured in media comprising greater than 5 mM of potassium), (a) a pharmaceutical composition thereof, (b) a method of treating a tumor in a subject in need thereof, comprising administering the population of immune cells; or (3) c-Jun+/anti-ROR-1 CAR T cells cultured in media comprising greater than 5 mM of potassium (a) display enhanced target cell killing ability, (b) alter phenotypic T cell markers, (c) wherein the immune cells have been modified with an exogenous polynucleotide encoding the ROR-1 binding CAR and the c-Jun polypeptides, (d) wherein the CAR comprises a transmembrane domain, (e) wherein the ROR-1 binding domain comprises an scFv, or (f) the media further comprises a CD3/CD28 agonist.
Vodnala teaches that 45 mM elevated (in relation to 5 mM) potassium concentration in the growth medium preserves epigenetic stemness and increases anti-tumor function of T cells [e.g., figs 3-4; pgs. 6, 11].
It would have been prima facie obvious to a person having ordinary skill in the art (PHOSITA) before the effective filing date of the claimed invention to substitute the unspecified potassium concentration of the AIMV media for culturing c-Jun+/anti-ROR-1 CAR T cells as taught by WO902, with the 45 mM potassium concentration for T cell culture media as taught by Vodnala, in the context of designing and developing a method for CAR T cell culturing for adoptive cell therapies. A PHOSITA would have been motivated to substitute the unspecified potassium concentration of the AIMV media for culturing c-Jun+/anti-ROR-1 CAR T cells as taught by WO902, with the 45 mM potassium concentration for T cell culture media as taught by Vodnala, because Vodnala teaches the 45 mM potassium ion concentration preserves stemness and increases anti-tumor function. WO902 and Vodnala necessarily disclose the population of immune cells prepared by the method by teaching the instant claimed method. There would have been a reasonable expectation of success for a PHOSITA to substitute the unspecified potassium concentration of the AIMV media for culturing c-Jun+/anti-ROR-1 CAR T cells as taught by WO902, with the 45 mM potassium concentration for T cell culture media as taught by Vodnala, because Vodnala teaches the 45 mM potassium ion concentration preserves stemness and increases anti-tumor function. This rationale aligns with the principle of simple substitution of one known element for another to obtain predictable results, supporting a conclusion of obviousness (see MPEP § 2141).
Further, it would have been obvious to a PHOSITA to modify the modified method of preparing c-Jun+/anti-ROR-1 CAR T cells cultured in 45 mM potassium ion as taught by WO902 and Vodnala (see above) to include that the c-Jun+/anti-ROR-1 CAR T cells cultured in media comprising greater than 5 mM of potassium (a) display enhanced target cell killing ability, (b) alter phenotypic T cell markers, (c) wherein the immune cells have been modified with an exogenous polynucleotide encoding the ROR-1 binding CAR and the c-Jun polypeptides, (d) wherein the CAR comprises a transmembrane domain, (e) wherein the ROR-1 binding domain comprises an scFv, or (f) the media further comprises a CD3/CD28 agonist as taught by WO902, because WO902 teaches the c-Jun+/anti-ROR-1 CAR T cells, Vodnala teaches the potassium concentration for the culture media (for benefits, see above), and WO902 further teaches additional modified methods applicable to c-Jun+/anti-ROR-1 CAR T cells and/or uses thereof. There is an expectation of success for a PHOPSITA to modify method of preparing c-Jun+/anti-ROR-1 CAR T cells cultured in 45 mM potassium ion as taught by WO902 and Vodnala (see above) to include that the c-Jun+/anti-ROR-1 CAR T cells cultured in media comprising greater than 5 mM of potassium (a) display enhanced target cell killing ability, (b) alter phenotypic T cell markers, (c) wherein the immune cells have been modified with an exogenous polynucleotide encoding the ROR-1 binding CAR and the c-Jun polypeptides, (d) wherein the CAR comprises a transmembrane domain, (e) wherein the ROR-1 binding domain comprises an scFv, or (f) the media further comprises a CD3/CD28 agonist as taught by WO902, because WO902 teaches the c-Jun+/anti-ROR-1 CAR T cells, Vodnala teaches the potassium concentration for the culture media (for benefits, see above), and WO902 further teaches additional modified methods applicable to c-Jun+/anti-ROR-1 CAR T cells and/or uses thereof. This rationale aligns with the principle of simple substitution of one known element for another to obtain predictable results, supporting a conclusion of obviousness (see MPEP § 2141).
Thus, the invention as a whole is prima facie obvious over the references, especially in the absence of evidence to the contrary.
Claim(s) 41 is/are rejected under 35 U.S.C. 103 as being unpatentable over WO 2019/118902 A2 (hereinafter “WO902”), in view of Vodnala et al. (Science 363, 1417 (2019) 29 March 2019; hereinafter “Vodnala”) as applied to claim 3 above, and further in view of WO 2020/132226 A1 (hereinafter “WO226”).
The teachings of WO902 as recited above apply for claim 3.
WO902 further teaches an exogenous polynucleotide encoding the c-Jun polypeptide [e.g., pg. 4, lines 5-15].
WO902 does not expressly teach the c-Jun encoding polynucleotide comprises the sequence of instant SEQ ID NO: 12.
Regarding instant claim 41, WO226 teaches compositions and methods for reprogramming diseased cells, and that the composition comprises a polynucleotide comprising one or more transcription factors [e.g., title, abstract]. WO226 further teaches c-Jun (also known as Jun, ) is part of the AP1 complex responsible for cell proliferation, differentiation and apoptosis and teaches the Human Jun proto-oncogene/AP-1 transcription factor gene having a nucleotide of SEQ 216 [e.g., table 1D, paras 0284-285], which is the same as the instant claimed c-Jun nucleotide of instant SEQ ID NO: 12 (see alignment below).
Alignment of instant c-Jun nucleotide SEQ ID NO: 12 with WO226 c-Jun nucleotide of SEQ ID NO: 216:
Query Match 100.0%; Score 3257; Length 3257;
Best Local Similarity 100.0%;
Matches 3257; Conservative 0; Mismatches 0; Indels 0; Gaps 0;
Qy 1 GCTCAGAGTTGCACTGAGTGTGGCTGAAGCAGCGAGGCGGGAGTGGAGGTGCGCGGAGTC 60
||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
Db 1 GCTCAGAGTTGCACTGAGTGTGGCTGAAGCAGCGAGGCGGGAGTGGAGGTGCGCGGAGTC 60
Qy 61 AGGCAGACAGACAGACACAGCCAGCCAGCCAGGTCGGCAGTATAGTCCGAACTGCAAATC 120
||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
Db 61 AGGCAGACAGACAGACACAGCCAGCCAGCCAGGTCGGCAGTATAGTCCGAACTGCAAATC 120
Qy 121 TTATTTTCTTTTCACCTTCTCTCTAACTGCCCAGAGCTAGCGCCTGTGGCTCCCGGGCTG 180
||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
Db 121 TTATTTTCTTTTCACCTTCTCTCTAACTGCCCAGAGCTAGCGCCTGTGGCTCCCGGGCTG 180
Qy 181 GTGTTTCGGGAGTGTCCAGAGAGCCTGGTCTCCAGCCGCCCCCGGGAGGAGAGCCCTGCT 240
||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
Db 181 GTGTTTCGGGAGTGTCCAGAGAGCCTGGTCTCCAGCCGCCCCCGGGAGGAGAGCCCTGCT 240
Qy 241 GCCCAGGCGCTGTTGACAGCGGCGGAAAGCAGCGGTACCCACGCGCCCGCCGGGGGAAGT 300
||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
Db 241 GCCCAGGCGCTGTTGACAGCGGCGGAAAGCAGCGGTACCCACGCGCCCGCCGGGGGAAGT 300
Qy 301 CGGCGAGCGGCTGCAGCAGCAAAGAACTTTCCCGGCTGGGAGGACCGGAGACAAGTGGCA 360
||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
Db 301 CGGCGAGCGGCTGCAGCAGCAAAGAACTTTCCCGGCTGGGAGGACCGGAGACAAGTGGCA 360
Qy 361 GAGTCCCGGAGCCAACTTTTGCAAGCCTTTCCTGCGTCTTAGGCTTCTCCACGGCGGTAA 420
||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
Db 361 GAGTCCCGGAGCCAACTTTTGCAAGCCTTTCCTGCGTCTTAGGCTTCTCCACGGCGGTAA 420
Qy 421 AGACCAGAAGGCGGCGGAGAGCCACGCAAGAGAAGAAGGACGTGCGCTCAGCTTCGCTCG 480
||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
Db 421 AGACCAGAAGGCGGCGGAGAGCCACGCAAGAGAAGAAGGACGTGCGCTCAGCTTCGCTCG 480
Qy 481 CACCGGTTGTTGAACTTGGGCGAGCGCGAGCCGCGGCTGCCGGGCGCCCCCTCCCCCTAG 540
||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
Db 481 CACCGGTTGTTGAACTTGGGCGAGCGCGAGCCGCGGCTGCCGGGCGCCCCCTCCCCCTAG 540
Qy 541 CAGCGGAGGAGGGGACAAGTCGTCGGAGTCCGGGCGGCCAAGACCCGCCGCCGGCCGGCC 600
||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
Db 541 CAGCGGAGGAGGGGACAAGTCGTCGGAGTCCGGGCGGCCAAGACCCGCCGCCGGCCGGCC 600
Qy 601 ACTGCAGGGTCCGCACTGATCCGCTCCGCGGGGAGAGCCGCTGCTCTGGGAAGTGAGTTC 660
||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
Db 601 ACTGCAGGGTCCGCACTGATCCGCTCCGCGGGGAGAGCCGCTGCTCTGGGAAGTGAGTTC 660
Qy 661 GCCTGCGGACTCCGAGGAACCGCTGCGCACGAAGAGCGCTCAGTGAGTGACCGCGACTTT 720
||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
Db 661 GCCTGCGGACTCCGAGGAACCGCTGCGCACGAAGAGCGCTCAGTGAGTGACCGCGACTTT 720
Qy 721 TCAAAGCCGGGTAGCGCGCGCGAGTCGACAAGTAAGAGTGCGGGAGGCATCTTAATTAAC 780
||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
Db 721 TCAAAGCCGGGTAGCGCGCGCGAGTCGACAAGTAAGAGTGCGGGAGGCATCTTAATTAAC 780
Qy 781 CCTGCGCTCCCTGGAGCGAGCTGGTGAGGAGGGCGCAGCGGGGACGACAGCCAGCGGGTG 840
||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
Db 781 CCTGCGCTCCCTGGAGCGAGCTGGTGAGGAGGGCGCAGCGGGGACGACAGCCAGCGGGTG 840
Qy 841 CGTGCGCTCTTAGAGAAACTTTCCCTGTCAAAGGCTCCGGGGGGCGCGGGTGTCCCCCGC 900
||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
Db 841 CGTGCGCTCTTAGAGAAACTTTCCCTGTCAAAGGCTCCGGGGGGCGCGGGTGTCCCCCGC 900
Qy 901 TTGCCACAGCCCTGTTGCGGCCCCGAAACTTGTGCGCGCAGCCCAAACTAACCTCACGTG 960
||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
Db 901 TTGCCACAGCCCTGTTGCGGCCCCGAAACTTGTGCGCGCAGCCCAAACTAACCTCACGTG 960
Qy 961 AAGTGACGGACTGTTCTATGACTGCAAAGATGGAAACGACCTTCTATGACGATGCCCTCA 1020
||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
Db 961 AAGTGACGGACTGTTCTATGACTGCAAAGATGGAAACGACCTTCTATGACGATGCCCTCA 1020
Qy 1021 ACGCCTCGTTCCTCCCGTCCGAGAGCGGACCTTATGGCTACAGTAACCCCAAGATCCTGA 1080
||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
Db 1021 ACGCCTCGTTCCTCCCGTCCGAGAGCGGACCTTATGGCTACAGTAACCCCAAGATCCTGA 1080
Qy 1081 AACAGAGCATGACCCTGAACCTGGCCGACCCAGTGGGGAGCCTGAAGCCGCACCTCCGCG 1140
||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
Db 1081 AACAGAGCATGACCCTGAACCTGGCCGACCCAGTGGGGAGCCTGAAGCCGCACCTCCGCG 1140
Qy 1141 CCAAGAACTCGGACCTCCTCACCTCGCCCGACGTGGGGCTGCTCAAGCTGGCGTCGCCCG 1200
||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
Db 1141 CCAAGAACTCGGACCTCCTCACCTCGCCCGACGTGGGGCTGCTCAAGCTGGCGTCGCCCG 1200
Qy 1201 AGCTGGAGCGCCTGATAATCCAGTCCAGCAACGGGCACATCACCACCACGCCGACCCCCA 1260
||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
Db 1201 AGCTGGAGCGCCTGATAATCCAGTCCAGCAACGGGCACATCACCACCACGCCGACCCCCA 1260
Qy 1261 CCCAGTTCCTGTGCCCCAAGAACGTGACAGATGAGCAGGAGGGCTTCGCCGAGGGCTTCG 1320
||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
Db 1261 CCCAGTTCCTGTGCCCCAAGAACGTGACAGATGAGCAGGAGGGCTTCGCCGAGGGCTTCG 1320
Qy 1321 TGCGCGCCCTGGCCGAACTGCACAGCCAGAACACGCTGCCCAGCGTCACGTCGGCGGCGC 1380
||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
Db 1321 TGCGCGCCCTGGCCGAACTGCACAGCCAGAACACGCTGCCCAGCGTCACGTCGGCGGCGC 1380
Qy 1381 AGCCGGTCAACGGGGCAGGCATGGTGGCTCCCGCGGTAGCCTCGGTGGCAGGGGGCAGCG 1440
||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
Db 1381 AGCCGGTCAACGGGGCAGGCATGGTGGCTCCCGCGGTAGCCTCGGTGGCAGGGGGCAGCG 1440
Qy 1441 GCAGCGGCGGCTTCAGCGCCAGCCTGCACAGCGAGCCGCCGGTCTACGCAAACCTCAGCA 1500
||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
Db 1441 GCAGCGGCGGCTTCAGCGCCAGCCTGCACAGCGAGCCGCCGGTCTACGCAAACCTCAGCA 1500
Qy 1501 ACTTCAACCCAGGCGCGCTGAGCAGCGGCGGCGGGGCGCCCTCCTACGGCGCGGCCGGCC 1560
||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
Db 1501 ACTTCAACCCAGGCGCGCTGAGCAGCGGCGGCGGGGCGCCCTCCTACGGCGCGGCCGGCC 1560
Qy 1561 TGGCCTTTCCCGCGCAACCCCAGCAGCAGCAGCAGCCGCCGCACCACCTGCCCCAGCAGA 1620
||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
Db 1561 TGGCCTTTCCCGCGCAACCCCAGCAGCAGCAGCAGCCGCCGCACCACCTGCCCCAGCAGA 1620
Qy 1621 TGCCCGTGCAGCACCCGCGGCTGCAGGCCCTGAAGGAGGAGCCTCAGACAGTGCCCGAGA 1680
||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
Db 1621 TGCCCGTGCAGCACCCGCGGCTGCAGGCCCTGAAGGAGGAGCCTCAGACAGTGCCCGAGA 1680
Qy 1681 TGCCCGGCGAGACACCGCCCCTGTCCCCCATCGACATGGAGTCCCAGGAGCGGATCAAGG 1740
||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
Db 1681 TGCCCGGCGAGACACCGCCCCTGTCCCCCATCGACATGGAGTCCCAGGAGCGGATCAAGG 1740
Qy 1741 CGGAGAGGAAGCGCATGAGGAACCGCATCGCTGCCTCCAAGTGCCGAAAAAGGAAGCTGG 1800
||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
Db 1741 CGGAGAGGAAGCGCATGAGGAACCGCATCGCTGCCTCCAAGTGCCGAAAAAGGAAGCTGG 1800
Qy 1801 AGAGAATCGCCCGGCTGGAGGAAAAAGTGAAAACCTTGAAAGCTCAGAACTCGGAGCTGG 1860
||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
Db 1801 AGAGAATCGCCCGGCTGGAGGAAAAAGTGAAAACCTTGAAAGCTCAGAACTCGGAGCTGG 1860
Qy 1861 CGTCCACGGCCAACATGCTCAGGGAACAGGTGGCACAGCTTAAACAGAAAGTCATGAACC 1920
||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
Db 1861 CGTCCACGGCCAACATGCTCAGGGAACAGGTGGCACAGCTTAAACAGAAAGTCATGAACC 1920
Qy 1921 ACGTTAACAGTGGGTGCCAACTCATGCTAACGCAGCAGTTGCAAACATTTTGAAGAGAGA 1980
||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
Db 1921 ACGTTAACAGTGGGTGCCAACTCATGCTAACGCAGCAGTTGCAAACATTTTGAAGAGAGA 1980
Qy 1981 CCGTCGGGGGCTGAGGGGCAACGAAGAAAAAAAATAACACAGAGAGACAGACTTGAGAAC 2040
||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
Db 1981 CCGTCGGGGGCTGAGGGGCAACGAAGAAAAAAAATAACACAGAGAGACAGACTTGAGAAC 2040
Qy 2041 TTGACAAGTTGCGACGGAGAGAAAAAAGAAGTGTCCGAGAACTAAAGCCAAGGGTATCCA 2100
||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
Db 2041 TTGACAAGTTGCGACGGAGAGAAAAAAGAAGTGTCCGAGAACTAAAGCCAAGGGTATCCA 2100
Qy 2101 AGTTGGACTGGGTTGCGTCCTGACGGCGCCCCCAGTGTGCACGAGTGGGAAGGACTTGGC 2160
||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
Db 2101 AGTTGGACTGGGTTGCGTCCTGACGGCGCCCCCAGTGTGCACGAGTGGGAAGGACTTGGC 2160
Qy 2161 GCGCCCTCCCTTGGCGTGGAGCCAGGGAGCGGCCGCCTGCGGGCTGCCCCGCTTTGCGGA 2220
||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
Db 2161 GCGCCCTCCCTTGGCGTGGAGCCAGGGAGCGGCCGCCTGCGGGCTGCCCCGCTTTGCGGA 2220
Qy 2221 CGGGCTGTCCCCGCGCGAACGGAACGTTGGACTTTTCGTTAACATTGACCAAGAACTGCA 2280
||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
Db 2221 CGGGCTGTCCCCGCGCGAACGGAACGTTGGACTTTTCGTTAACATTGACCAAGAACTGCA 2280
Qy 2281 TGGACCTAACATTCGATCTCATTCAGTATTAAAGGGGGGAGGGGGAGGGGGTTACAAACT 2340
||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
Db 2281 TGGACCTAACATTCGATCTCATTCAGTATTAAAGGGGGGAGGGGGAGGGGGTTACAAACT 2340
Qy 2341 GCAATAGAGACTGTAGATTGCTTCTGTAGTACTCCTTAAGAACACAAAGCGGGGGGAGGG 2400
||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
Db 2341 GCAATAGAGACTGTAGATTGCTTCTGTAGTACTCCTTAAGAACACAAAGCGGGGGGAGGG 2400
Qy 2401 TTGGGGAGGGGCGGCAGGAGGGAGGTTTGTGAGAGCGAGGCTGAGCCTACAGATGAACTC 2460
||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
Db 2401 TTGGGGAGGGGCGGCAGGAGGGAGGTTTGTGAGAGCGAGGCTGAGCCTACAGATGAACTC 2460
Qy 2461 TTTCTGGCCTGCCTTCGTTAACTGTGTATGTACATATATATATTTTTTAATTTGATGAAA 2520
||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
Db 2461 TTTCTGGCCTGCCTTCGTTAACTGTGTATGTACATATATATATTTTTTAATTTGATGAAA 2520
Qy 2521 GCTGATTACTGTCAATAAACAGCTTCATGCCTTTGTAAGTTATTTCTTGTTTGTTTGTTT 2580
||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
Db 2521 GCTGATTACTGTCAATAAACAGCTTCATGCCTTTGTAAGTTATTTCTTGTTTGTTTGTTT 2580
Qy 2581 GGGTATCCTGCCCAGTGTTGTTTGTAAATAAGAGATTTGGAGCACTCTGAGTTTACCATT 2640
||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
Db 2581 GGGTATCCTGCCCAGTGTTGTTTGTAAATAAGAGATTTGGAGCACTCTGAGTTTACCATT 2640
Qy 2641 TGTAATAAAGTATATAATTTTTTTATGTTTTGTTTCTGAAAATTCCAGAAAGGATATTTA 2700
||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
Db 2641 TGTAATAAAGTATATAATTTTTTTATGTTTTGTTTCTGAAAATTCCAGAAAGGATATTTA 2700
Qy 2701 AGAAAATACAATAAACTATTGGAAAGTACTCCCCTAACCTCTTTTCTGCATCATCTGTAG 2760
||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
Db 2701 AGAAAATACAATAAACTATTGGAAAGTACTCCCCTAACCTCTTTTCTGCATCATCTGTAG 2760
Qy 2761 ATACTAGCTATCTAGGTGGAGTTGAAAGAGTTAAGAATGTCGATTAAAATCACTCTCAGT 2820
||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
Db 2761 ATACTAGCTATCTAGGTGGAGTTGAAAGAGTTAAGAATGTCGATTAAAATCACTCTCAGT 2820
Qy 2821 GCTTCTTACTATTAAGCAGTAAAAACTGTTCTCTATTAGACTTTAGAAATAAATGTACCT 2880
||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
Db 2821 GCTTCTTACTATTAAGCAGTAAAAACTGTTCTCTATTAGACTTTAGAAATAAATGTACCT 2880
Qy 2881 GATGTACCTGATGCTATGGTCAGGTTATACTCCTCCTCCCCCAGCTATCTATATGGAATT 2940
||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
Db 2881 GATGTACCTGATGCTATGGTCAGGTTATACTCCTCCTCCCCCAGCTATCTATATGGAATT 2940
Qy 2941 GCTTACCAAAGGATAGTGCGATGTTTCAGGAGGCTGGAGGAAGGGGGGTTGCAGTGGAGA 3000
||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
Db 2941 GCTTACCAAAGGATAGTGCGATGTTTCAGGAGGCTGGAGGAAGGGGGGTTGCAGTGGAGA 3000
Qy 3001 GGGACAGCCCACTGAGAAGTCAAACATTTCAAAGTTTGGATTGTATCAAGTGGCATGTGC 3060
||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
Db 3001 GGGACAGCCCACTGAGAAGTCAAACATTTCAAAGTTTGGATTGTATCAAGTGGCATGTGC 3060
Qy 3061 TGTGACCATTTATAATGTTAGTAGAAATTTTACAATAGGTGCTTATTCTCAAAGCAGGAA 3120
||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
Db 3061 TGTGACCATTTATAATGTTAGTAGAAATTTTACAATAGGTGCTTATTCTCAAAGCAGGAA 3120
Qy 3121 TTGGTGGCAGATTTTACAAAAGATGTATCCTTCCAATTTGGAATCTTCTCTTTGACAATT 3180
||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
Db 3121 TTGGTGGCAGATTTTACAAAAGATGTATCCTTCCAATTTGGAATCTTCTCTTTGACAATT 3180
Qy 3181 CCTAGATAAAAAGATGGCCTTTGCTTATGAATATTTATAACAGCATTCTTGTCACAATAA 3240
||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
Db 3181 CCTAGATAAAAAGATGGCCTTTGCTTATGAATATTTATAACAGCATTCTTGTCACAATAA 3240
Qy 3241 ATGTATTCAAATACCAA 3257
|||||||||||||||||
Db 3241 ATGTATTCAAATACCAA 3257
Further, it would have been obvious to a PHOSITA to modify the c-Jun nucleotide sequence of the c-Jun+/anti-ROR-1 CAR T cells cultured in 45 mM potassium ion as taught by WO902 and Vodnala (see above) to include the c-Jun nucleotide sequence of WO226, because WO902 teaches a c-Jun expressing cell and a c-Jun encoding polynucleotide but not the c-Jun nucleotide sequence, and WO226 teaches the c-Jun nucleotide sequence. There is an expectation of success for a PHOPSITA to substitute c-Jun nucleotide sequence of the c-Jun+/anti-ROR-1 CAR T cells cultured in 45 mM potassium ion as taught by WO902 and Vodnala (see above) with the c-Jun nucleotide sequence taught by WO226, because WO902 teaches a c-Jun expressing cell and a c-Jun encoding polynucleotide but not the c-Jun nucleotide sequence, and WO226 teaches the c-Jun nucleotide sequence. This rationale aligns with the principle of simple substitution of one known element for another to obtain predictable results, supporting a conclusion of obviousness (see MPEP § 2141).
Thus, the invention as a whole is prima facie obvious over the references, especially in the absence of evidence to the contrary.
Claim(s) 66 and 68-69 is/are rejected under 35 U.S.C. 103 as being unpatentable over WO 2019/118902 A2 (hereinafter “WO902”), in view of Vodnala et al. (Science 363, 1417 (2019) 29 March 2019; hereinafter “Vodnala”) as applied to claim 3 above, and further in view of WO 2015/066551 A2 (hereinafter “WO551”).
The teachings of WO902 and Vodnala as recited above apply for claim 3.
WO902 further teaches an exogenous polynucleotide encoding the c-Jun polypeptide [e.g., pg. 4, lines 5-15].
WO902 and Vodnala not expressly teach the ROR-1 binding domain of the anti-ROR-1 CAR T comprises instant SEQ ID NO: 83.
Regarding instant claims 66, 68-69, WO551 teaches genetically engineered T cells, including CAR T cells for cancer therapy [e.g., paras 0003-0006]. WO551 teaches ROR1 CAR T cells and ROR1 binding domain “R12” of SEQ ID NO: 82 [e.g., paras 0032, 0075-0076, 0123; figs. 10, 12], which is the same as instant ROR-1 binding protein of instant SEQ ID NO: 83 (see alignment below).
Alignment of instant ROR-1 binding protein domain of instant SEQ ID NO: 83 with WO551 ROR-1 “R12” scFv of SEQ ID NO: 82:
Query Match 100.0%; Score 1313; Length 248;
Best Local Similarity 100.0%;
Matches 248; Conservative 0; Mismatches 0; Indels 0; Gaps 0;
Qy 1 QEQLVESGGRLVTPGGSLTLSCKASGFDFSAYYMSWVRQAPGKGLEWIATIYPSSGKTYY 60
||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
Db 1 QEQLVESGGRLVTPGGSLTLSCKASGFDFSAYYMSWVRQAPGKGLEWIATIYPSSGKTYY 60
Qy 61 ATWVNGRFTISSDNAQNTVDLQMNSLTAADRATYFCARDSYADDGALFNIWGPGTLVTIS 120
||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
Db 61 ATWVNGRFTISSDNAQNTVDLQMNSLTAADRATYFCARDSYADDGALFNIWGPGTLVTIS 120
Qy 121 SGGGGSGGGGSGGGGSELVLTQSPSVSAALGSPAKITCTLSSAHKTDTIDWYQQLQGEAP 180
||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
Db 121 SGGGGSGGGGSGGGGSELVLTQSPSVSAALGSPAKITCTLSSAHKTDTIDWYQQLQGEAP 180
Qy 181 RYLMQVQSDGSYTKRPGVPDRFSGSSSGADRYLIIPSVQADDEADYYCGADYIGGYVFGG 240
||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
Db 181 RYLMQVQSDGSYTKRPGVPDRFSGSSSGADRYLIIPSVQADDEADYYCGADYIGGYVFGG 240
Qy 241 GTQLTVTG 248
||||||||
Db 241 GTQLTVTG 248
Further, it would have been obvious to a PHOSITA to modify ROR-1 binding domain sequence of the c-Jun+/anti-ROR-1 CAR T cells cultured in 45 mM potassium ion as taught by WO902 and Vodnala (see above) to include the ROR-1 binding domain of the “R12” scFv anti-ROR-1 CAR T sequence (same as instant SEQ ID NO: 83) as taught by WO551, because both WO902 and WO551 teach anti-ROR1 CAR T cells for cancer therapy and WO551 teaches the ROR1 binding domain scFv sequence. There is an expectation of success for a PHOPSITA to substitute the ROR-1 binding domain sequence of the c-Jun+/anti-ROR-1 CAR T cells cultured in 45 mM potassium ion as taught by WO902 and Vodnala (see above) with the “R12” anti-ROR-1 scFv domain sequence as taught by WO551, because both WO902 and WO551 teach anti-ROR1 CAR T cells for cancer therapy and WO551 teaches the ROR1 binding domain scFv sequence. This rationale aligns with the principle of simple substitution of one known element for another to obtain predictable results, supporting a conclusion of obviousness (see MPEP § 2141).
Thus, the invention as a whole is prima facie obvious over the references, especially in the absence of evidence to the contrary.
Claim(s) 99 is/are rejected under 35 U.S.C. 103 as being unpatentable over WO 2019/118902 A2 (hereinafter “WO902”), in view of Vodnala et al. (Science 363, 1417 (2019) 29 March 2019; hereinafter “Vodnala”) as applied to claim 3 above, and further in view of WO 2014/031687 A1 (hereinafter “WO687”) and WO 2006/046217 A2 (hereinafter “WO217”).
The teachings of WO902 and Vodnala as recited above apply for claim 3.
WO902 further teaches a c-Jun-P2A-CAR, 4-1BB domain, a CD3z intracellular signaling domain, a CD28 costimulatory domain [e.g., pg. 62, lines 1-15; pg. 50, lines 21-33; pg. 51, lines 1-19].
WO902 and Vodnala not expressly teach the anti-ROR-1 CAR construct having at least 60% sequence identity to instant SEQ ID NO: 86.
Regarding instant claim 99, WO687 teaches methods and compositions for cellular immunotherapy, such as cancer therapy, and teaches an anti-ROR-1 CAR construct (Leader_R12-CD28tm/41BB-Z-T2A-tEGFR fusion protein, SEQ ID 42) [e.g., title, abstract, field of invention, background of invention; pg. 111, table 14; ], which has a 67.7% overall sequence identity (97.6% local similarity) with the instant claimed c-Jun+/anti-ROR-1 construct SEQ ID NO: 86 (see alignment below).
Alignment of c-Jun+/anti-ROR-1 CAR construct of instant SEQ ID NO: 86 with WO687 anti-ROR1 CAR construct of SEQ ID NO: 42):
Query Match 67.7%; Score 4307.5; Length 845;
Best Local Similarity 97.6%;
Matches 805; Conservative 0; Mismatches 15; Indels 5; Gaps 3;
Qy 374 QEQLVESGGRLVTPGGSLTLSCKASGFDFSAYYMSWVRQAPGKGLEWIATIYPSSGKTYY 433
||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
Db 23 QEQLVESGGRLVTPGGSLTLSCKASGFDFSAYYMSWVRQAPGKGLEWIATIYPSSGKTYY 82
Qy 434 ATWVNGRFTISSDNAQNTVDLQMNSLTAADRATYFCARDSYADDGALFNIWGPGTLVTIS 493
||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
Db 83 ATWVNGRFTISSDNAQNTVDLQMNSLTAADRATYFCARDSYADDGALFNIWGPGTLVTIS 142
Qy 494 SGGGGSGGGGSGGGGSELVLTQSPSVSAALGSPAKITCTLSSAHKTDTIDWYQQLQGEAP 553
||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
Db 143 SGGGGSGGGGSGGGGSELVLTQSPSVSAALGSPAKITCTLSSAHKTDTIDWYQQLQGEAP 202
Qy 554 RYLMQVQSDGSYTKRPGVPDRFSGSSSGADRYLIIPSVQADDEADYYCGADYIGGYVFGG 613
||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
Db 203 RYLMQVQSDGSYTKRPGVPDRFSGSSSGADRYLIIPSVQADDEADYYCGADYIGGYVFGG 262
Qy 614 GTQLTVTGGGGSGKPCPPCKCPMFWVLVVVGGVLACYSLLVTVAFIIFWVKRGRKKLLYI 673
|||||||| | |||| ||||||||||||||||||||||||||||||||||||||||
Db 263 GTQLTVTGESKYGPPCPP--CPMFWVLVVVGGVLACYSLLVTVAFIIFWVKRGRKKLLYI 320
Qy 674 FKQPFMRPVQTTQEEDGCSCRFPEEEEGGCELRVKFSRSADAPAYQQGQNQLYNELNLGR 733
||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
Db 321 FKQPFMRPVQTTQEEDGCSCRFPEEEEGGCELRVKFSRSADAPAYQQGQNQLYNELNLGR 380
Qy 734 REEYDVLDKRRGRDPEMGGKPRRKNPQEGLYNELQKDKMAEAYSEIGMKGERRRGKGHDG 793
||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
Db 381 REEYDVLDKRRGRDPEMGGKPRRKNPQEGLYNELQKDKMAEAYSEIGMKGERRRGKGHDG 440
Qy 794 LYQGLSTATKDTYDALHMQALPPR--SGATNFSLLKQAGDVEENPGP-MLLLVTSLLLCE 850
|||||||||||||||||||||||| | | ||||||||| ||||||||||||
Db 441 LYQGLSTATKDTYDALHMQALPPRLEGGGEGRGSLLTCGDVEENPGPRMLLLVTSLLLCE 500
Qy 851 LPHPAFLLIPRKVCNGIGIGEFKDSLSINATNIKHFKNCTSISGDLHILPVAFRGDSFTH 910
||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
Db 501 LPHPAFLLIPRKVCNGIGIGEFKDSLSINATNIKHFKNCTSISGDLHILPVAFRGDSFTH 560
Qy 911 TPPLDPQELDILKTVKEITGFLLIQAWPENRTDLHAFENLEIIRGRTKQHGQFSLAVVSL 970
||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
Db 561 TPPLDPQELDILKTVKEITGFLLIQAWPENRTDLHAFENLEIIRGRTKQHGQFSLAVVSL 620
Qy 971 NITSLGLRSLKEISDGDVIISGNKNLCYANTINWKKLFGTSGQKTKIISNRGENSCKATG 1030
||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
Db 621 NITSLGLRSLKEISDGDVIISGNKNLCYANTINWKKLFGTSGQKTKIISNRGENSCKATG 680
Qy 1031 QVCHALCSPEGCWGPEPRDCVSCRNVSRGRECVDKCNLLEGEPREFVENSECIQCHPECL 1090
||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
Db 681 QVCHALCSPEGCWGPEPRDCVSCRNVSRGRECVDKCNLLEGEPREFVENSECIQCHPECL 740
Qy 1091 PQAMNITCTGRGPDNCIQCAHYIDGPHCVKTCPAGVMGENNTLVWKYADAGHVCHLCHPN 1150
||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
Db 741 PQAMNITCTGRGPDNCIQCAHYIDGPHCVKTCPAGVMGENNTLVWKYADAGHVCHLCHPN 800
Qy 1151 CTYGCTGPGLEGCPTNGPKIPSIATGMVGALLLLLVVALGIGLFM 1195
|||||||||||||||||||||||||||||||||||||||||||||
Db 801 CTYGCTGPGLEGCPTNGPKIPSIATGMVGALLLLLVVALGIGLFM 845
WO217 teaches methods and systems for analyzing transcription factors (e.g., c-Jun), teaches that the transcription factors may be used as cancer therapeutics, and further teaches a human c-Jun proto-oncogene protein sequence of SEQ ID NO: 6 [e.g., abstract, background; para 0126, paras 0338-0346], which is the same as instant claimed c-Jun sequence of SEQ ID NO: 13 (per Applicant disclosure table 14, the CAR construct of SEQ ID NO: 86 comprises a C-Jun of SEQ ID NO: 13).
Alignment of c-Jun of instant SEQ ID NO: 13 with WO217 c-Jun proto-oncogene of SEQ ID NO: 6:
Query Match 100.0%; Score 1693; Length 331;
Best Local Similarity 100.0%;
Matches 331; Conservative 0; Mismatches 0; Indels 0; Gaps 0;
Qy 1 MTAKMETTFYDDALNASFLPSESGPYGYSNPKILKQSMTLNLADPVGSLKPHLRAKNSDL 60
||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
Db 1 MTAKMETTFYDDALNASFLPSESGPYGYSNPKILKQSMTLNLADPVGSLKPHLRAKNSDL 60
Qy 61 LTSPDVGLLKLASPELERLIIQSSNGHITTTPTPTQFLCPKNVTDEQEGFAEGFVRALAE 120
||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
Db 61 LTSPDVGLLKLASPELERLIIQSSNGHITTTPTPTQFLCPKNVTDEQEGFAEGFVRALAE 120
Qy 121 LHSQNTLPSVTSAAQPVNGAGMVAPAVASVAGGSGSGGFSASLHSEPPVYANLSNFNPGA 180
||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
Db 121 LHSQNTLPSVTSAAQPVNGAGMVAPAVASVAGGSGSGGFSASLHSEPPVYANLSNFNPGA 180
Qy 181 LSSGGGAPSYGAAGLAFPAQPQQQQQPPHHLPQQMPVQHPRLQALKEEPQTVPEMPGETP 240
||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
Db 181 LSSGGGAPSYGAAGLAFPAQPQQQQQPPHHLPQQMPVQHPRLQALKEEPQTVPEMPGETP 240
Qy 241 PLSPIDMESQERIKAERKRMRNRIAASKCRKRKLERIARLEEKVKTLKAQNSELASTANM 300
||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
Db 241 PLSPIDMESQERIKAERKRMRNRIAASKCRKRKLERIARLEEKVKTLKAQNSELASTANM 300
Qy 301 LREQVAQLKQKVMNHVNSGCQLMLTQQLQTF 331
|||||||||||||||||||||||||||||||
Db 301 LREQVAQLKQKVMNHVNSGCQLMLTQQLQTF 331
Further, it would have been obvious to a PHOSITA to modify the CAR sequence of the c-Jun+/anti-ROR-1 CAR T cells cultured in 45 mM potassium ion as taught by WO902 and Vodnala (see above) to include (1) the ROR-1 binding CAR construct taught by WO687 and (2) the c-Jun sequence taught by WO217, because (1) both WO902 and WO687 teach anti-ROR1 CAR T cells for cancer, and WO687 teaches the ROR1 CAR sequence and (2) both WO902 and WO217 teach c-Jun expression for cancer therapy, WO902 teaches a c-Jun+/anti-ROR-1 CAR, and WO217 teaches the human c-Jun sequence. There is an expectation of success for a PHOPSITA to substitute the CAR sequence of the c-Jun+/anti-ROR-1 CAR T cells cultured in 45 mM potassium ion as taught by WO902 and Vodnala (see above) to include (1) the ROR-1 binding CAR construct taught by WO687 and (2) the c-Jun sequence taught by WO217, because WO902 teaches the general structure of a c-Jun+/anti-ROR-1 CAR T cell for the treatment of cancer, WO687 teaches the ROR-1-binding CAR construct sequence, and WO217 teaches the c-Jun sequence, and all of the applied references teach an applicability to the field of cancer therapies. This rationale aligns with the principle of simple substitution of one known element for another to obtain predictable results, supporting a conclusion of obviousness (see MPEP § 2141).
Thus, the invention as a whole is prima facie obvious over the references, especially in the absence of evidence to the contrary.
Claim(s) 169 is/are rejected under 35 U.S.C. 103 as being unpatentable over WO 2019/118902 A2 (hereinafter “WO902”), in view of Vodnala et al. (Science 363, 1417 (2019) 29 March 2019; hereinafter “Vodnala”) as applied to claim 3 above, and further in view of US 2016/0185861 A1 (hereinafter “US861”).
The teachings of WO902 and Vodnala as recited above apply for claim 3.
WO902 further teaches the composition of CAR T cells are selected from CD4+ T cells, CD8+ T cells or a combination of CD4+ and CD8+ T cells [e.g., pg. 44, lines 1-29; pg. 98, claim 11]. WO902 further teaches upregulated c-Jun are associated with naïve (CCR7+/CD45RA+) T cells [e.g., pg. 83, lines 9-19].
WO902 and Vodnala not expressly teach that at least 20% of the c-Jun+/anti-ROR-1 CD4+ CAR T cells are CCR7+/CD45RA+.
Regarding instant claim 169, US861 teaches methods of making CARs for cancer therapy, including ROR-1 CAR T cells [e.g., title, abstract; paras 003-008, 056, 0130, 0257, 0288]. US861 further teaches that the population of immune cells (e.g., CAR T cells) comprises greater than 20% Tscm CD8+ CAR T cells and discloses Tscm are CCR7+/CD45RA+ cells [e.g., para 0074; figs. 2D, 2G, ]. US861 teaches the Tscm subset is able to differentiate into other T cell subsets and also presented stronger proliferation ability than other subsets [e.g., para 0507].
Further, it would have been obvious to a PHOSITA to modify the T cell subset composition of the c-Jun+/anti-ROR-1 CAR T cells cultured in 45 mM potassium ion as taught by WO902 and Vodnala (see above) to include that at least 20% of the CAR T cells are CCR7+/CD45RA+ Tscm as taught by US861, because both WO902 and US861 teach ROR-1 directed CAR T cells for cancer therapy, and US681 further teaches that CAR T cell compositions comprising greater than 20% Tscm result in stronger proliferation and have the ability to differentiate into other T cell subsets. There is an expectation of success for a PHOPSITA to substitute the T cell subset composition of the c-Jun+/anti-ROR-1 CAR T cells cultured in 45 mM potassium ion as taught by WO902 and Vodnala (see above) with a requirement that at least 20% of the CAR T cells are CCR7+/CD45RA+ Tscm as taught by US861, because US681 further teaches that CAR T cell compositions comprising greater than 20% Tscm result in stronger proliferation and have the ability to differentiate into other T cell subsets. This rationale aligns with the principle of simple substitution of one known element for another to obtain predictable results, supporting a conclusion of obviousness (see MPEP § 2141).
Thus, the invention as a whole is prima facie obvious over the references, especially in the absence of evidence to the contrary.
Conclusion
No claims are currently allowed.
Any inquiry concerning this communication or earlier communications from the examiner should be directed to AMY M CHATTIN whose telephone number is (571)270-0646. The examiner can normally be reached T-F 0600-1600 PST.
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If attempts to reach the examiner by telephone are unsuccessful, the examiner’s supervisor, Julie Wu can be reached at (571) 272-5205. The fax phone number for the organization where this application or proceeding is assigned is 571-273-8300.
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/AMY M. CHATTIN/Examiner, Art Unit 1643
/JULIE WU/Supervisory Patent Examiner, Art Unit 1643